[go: up one dir, main page]

WO2025098212A1 - Dérivé de n, n-diméthyltryptamine, composition pharmaceutique associée, son procédé de préparation et son utilisation - Google Patents

Dérivé de n, n-diméthyltryptamine, composition pharmaceutique associée, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2025098212A1
WO2025098212A1 PCT/CN2024/128363 CN2024128363W WO2025098212A1 WO 2025098212 A1 WO2025098212 A1 WO 2025098212A1 CN 2024128363 W CN2024128363 W CN 2024128363W WO 2025098212 A1 WO2025098212 A1 WO 2025098212A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
deuterated
alkyl
hydrogen
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/128363
Other languages
English (en)
Chinese (zh)
Inventor
丁泽鉴
周皓
田峦鸢
李莉娥
陈雷
宁有坚
汪淼
李鹏飞
舒雪莲
姜璀霞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yichang Humanwell Pharmaceutical Co Ltd
Original Assignee
Yichang Humanwell Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yichang Humanwell Pharmaceutical Co Ltd filed Critical Yichang Humanwell Pharmaceutical Co Ltd
Publication of WO2025098212A1 publication Critical patent/WO2025098212A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the present application belongs to the field of pharmaceutical chemistry, and specifically relates to an N,N-dimethyltryptamine derivative and a pharmaceutical composition, a preparation method and use thereof.
  • Serotonin receptors are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems, mediating excitatory and inhibitory neurotransmission. Serotonin receptors are activated by the neurotransmitter serotonin (5-hydroxytryptamine). In autopsies of patients with depression, an increase in density in the cortex can be detected. Long-term use of a variety of antidepressants can downregulate the density of 5-HT 2A receptors and exert antidepressant effects by affecting the forebrain subcortical circuit. In addition, 5-HT 2A receptors are important factors in sleep regulation and cognitive function (Eison, Behav Brain Res. 73 (1-2): 177-81.
  • 5-HT 2A receptors have become a hot topic of extensive research as a target for the treatment of mental disorders such as depression.
  • Major depressive disorder (MDD) is a chronic recurrent mental disorder with clinical manifestations of persistent low mood, loss of interest, loss of appetite, sleep disorders, etc.
  • the pathogenesis of depression is complex and has not yet been clarified (Chen, Sleep, Vol. 46, Issue Supplement_1, A284-A285, 2023).
  • antidepressant SSRI drugs that act on 5-HT 2A receptors include ritanserin, YM-992 (lubazodone), volinanserin, LY-367265 and nefazodone. They all have high affinity for 5-HT 2A receptors and show effective efficacy in treating depression.
  • New fast-acting antidepressant psychotherapeutic hallucinogenic compounds such as psilocybin, lysergic acid diethylamide (LSD), and ketamine, have a rapid onset of action and are effective in relieving anxiety and depressive symptoms ( Curr Top Behav Neurosci, 36:45-73, 2018).
  • psilocybin has a strong agonist effect on 5-HT 2B receptors and is cardiotoxic; both LSD and psilocybin show rapid tolerance to serotonin receptors, and neither is well suited to repeated dosing regimens.
  • the present application provides a compound as shown in formula (1), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof:
  • R1 and R2 are each independently selected from the group consisting of hydroxy, unsubstituted C1 - C6 alkyl, substituted C1- C6 alkyl, unsubstituted C1 - C6 alkoxy, substituted C1 - C6 alkoxy, unsubstituted C3 - C6 cycloalkyl, substituted C3 - C6 cycloalkyl , unsubstituted aryl, substituted aryl, unsubstituted heteroaryl and substituted heteroaryl; or
  • R1 and R2 form an unsubstituted nitrogen-containing heterocyclic ring or a substituted nitrogen-containing heterocyclic ring with the nitrogen atom to which they are directly attached;
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium and substituted C 1 -C 6 alkyl; or, R 3 and R 4 or R 5 and R 6 and their connecting carbon atoms form a -C(O)- group or a -C(S)- group;
  • R7 is one, two, three or four and is independently selected from hydrogen, deuterium, amino, halogen, unsubstituted C1 - C6 alkyl, substituted C1 - C6 alkyl, unsubstituted C1- C6 alkoxy, substituted C1 -C6 alkoxy, C1 - C6 alkanoyloxy, aryloxy, heteroaryloxy, C1 - C6 alkoxy-substituted C1 - C6 alkanoyloxy, C1 - C6 alkanesulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, phosphoryloxy and hydroxyl ;
  • R 8 is hydrogen, deuterium, substituted C 1 -C 6 alkyl, unsubstituted C 3 -C 6 cycloalkyl or substituted C 3 -C 6 cycloalkyl;
  • Y is N or CR 11 ; when Y is N, R 9 and R 10 are each independently hydrogen, hydroxyl, thiol; or R 9 and the carbon atom to which it is connected form a -C(O)- group or a -C(S)- group; when Y is CR 11 , R 10 and R 11 form a bond, and R 9 is hydrogen, hydroxyl, amino, di(C 1 -C 4 alkyl)amino or thiol.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, and a pharmaceutically acceptable carrier.
  • the present application provides a method for preparing the above-mentioned DMT derivative or its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs.
  • the present application provides the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, or pharmaceutical composition thereof, for pharmaceutical use.
  • the present application provides the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, or pharmaceutical composition thereof, for stimulating 5-HT 2A receptor.
  • the present application provides the above-mentioned DMT derivatives or their stereoisomers, pharmaceutically acceptable salts, solvates, deuterated substances, metabolites or prodrugs, or pharmaceutical compositions thereof, for use in treating 5-HT 2A receptor-related diseases/disorders.
  • the present application provides the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvent Use of a deuterated compound, deuterated compound, metabolite or prodrug, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a 5-HT 2A receptor-related central nervous system disease, disorder or condition and/or a neurological disease, disorder or condition.
  • the present application provides a method for treating a 5-HT 2A receptor-related disease/disorder in a patient, the method comprising administering the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, or a pharmaceutical composition thereof to a patient in need.
  • the present application provides a DMT derivative and a preparation method and use thereof, which overcomes the shortcomings of the prior art such as limited types of antidepressant drugs, adverse reactions, hallucinogenic side effects, etc.
  • the DMT derivative of the present application has good binding ability with 5-HT 2A .
  • the present application provides a compound as shown in formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof,
  • R1 and R2 are each independently selected from the following groups: hydroxyl, unsubstituted C1 - C6 alkyl, substituted C1 - C6 alkyl, unsubstituted C1- C6 alkoxy, substituted C1 -C6 alkoxy, unsubstituted C3 - C6 cycloalkyl, substituted C3 - C6 cycloalkyl , unsubstituted aryl, substituted aryl, unsubstituted heteroaryl and substituted heteroaryl; herein, the substituted C1 - C6 alkyl, substituted C1 - C6 alkoxy, substituted C3- C6 cycloalkyl, substituted aryl or substituted heteroaryl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C1 -C3 alkyl , C1 - C3 alkoxy, hydroxyl, halogen, halogenated C1 - C3 alky
  • R1 and R2 form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached;
  • the substituted nitrogen-containing heterocycle refers to being substituted by 1-3 groups independently selected from the following groups: unsubstituted C1 - C6 alkyl, and substituted C1 - C6 alkyl;
  • the substituted C1 - C6 alkyl refers to being substituted by 1-3 groups independently selected from the following groups: deuterium, C1 - C3 alkyl, C1 - C3 alkoxy, halogen, halogenated C1 - C3 alkyl, C3 - C6 cycloalkyl, aryl and heteroaryl;
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium and substituted C 1 -C 6 alkyl; or, R 3 and R 4 or R 5 and R 6 form a -C(O)- group or a -C(S)- group with the carbon atom to which they are connected;
  • the substituted C 1 -C 6 alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, aryl and heteroaryl;
  • R7 is one, two, three or four and each is independently selected from hydrogen, deuterium, amino, halogen, unsubstituted C1 - C6 alkyl, substituted C1 - C6 alkyl, unsubstituted C1-C6 alkoxy, substituted C1 - C6 alkoxy, C1 - C6 alkanoyloxy, aryloxy, heteroaryloxy, C1 -C6 alkoxy substituted C1- C6 alkanoyloxy, C1 - C6 alkanesulfonyloxy , arylsulfonyloxy, substituted arylsulfonyloxy , phosphoryloxy and hydroxy; herein, the substituted C1 - C6 alkyl, substituted C1 - C6 alkoxy or substituted arylsulfonyloxy refers to substituted by 1-3 groups independently selected from the following groups: deuterium , C1- C3 alkyl, C1 -
  • R8 is hydrogen, deuterium, substituted C1 - C6 alkyl, unsubstituted C3 - C6 cycloalkyl or substituted C3 - C6 cycloalkyl, wherein the substituted C3- C6 cycloalkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C1 - C3 alkyl, C1 - C3 alkoxy, halogen, halogenated C1 - C3 alkyl, C3 - C6 cycloalkyl, aryl and heteroaryl; the substituted C1 - C6 alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C1 - C3 alkoxy, halogen, halogenated C1 - C3 alkyl, C3 - C6 cycloalkyl, aryl and heteroaryl;
  • Y is N or CR 11 ; when Y is N, R 9 and R 10 are each independently hydrogen, hydroxyl or thiol, or R 9 and R 10 and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group; when Y is CR 11 , R 10 and R 11 form a bond, and R 9 is hydrogen, hydroxyl, amino, di(C 1 -C 4 alkyl)amino or thiol.
  • the present application provides a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein, when Y is CR11 , R10 and R11 form a bond, R8 is hydrogen, R9 is hydrogen, one or two of R3 and R4 are deuterium, and R5 and R6 are both hydrogen, R1 and R2 are not selected from the following groups: methyl, deuterated methyl, ethyl, propyl, deuterated ethyl and deuterated propyl; and/or
  • R 10 forms a bond with R 11
  • R 9 is hydrogen
  • R 3 , R 4 , R 5 and R 6 are all deuterium
  • R 1 and R 2 are all deuterated methyl
  • R 7 is not hydrogen, fluorine, methoxy, deuterated methoxy, benzylphosphoryloxy, phosphoryloxy or hydroxy
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 3 , R 4 , R 5 and R 6 are all hydrogen
  • R 1 and R 2 cannot be deuterated methyl at the same time, and when R 1 is deuterated methyl, deuterated ethyl or deuterated propyl, R 2 is not methyl, ethyl, propyl or deuterated ethyl; and/or
  • R 10 forms a bond with R 11
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 3 , R 4 , R 5 and R 6 are all hydrogen
  • R 1 is methyl, ethyl, propyl, isopropyl, allyl or cyclopropyl
  • R 2 is methyl, ethyl, propyl, isopropyl, allyl, isobutyl, cyclopropylmethyl, cyclopropyl, benzyl or phenyl
  • R 7 is not hydrogen, hydroxy, fluoro, methyl or methoxy; and/or;
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 3 , R 4 , R 5 and R 6 are all hydrogen
  • R 1 is propylethyl
  • R 2 is propyl
  • R 7 is not hydroxy, methoxy, acetoxy, phosphoryloxy, p-nitrobenzenesulfonyloxy, p-trifluoromethylbenzoyloxy, p-fluorobenzoyloxy, pivaloyloxy, methanesulfonyloxy, amino, fluorine, chlorine, bromine, iodine, methyl or trifluoromethyl; and/or
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 3 , R 4 , R 5 and R 6 are all hydrogen
  • R 1 is methyl
  • R 2 is methyl or ethyl
  • R 7 is not hydroxy, methoxy, acetoxy, phosphoryloxy, amino, fluorine, chlorine, bromine, iodine, methyl or trifluoromethyl
  • R 8 is hydrogen
  • R 9 is hydrogen
  • at least two of R 3 , R 4 , R 5 and R 6 are deuterium and the rest are hydrogen or all are deuterium
  • R 1 is methyl
  • R 2 is methyl
  • R 7 is not methoxy
  • R10 and R11 form a bond
  • R8 is hydrogen
  • R9 is hydrogen
  • R3 , R4 , R5 and R6 are all hydrogen
  • R1 and R2 form a nitrogen-containing heterocyclic ring with the nitrogen atom to which they are directly attached
  • R7 is not hydrogen, hydroxy, methoxy, fluorine, chlorine, bromine or iodine.
  • the present application provides a compound as shown in formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein the compound does not include the following compounds: 5-hydroxy-N,N-dimethyltryptamine, 5-bromo-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, Psilocybin, Psilocin, 5-methoxy-N,N-diallyltryptamine, 5-methoxy-N-allyl-N-methyltryptamine, 4-hydroxy-N,N-diethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, 4-hydroxy-N.N-dipropyltryptamine, 5-methoxy-N,N-dipropyltryptamine, 5-methoxy-N-isopropyl-N-methyltryptamine or
  • formula (I) is formula (IA):
  • R 1 -R 8 are as defined in formula (I), R 9 and R 10 are each independently hydrogen, hydroxyl or thiol, or R 9 and R 10 and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group; or
  • formula (I) is formula (IB):
  • R 1 to R 8 are as defined in formula (I), and R 9 is hydrogen, hydroxy, amino, di(C 1 -C 4 alkyl)amino or mercapto.
  • R1 and R2 in Formula (I), (IA) or (IB) are selected from the following groups: hydroxyl, unsubstituted C1 - C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1 - C6 alkoxy, substituted C1 - C6 alkoxy, unsubstituted C3 - C6 cycloalkyl, substituted C3 - C6 cycloalkyl, unsubstituted aryl and unsubstituted heteroaryl; herein, the substituted C1 - C6 alkyl, substituted C1 - C6 alkoxy or substituted C3 - C6 cycloalkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C1 - C3 alkyl, C1 - C3 alkoxy, hydroxyl, halogen, halogenated C1 - C3 alkyl, halogenated C1
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl;
  • the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy;
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • the aryl group is phenyl or naphthyl
  • the heteroaryl group is pyridyl or pyrimidinyl
  • the substituents of the substituted C 1 -C 6 alkyl are independently selected from the following 1-3 groups: deuterium, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, cyclopropyl, phenyl and pyridyl;
  • the substituents of the substituted C 1 -C 6 alkoxy group are independently selected from the following 1 to 3 groups: deuterium, fluorine, chlorine, bromine and iodine.
  • the substituents of the substituted C 3 -C 6 cycloalkyl are independently selected from the following 1-3 groups: deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, cyclopropyl, phenyl and pyridyl.
  • R1 and R2 in Formula (I), (IA) or (IB) are selected from the following groups: hydroxyl, methyl, ethyl, n-propyl, isopropyl, substituted isopropyl, n-butyl, tert-butyl, cyclopropyl, substituted cyclopropyl, deuterated methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl;
  • the substituted isopropyl refers to substituted by hydroxyl
  • the substituted cycloalkyl refers to substituted by a group selected from the following groups: deuterium, fluorine, chlorine, bromine and iodine
  • the substituted phenyl refers to substituted by a substituent selected from the following groups: deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy,
  • R1 and R2 in Formula (I), Formula (IA) or Formula (IB) are each independently selected from the following groups: hydroxyl, methyl, deuterated methyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, deuterated cyclopropyl, fluorocyclopropyl, deuterated methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl; here, the substituted phenyl refers to substituted by a group selected from the following groups: methoxy and trifluoromethyl.
  • R 1 and R 2 in Formula (I), Formula (IA) or Formula (IB) are each independently selected from the following groups: hydroxy, methyl, trideuteromethyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterocyclopropyl, 2,2-dideuterocyclopropyl, 2,2,3,3-tetradeuterocyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, phenyl and (5-trifluoromethyl-2-methoxy)phenyl.
  • R1 and R2 in Formula (I), Formula (IA) or Formula (IB) form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached; here, the unsubstituted nitrogen-containing heterocycle is piperidine or piperazine, and the substituted nitrogen-containing heterocycle is a substituted piperazine or piperidine; here, the substituted nitrogen-containing heterocycle is substituted by 1-3 substituents independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl and phenyl.
  • R1 and R2 in Formula (I), Formula (IA) or Formula (IB) form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached; the unsubstituted nitrogen-containing heterocycle is piperidine, or the substituted nitrogen-containing heterocycle is 4-(cyclopropylmethyl)piperazine.
  • R 3 , R 4 , R 5 , and R 6 in Formula (I), (IA), or (IB) are independently selected from hydrogen and deuterium; or, R 3 , R 4 or R 5 , R 6 and the carbon atom to which they are attached form a -C(O)- group or a -C(S)- group.
  • R7 in Formula (I), Formula (IA) or Formula (IB) is one, two, three or four, and each R7 is independently selected from the following substituents: hydrogen, deuterium, amino, fluorine, chlorine, bromine, unsubstituted C1 - C6 alkyl, substituted C1 - C6 alkyl, unsubstituted C1 - C6 alkoxy, substituted C1- C6 alkoxy, C1 - C6 alkanoyloxy, benzoyloxy, C1 - C6 alkoxy substituted C1 - C6 alkanoyloxy, C1 - C6 alkanesulfonyloxy, benzenesulfonyloxy, substituted benzenesulfonyloxy, phosphoryloxy and hydroxyl;
  • the substituted C1 - C6 alkyl, substituted C1 - C6 alkoxy or substituted benzenesulfonyloxy refers
  • R7 in Formula (I), Formula (IA) or Formula (IB) is one, two, three or four, and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfony
  • R7 in Formula (I), Formula (IA) or Formula (IB) is one, two, three or four, and each is independently selected from the following groups: hydrogen, deuterium, amino, hydroxyl, fluorine, chlorine, bromine, 1,1-dideuteroethyl, methoxy, (4-acetoxy)benzyloxy, acetoxy, methoxycarbonyloxy, phosphoryloxy, and methanesulfonyloxy.
  • R in Formula (I), (IA) or (IB) is at the 4th position (uppermost position), 5th position, 6th position or 7th position (lowermost position) of the phenyl ring to which it is attached, in counterclockwise order:
  • R 8 in Formula (I), Formula (IA) or Formula (IB) is selected from the group consisting of hydrogen, C 3 -C 6 cycloalkyl, substituted C 1 -C 6 alkyl.
  • R 8 in formula (I) is selected from the following substituents: hydrogen, cyclopropylmethyl, deuterated methyl.
  • the present application provides a compound represented by formula (I), formula (IA) or formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R1 and R2 in formula (I), formula (IA) or formula (IB) are each independently selected from the following groups: hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, substituted cyclopropyl, deuterated methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl; herein, the substituted cycloalkyl refers to substituted by a group selected from the following groups: deuterium, fluorine, chlorine, bromine and iodine; the substituted
  • R1 and R2 and the nitrogen atom to which they are directly attached form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle;
  • the nitrogen-containing heterocycle is piperidine or piperazine;
  • the substituted nitrogen-containing heterocycle refers to being substituted by 1 to 3 groups independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl and phenyl;
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen and deuterium; or, R 3 , R 4 or R 5 , R 6 and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group;
  • R7 is one, two, three or four, and each is independently selected from the following substituents: hydrogen, deuterium, amino, fluorine, chlorine, bromine, unsubstituted C1 - C6 alkyl, substituted C1 - C6 alkyl, unsubstituted C1 -C6 alkoxy, substituted C1- C6 alkoxy, C1 - C6 alkanoyloxy, benzoyloxy, C1 - C6 alkoxy substituted C1 - C6 alkanoyloxy, C1 - C6 alkanesulfonyloxy , benzenesulfonyloxy, substituted benzenesulfonyloxy, phosphoryloxy and hydroxyl;
  • the substituted C1 - C6 alkyl, substituted C1 - C6 alkoxy or substituted benzenesulfonyloxy refers to being substituted by 1 to 3 groups independently selected from the following groups: deuterium, C
  • R 8 is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;
  • R 9 is hydrogen, amino or di(C 1 -C 4 alkyl)amino, or R 9 and R 10 and the carbon atom to which they are connected form a -C(O)- group.
  • the present application provides a compound represented by formula (I), formula (IA) or formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R 1 and R 2 in formula (I), formula (IA) or formula (IB) are each independently selected from the following groups: hydroxyl, methyl, ethyl, n-propyl, 2-hydroxyisopropyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, deuterated cyclopropyl, fluorocyclopropyl, deuterated substituted methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl;
  • the substituted phenyl refers to substituted by a group selected from the following: methoxy and trifluoromethyl;
  • R1 and R2 form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached;
  • the nitrogen-containing heterocycle is piperidine or piperazine;
  • the substituted nitrogen-containing heterocycle refers to being substituted by 1 to 3 groups independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl and phenyl;
  • R 3 , R 4 , R 5 and R 6 are all deuterium; or, R 3 , R 4 , R 5 and R 6 are all hydrogen;
  • R7 is one, two, three or four, and each is independently selected from the following substituents: hydrogen, deuterium, amino, fluorine, chlorine, bromine, unsubstituted C1 - C6 alkyl, substituted C1 - C6 alkyl, unsubstituted C1 -C6 alkoxy, substituted C1- C6 alkoxy, C1 - C6 alkanoyloxy, benzoyloxy, C1 - C6 alkoxy substituted C1 - C6 alkanoyloxy, C1 - C6 alkanesulfonyloxy , benzenesulfonyloxy, substituted benzenesulfonyloxy, phosphoryloxy and hydroxyl;
  • the substituted C1 - C6 alkyl, substituted C1 - C6 alkoxy or substituted benzenesulfonyloxy refers to being substituted by 1 to 3 groups independently selected from the following groups: deuterium, C
  • R 8 is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;
  • R 9 is hydrogen, amino or di(C 1 -C 4 alkyl)amino, or R 9 and R 10 and the carbon atom to which they are connected form a -C(O)- group.
  • the present application provides a compound represented by formula (I), formula (IA) or formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R 1 and R 2 in formula (I), formula (IA) or formula (IB) are each independently selected from the following groups: hydroxyl, methyl, deuterated methyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterated cyclopropyl, 2,2-dideuterated cyclopropyl, 2,2,3,3-tetradeuterated cyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, phenyl and (5-trifluoromethyl-2-methoxy)pheny
  • R 1 and R 2 together with the nitrogen atom to which they are directly attached form piperidine or 4-(cyclopropylmethyl)piperazine;
  • R 3 , R 4 , R 5 and R 6 are all deuterium; or, R 3 , R 4 , R 5 and R 6 are all hydrogen;
  • R 7 is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phospho
  • R 8 is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;
  • Y is N or CR 11 , wherein R 10 and R 11 form a bond
  • R9 is hydrogen, amino or dimethylamino, or R9 and R10 and the carbon atom to which they are connected form a -C(O)- group.
  • the present application provides a compound represented by formula (I), formula (IA) or formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R 1 and R 2 in formula (I), formula (IA) or formula (IB) are each independently selected from the following groups: hydroxyl, methyl, trideuterated methyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterated cyclopropyl, 2,2-dideuterated cyclopropyl, 2,2,3,3-tetradeuterated cyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, Phenyl and (5-trifluoromethyl-2-methoxy)phen
  • R 1 and R 2 together with the nitrogen atom to which they are directly attached form piperidine or 4-(cyclopropylmethyl)piperazine;
  • R 3 , R 4 , R 5 and R 6 are all deuterium; or, R 3 , R 4 , R 5 and R 6 are all hydrogen;
  • R 7 is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phospho
  • R 8 is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;
  • Y is N or CR 11 , wherein R 10 and R 11 form a bond
  • R9 is hydrogen, amino or dimethylamino, or R9 and R10 and the carbon atom to which they are connected form a -C(O)- group.
  • the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R 1 and R 2 in formula (IB) are each independently selected from the following groups: hydroxyl, methyl, trideuterated methyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterated cyclopropyl, 2,2-dideuterated cyclopropyl, 2,2,3,3-tetradeuterated cyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, phenyl and (5-trifluoromethyl-2-methoxy)phenyl;
  • R 3 , R 4 , R 5 and R 6 are all deuterium
  • R 7 is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phospho
  • R 8 is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;
  • Y is N or CR 11 , wherein R 10 and R 11 form a bond
  • R9 is hydrogen, amino or dimethylamino.
  • the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein in formula (IB), R 1 is -CD 3 , R 2 is cyclopropyl or cyclopropylmethyl;
  • R 3 , R 4 , R 5 and R 6 are all deuterium
  • R 7 is one, two, three or four and is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetyloxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl:
  • R 8 is a substituent selected from the following: hydrogen
  • R9 is hydrogen, amino or dimethylamino.
  • the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R 1 and R 2 in formula (I), formula (IA) or formula (IB) form piperidine or 4-(cyclopropylmethyl)piperazine with the nitrogen atom to which they are directly attached;
  • R 3 , R 4 , R 5 and R 6 are all deuterium; or, R 3 , R 4 , R 5 and R 6 are all hydrogen;
  • R 7 is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phospho
  • R 8 is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;
  • R9 is hydrogen, amino or dimethylamino.
  • the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R 1 and R 2 in formula (I), formula (IA) or formula (IB) form piperidine or 4-(cyclopropylmethyl)piperazine with the nitrogen atom to which they are directly attached;
  • R 3 , R 4 , R 5 and R 6 are all hydrogen
  • R 7 is one, two, three or four and is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetyloxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl;
  • R 8 is a substituent selected from the group consisting of hydrogen and cyclopropylmethyl
  • R9 is hydrogen
  • the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein in formula (I), formula (IA) or formula (IB), R 1 is methyl, and R 2 is 2-hydroxyisopropyl;
  • R 3 , R 4 , R 5 and R 6 are all hydrogen
  • R 7 is one, two, three or four and is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetyloxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl;
  • R8 is hydrogen
  • R9 is hydrogen
  • the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein formula (I), formula (IA) or formula (IB) wherein R 1 is methyl and R 2 is cyclopropyl;
  • R 3 , R 4 , R 5 and R 6 are all hydrogen
  • R 7 is one, two, three or four and is independently selected from the following groups: deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl;
  • R8 is hydrogen
  • R9 is hydrogen
  • the compound provided by the present invention is a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein formula (I) is formula (IC):
  • n is 0 or 1;
  • R1 is unsubstituted C1 - C6 alkyl or substituted C1 - C6 alkyl, wherein the substituted C1 - C6 alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C1 -C3 alkyl, C1 - C3 alkoxy, hydroxy, halogen, halogenated C1 - C3 alkyl, halogenated C1- C3 alkoxy, C3 -C6 cycloalkyl , aryl and heteroaryl ;
  • R7 is one, two, three or four and each is independently selected from hydrogen, deuterium, amino, halogen, unsubstituted C1 - C6 alkyl, substituted C1 - C6 alkyl, unsubstituted C1-C6 alkoxy, substituted C1 - C6 alkoxy, C1 - C6 alkanoyloxy, aryloxy, heteroaryloxy, C1 -C6 alkoxy substituted C1- C6 alkanoyloxy, C1-C6 alkanesulfonyloxy , arylsulfonyloxy , substituted arylsulfonyloxy , phosphoryloxy and hydroxy; herein, the substituted C1 - C6 alkyl, substituted C1 - C6 alkoxy or substituted arylsulfonyloxy refers to substituted by 1-3 groups independently selected from the following groups: deuterium , C1- C3 alkyl, C1 -
  • the present application provides a compound of formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein n is 0.
  • the compound provided herein is as shown in formula (IC), or its stereoisomers, pharmaceutically An acceptable salt, solvate, deuterated compound, metabolite or prodrug, wherein R 1 is -CD 3 .
  • substituted phenyl refers to substituted by 1 to 3 groups independently selected from the following groups: halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxy, phenyl and C 1 -C 6 alkanoyloxy.
  • R7 is one, two
  • the present application provides a compound as shown in formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R 7 is one, two, three or four and is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy,
  • the present application provides a compound of formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R7 is one, two, three or four, and each is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine and hydroxyl.
  • the present application provides a compound as shown in formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R7 is at the 4-position, 5-position, 6-position or 7-position of the benzene ring to which it is attached (i.e., the position determined by the indole structure).
  • the present application provides a compound of formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein n is 1: R 1 is -CD 3 : R 7 is one, two, three or four, and each is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine and hydroxyl.
  • IC formula
  • the compound of formula (I) is selected from the following compounds, and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs thereof:
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, and a pharmaceutically acceptable carrier.
  • the present application also discloses a pharmaceutical composition, comprising: an effective dose of a DMT derivative or a stereoisomer thereof represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition further comprises one or more additional therapeutic agents.
  • This or these pharmaceutically acceptable excipients can be, for example, selected from carriers (e.g., solid, liquid or semisolid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or extenders; and liquid diluents such as solvents and co-solvents), granulating agents, binders, glidants, coating agents, release controlling agents (e.g., polymers or waxes that retard or delay release), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tonicity regulators, thickeners, flavor enhancers, sweeteners, pigments, plasticizers, taste masking agents, stabilizers or any other excipients conventionally used in pharmaceutical compositions.
  • carriers e.g., solid, liquid or semisolid carriers
  • adjuvants e.g., solid diluents such as fillers or extenders; and liquid d
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects (e.g., human subjects) without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • the pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal or transdermal administration.
  • Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets or patches such as buccal patches.
  • the present application provides a method for preparing a DMT derivative represented by the above formula (I), formula (IA), formula (IB) or formula (IC) or a stereoisomer, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug thereof, the preparation method comprising the following steps:
  • the compound of formula (I-4) is subjected to a thiocarbonylation reaction to obtain a compound of formula (I-5);
  • the method comprises the following steps: a compound of formula (I-6) is subjected to a substitution reaction with a compound of formula (I-7) to obtain a compound of formula (I-8);
  • X represents a leaving group such as bromine, etc., and other groups are defined as formula (I).
  • the present invention provides a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated A compound, metabolite or prodrug, or a pharmaceutical composition thereof, for pharmaceutical use.
  • the present application provides a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application and its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs, or pharmaceutical compositions thereof, for stimulating 5-HT 2A receptors.
  • the present application provides a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application and its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs, or pharmaceutical compositions thereof, for the treatment of 5-HT 2A receptor-related diseases/disorders.
  • the present application provides the use of a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated substance, a metabolite or a prodrug thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating 5- HT2A receptor-related central nervous system diseases, disorders or conditions and/or neurological diseases, disorders or conditions.
  • a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated substance, a metabolite or a prodrug thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating 5- HT2A receptor-related central nervous system diseases, disorders or conditions and/or neurological diseases, disorders or conditions.
  • the present application provides the above-mentioned use, and the 5-HT 2A receptor-related central nervous system diseases, disorders or conditions and/or neurological diseases, disorders or conditions can be selected from: major depressive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, cancer-related diseases, decreased drive, burnout, cluster headache, migraine, Parkinson's disease, schizophrenia, eating disorders, nausea or vomiting, and abuse of addictive psychoactive substances.
  • the present application provides a method for treating a 5-HT 2A receptor-related disease/disorder in a patient, the method comprising administering to a patient in need thereof a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application, or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, or a pharmaceutical composition thereof.
  • a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, or a pharmaceutical composition thereof.
  • the present application provides a method for treating or preventing a patient's central nervous system disease, disorder or condition and/or neurological disease, disorder or condition, the method comprising administering to a patient in need thereof a DMT derivative or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug of formula (I), formula (IA), formula (IB) or formula (IC) described herein, or the pharmaceutical composition.
  • the central nervous system disease, disorder or condition and/or neurological disease, disorder or condition may be selected from: major depressive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, cancer-related illness, drive loss, burnout, cluster headache, migraine, Parkinson's disease, schizophrenia, eating disorders, nausea or vomiting, and abuse of addictive psychoactive substances.
  • the present application provides a method for treating a 5-HT 2A receptor-related disease/disorder in a patient, the method comprising administering a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described herein, or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, or the pharmaceutical composition.
  • the present application provides a method for agonizing 5-HT 2A receptors to treat or prevent a patient's central nervous system disease, disorder or condition and/or neurological disease, disorder or condition, the method comprising administering to a patient in need thereof a DMT derivative of formula (I), formula (IA), formula (IB) or formula (IC) or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, or the pharmaceutical composition described herein.
  • the central nervous system disease, disorder or condition and/or neurological disease, disorder or condition may be selected from: major depressive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, cancer-related disorders, drive loss, burnout, cluster headache, migraine, Parkinson's disease, schizophrenia, eating disorders, nausea or vomiting, and abuse of addictive psychoactive substances.
  • the compound of the present application can bind to the 5-HT 2A receptor, has good 5-HT 2A receptor binding activity, and has a short half-life, rapid metabolism, is suitable for medicinal use, and has clinical application value.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present application include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds are optionally further replaced by one or more of their corresponding isotopes, wherein hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), carbon isotopes include 12 C, 13 C and 14 C, nitrogen isotopes include 14 N and 15 N, oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also
  • alkyl refers to a linear and branched monovalent saturated hydrocarbon group with a main chain comprising 1 to 10 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • the alkyl group may be further substituted by any substituent.
  • cycloalkyl refers to a monovalent saturated carbocyclic hydrocarbon group, a single ring, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • the cycloalkyl group may be optionally further substituted by any substituent.
  • heterocycloalkane refers to a saturated cyclic hydrocarbon group containing at least one heteroatom, a monocyclic ring, and the heteroatom is N, O, S, P and its oxidized form, and non-limiting examples include aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thiidine, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc.
  • the heterocycloalkane may be optionally further substituted by any substituent.
  • aryl refers to a 6-14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atom pairs) group with a conjugated ⁇ electron system, preferably 6-10 members, such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently and optionally selected from one or more substituents in hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur.
  • Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclic or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring.
  • pharmaceutically acceptable salt refers to a salt which retains the biological effectiveness and properties of the free acid or free base and is obtained by reacting the free acid with a non-toxic inorganic base or organic base, or by reacting the free acid with a non-toxic inorganic acid or organic acid.
  • carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • excipient refers to an inert substance added to a pharmaceutical composition to further rely on the administration of a compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrants, etc.
  • prodrug refers to a compound that can be converted into a biologically active compound of the present application under physiological conditions or by solvolysis.
  • the prodrug of the present application is prepared by modifying the phenolic group in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present application is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl groups respectively.
  • prodrugs include, but are not limited to, phenolic hydroxyl groups and sodium phosphate derivatives of the compounds of the present application.
  • an effective dose refers to the amount of a compound that elicits a physiological or medical translation in a tissue, system or subject that is being sought, including an amount of the compound that, when administered to a subject, is sufficient to prevent the occurrence of one or more symptoms of the disorder or condition being treated or to alleviate them to some extent.
  • solvate refers to the compounds of the present application or their salts, which also include a stoichiometric or non-stoichiometric solvent bound by non-covalent forces between molecules.
  • solvent is water, it is a hydrate.
  • alkyl optionally substituted with Cl means that alkyl may but need not be substituted with Cl, and the description includes the situation where alkyl is substituted with Cl and the situation where alkyl is not substituted with Cl.
  • ACN acetonitrile
  • LiAlD 4 lithium aluminum hydride deuterated
  • LiAlH 4 Lithium aluminum hydride
  • PE petroleum ether
  • High performance liquid chromatography was determined by Thermo UltiMate 3000 liquid chromatograph, using Venusil ASB C18 (4.6*250mm, 5 ⁇ m) chromatographic column for detection.
  • Mobile phase B CH 3 CN
  • Flow rate 1.0mL/min
  • Column temperature 35°C
  • Detection wavelength UV-215nm
  • Injection volume 2 ⁇ L
  • Gradient elution conditions Elution at a flow rate of 1.0mL/min throughout the process, first eluting with 95% A and 5% B for 10min, then eluting with 20% A and 80% B for 5min, and finally eluting with 95% A and 5% B for 5min.
  • the percentage is the volume percentage of the mobile phase in the elution solution.
  • Example 1 Synthesis of 5-(1,1-dideuteroethyl)-3-[1,1,2,2-tetradeuteroyl-2-(dimethylamino)ethyl]-1H-indole, the route is as follows:
  • Example 5 Synthesis of 5-(1,1-dideuteroethyl)-3-[1,1,2,2-tetradeuteroyl-2-(diethylamino)ethyl]-1H-indole, the route is as follows:
  • Example 7 Synthesis of 3-[1,1,2,2-tetradeuteride-2-(diethylamino)ethyl]-1H-indole-5,6-diphenol, the route is as follows:
  • Example 8 Synthesis of 6-methoxy-3- ⁇ 1,1,2,2-tetradeuteride-2-[di(propyl-2-yl)amino]ethyl ⁇ -1H-indole, the route is as follows:
  • Example 9 Synthesis of 5-(1,1-dideuteroethyl)-3- ⁇ 1,1,2,2-tetradeuteroyl-2-[di(propyl-2-yl)amino]ethyl ⁇ -1H-indole, the route is as follows:
  • Example 10 Synthesis of 3- ⁇ 1,1,2,2-tetradeuteride-2-[di(propyl-2-yl)amino]ethyl ⁇ -1H-indole-7-ol, the route is as follows:
  • Example 11 Synthesis of 3- ⁇ 1,1,2,2-tetradeuteride-2-[di(propan-2-yl)amino]ethyl ⁇ -1H-indole-5,6-diphenol, the route is as follows:
  • Example 12 Synthesis of 3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole, The line looks like this:
  • Example 13 Synthesis of 3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole-4-ol, the route is as follows:
  • Example 14 Synthesis of 3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole-5-ol, the route is as follows:
  • Example 15 Synthesis of 3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole-6-phenol, the route is as follows:
  • Example 16 Synthesis of 3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole-7-ol, the route is as follows:
  • Example 17 Synthesis of 3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole-5,6-diphenol, the route is as follows:
  • Example 18 Synthesis of 4-bromo-3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole, the route is as follows:
  • Example 20 Synthesis of 6-bromo-3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole, the route is as follows:
  • Example 21 Synthesis of 7-bromo-3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole, the route is as follows:
  • Example 22 Synthesis of 5,6-dibromo-3- ⁇ 2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl ⁇ -1H-indole, the route is as follows:
  • Example 28 Synthesis of 3-(2- ⁇ [2-methoxy-5-(trifluoromethyl)phenyl](methyl)amino ⁇ ethyl)-1H-indole, the route is as follows:
  • 3-(2-bromoethyl)indole 200 mg, 0.89 mmol, 1.0 eq was weighed, 10 mL ACN was added to dissolve, 1-cyclopropylmethylpiperazine (188 mg, 1.34 mmol, 1.5 eq) and TEA (270 mg, 2.67 mmol, 3.0 eq) were weighed and added, and the mixture was placed in an oil bath at 60°C. After 8 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of compound 30. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • 3-(2-bromoethyl)indole 200 mg, 0.89 mmol, 1.0 eq was weighed, 10 mL ACN was added to dissolve, 2-(methylamino)propan-2-ol (119 mg, 1.34 mmol, 1.5 eq) and TEA (450 mg, 4.45 mmol, 5.0 eq) were weighed and added, and an oil bath was added at 60°C. After 12 h, the molecular weight of compound 31 was detected by LC-MS. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • 3-(2-bromoethyl)indole 200 mg, 0.89 mmol, 1.0 eq was weighed, 10 mL of acetonitrile was added to dissolve, N-methylcyclopropylamine hydrochloride (191 mg, 1.78 mmol, 2.0 eq) and TEA (450 mg, 4.45 mmol, 5.0 eq) were weighed and added, and the mixture was placed in an oil bath at 80°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of compound 33.
  • 5-HT 2A -HEK293 cells were purchased from WuXi AppTec; polyethyleneimine was purchased from Sigma, P3143; 96-well plates were purchased from Agilent, #5042-1385; [ 3 H]-Ketanserin was purchased from Sigma, S006; Filtermate collector was purchased from Perkin Elmer, C961961; TopSeal-A sealing membrane was purchased from Perkin Elmer, #6050185; Unifilter-96GF/C filter plate was purchased from Perkin Elmer; Microscint 20cocktail scintillation fluid was purchased from PerkinElmer, #6013329.
  • test compound was dissolved in DMSO to 0.02 mM and diluted 4-fold to 8 concentrations; the detection buffer solution was 50 mM Tris-HCl, pH 7.4, and the washing buffer solution was 50 mM Tris-HCl, pH 7.4.
  • % inhibition rate (1-(assay well-mean_LC)/(mean_HC-mean_LC))*100%.
  • 384-well plates were purchased from Greiner, #781090; Fluo-4 Direct TM crystals were purchased from Invitrogen, F10471.
  • test compound was serially diluted 4-fold to 10 concentrations for later use; probenecid was dissolved in FLIPR assay buffer to prepare a 2.5 mM test solvent for later use; 25 mg of poly-L-lysine hydrobromide was added to 500 mL of ddH 2 O to prepare a coating solution; a vial of Fluo-4 Direct TM crystals was thawed and 10 mL of FLIPR assay buffer was added to the vial to prepare Fluo-4 Direct TM loading buffer;
  • liver microsome incubation system The samples obtained at each time point in the liver microsome incubation system were precipitated with 3 volumes of acetonitrile, centrifuged, and the supernatant was transferred to a liquid sample bottle with a pipette; NADPH regeneration system (15mM NADPH and 3.2mM magnesium chloride); UGT incubation system (10.8mM UDPGA, 10.8mM D-glucaric acid-1,4-lactone and 83.8 ⁇ g/mL alamethicone)
  • the system includes 0.1M buffer, 6mg/mL rat liver microsomal protein, NADPH regeneration system, UGT incubation system and the test compound at an appropriate concentration, incubated at 37°C, 600rpm, each sample was paralleled 3 times, testosterone was used as the positive control of phase I metabolic reaction, 7-hydroxycoumarin was used as the positive control of phase II metabolic reaction, and the system without NADPH regeneration system and UGT system was used as the negative control.
  • 3 volumes of acetonitrile were added to terminate the reaction.
  • the liquid chromatography peak area value was statistically analyzed, and the obtained data was imported into Excel software for processing and analysis to obtain the residual percentage content-time scatter plot of each compound after metabolism in the liver microsome incubation system and its half-life (T 1/2 ) value.
  • T 1/2 half-life
  • A0 HPLC peak area response value of the compound in the liver microsome incubation system at 0h.
  • This figure can show the metabolic trend of the compound in the liver microsome incubation system.
  • k The slope of the trend line fitted on the ln(Percent Remaining%)-time graph.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de N, N-diméthyltryptamine, une composition pharmaceutique de celui-ci, son procédé de préparation et son utilisation. Le dérivé de N, N-diméthyltryptamine est tel que représenté par la formule (I), et des substituants et définitions spécifiques sont tels que décrits dans la description. Le dérivé de N, N-diméthyltryptamine présente une bonne capacité de liaison à 5-HT2A, et le composé ou la composition pharmaceutique de celui-ci sont utilisés pour traiter des maladies, troubles ou états du système nerveux central associés au récepteur 5-HT2A et/ou des maladies, troubles ou états neurologiques.
PCT/CN2024/128363 2023-11-06 2024-10-30 Dérivé de n, n-diméthyltryptamine, composition pharmaceutique associée, son procédé de préparation et son utilisation Pending WO2025098212A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202311463634 2023-11-06
CN202311463634.6 2023-11-06
CN202411096546 2024-08-09
CN202411096546.1 2024-08-09

Publications (1)

Publication Number Publication Date
WO2025098212A1 true WO2025098212A1 (fr) 2025-05-15

Family

ID=95694947

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/128363 Pending WO2025098212A1 (fr) 2023-11-06 2024-10-30 Dérivé de n, n-diméthyltryptamine, composition pharmaceutique associée, son procédé de préparation et son utilisation

Country Status (2)

Country Link
TW (1) TW202519206A (fr)
WO (1) WO2025098212A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022076642A1 (fr) * 2020-10-08 2022-04-14 Lennham Pharmaceuticals, Inc. Dérivés deutérés de la psilocybine et leurs utilisations
WO2022183287A1 (fr) * 2021-03-02 2022-09-09 Mindset Pharma Inc. Dérivés d'indole utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés à ceux-ci
CN115397810A (zh) * 2020-02-04 2022-11-25 明德赛特制药公司 用于治疗cns病症的作为血清素能致幻剂的赛洛辛衍生物
CN115667217A (zh) * 2020-05-19 2023-01-31 赛本爱尔兰有限公司 氘化的色胺衍生物和使用方法
WO2023108174A1 (fr) * 2021-12-10 2023-06-15 Terran Biosciences, Inc. Analogues de 6-méthoxy-n,n-diméthyltryptamine
WO2023186963A1 (fr) * 2022-03-31 2023-10-05 Cybin Irl Limited Combinaison d'oxyde nitreux et d'agonistes du récepteur 5-ht2a

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115397810A (zh) * 2020-02-04 2022-11-25 明德赛特制药公司 用于治疗cns病症的作为血清素能致幻剂的赛洛辛衍生物
CN115427395A (zh) * 2020-02-04 2022-12-02 明德赛特制药公司 用于治疗cns病症的作为血清素能致幻剂的赛洛辛衍生物
CN115667217A (zh) * 2020-05-19 2023-01-31 赛本爱尔兰有限公司 氘化的色胺衍生物和使用方法
WO2022076642A1 (fr) * 2020-10-08 2022-04-14 Lennham Pharmaceuticals, Inc. Dérivés deutérés de la psilocybine et leurs utilisations
WO2022183287A1 (fr) * 2021-03-02 2022-09-09 Mindset Pharma Inc. Dérivés d'indole utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés à ceux-ci
WO2023108174A1 (fr) * 2021-12-10 2023-06-15 Terran Biosciences, Inc. Analogues de 6-méthoxy-n,n-diméthyltryptamine
WO2023186963A1 (fr) * 2022-03-31 2023-10-05 Cybin Irl Limited Combinaison d'oxyde nitreux et d'agonistes du récepteur 5-ht2a

Also Published As

Publication number Publication date
TW202519206A (zh) 2025-05-16

Similar Documents

Publication Publication Date Title
JP7025508B2 (ja) ハンチントン病の治療方法
CN101827593B (zh) 用于治疗(特别是)囊性纤维化的异噻唑并吡啶酮
CN101687883B (zh) 囊性纤维化跨膜传导调节因子的调节剂
CA2756568C (fr) Inhibiteurs de kinases et procede de traitement du cancer avec ceux-ci
WO2022017339A1 (fr) Dérivé pyridazinique condensé, son procédé de préparation et son utilisation pharmaceutique
JP5621148B2 (ja) ５−ｈｔ２ｂ受容体拮抗活性を有する新規ピラゾール−３−カルボキサミド誘導体
JP2016527296A (ja) Ｃｆｔｒモジュレーターとしてのチエノ［２，３−ｃ］ピラン
KR20130108065A (ko) 인산화 효소 억제제와 이를 이용한 종양을 치료하는 방법.
TWI826819B (zh) 一種作為ｂｔｋ抑制劑的化合物及其製備方法與用途
CN103402995B (zh) 吲哚、吲唑衍生物或其盐
CN110234638A (zh) 杂芳基苯氧基苯甲酰胺kappa阿片类配体
CN104837490A (zh) 作为无义突变抑制子的嘧啶并[4,5-b]喹啉-4,5(3H,10H)-二酮
WO2020233618A1 (fr) Inhibiteurs de nécrose cellulaire programmée, leur procédé de préparation et leur utilisation
JP2018138609A (ja) ナフチリジンジオン誘導体
JP2021526156A (ja) ジメチルホスフィンオキシド化合物
WO2024083204A1 (fr) Forme saline et forme cristalline d'un inhibiteur de dérivé hétérocyclique, son procédé de préparation et son utilisation
BRPI0718510A2 (pt) Derivados de 3-amino piridina para o tratamento de desordens metabólicas
CN116655602A (zh) PI3Kα变构抑制剂
WO2023078451A1 (fr) Composé utile en tant qu'inhibiteur de kinase cdk7 et son utilisation
WO2025098212A1 (fr) Dérivé de n, n-diméthyltryptamine, composition pharmaceutique associée, son procédé de préparation et son utilisation
WO2025021115A1 (fr) Dérivé de pyrrolidine polysubstitué, son procédé de préparation et son utilisation
WO2017117239A1 (fr) Composés et méthodes pour le traitement de la mucoviscidose
WO2024193640A1 (fr) Inhibiteur de cdk
WO2024146528A1 (fr) Dérivé de 2-indolone et son utilisation
WO2025021033A1 (fr) Inhibiteur du récepteur du facteur de croissance des fibroblastes, composition pharmaceutique et utilisation associées

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24887824

Country of ref document: EP

Kind code of ref document: A1