[go: up one dir, main page]

WO2025242125A1 - Composés azacycloalcanes, composition pharmaceutique et utilisation associées - Google Patents

Composés azacycloalcanes, composition pharmaceutique et utilisation associées

Info

Publication number
WO2025242125A1
WO2025242125A1 PCT/CN2025/096254 CN2025096254W WO2025242125A1 WO 2025242125 A1 WO2025242125 A1 WO 2025242125A1 CN 2025096254 W CN2025096254 W CN 2025096254W WO 2025242125 A1 WO2025242125 A1 WO 2025242125A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
group
halogens
alkyl
groups
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/CN2025/096254
Other languages
English (en)
Chinese (zh)
Inventor
袁曙光
李海剑
李毅
梁文冠
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.)
Alphamol Science Ltd Shenzhen
Original Assignee
Alphamol Science Ltd Shenzhen
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 Alphamol Science Ltd Shenzhen filed Critical Alphamol Science Ltd Shenzhen
Publication of WO2025242125A1 publication Critical patent/WO2025242125A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This invention relates to a nitrogen-containing heterocyclic alkane compound, its pharmaceutical composition, and its application.
  • Pain is an unpleasant sensation or feeling associated with physical or underlying tissue damage. If pain lasts for more than a month, or exceeds the expected duration of the acute process of injury, healing, and repair, it is considered chronic pain, which typically lasts for months, years, or decades.
  • Opioid receptors are a class of G protein-coupled receptors widely distributed in the central nervous system and peripheral tissues, participating in various physiological and pathological processes. Opioid receptors play a crucial role in pain transmission and modulation.
  • opioid receptors There are several types of opioid receptors, among which classic opioid receptors include ⁇ , ⁇ , and ⁇ receptors (doi.org/10.1038/s41583-018-0028-x).
  • Analgesics act on opioid receptors in the central nervous system, especially activating ⁇ receptors, inhibiting the upward transmission of pain signals in the central nervous system pathways.
  • opioids are addictive, and long-term use can lead to drug dependence and tolerance.
  • opioids can cause central nervous system and intestinal side effects, such as respiratory depression, sedation, addiction, and constipation (doi.org/10.1038/s41598-018-27313-4). Constipation, as the most common side effect of opioids, can severely impact patients' quality of life (DOI:10.1097/AJP.0000000000000852). Therefore, developing opioid receptor agonists to overcome the side effect of constipation is an urgent problem to be solved.
  • This invention relates to a series of azacyclic alkanes and their use in the preparation of medicaments for opioid receptor agonist-related diseases. Specifically, it relates to compounds of formula I or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
  • the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof, as an opioid receptor agonist;
  • n1 is 0 or 1
  • R1 is selected from hydrogen, hydroxyl, amino, mercapto, C1 - C6 alkoxy, C1 - C6 alkylamino, nitrogen-containing C1 - C6 heteroalkyl, oxygen-containing C1 - C6 heteroalkyl, sulfur-containing C1 - C6 heteroalkyl, halogen, C1 - C6 carboxyl, C1 - C6 amide, C2 - C6 ester, and C2 - C6 ester substituted with 1, 2, or 3 halogens;
  • the sulfur-containing C1 - C6 heteroalkyl group contains one S heteroatom, which can replace the C atom in the alkyl chain at a position allowed by the normal valence state, and the S atom is not directly connected to the substituted group;
  • the oxygen-containing C1 - C6 heteroalkyl group contains one O heteroatom.
  • the O atom can replace the C atom in the alkyl chain at a position allowed by the normal valence state, and the O atom is not directly connected to the substituted group.
  • the nitrogen-containing C1 - C6 heteroalkyl group contains one N heteroatom, which can replace the C atom in the alkyl chain at a position allowed by the normal valence state, and the N atom is not directly connected to the substituted group;
  • heteroatoms of the C4 - C8 aliphatic heterocycle are independently selected from one or more of N, O, S and P, and the number of heteroatoms is 1, 2, 3 or 4;
  • heteroatoms of the C3 - C18 aromatic heterocycle are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.
  • certain groups in the compound of Formula I or its pharmaceutically acceptable salt have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the invention (hereinafter referred to as "in some embodiments"):
  • the C1 - C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, or isohexyl.
  • the C1 - C6 alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, n-hexyloxy, or isohexyloxy.
  • the C1 - C6 alkylamino group may be methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentamino, isopentamino, neopentamino, n-hexylamino, or isohexylamino.
  • the C1 - C6 alkylthiols may be methylthiols, ethimylthiols, n-propanthiols, isopropanthiols, n-butanthiols, isobutanthiols, sec-butanthiols, tert-butanthiols, n-pentanthiols, isopentanthiols, neopentanthiols, n-hexylthiols, or isohexylthiols.
  • the C2 - C6 ester group may be -CO2C1 - C5 alkyl or -OCOC1 - C5 alkyl.
  • the alkyl group in the -CO2C1 - C5 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n - butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or isopentyl.
  • the -OCOC 1 -C 5 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or isopentyl.
  • the halogen may be fluorine, chlorine, bromine, or iodine.
  • the sulfur-containing C1 - C6 heteroalkyl group may be -CH2 -S- CH3 , -CH2CH2 - S -CH3, -CH2CH2 - S - CH2CH3 , -CH2CH2 - S - CH2CH2CH3 , -CH2CH2CH2 - S - CH2CH3 , or -CH2CH2CH2 - S - CH2CH2CH3 .
  • the oxygen-containing C 1 -C 6 heteroalkyl group can be -CH 2 -OH, -CH 2 CH 2 -OH, -CH 2 CH 2 CH 2 -OH, -CH 2 CH 2 CH 2 CH 2 -OH, -CH 2 CH 2 CH 2 CH 2 CH 2 -OH, -CH 2 CH 2 CH 2 CH 2 CH 2 -OH, -CH 2 -O ⁇ CH.
  • the nitrogen-containing C 1 -C 6 heteroalkyl group can be -CH 2 -NH 2 , -CH 2 CH 2 -NH 2 , -CH 2 CH 2 CH 2 -NH 2 , -CH 2 CH 2 CH 2 CH 2 -NH 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 -NH 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 -NH 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 CH 2 -NH-CH 3 , -CH 2 -N-(CH 3 ) 2 , -CH 2 CH 2 -NH-CH 2 CH 3 , -CH 2 CH 2 -N-(CH 3 ) 2 , -CH 2 CH 2 -NH-CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 -N-(CH 3 ) 2 , -CH 2 CH 2 -NH-CH 2 CH 2 CH 3
  • the C1 - C6 sulfoxide group may be methyl sulfoxide, ethylene sulfoxide, n-propane sulfoxide, isopropane sulfoxide, n-butane sulfoxide, isobutane sulfoxide, sec-butane sulfoxide, tert-butane sulfoxide, n-pentane sulfoxide, isopentane sulfoxide, neopentane sulfoxide, n-hexane sulfoxide, or isohexane sulfoxide.
  • the C1 - C6 sulfone group may be methyl sulfone, ethyl sulfone, n-propane sulfone, isopropane sulfone, n-butane sulfone, isobutane sulfone, sec-butane sulfone, tert-butane sulfone, n-pentane sulfone, isopentane sulfone, neopentane sulfone, n-hexane sulfone, or isopentane sulfone.
  • the C1 - C6 carboxyl group may be -COOH, -CH2COOH , -CH(CH3 ) COOH, -CH2CH2COOH, -CH( CH3 ) CH2COOH , -CH2CH( CH3 )COOH, -C( CH3 ) 2COOH , -CH2CH2CH2COOH, -CH ( CH3 ) CH2CH2COOH , -CH2CH ( CH3) CH2COOH , -CH2CH2CH ( CH3 )COOH, -C( CH3 ) 2CH2CH2COOH , -CH2C ( CH3 ) 2CH2COOH , -CH2CH2C( CH3 ) 2COOH , -CH2CH2C( CH3 ) 2COOH , -CH ( CH3 ) CH2COOH , -CH ( CH3 ) CH2COOH , -CH ( CH3 ) CH2 ...
  • the C1 - C6 amide group may be -CONHC1 - C5 alkyl, -CON( C1 - C3 alkyl) 2 , -NHCOC1 - C5 alkyl, or -N( C1 - C2 alkyl) COC1 - C3 alkyl.
  • the C1 - C5 alkyl group in the -CONHC 1 - C5 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or neopentyl.
  • the C1 - C5 alkyl group in the -NHCOC 1 - C5 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or neopentyl.
  • the C1 - C3 alkyl group in -CON( C1 - C3alkyl ) 2 may be methyl, ethyl, n-propyl or isopropyl.
  • the C1 - C3 alkyl group in the -N( C1 - C2 alkyl) COC1 - C3 alkyl group may be methyl, ethyl, n-propyl or isopropyl.
  • the C1 - C2 alkyl group in the -N( C1 - C2 alkyl) COC1 - C3 alkyl group may be methyl or ethyl.
  • the C3 - C8 cycloalkyl group may be cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or cyclooctane.
  • the heteroatoms of the C4 - C8 alicyclic ring may be independently selected from N and/or O.
  • the number of heteroatoms in the C4 - C8 aliphatic heterocycle may be one or two.
  • the C4 - C8 alicyclic ring may be a 3-6 member alicyclic ring.
  • the C4 - C8 alicyclic heterocycle refers to a group formed by a heterocyclic compound without aromatic characteristics, such as piperidine, piperazine, dioxane, or morpholine.
  • the C6 - C18 aryl group may be phenyl, naphthyl, or biphenyl.
  • the C3 - C18 heteroaryl group may be a 5-10 member heteroaryl group, preferably a 5-6 member heteroaryl group.
  • the heteroatom of the C3 - C18 heteroaryl group may be independently selected from one or two of N, O, and S.
  • the C3 - C18 heteroaryl group refers to a monocyclic or polycyclic aromatic heterocycle, and the ring contains at least one heteroatom, such as furanyl, pyranyl, pyrroliyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, or tetrazolyl.
  • heteroatom such as furanyl, pyranyl, pyrroliyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, or tetrazoly
  • n1 is 0 or 1.
  • R1 is selected from hydrogen, hydroxyl and C2 - C6 ester groups, preferably R1 is hydroxyl.
  • R2 is selected from the following groups:
  • a C1 - C6 alkyl group substituted with a carbonyl group, wherein the carbonyl group is -(C O) R3 , wherein R3 is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1-3 halogens, hydroxyl groups, oxygen-containing C1 - C6 heteroalkyl groups, amino groups, nitrogen-containing C1 - C6 heteroalkyl groups, and C1 - C6 alkylamine groups; wherein the sulfur-containing C1 - C6 heteroalkyl group contains one S heteroatom, the S atom can substitute for the C atom in the alkyl chain at a position allowed by the normal valence state, and the S atom is not directly connected to the substituted group;
  • the oxygen-containing C1 - C6 heteroalkyl group contains one O heteroatom.
  • the O atom can replace the C atom in the alkyl chain at a position allowed by the normal valence state, and the O atom is not directly connected to the substituted group.
  • the nitrogen-containing C1 - C6 heteroalkyl group contains one N heteroatom, which can replace the C atom in the alkyl chain at a position allowed by the normal valence state, and the N atom is not directly connected to the substituted group.
  • R2 is selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1, 2, or 3 halogens, C1 - C6 alkoxy groups, C1 - C6 alkylthiol groups, cyano groups, C2 - C6 ester groups, and ureido groups substituted with C1 - C6 alkyl groups;
  • a C1 - C6 alkyl group substituted with a carbonyl group, wherein the carbonyl group is -(C O) R3 , and R3 is a C1 - C6 alkylamine group.
  • R2 is selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1, 2, or 3 halogens, C1 - C6 alkoxy groups, and ureido groups substituted with C1 - C6 alkyl groups;
  • R2 is selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogen, cyano, C1 - C6 alkyl, C1- C6 alkyl substituted with 1, 2, or 3 halogens, and C1 - C6 alkoxy.
  • R2 is selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, or tri-substituted, and the substituent is selected from halogen, cyano, C1 - C6 alkyl, C1 - C6 alkyl substituted with 1, 2, or 3 halogens, C1 - C6 alkylthiol, and C1 - C6 alkoxy.
  • a substituted phenyl group wherein the substitution is mono-, di-, or tri-substituted; the substituent is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1, 2, or 3 halogens, C1 - C6 alkoxy groups, C1 - C6 alkoxy groups substituted with 1, 2, or 3 halogens, C1 - C6 alkylamino groups, C3 - C8 cycloalkyl groups, C1 - C6 alkylthiols, C1 - C6 sulfoxide groups, C1 - C6 sulfone groups, and cyano groups; wherein the amino group may be substituted with C1 - C6 alkyl groups substituted with 0-3 halogens;
  • a substituted phenyl group wherein the substitution is mono-, di-, or tri-substituted; the substituent is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1, 2, or 3 halogens, cyano, C1 - C6 alkoxy, C1 - C6 alkylamino, C1 - C6 alkylmercapto, and sulfur-containing C1 - C6 heteroalkyl groups; wherein the amino group is substituted with a C1 - C6 alkyl group;
  • R1 is preferably derived from a hydroxyl group and a C2 - C3 ester group
  • R2 is preferably derived from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogens, C1 - C3 alkyl groups substituted with 1-3 halogens, C1 - C3 alkoxy groups, C1-C3 alkoxy groups substituted with 1, 2 , or 3 halogens, C1 - C3 alkyl mercapto groups, sulfur-containing C1 - C3 heteroalkyl groups, hydroxyl groups, oxygen-containing C1 - C3 heteroalkyl groups, amino groups, nitrogen-containing C1 - C3 heteroalkyl groups, C1 - C3 alkylamino groups, C1 - C3 carboxyl groups, C2- C3 ester groups, C1 - C3 amide groups, urea groups, cyano groups, and urea groups substituted with 0, 1 , 2, or 3 halogens;
  • a substituted pyridyl group wherein the pyridyl group is selected from 2-pyridyl, 3-pyridyl and 4-pyridyl; wherein the substitution includes mono-, di- or tri-substituted groups, and the substituent is selected from halogen, C1 - C3 alkyl substituted with 1 , 2 or 3 halogens, C1 - C3 alkoxy, C1 - C3 alkoxy substituted with 1, 2 or 3 halogens, C1 - C3 alkyl mercapto, sulfur-containing C1 - C3 heteroalkyl, hydroxyl, oxygen-containing C1 - C3 heteroalkyl, amino, C1 - C3 alkylamino, nitrogen-containing C1 - C3 heteroalkyl, C1 - C3 carboxyl, C2 - C3 ester, C1-C3 amide, urea, cyano and urea substituted with 0, 1 , 2 or 3 hal
  • a substituted phenyl group wherein the substitution is mono-, di-, or tri-substituted; the substituent is selected from halogens, C1 - C3 alkyl groups substituted with 1, 2, or 3 halogens, C1 - C3 alkoxy groups, C1 -C3 alkoxy groups substituted with 1, 2, or 3 halogens, and C1 -C4 alkylamino groups; wherein, when mono-substituted, the substituent is selected from halogens, C2 - C3 alkyl groups, C1 - C3 alkyl groups substituted with 1, 2 , or 3 halogens, C1 - C3 alkoxy groups, C1-C3 alkylamino groups, C3 - C8 cycloalkyl groups, C1 - C3 alkylthiols, sulfur-containing C1 - C3 heteroalkyl groups, C1 - C3 sulfoxide groups, C1 - C3 s
  • the substituent is selected from substituted phenyl groups and is monosubstituted, the substituent is preferably selected from halogens, C1 - C3 alkoxy groups, and cyano groups;
  • the substituent is selected from substituted phenyl groups and is disubstituted, the substituent is preferably selected from halogens, C1 - C3 alkoxy groups, and cyano groups;
  • the substituent is preferably selected from halogen, C1 - C3 alkoxy, C1 - C3 alkyl mercapto, and cyano.
  • R1 is preferably selected from hydroxyl groups
  • R2 is preferably selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogens, C1 - C5 alkyl groups substituted with 1-3 halogens, C1 - C3 alkoxy groups substituted with 1 , 2, or 3 halogens, C1 - C3 alkyl groups, sulfur-containing C1 - C3 heteroalkyl groups, and C1 - C3 amide groups;
  • a substituted pyridyl group wherein the pyridyl group is selected from 2-pyridyl, 3-pyridyl and 4-pyridyl; wherein the substitution is mono-, di- or tri-substituted, and the substituent is selected from halogen, C1 - C3 alkyl group substituted with 1, 2 or 3 halogens, C1 - C3 alkoxy group, C1-C3 alkoxy group substituted with 1, 2 or 3 halogens and C1 - C3 amide group;
  • the groups are preferably selected from the following:
  • a substituted phenyl group wherein the substitution is divided into mono-, di-, or tri-substituted; the substituent is selected from halogen, cyano, C1 - C6 alkyl mercapto and C1 - C3 alkyl group substituted with 1, 2, or 3 halogens, wherein the substituent is selected from halogen and cyano when mono-substituted;
  • n1 is either 0 or 1;
  • R1 is selected from hydrogen, hydroxyl, amino, mercapto, C1 - C6 alkoxy, C1 -C6 alkylamino, C1 - C6 alkylmercapto, halogen, C2- C6 ester, C2-6 ester substituted with 1-3 halogens, C2 - C6 ester substituted with hydroxyl, C2 - C6 ester substituted with amino , and carboxyl.
  • R 2 is selected from the following groups:
  • a C1 - C6 alkyl group substituted with a carbonyl group, wherein the carbonyl group is -(C O) R3 , wherein R3 is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1-3 halogens, hydroxyl groups, oxygen-containing C1 - C6 heteroalkyl groups, amino groups and C1 - C6 alkylamino groups;
  • a substituted phenyl group wherein the substitution is mono-, di-, or tri-substituted; the substituent is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1, 2, or 3 halogens, C1 - C6 alkoxy groups, C1 - C6 alkoxy groups substituted with 1, 2, or 3 halogens, C1 - C6 alkylamino groups, C3 - C8 cycloalkyl groups, C1 - C6 alkylthiols, C1 - C6 sulfoxide groups, C1 - C6 sulfone groups, and cyano groups; wherein the amino group may be substituted with C1 - C6 alkyl groups substituted with 0-3 halogens;
  • the oxygen-containing C1 - C6 heteroalkyl group contains one O heteroatom.
  • the O atom can replace the C atom in the alkyl chain at a position allowed by the normal valence state, and the O atom is not directly connected to the substituted group.
  • the nitrogen-containing C1 - C6 heteroalkyl group contains one N heteroatom, which can replace the C atom in the alkyl chain at a position allowed by the normal valence state, and the N atom is not directly connected to the substituted group.
  • n1 is 0 or 1;
  • R1 is selected from hydrogen, hydroxyl, and C2 - C6 ester groups
  • R 2 is selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1-3 halogens, C1 - C6 alkoxy groups, C1 - C6 alkylthiol groups, cyano groups, C2 - C6 ester groups, and ureo groups substituted with C1 - C6 alkyl groups;
  • a C1 - C6 alkyl group substituted with a carbonyl group, wherein the carbonyl group is -(C O) R3 , and R3 is a C1 - C6 alkylamine group;
  • a substituted phenyl group wherein the substitution is mono-, di-, or tri-substituted; the substituent is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1, 2, or 3 halogens, cyano, C1 - C6 alkoxy, C1 - C6 alkylamino, and C1 - C6 alkylthiol; wherein the amino group is substituted with a C1 - C6 alkyl group;
  • n1 is 0 or 1;
  • R1 is selected from hydrogen, hydroxyl, and C2 - C6 ester groups
  • R 2 is selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogens, C1 - C6 alkyl groups, C1 - C6 alkyl groups substituted with 1-3 halogens, C1 - C6 alkoxy groups, and ureido groups substituted with C1 - C6 alkyl groups;
  • n1 is 0 or 1;
  • R1 is a hydroxyl group
  • R 2 is selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, tri-, or tetra-substituted, and the substituent is selected from halogen, cyano, C1 - C6 alkyl, C1 - C6 alkyl substituted with 1-3 halogens, and C1 - C6 alkoxy.
  • n1 is 0 or 1;
  • R1 is a hydroxyl group
  • R 2 is selected from the following groups:
  • a substituted phenyl group wherein the substitution is mono-, di-, or tri-substituted, and the substituent is selected from halogen, cyano, C1 - C6 alkyl, C1 - C6 alkyl substituted with 1-3 halogens, C1 - C6 alkylthiol and C1 - C6 alkoxy;
  • R2 is
  • R1 is hydrogen, -OH, or
  • the compound of formula I is any of the following compounds:
  • the opioid receptor agonist can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art.
  • the opioid receptor agonist is used in vitro.
  • the present invention also provides a compound of Formula I as described above, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention also provides a compound of Formula I as described above, or a pharmaceutically acceptable salt thereof, for use as an analgesic medicament.
  • the present invention also provides the use of a compound of Formula I as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I as described above or a pharmaceutically acceptable salt thereof, in the preparation of an analgesic medicament.
  • the present invention also provides the use of a compound of Formula I as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I as described above or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating diseases associated with opioid receptors;
  • the preferred opioid receptor-related disease is pain
  • the opioid receptor is preferably a ⁇ -opioid receptor.
  • the present invention also provides a method for treating pain relief, comprising administering to a subject requiring treatment a compound of Formula I as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I as described above.
  • This invention provides a compound represented by Formula I as described above, and a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula I is not one of the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a compound represented by Formula I above or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable salt” refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
  • an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • hydroxyl group means —OH.
  • amine means -NH2 .
  • thiol means -SH.
  • alkyl refers to a saturated straight-chain or branched monovalent hydrocarbon group having a certain number of carbon atoms.
  • C1–6 alkyl refers to alkyl groups having 1–6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6), including C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-di
  • cycloalkyl refers to a C3 - C8 cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or cyclooctane.
  • cycloalkane refers to C3 - C8 cycloalkane, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or cyclooctane.
  • alkoxy refers to -O-alkyl, wherein the alkyl group is an alkyl group as defined above.
  • C X -C Y ester group refers to -O-CO-alkyl or -CO-O-alkyl, wherein the alkyl group is an alkyl group as defined above, and X and Y represent the total number of carbon atoms, for example, CO-O-CH 3 is a C 2 ester group.
  • C X -C Y carboxyl refers to "-alkyl-COOH", where the alkyl group is an alkyl group as defined above, and X and Y represent the total number of carbon atoms, for example, -CH 2 COOH is a C 2 carboxyl group.
  • C X -C Y sulfoxide refers to -SO-alkyl, wherein the alkyl group is an alkyl group as defined above.
  • C X -C Y sulfone refers to -SO 2 - alkyl, wherein the alkyl group is an alkyl group as defined above.
  • C X -C Y aminoalkyl refers to an amino-substituted alkyl group "-NH-alkyl” or “-N-(alkyl) 2 ", where the alkyl group is an alkyl group as defined above.
  • C X -C Y alkylamino refers to an amino-substituted alkyl group "-NH-alkyl” or “-N-(alkyl) 2 ", where the alkyl group is an alkyl group as defined above.
  • C X -C Y amide group refers to -NH-CO-alkyl, -N(alkyl)-CO-alkyl, -CO-NH-alkyl or -CO-N-(alkyl) 2 , wherein the alkyl group is an alkyl group as defined above.
  • alkylthiol refers to -S-alkyl, wherein the alkyl group is an alkyl group as defined above.
  • sulfur-containing C1 - C6 heteroalkyl refers to " -R4 - SR5 ", wherein R4 is selected from alkyl, R5 is selected from alkyl or hydrogen, and the alkyl is an alkyl group as defined above.
  • oxygen-containing C1 - C6 heteroalkyl means " -R4 - OR5 ", where R4 is selected from alkyl and R5 is selected from alkyl or hydrogen, and the alkyl is an alkyl as defined above.
  • nitrogen-containing C1 - C6 heteroalkyl refers to " -R4 - NR5 ", wherein R4 is selected from alkyl, R5 is selected from alkyl or hydrogen, and the alkyl is an alkyl group as defined above.
  • urea group refers to NH-CO-NH 2 .
  • C6 - C18 aryl refers to an aromatic carbon ring that does not contain any heteroatoms, and may be phenyl, naphthyl, or biphenyl.
  • C3 - C18 heteroaryl refers to a monocyclic or polycyclic aromatic heterocycle containing at least one heteroatom, which may be one, two, three, or four.
  • the heteroatom is selected from one, two, or three of N, O, and S, such as furanyl, pyranyl, pyrroliyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, or tetrazolyl.
  • C4 - C8 alicyclic heterocycle refers to a group formed by a heterocyclic compound without aromatic characteristics, wherein the heteroatom is independently selected from one or more of N, O, S and P (e.g., the heteroatom is independently selected from N and/or O), and the number of heteroatoms is 1, 2, 3 or 4 (e.g., the number of heteroatoms is 1 or 2), such as piperidine, piperazine, dioxane or morpholine.
  • substituted indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise explicitly stated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.
  • the descriptive phrase “...independently being” used in this application should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase “...independently being” can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.
  • treatment means a therapeutic therapy.
  • treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the disease or one or more biological manifestations of the condition.
  • the term "therapeutic effective amount” means an amount of compound sufficient to effectively treat or prevent the disease or condition described herein when administered to a patient.
  • the “therapeutic effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art. Dosages exceeding this range may also be used depending on the dosage form and the severity of the disease.
  • the reagents and raw materials used in this invention are all commercially available.
  • This invention provides the application of azacycloalkane compounds and their salts as pharmaceuticals.
  • This invention also provides an opioid receptor agonist without side effects of constipation or bowel dysfunction, and without addictive properties, which can be used as an analgesic.
  • Compound (I) can be synthesized using the following synthetic method.
  • Intermediate III is obtained by reacting intermediate I and intermediate II under low-temperature conditions in the presence of a strong base (such as n-butyllithium) and in an ether solvent (such as diethyl ether, tetrahydrofuran, etc.).
  • a strong base such as n-butyllithium
  • an ether solvent such as diethyl ether, tetrahydrofuran, etc.
  • Intermediate III can be reacted to yield intermediate IV in the presence of an acid (such as hydrochloric acid, trifluoroacetic acid, etc.) using ethyl acetate as a solvent.
  • the reaction can be carried out at atmospheric pressure, typically for tens of minutes to several hours at room temperature.
  • intermediate IV and intermediate V can react to yield product A.
  • a reducing agent such as sodium cyanoborohydride
  • an alcohol solvent such as methanol
  • Intermediate VI and intermediate VII can be reacted in the presence of a strong base (such as potassium hexamethyldisilamide) and in a suitable solvent (such as toluene, tetrahydrofuran) to yield intermediate VIII.
  • a strong base such as potassium hexamethyldisilamide
  • a suitable solvent such as toluene, tetrahydrofuran
  • the reaction can be carried out under normal pressure.
  • the reaction is usually carried out at 0°C to room temperature for several hours to tens of hours.
  • 2-Bromo-1,3-difluorobenzene (15.0 g, 77.72 mmol) was placed in a round-bottom flask, and Et2O (200 mL) was added. The mixture was cooled to -78 °C, and then n-butyllithium (16.63 g, 97.15 mmol) was added. After stirring the mixture at -78 °C for 1 hour, a solution of tert-butyl 3-oxozycyclobutane-1-carboxylate (4.95 g, 77.72 mmol) in Et2O (100 mL) was added dropwise.
  • 1,4-dioxane hydrochloride (10 mL) was added dropwise to a solution of 1,4-dioxane (10 mL) of 7-bromo-1-cyclopropyl-6-fluoro- 4 -oxo-1,4-dihydroquinoline-3-carboxylic acid (1.0 g, 3.71 mmol). After reacting at room temperature for half an hour, the pH of the reaction mixture was adjusted to 9 with saturated NaHCO3. The mixture was concentrated under reduced pressure.
  • 3-Oxadiazine-1-carboxylic acid tert-butyl ester (5.13 g, 30 mmol) was dissolved in THF (50 mL), purged with nitrogen, and placed in an ice-water mixing bath at 0 °C under nitrogen protection. After cooling for 15 minutes, 4-chlorophenyl magnesium bromide (1 N, 30 mL) was added dropwise to the mixture, and the mixture was slowly heated to room temperature under ice bath conditions and reacted overnight at room temperature. After the reaction was complete, saturated NH4Cl was added to the reaction system under ice bath conditions to quench the reaction.
  • a series of derivatives can be obtained by replacing similar raw materials using the same preparation route described above.
  • the compounds of this invention can activate the ⁇ -opioid receptor (MOR).
  • MOR ⁇ -opioid receptor
  • Activated MOR can regulate intracellular cAMP levels, which then enter the cell nucleus and bind to the CRE region of the reporter gene luciferase, initiating reporter gene expression.
  • the luciferase reacts with its substrate to emit fluorescence, and the agonistic activity of the compound can be reflected by measuring the fluorescence signal.
  • HTRF cAMP Gi kit Perkin Elmer, 62AM9PEB; this kit contains 1X stimulation buffer, Eu-Cryptate, and Anti-cAMP-d2-antibody). IBMX (Sigma, I5879). Forskolin (Sigma, E7384).
  • Compound preparation The compound was dissolved in DMSO to prepare a stock solution with a final concentration of 10 mM. The compound was then serially diluted using a 1X stimulation buffer, with an initial concentration of 0.08 mM and 6 concentration gradients, to a final concentration of 0.4 nM. Forskolin was diluted with a 1X stimulation buffer (final concentration: 40 ⁇ M).
  • Cell plating Thaw frozen cells, centrifuge at 1000 rpm for 5 min, discard the supernatant, wash cells twice with HBSS buffer, resuspend cells with 1X stimulation buffer, adjust cell density to 5.0 x 105 cells/mL, and add 5 ⁇ L (50,000 cells) to each well of a 96-well plate. Incubate the cell plate at 37°C for 60 min.
  • detection reagents Dilute Eu-Cryptate and Anti-cAMP-d2-antibody to 1X with detection buffer. Add 10 ⁇ L of detection reagent to each well according to the microplate layout diagram, shake for 20 s, and incubate the cell plate in a 25°C incubator for 60 min. Read the plate on a BMG PHERAstar.
  • the percentage of activity was calculated using LibreOffice software.
  • %Effect 100 ⁇ (Sample Raw Value - Low Control Average) / (High Control Average - Low Control Average) was used.
  • GraphPad Prism 5 data analysis software was used, and the Dose-response-Stimulation-log[agonist] vs. response-Variable slope mode was selected for fitting analysis to obtain the EC50 value of each tested sample.
  • mice SPF grade animals, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.), male, 18-22g;
  • mice were acclimatized for one week after purchase. Mice were placed on a hot plate (55.0 ⁇ 0.5°C) to determine the heat response latency (pain threshold). Mice with a pain threshold of 5–30 s were used in the experiment. All mice were randomly divided into 11 groups of 8 animals each based on their baseline pain threshold.
  • mice in each group were given either a solvent (10% DMSO + 10% Solutol HS-15 + 80% saline) or a compound. Details of the administration are shown in Table 2.
  • mice in each group were tested 120 minutes after drug administration. Mice were placed on a hot plate (55.0 ⁇ 0.5°C) to measure the latency of the thermal response (pain threshold). The time taken for mice to lick or lift their hind paws to reach the pain threshold was recorded, and the percentage of maximum possible effect (%MPE) was calculated.
  • %MPE percentage of maximum possible effect
  • test case group showed significant analgesic effect within 60 minutes after administration.
  • test case group showed strong analgesic effect with an effective analgesic time of up to 4 hours.
  • test case group showed significant heat-resistant analgesic effect 60 minutes after administration and still had good analgesic effect 120 minutes after administration ("normal group” refers to the solvent control group of G1).
  • mice SPF grade animals, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.), male, 18-22g;
  • mice were acclimatized for one week after purchase. All mice were trained for 30 minutes in the experimental equipment at the mine before being grouped into experimental groups. All mice were randomly divided into 8 groups based on their baseline pain threshold, with 8 animals in each group.
  • mice in each group were administered either a solvent (10% DMSO + 10% Solutol HS-15 + 80% saline) or a compound, with morphine, an opioid receptor agonist, as the positive control.
  • the dosage was increased daily from 10 mg/kg on day 1 to 50 mg/kg. This experiment was conducted by a third-party institution qualified to administer morphine. Dosage details are shown in Table 5.
  • mice Two hours after the last administration, mice were intraperitoneally injected with the addictive drug naloxone (5 mg/kg).
  • naloxone the addictive drug
  • General physical signs such as jumping frequency and spontaneous activity, were observed in a mining test within 30 minutes after naloxone administration. Mice were observed and their activity status was recorded in individual cages for 30 minutes. The results are shown in Table 6.
  • mice SPF grade animals, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.), male, 18-22g;
  • mice were acclimatized for one week after purchase. All mice were randomly divided into 9 groups according to their weight, with 16 animals in each group.
  • mice in each group were administered a solvent (10% DMSO + 10% Solutol HS-15 + 80% physiological saline) or the corresponding compound.
  • the constipation model group was established using loperamide hydrochloride, an antidiarrheal drug. This drug was used as the modeling agent for the constipation model group to reflect indicators of constipation in the animals.
  • the positive control was DAMGO (CAS: 78123-71-4), a selective MOR receptor agonist. See Table 7 for grouping and administration details.
  • each of the first eight mice in each group was given 0.2 mL of ink.
  • the animals were sacrificed half an hour later, and the abdominal cavity of the mice was opened with surgical scissors.
  • the intestinal segment starting from the pylorus and ending at the ileocecal junction was selected, laid flat on a table, and its length was measured. The value obtained was the "total length of the intestinal segment".
  • Intestinal propulsion rate (%) Ink travel length (cm) / Total intestinal length (cm) * 100%.
  • mice remained in each group.
  • the prepared ink was administered into the stomachs of each mouse, with 0.2 mL of ink given at a time.
  • the ink administration time was half an hour after the last administration.
  • the defecation experiment started at the time of ink administration. Feces were collected from each group after 6 hours, and the number and weight of black feces excreted in each group were calculated. The specific results are shown in Table 10.
  • mice administered the compound of this application had a high small intestinal propulsion rate, indicating that the compound of this application has no constipation side effect; and the mice administered the compound of this application had normal stool volume, indicating that the compound of this application will not cause intestinal dysfunction.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés azacycloalcanes, une composition pharmaceutique et une utilisation associées. La présente invention concerne l'utilisation des composés représentés par la formule (I) ou des sels pharmaceutiquement acceptables de ceux-ci, ou une composition pharmaceutique comprenant les composés représentés par la formule (I) en tant qu'agoniste du récepteur opioïde. Lorsque les composés sont utilisés en tant qu'agonistes du récepteur opioïde, les composés ne provoquent pas de constipation et d'effets secondaires de trouble de la fonction intestinale, ne provoquent pas d'addiction, et peuvent ainsi être utilisés en tant que médicaments pour le soulagement de la douleur.
PCT/CN2025/096254 2024-05-21 2025-05-21 Composés azacycloalcanes, composition pharmaceutique et utilisation associées Pending WO2025242125A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410628768 2024-05-21
CN202410628768.7 2024-05-21

Publications (1)

Publication Number Publication Date
WO2025242125A1 true WO2025242125A1 (fr) 2025-11-27

Family

ID=97764051

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/096254 Pending WO2025242125A1 (fr) 2024-05-21 2025-05-21 Composés azacycloalcanes, composition pharmaceutique et utilisation associées

Country Status (2)

Country Link
CN (1) CN121021433A (fr)
WO (1) WO2025242125A1 (fr)

Also Published As

Publication number Publication date
CN121021433A (zh) 2025-11-28

Similar Documents

Publication Publication Date Title
EP2358371B1 (fr) Antagonistes du récepteur p2x3 pour le traitement de la douleur
US8247401B2 (en) P2X3 receptor antagonists for treatment of pain
US8835488B2 (en) Opioid receptor ligands and methods of using and making same
CA2703915C (fr) Antagonistes du recepteur p2x3 utilises dans le traitement de la douleur
JP6746107B2 (ja) スルホンアミド誘導体またはその薬学的に許容される酸付加塩
EP2410858B1 (fr) Antagonistes du récepteur p2x3 pour le traitement de la douleur
JP6301842B2 (ja) 複素環アミド誘導体及びそれを含有する医薬
JP2019522005A (ja) 芳香族アセチレンまたは芳香族エチレン系化合物、その中間体、製造方法、薬物組成物および使用
RU2650111C2 (ru) Конденсированные пирролдикарбоксамиды и их применение в качестве фармацевтических средств
JP2016521749A (ja) ナトリウムチャネル阻害剤としての二環式スルホンアミド化合物
BR112016008133B1 (pt) amino-heteroaril benzamidas como inibidores de quinase, seus usos, e composição farmacêutica
JP2012524065A (ja) ＧＡＢＡＢ受容体リガンドとしてのγ−アミノ酪酸誘導体
US20190169175A1 (en) Novel pyridinium compounds
JP2022065012A (ja) Ｄ－アミノ酸オキシダーゼ（ｄａａｏ）阻害剤としての新規な置換ベンゾイミダゾール誘導体
TW202304864A (zh) 1,3-取代的環丁基衍生物及其用途
JP7185631B2 (ja) 抗線維化化合物
WO2025242125A1 (fr) Composés azacycloalcanes, composition pharmaceutique et utilisation associées
JP2017505797A (ja) Ｇｐｒ１４２アゴニスト化合物
CN107428682B (zh) 酰胺类衍生物、其制备方法及其在医药上的用途
TW200831463A (en) Nitrate esters of aminoalcohols
JP2025520719A (ja) Ｎａｖ１．８阻害剤
EP2781508B1 (fr) Composés cycliques condensés contenant de l'azote pour utilisation en tant qu'antagonistes du crth2
WO2017198180A1 (fr) Triazolopyridine contenant du fluor et procédé de préparation, composition pharmaceutique et application correspondants
TW202440081A (zh) σ-1受體拮抗劑及其應用
TW202540100A (zh) 作為parp1抑制劑之化合物及包含其之醫藥組合物