CN115925699A - Condensed ring compound with analgesic activity and preparation method and application thereof - Google Patents

Condensed ring compound with analgesic activity and preparation method and application thereof Download PDF

Info

Publication number
CN115925699A
CN115925699A CN202211366859.5A CN202211366859A CN115925699A CN 115925699 A CN115925699 A CN 115925699A CN 202211366859 A CN202211366859 A CN 202211366859A CN 115925699 A CN115925699 A CN 115925699A
Authority
CN
China
Prior art keywords
radical
alkylamino
alkoxy
hydrogen
carbocyclyl
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.)
Granted
Application number
CN202211366859.5A
Other languages
Chinese (zh)
Other versions
CN115925699B (en
Inventor
请求不公布姓名
张爱琴
杨谋伟
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.)
Nanjing Zhihe Medical Technology Co ltd
Original Assignee
Nanjing Zhihe Medical Technology 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 Nanjing Zhihe Medical Technology Co ltd filed Critical Nanjing Zhihe Medical Technology Co ltd
Publication of CN115925699A publication Critical patent/CN115925699A/en
Application granted granted Critical
Publication of CN115925699B publication Critical patent/CN115925699B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
    • C07F9/6518—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

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

Abstract

The invention provides a fused ring compound with analgesic activity as shown in formula I, a preparation method and application thereof.

Description

Condensed ring compound with analgesic activity and preparation method and application thereof
Technical Field
The application relates to the technical field of medicines, in particular to a condensed ring compound and a composition using the condensed ring compound as an active ingredient, and application of the condensed ring compound and the composition thereof in preparing analgesic drugs.
Background
Pain is a self-protective reaction caused by tissue damage or potential tissue damage, is accompanied by emotional restlessness, stress and other physiological conditions, and is a common symptom or accompanying symptom of various clinical diseases. The pain is divided into acute pain and chronic pain, and the acute pain is mainly caused by operations, severe physical trauma and other reasons; chronic pain is often caused by nociceptive pain, inflammation, neuropathic pain, migraine, and the like.
Analgesics (Analgesics) are a kind of medicine which acts on the central nervous system, can effectively relieve or eliminate pain sensation without influencing other sensations, and have important significance in emergency treatment. The analgesic Drugs currently reported to be on the market mainly comprise two major classes, namely opioid alkaloids (Opioids), nonsteroidal Anti-inflammatory Drugs (NSAIDs), and the like, but opioid receptor Drugs still dominate the market. Opioid receptors include the classical receptors μ, δ, κ and the non-classical Nociceptin (NOP) receptors. Mu-receptor agonists are most effective in analgesia, but often increase addiction and even cause respiratory depression; the addiction of delta receptor agonists is less, but the analgesic effect is far less than that of mu receptor agonists; kappa receptor agonists have an analgesic effect between them, but are likely to cause side effects such as hallucinations, mydriasis, dysphoria, and the like. Currently, morphine, oxycodone, fentanyl, sufentanil, remifentanil, methadone and the like are the main opioid receptor agonists. There is concern that abuse of opioids currently also allows researchers to expand new research directions, but most are in the early clinical stage. Antipyretic analgesics are a class of drugs that can relieve fever and relieve local pain, exert antipyretic and analgesic effects by inhibiting synthesis and release of Prostaglandins (PGs) in the hypothalamus, and generally have anti-inflammatory effects. The medicine has good effect on dull pain such as local pain, neuralgia, arthralgia and menstrual pain, but has poor effect on other kinds of pain. The current clinical common use is as follows: aspirin, ibuprofen, sertraline, and knoxia, among others, but the use of such drugs is considered in a variety of situations.
Analgesics have major side effects at present. Therefore, the development of analgesics of good quality is still in the spotlight.
Disclosure of Invention
The invention provides a novel fused ring compound and a composition thereof, the compound has strong stability and obvious analgesic activity, and is suitable for being developed into various dosage forms.
The compound provided by the invention can overcome the defects of the prior art, has higher efficacy in organisms, has long duration of analgesic effect and has no obvious side effect.
The present invention provides a compound having formula I:
Figure BDA0003921880740000021
or solvates, pharmaceutically acceptable salts, enantiomers, diastereomers, and racemic mixtures thereof;
in formula I:
y is selected from CH or N;
R 1 、R 2 、R 3 each independently selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxy, acetyl, carboxaldehyde, mesyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Carbocyclic radical, C 2 - 8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as follows;
l is selected from
Figure BDA0003921880740000031
Figure BDA0003921880740000032
R 4 Is selected from
Figure BDA0003921880740000033
T is selected from O or S;
m is selected from 1,2, or 3;
R 5 、R 6 each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R 5 、R 6 Connecting to form a ring;
R 7 is selected from C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as set forth below;
R 8 、R 9 each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R 8 、R 9 Connecting to form a ring;
R a 、R b each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R a 、R b Connecting to form a ring;
R c 、R d each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R c 、R d Connecting to form a ring;
X 1 selected from O, or N;
X 1 when is O, R 11 Is absent;
R 10 is selected from C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as follows;
R 11 selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3 - 8 Carbocyclic radical, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as set forth below;
X 2 、X 3 each independently selected from O, NH, or S;
R 12 、R 13 each independently selected from hydrogen, na, K, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 Heteroaryl, or R 12 、R 13 Connecting to form a ring; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may further optionally be substituted with one OR more of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, - (C = O) OR 16 、-(C＝S)NHR 16 Substitution;
R 14 selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 An alkylamino group;
R 15 is selected from
Figure BDA0003921880740000041
Z is selected from CH or N;
R 16 selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 An alkylamino group,
Figure BDA0003921880740000051
R 17 Selected from the group consisting of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, methylthio, acetyl, methylsulfonyl, ethylsulfonyl;
R 18 is selected from C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above-mentioned carbocyclyl, heterocyclyl, aryl, heteroaryl may be further optionally substituted with one or more groups a as follows;
the group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
The invention provides a compound, which has the following structure of formula II:
Figure BDA0003921880740000052
definition of substituents in formula II is defined for formula I.
The invention provides a compound having the structure of formula iii:
Figure BDA0003921880740000053
the definition of the substituents in formula III is as defined for formula I.
The present invention provides compounds having the structure of formula IV below:
Figure BDA0003921880740000061
the definition of the substituents in formula IV is as defined for formula I.
The present invention provides compounds having the structure of formula V:
Figure BDA0003921880740000062
the definition of the substituents in formula V is as defined for formula I.
In some embodiments, in formulas (I) - (V) above, Y is selected from CH, or N;
in some embodiments, in formulas (I) - (V) above, R 1 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercaptoMethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Carbocyclic radical, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; wherein the above alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl may be further optionally substituted with one or more groups A as follows;
preferably, R 1 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, cyano, trifluoromethyl, C 1-8 Alkyl radical, C 1 - 8 An alkoxy group; more preferably, R 1 Is hydrogen.
In some embodiments, in formulas (I) - (V) above, R 2 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxy, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; wherein the above alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as follows;
preferably, R 2 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxy, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6 - 18 Aryl radical, C 3-12 A heteroaryl group;
more preferably, R 2 Selected from F, cl, hydroxy, hydroxyethyl, methoxy, cyano, trifluoromethyl, methylsulfonyl.
In some embodiments, in formulas (I) - (V) above, R 3 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethylMercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, carboxaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Carbocyclic radical, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; wherein the above alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl may be further optionally substituted with one or more groups A as follows;
preferably, R 3 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxy, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6 - 18 Aryl radical, C 3-12 A heteroaryl group;
more preferably, R 3 Selected from hydrogen, or methyl.
In some embodiments, in formulas (I) - (II) above, L is
Figure BDA0003921880740000071
Wherein the content of the first and second substances,
r is as defined above 5 、R 6 Each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R 5 、R 6 Connecting to form a ring;
preferably, R 5 、R 6 Each independently selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R 5 And R 6 Are all hydrogen;
r is as defined above 7 Is selected from C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3 - 8 Carbocyclic radical, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynylThe group, carbocyclyl, heterocyclyl, aryl, heteroaryl may be further optionally substituted with one or more groups a;
preferably, R 7 Is C 1-8 An alkyl group;
more preferably, R 7 Selected from isopropyl, or tert-butyl;
in some embodiments, in formulas (I) and/or (III) above, L is
Figure BDA0003921880740000081
Wherein the content of the first and second substances,
r is as defined above 8 、R 9 Each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R 8 、R 9 Connecting to form a ring;
preferably, R 8 、R 9 Each independently selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R 8 And R 9 Are all hydrogen;
x is above 1 Selected from O, or N;
preferably, X 1 Is O, when R 11 Is absent;
r is as defined above 10 Is selected from C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3 - 8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as follows;
preferably, R 10 Is selected from C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group;
more preferably, R 10 Selected from methyl, or isopropyl;
r is as defined above 11 Is selected from C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3 - 8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as follows; in particular, when X 1 Is N;
in some embodiments, in formulas (I) and/or (IV) above, L is
Figure BDA0003921880740000091
Wherein the content of the first and second substances,
r is as defined above a 、R b Each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R a 、R b Connecting to form a ring;
preferably, R a 、R b Each independently selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R a And R b Are all hydrogen;
r is as defined above c 、R d Each independently selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R a 、R b Connecting to form a ring;
preferably, R c 、R d Each independently selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R a And R b Are each hydrogen, or R a And R b One of which is hydrogen and the other is methyl;
x is above 1 、R 10 And R 11 As defined above;
in some embodiments, in formula (I) and/or (V) above, L is
Figure BDA0003921880740000092
Wherein, the first and the second end of the pipe are connected with each other,
above X 2 、X 3 Each independently selected from O, NH, or S;
preferably, X 2 、X 3 Each independently selected from O, or NH;
r is as defined above 12 、R 13 Each independently selected from hydrogen, na, K, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclic radical, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 Heteroaryl, or R 12 、R 13 Connecting to form a ring; wherein the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl may be further optionally substituted with one OR more of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, - (C = O) OR 16 、-(C＝S)NHR 16 Substitution;
preferably, R 12 、R 13 Each independently selected from hydrogen, na, C 1-8 Alkyl radical, C 6-18 Aryl, or R 12 、R 13 Connecting to form a ring; wherein the above alkyl, alkoxy, aryl, may be further optionally substituted with one OR more of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxy, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, - (C = O) OR 16 、-(C＝S)NHR 16 Substitution;
more preferably, R 12 、R 13 Each independently selected from hydrogen, na, C 1-8 Alkyl radical, C 6-18 Aryl, or R 12 、R 13 Connected to form a 5-6 membered ring; wherein the above alkyl group may be further substituted by- (C = O) OR 16 Substitution; wherein the content of the first and second substances,
r is as defined above 16 Selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, or
Figure BDA0003921880740000101
In some embodiments, in formulas (I) - (V) above, R 4 Is composed of
Figure BDA0003921880740000102
Wherein, the first and the second end of the pipe are connected with each other,
t is selected from O or S;
m is selected from 1,2, or 3;
preferably, m is selected from 1, or 2;
r is as defined above 14 Selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 An alkylamino group;
preferably, R 14 Selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R 14 Selected from hydrogen, methyl, or ethyl;
r is as defined above 15 Is composed of
Figure BDA0003921880740000103
Wherein, the first and the second end of the pipe are connected with each other,
z is selected from CH or N;
r is as defined above 17 Selected from the group consisting of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, methylthio, acetyl, methylsulfonyl, ethylsulfonyl;
preferably, R 17 Selected from hydroxy, methylthio, isopropoxy, acetyl;
r is as defined above 18 Is selected from C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above carbocyclyl, heterocyclyl, aryl, heteroaryl may be further optionally substituted with one or more of the following groups a;
preferably, R 18 Is selected from C 5-6 Carbocyclic group, or C 2-5 A heterocyclic group; wherein the above-mentioned carbocyclyl and heterocyclyl may be further optionally substituted with one or more groups A as follows;
the group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
The present invention provides compounds having the following structure:
Figure BDA0003921880740000111
/>
Figure BDA0003921880740000121
/>
Figure BDA0003921880740000131
/>
Figure BDA0003921880740000141
/>
Figure BDA0003921880740000151
in another aspect, the present invention provides, in some embodiments, a pharmaceutical composition comprising a compound as described above, or a solvate, pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture (as the active ingredient), and an inert carrier.
The composition can be applied in the form of a composition comprising: injections, powders, sprays, inhalants, tablets, pills, capsules, lozenges, gums, powders, granules, gels, creams, ointments, patches, suppositories, suspensions, syrups.
The composition, wherein the active ingredient is in a unit dose of 0.01mg to 1.0g of the body weight of an individual in need of treatment.
In some embodiments, the present invention provides the use of the above pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of a related disease or disorder.
The related diseases or symptoms comprise neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive decline, appetite dysfunction, emotional dysfunction, sunset syndrome and Alzheimer disease.
A method of treating a disease or condition comprising administering to an individual in need of treatment a therapeutically effective amount of said compound or said composition.
The compound disclosed by the invention has the function of inhibiting beta-amyloid deposition.
Compared with TM, the compound disclosed by the invention has a more remarkable analgesic effect.
Compared with TM, the compound disclosed by the invention has stronger blood brain barrier penetration and larger in vivo exposure, and particularly the compound RE-33 has the most excellent performance in the aspects.
In the present invention, in order to make the present invention more thoroughly understood by each skilled person, each term has the following definitions.
"amino" as used herein refers to a functional group having 1 nitrogen atom and 0, 1, or 2 hydrogen atoms.
Halogen herein means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
"C1-8 alkyl" refers to a straight, branched, or cyclic hydrocarbon group having 1 to 8 carbon atoms. Such as methyl, ethyl, propyl, isopropyl, isobutyl, pentyl, methylpentyl, 2-methylhexyl, isooctane, cyclopentyl, cyclohexyl and the like.
"C1-8 alkoxy" refers to a straight, branched, or cyclic hydrocarbon group of 1 to 8 carbon atoms interrupted by an-OH or-O-group at any reasonable position. Such as methoxy, ethoxy, isopropoxy, isobutoxy, tert-butoxy, 2-methoxypropyl, (S) - (+) -1-methoxy-2-propyl, 1-propoxy-2-propyl, ethylene glycol monobutyl and the like.
"C1-8 alkylamino" means an insertion of-N-or-N-at any reasonable position in "C1-8 alkyl" -NH-, -NH2 radicals. For example, methylamino, ethylamino, diisopropylamino, N-methyl-N-propylamino, di-N-propylamino, N-ethylisopropylamino, 2- (isopropylamino) ethyl and the like.
"C2-8 alkenyl" means a straight, branched or cyclic hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond in the molecule. Such as allyl, butenyl, cis-2-pentenyl, trans-2-hexenyl, 3,3-dimethyl-1-butenyl, 2,5-dimethyl-3-hexenyl, 2,4,4-trimethyl-2-pentenyl, cis-2-pentenyl, trans-2-hexenyl, cyclohexenyl, 3-methyl-1-cyclohexenyl and the like.
"C2-8 alkynyl" refers to a straight, branched or cyclic hydrocarbon group containing at least one carbon-carbon triple bond in a molecule having 2 to 8 carbon atoms. For example, 2-propynyl, 3,3-dimethyl-1-butynyl, cyclopropylethynyl, 2-pentynyl, 4-methyl-2-hexynyl, isopropylethynyl such as methyl, cyclopentylethynyl, cyclohexylethynyl, 3-cyclopentyl-1-propynyl, 4-octynyl, prop-1-ynylcyclopropyl, 1-ethynyl-1-methylcyclohexyl, and the like.
"C3-8 carbocyclyl" refers to a saturated or unsaturated aliphatic cyclic hydrocarbon group having 3 to 8 carbon atoms. Wherein the cyclic hydrocarbon group may be selected from a single ring, or a polycyclic condensed group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, dicyclopentanyl, methylcyclohexyl, ethylcyclohexyl, naphthylalkyl, 3-cyclopentyl-1-propyl, 1,3-cyclohexadienyl, 1-methyl-1-cyclohexenyl and the like.
"C2-8 heterocyclyl" means a saturated or unsaturated monocyclic or polycyclic group containing heteroatoms in at least one ring of 2 to 8 carbon atoms, and each ring of such polycyclic heterocycloalkyl group may have different linking modes, such as fused, bridged, spiro, and the like. For example, pyrrolidinyl, piperidinyl, morpholinyl, homopiperazinyl, 4-pyrrolidin-1-yl-piperidinyl, 3-methylpiperidinyl, N-ethylpiperidinyl, furanyl, thienyl, pyrazolyl, oxazolyl, tetrahydro-3-thiophenyl, 4-methyl-1-piperazinylethyl and the like.
"C6-18 aryl" refers to a group having 6 to 18 carbon atoms and at least one aromatic ring, and each ring of the polycyclic aryl group may have different connection modes such as fused, bridged, etc., in addition to a covalent group, and the fused ring may be saturated or unsaturated. Such as phenyl, indanyl, indenyl, diphenylmethyl, alpha-tetrahydronaphthyl, and the like.
"C3-12 heteroaryl" means a monocyclic or polycyclic aromatic heterocyclic group having 3 to 12 carbon atoms and containing at least one hetero atom, and each ring of the polycyclic heteroaryl group may have different linkage modes such as condensed, bridged, etc., for example, furyl, thienyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, indolyl, pyrazinyl, quinolyl, pyridazinyl, indenyl, indanyl, benzofuryl, etc.
The double bond containing compounds of the present invention include all configurational isomers (e.g., cis and trans isomers).
The "hetero atom" in the present invention includes a nitrogen atom, an oxygen atom, a phosphorus atom, a boron atom, a sulfur atom, a selenium atom and the like.
The compounds of the present invention have one or more asymmetric centers and the present invention therefore relates to the use of optical isomers and stereoisomers of all these compounds and mixtures thereof. Also included are the use of compounds having tautomers and mixtures thereof.
The compounds of the present invention contain a basic nitrogen atom (heterocyclic or aliphatic amino group, etc.) and are susceptible to oxidation by an oxidizing agent such as oxygen in air, hydrogen peroxide, selected from N-oxides to form other compounds of the present invention. Thus, the N-oxide derivative converted is part of a compound selected from the group of compounds of the present invention.
The term "optionally" in the present invention means having 1 or more variables, then each instance of a substituent is selected from the available variable definitions independently of the other selection definition variables. Thus, each substituent may be the same or different from the others.
"treating" or "treatment" refers to the effect of substantially reversing, alleviating the symptoms of, or causing the progression of a condition in an individual by administering to the individual a drug or pharmaceutical composition.
The term "subject in need of treatment" as used herein refers to a warm-blooded or cold-blooded animal, such as a human, rat, mouse, rabbit, dog, pig, sheep, chicken, duck, goose, cat, cow, horse, etc.
The term "compound and salt thereof" as used herein refers to a complex of a compound bound with a corresponding acid, the property depending on the characteristics of the compound, and an addition salt of the compound with an acid, for example, an inorganic acid salt such as hydrochloride, sulfate, hydrobromide, etc. Organic acid salts such as maleate, fumarate, acetate, propionate, malate, tartrate, malonate, succinate, citrate, cinnamate, mandelate, methanesulfonate, p-toluenesulfonate, salicylate and the like.
The term "compound and salt thereof" as used herein refers to addition salts of the compound with a base, and salts with an inorganic base such as sodium, potassium, ammonium, calcium, magnesium, and the like. Salts of organic amines such as diethylamine salt, ethylenediamine salt, meglumine salt, tromethamine salt, arginine salt, lysine salt, histidine salt, piperidine salt and the like.
The term "inert carrier" as used herein refers to a substance that helps an individual to take or absorb an active substance in a pharmaceutical composition without causing significant adverse effects to the patient or individual, and includes glucose, disintegrants, fillers, flavoring agents, lubricants, fatty acid esters, hydroxymethylcellulose, stabilizers, emulsifiers, colorants, starches, sodium saccharin, cellulose, and the like.
The "disease or condition" referred to in the present invention refers to neuropathic pain, joint pain, postoperative pain, obstetric pain, herpes zoster pain, gout, joint degeneration pain, discogenic pain, trigeminal neuralgia, intractable headache, tumor pain, angina pectoris, idiopathic chest and abdominal pain, oral pain, facial pain, internal organ pain, etc.
The diseases or symptoms comprise insomnia, alzheimer's disease, sunset syndrome, parkinson's disease, hypomnesis, attention deficit, intellectual disturbance, addiction and the like.
The term "composition" as used herein means any product comprising or resulting from the specified amount of a compound of the present invention, either by direct or indirect means.
The compounds of the present invention may be used alone or in combination with one or more other drugs for the treatment, prevention or treatment of the diseases or conditions for which the compounds of the present invention are indicated. The combination can have more remarkable curative effect.
The compounds of the invention occupy a unit dose of 0.01mg to 1.0g, more preferably 0.1mg to 0.5g, of the body weight of an individual in need thereof.
Drawings
FIG. 1 shows the results of analgesic testing of compounds of the present invention with TM.
FIG. 2 shows the beta-amyloid deposition inhibitory activity of the compounds of the present invention.
Detailed Description
The invention is further described below with reference to the following examples, which are not intended to be limiting. The experimental solvents or reagents used in the following examples were all commercially available unless otherwise specified.
The first embodiment is as follows: preparation of intermediate E
Figure BDA0003921880740000201
Step 1: and (3) synthesis of an intermediate B:
(2S) -2-methyl-2-piperidinecarboxylic acid (14.3g, 0.1mol, 1.0eq) was dissolved in acetonitrile (200 mL), and triethylamine (30.4g, 0.3mol, 3.0eq) was added. The reaction system was cooled to 0 to 5 ℃ and Boc anhydride (21.8g, 0.1mol, 1.0eq) was carefully added dropwise. After the addition, the system was left to react at room temperature for 15 hours. Acetonitrile was removed under reduced pressure and the residue was slowly added to water (250 mL). Extraction with ethyl acetate (2 × 250ml), concentration of the organic phase and column chromatography gave 11.9g of intermediate B, yield: 49％，[M+H] + ＝244.10。
Step 2: and (3) synthesis of an intermediate D:
intermediate B (24.3g, 0.1mol, 1.0eq) was dissolved in ethyl acetate (500 mL), HOBt (13.5g, 0.1mol, 1.0eq) and EDCI (19.1g, 0.1mol, 1.0eq) were added, and after stirring for 1 hour, C (12.7g, 0.1mol, 1.0eq) was added. The reaction was stirred at rt for 6 h, washed with water (2 x 300ml), concentrated under reduced pressure, and isolated by column chromatography to give 15.5g of intermediate D, yield: 44%, [ M + H%] + ＝353.19。
And step 3: synthesis of intermediate E:
intermediate D (3.5g, 10mmol, 1.0eq) was dissolved in acetic acid (60 mL), and the mixture was heated to 100 ℃ to react for 3 hours. Concentration removed acetic acid, the residue was dissolved in DCM (60 mL), then trifluoroacetic acid (10 mL) was added, stirring was continued for 3 hours, water washed (2 × 300ml), concentrated under reduced pressure, column chromatography isolated to give 0.7g of intermediate E, yield: 30%, [ M + H%] + ＝235.11。
Example two: preparation of Compound RE-01
Figure BDA0003921880740000202
Step 1: synthesis of intermediate G:
dissolving the intermediate F (21.7g, 0.1mol, 1.0eq) in tetrahydrofuran (THF, 300 mL), slowly adding sodium hydroxide (12.0g, 0.3mol, 3.0eq) and 2-bromopropane (12.3g, 0.1mol, 1.0eq) under the protection of nitrogen, heating to 60 ℃ for reacting for 3 hours, washing with water (2 x 200mL), adjusting the organic phase to acidity (pH value is 2-3) by using hydrochloric acid (2.0M), concentrating under reduced pressure, and separating by column chromatography to obtain 9.1G of intermediate G, wherein the yield is as follows: 35%, [ M + H%] + ＝259.16。
Step 2: synthesis of intermediate H:
to a three-necked flask, intermediate G (25.9g, 0.1mol, 1.0eq), 1,4-dioxane (500 mL) and water (50 mL) were added under nitrogen, cyclopentylboronic acid (11.4g, 0.1mol, 1.0eq), dichloro [1,1' -bis (diphenylphosphino) ferrocene]Palladium (7.3g, 0.01mol, 0.1eq) and cesium carbonate (32.6g, 0.1mol, 1.0eq) were heated to reflux reaction for 16 hoursCooling, adjusting pH to 3-4 with hydrochloric acid (2.0M), concentrating, adding water (300 mL), extracting with ethyl acetate (2 x 300mL), concentrating the organic phase, and separating by column chromatography to obtain 13.6g of an intermediate H, wherein the yield is as follows: 55%, [ M + H%] + ＝249.14。
And step 3: synthesis of intermediate I:
under nitrogen protection, intermediate H (2.5g, 0.01mol, 1.0eq) was added to a three-necked flask, dissolved in dichloromethane (100 mL), HOBt (1.4g, 0.01mol, 1.0eq) and EDCI (1.9g, 0.01mol, 1.0eq) were added, after stirring for 1 hour, intermediate E (2.4g, 0.01mol, 1.0eq) was added, stirring at room temperature for 6 hours, washed with water (2 × 50ml), concentrated under reduced pressure, and column chromatography was performed to obtain 1.6g of intermediate I, yield: 35%, [ M + H%] + ＝465.09。
And 4, step 4: synthesis of Compound RE-01:
under nitrogen protection, intermediate I (4.6g, 0.01mol, 1.0eq) was added to a three-necked flask, dissolved in THF (100 mL), added with sodium hydride (0.48g, 0.02mol, 2.0eq) and chloromethyl isobutyrate (1.4 g,0.01mol, 1.0eq), stirred at room temperature for 16 hours, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain 1.4g of compound RE-01, yield: 25%, [ M + H%] + ＝565.13。 1 H NMR(CDCl 3 )δ8.45-8.43(m,1H),7.55-7.54(m,2H),7.41-7.39(m,1H),7.10(d,J＝6.5Hz,1H),6.51(s,2H),4.74-4.72(m,1H),3.62-3.60(m,1H),3.52-3.50(m,1H),2.83-2.82(m,1H),2.53-2.51(m,1H),2.06-2.05(m,1H),1.90-1.88(m,2H),1.76-1.74(m,3H),1.66-1.63(m,5H),1.59-1.57(m,2H),1.51-1.50(m,1H),1.48(d,J＝12.3Hz,3H),1.31-1.29(m,6H),1.14-1.12(m,6H)。
Example three: preparation of Compound RE-22 and Compound RE-23
Figure BDA0003921880740000221
Synthesis of Compound RE-22:
under nitrogen protection, intermediate I (4.6g, 0.01mol, 1.0eq) was added to a three-necked flask, dissolved in THF (100 mL), sodium hydrogen (1.4g, 0.02mol, 2.0eq) and diisopropyl chlorophosphate (2.0g, 0.01mol, 1.0eq) were added, and the mixture was stirred at room temperature for 16 hoursThen, the reaction mixture was filtered, hydrochloric acid (20 mL) and water (20 mL) were added, the reaction was continued for 16 hours, and the reaction mixture was concentrated to prepare a liquid phase, which was separated to obtain 0.7g of a compound RE-22 in a yield: 12%, [ M + H%] + ＝575.20。 1 H NMR(CDCl 3 )δ8.44-8.43(m,1H),7.52-7.50(m,2H),7.40-7.39(m,1H),7.07(d,J＝6.3Hz,1H),6.53(s,2H),4.72-4.70(m,1H),3.59-3.57(m,1H),3.51-3.49(m,1H),2.80-2.78(m,1H),2.04-2.03(m,1H),1.87-1.85(m,2H),1.73-1.71(m,3H),1.63-1.60(m,5H),1.55-1.53(m,2H),1.49-1.47(m,1H),1.44(d,J＝12.1Hz,3H),1.28-1.26(m,6H)。
Synthesis of Compound RE-23:
under the protection of nitrogen, compound RE-22 (5.7g, 0.01mol, 1.0eq) was added into a three-necked flask, dissolved in anhydrous THF (100 mL), thionyl chloride (2.4g, 0.02mol, 2.0eq) was added, the reaction was continued for 1 hour with stirring, methanol (10 mL) and triethylamine (3.0g, 0.03mol, 3.0eq) were added, the reaction was continued for 6 hours, and the mixture was filtered, concentrated under reduced pressure, to prepare a liquid phase, which was separated to obtain 0.6g of compound RE-23, yield: 10%, [ M + H%] + ＝603.10。 1 H NMR(CDCl 3 )δ8.43-8.42(m,1H),7.51-7.50(m,2H),7.38-7.37(m,1H),7.05(d,J＝6.2Hz,1H),6.55(s,2H),4.71-4.70(m,1H),3.79-3.77(m,6H),3.58-3.57(m,1H),3.50-3.48(m,1H),2.78-2.76(m,1H),2.03-2.02(m,1H),1.84-1.82(m,2H),1.72-1.69(m,3H),1.65-1.63(m,5H),1.54-1.52(m,2H),1.43-1.42(m,1H),1.41(d,J＝12.4Hz,3H),1.29-1.27(m,6H)。
Example four: preparation of Compound RE-24
Figure BDA0003921880740000231
Compound RE-22 (5.7g, 0.01mol, 1.0eq) was added to a three-necked flask under nitrogen, dissolved in acetone (100 mL) and water (10 mL), sodium hydroxide (4.0g, 0.1mol, 10.0eq) was added, stirred at room temperature for 16 hours, filtered, concentrated, and the resulting residue was recrystallized from acetone/water to give 1.3g of compound RE-24, yield: 21%, [ M + Na%] + ＝641.11。 1 H NMR(CDCl 3 )δ8.42-8.40(m,1H),7.50-7.48(m,2H),7.39-7.38(m,1H),7.02(d,J＝6.5Hz,1H),6.51(s,2H),4.71-4.70(m,1H),3.56-3.55(m,1H),3.51-3.48(m,1H),2.81-2.80(m,1H),2.02-2.01(m,1H),1.86-1.85(m,2H),1.72-1.70(m,3H),1.61-1.57(m,5H),1.53-1.51(m,2H),1.46-1.44(m,1H),1.41(d,J＝12.3Hz,3H),1.25-1.23(m,6H)。
Example five: preparation of Compound RE-25
Figure BDA0003921880740000232
In a three-necked flask under nitrogen protection, compound RE-22 (5.7g, 0.01mol, 1.0eq) was added, dissolved in anhydrous THF (100 mL), thionyl chloride (2.4g, 0.02mol, 2.0eq) was added, the reaction was continued for 1 hour with stirring, phenol (1.0g, 0.01mol, 1.0eq) and triethylamine (4.0g, 0.04mol, 4.0eq) were added, the reaction was continued for 6 hours, isopropyl L-alanine (1.7g, 0.01mol, 1.0eq) was added, the reaction was continued for 6 hours, filtration and concentration under reduced pressure was carried out to prepare 0.8g of compound RE-25 by liquid phase separation, yield: 11%, [ M + H%] + ＝764.19。 1 H NMR(CDCl 3 )δ8.47-8.46(m,1H),7.58-7.56(m,2H),7.45-7.42(m,3H),7.25-7.23(m,3H),7.15(d,J＝6.3Hz,1H),6.56(s,2H),4.89-4.87(m,1H),4.77-4.76(m,1H),3.65-3.64(m,2H),3.53-3.52(m,2H),2.86-2.85(m,1H),2.09-2.07(m,1H),1.96-1.94(m,2H),1.79-1.76(m,3H),1.68-1.65(m,5H),1.63-1.61(m,2H),1.55-1.54(m,1H),1.49(d,J＝12.1Hz,3H),1.35-1.33(m,6H),1.30(d,J＝12.2Hz,3H),1.23-1.21(m,6H)。
Example six: preparation of Compound RE-28
Figure BDA0003921880740000241
In a three-necked flask under nitrogen protection, RE-22 (5.7g, 0.01mol, 1.0eq) was added and dissolved in anhydrous THF (100 mL), thionyl chloride (2.4g, 0.02mol, 2.0eq) was added, the reaction was continued for 1 hour with stirring, ethylene glycol (0.6g, 0.01mol, 1.0eq) and triethylamine (4.0 g,0.04mol, 4.0eq) were added, the reaction was continued for 6 hours, and filtration and concentration under reduced pressure were carried out to prepare a liquid phase, which was separated to obtain 0.6g of RE-28, yield: 10%, [ M + H%] + ＝601.12。 1 H NMR(CDCl 3 )δ8.47-8.46(m,1H),7.57-7.55(m,2H),7.44-7.43(m,1H),7.13(d,J＝6.2Hz,1H),6.41(s,2H),4.76-4.75(m,1H),4.49-4.47(m,4H),3.64-3.63(m,1H),3.55-3.53(m,1H),2.86-2.84(m,1H),2.09-2.07(m,1H),1.95-1.93(m,2H),1.77-1.74(m,3H),1.68-1.64(m,5H),1.60-1.58(m,2H),1.55-1.53(m,1H),1.47(d,J＝12.4Hz,3H),1.32-1.30(m,6H)。
Example seven: synthesis of Compound TM
Figure BDA0003921880740000251
Step 1: preparation of Compound IM01
SM01 (7.5 g, 45.28mmol) was dissolved in a mixed solvent of acetonitrile (45 mL) and water (75 mL), triethylamine (13.75g, 135.85mmol) was added, the system was allowed to exotherm, the reaction system was cooled to 10 ℃ and a solution of Boc anhydride (14.83g, 67.93mmol) in acetonitrile (15 mL) was added, and after dropping, stirring was carried out at room temperature for 70h, and completion of the reaction was detected by TLC.
Most of acetonitrile was concentrated, the concentrated residue was poured into 2N aqueous sodium hydroxide (40 mL) and extracted three times with ethyl acetate, the aqueous phase was adjusted to pH 1-2 with 2N aqueous hydrochloric acid, a large amount of solid was precipitated, 16g of off-white solid was obtained by filtration, and the solid was dried by forced air drying at 50 ℃ for 3 hours to obtain off-white solid, i.e., compound IM01 (8.88 g), with a yield of 84.78%. [ M + H ]] + ＝230.15。
Step 2: preparation of Compound IM02
IM01 (8.88g, 38.73mmol) was dissolved in dichloromethane (60 mL), benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate (HBTU, 14.69g, 38.73mmol) and N, N-diisopropylethylamine (DIPEA, 13.02g,100.7 mmol) were added and stirred for 0.5h, followed by addition of a solution of SM02 (10.00g, 63.85mmol) in DCM (40 mL) and reacted overnight at room temperature with TLC detection complete.
The reaction system was poured into water, extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulphate and concentrated to give a brown oil, which was chromatographed to give compound IM02 (7.5 g) as a white solid in 52.74% yield. [ M + H ]] + ＝368.18。
And step 3: preparation of Compound IM03
IM02 (7.00g, 19.03mmol) was dissolved in acetic acid, heated to 100 ℃ for reaction 1h, and checked by TLC for completion.
After concentrating to remove most of the acetic acid, DCM was added to dilute, and sodium bicarbonate aqueous solution (ice water) was added to separate the liquids, and after the aqueous phase was extracted three times with DCM, the organic phases were combined and concentrated to give a beige foamy solid, compound IM03 (6.0 g), with a yield of 90.10%. [ M + H ]] + ＝350.15。
And 4, step 4: preparation of Compound IM04
IM03 (6.0 g, 17.16mmol) was dissolved in dioxane (50 mL), trifluoroacetic acid (TFA, 9.78g, 85.82mmol) was added under ice-bath, stirring overnight, and TLC was used to check completion of the reaction.
The reaction was concentrated to dryness to give a brown oil, crude compound IM04 (6.5 g), which was charged next on a 100% basis without further treatment.
And 5: preparation of Compound IM05
Dissolving SM03 (8.08g, 29.06mmol) in N, N-dimethylformamide (DMF, 70 mL) to obtain a solution with a khaki color, adding 1H-1,2,3-triazole (4.01g, 58.12mmol) and cesium carbonate (18.94g, 58.12mmol), heating to 40 ℃, discharging a small amount of gas, adding cuprous iodide (0.277g, 1.45mmol), gradually turning green, heating to 70 ℃, stirring for 1h, and detecting by TLC to finish the reaction.
The reaction was cooled to room temperature, poured into water, extracted once with Ethyl Acetate (EA), the aqueous phase was retained, made acidic with citric acid, extracted twice with EA, the organic phase was dried over anhydrous sodium sulfate and concentrated to give a tan oil, compound IM05 (13.0 g), in 100% yield. [ M + H ]] + ＝220.06。
Step 6: preparation of Compound TM
IM04 (3.0 g, 10.48mmol) was dissolved in dichloromethane (30 mL), and IM05 (2.30g, 10.48mmol), DIPEA (6.77g, 52.40mmol) and HBTU (3.98g, 10.48mmol) were added in sequence to the ice bath to start the reaction (the solution gradually changed to a brownish red color as the reaction proceeded), the reaction was stirred overnight and the reaction was completed by TLC.
Extraction was carried out three times with water and dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give a crude product (8.26 g), and column chromatography was carried out to give compound TM (1.05 g) with a yield of 22.20%. [ M + H ]] + ＝451.6。 1 HNMR(DMSO,400MHz):12.24(brs,1H),8.03(s,2H),7.79(d,J＝8.8Hz,1H),7.41-7.249(m,3H),7.17(d,J＝8.8,1H),3.90(s,3H),3.61(m,1H),2.67(s,3H),2.3(m,1H),2.05-1.95(m,4H),1.89(s,3H)。
Example eight: preparation of Compound RE-31
Figure BDA0003921880740000271
Compound TM (400mg, 0.887 mmol) was dissolved in DMF under ice bath, 60% sodium hydride (70.96mg, 1.774mmol) was added thereto, and after stirring for 30 minutes, chloromethyl isobutyrate (242.29mg, 1.774mmol) was added thereto, and the reaction was allowed to warm to room temperature for half an hour, overnight, and TLC detection was completed.
After quenching with water, extraction was performed 3 times with EA and water, the organic phases were combined, dried with anhydrous sodium sulfate, and the product was isolated by chromatography (PE: EA = 2:1) and concentrated to give a powdery solid, compound RE-31 (105 mg), in 21.47% yield. [ M + H ]] + ＝551.14。 1 HNMR(DMSO,400MHz):8.07(s,2H),7.82(d,J＝8.8Hz,1H),7.40(m,1H),7.33(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.04(s,1H),6.47(m,2H),3.89(s,3H),3.60(m,2H),2.56(s,3H),2.33-2.08(m,5H),1.95(s,3H),1.07(d,6H)。
Example nine: preparation of Compound RE-32
Figure BDA0003921880740000281
After dissolving TM (500mg, 1.109mmol) in DMF (5 mL) in ice, 60% sodium hydride (88.72mg, 2.218mmol) was added and stirred for 30 minutes, chloromethyl pivalate (334.03mg, 2.218mmol) was added and the reaction was completed by TLC for half an hour.
And (3) post-treatment: after the quenching with water, the reaction mixture was quenched,the product was isolated by chromatography (PE: EA = 2:1) after 3 extractions with EA and water, combined organic phases dried over anhydrous sodium sulfate, and concentrated to give compound RE-32 (100 mg) in 15.95% yield. [ M + H ]] + ＝565.18。 1 HNMR(DMSO,400MHz):8.08(s,2H),7.83(d,J＝8.4Hz,1H),7.34(m,2H),7.20(d,J＝8.0Hz,1H),7.02(s,1H),6.44(m,2H),3.90(s,3H),3.58(m,2H),2.51(s,3H),2.33-2.09(m,4H),1.96(s,3H),1.09(s,9H)。
Example ten: preparation of Compound RE-33
Figure BDA0003921880740000282
After dissolving TM (1.1g, 2.44mmol) in DMF (5.5 mL) under ice bath, adding 60% sodium hydride (0.195g, 4.88mmol) and stirring for 30 minutes, adding chloromethyl methyl carbonate (0.608g, 4.88mmol), reacting for half an hour, raising to room temperature, continuing the reaction for 5 hours, detecting by TLC, reacting the majority of the material, quenching with water, extracting with EA and water for 3 times, combining the organic phases, drying with anhydrous sodium sulfate, and successively carrying out chromatography to separate the liquid phase to obtain RE-33 (15 mg) as a product with a yield of 1.14%. [ M + H ]] + ＝539.17。
1 HNMR(DMSO,400MHz):8.07(s,2H),7.79(d,J＝8.8Hz,1H),7.47(d,J＝8.4Hz,1H),7.34(d,J＝8.8Hz,1H),7.20(d,J＝8.4Hz,1H),7.09(s,1H),6.46(m,2H),4.06(s,3H),3.96(s,3H),3.77-3.62(m,2H),2.67(s,3H),2.3-2.0(m,4H),1.91(s,3H)。
Example eleven: preparation of Compound RE-37
Figure BDA0003921880740000291
In a three-necked flask, compound TM (2.25g, 5.00mmol) was added under nitrogen atmosphere, dissolved in THF (35 mL), 60% sodium hydride (0.4 g,10.0 mmol) and diisopropyl chlorophosphate (1.0 g,5.0 mmol) were added, and the mixture was stirred at room temperature for 20 hours, filtered, added with hydrochloric acid (10 mL) and water (10 mL), allowed to react for 20 hours, and concentratedPreparation of a liquid phase separation Compound RE-37 (0.43 g), yield: 15.4%, [ M + H%] + ＝561.01。
Example twelve: preparation of Compound RE-38
Figure BDA0003921880740000292
/>
Under the protection of nitrogen, compound RE-37 (1.12g, 2.0mmol) was added to a three-necked flask, and dissolved in anhydrous THF (20 mL), thionyl chloride (0.472g, 4.0mmol) was added thereto, and the mixture was stirred and reacted for 1 hour, methanol (3 mL) and triethylamine (0.607g, 6.0mmol) were added thereto, and the reaction was continued for 6 hours, followed by filtration, concentration under reduced pressure, and preparative liquid phase separation to obtain compound RE-38 (0.13 g), yield: 11.0%, [ M + H%] + ＝589.19。
Example thirteen: preparation of Compound RE-39
Figure BDA0003921880740000301
Compound RE-37 (1.12g, 2.0mmol) was charged in a three-necked flask under nitrogen protection, dissolved in acetone (20 mL) and water (2 mL), and sodium hydroxide (0.8g, 20mmol) was added thereto, and stirred at room temperature for 18 hours, filtered, concentrated, and the resulting residue was recrystallized from acetone/water to give compound RE-39 (0.22 g), yield: 18.2%, [ M + H%] + ＝605.17。
The following compounds of the examples were prepared by a similar synthetic procedure with rational deprotection of the protecting groups:
Figure BDA0003921880740000302
/>
Figure BDA0003921880740000311
/>
Figure BDA0003921880740000321
/>
Figure BDA0003921880740000331
/>
Figure BDA0003921880740000341
example fourteen: determination of the Effect of acetate writhing on pain in mice
Preparing aqueous solutions of compounds TM, RE-01, RE-09, RE-19, RE-22, RE-23, RE-25, RE-26, RE-29, RE-31, RE-32, RE-33, RE-35, RE-37, RE-38, RE-40, RE-41, RE-45 and RE-47 respectively for later use. The concentrations of the above-mentioned compounds were 0.26mg/mL, 0.33mg/mL, 0.32mg/mL, 0.33mg/mL, 0.35mg/mL, 0.44mg/mL, 0.46mg/mL, 0.35mg/mL, 0.32mg/mL, 0.33mg/mL, 0.31mg/mL, 0.33mg/mL, 0.32mg/mL, 0.34mg/mL, 0.43mg/mL, 0.46mg/mL, 0.32mg/mL and 0.36mg/mL, respectively (the molar concentrations of the respective compounds were the same).
60 female KM mice, 18-22g, were divided into 20 groups of 3 mice each. The administration group and the TM control group are injected with 0.4mL of newly configured compound solution in the abdominal cavity respectively, and the model group is injected with equal volume of injection water in the abdominal cavity.
After administration for 30min, 0.2mL of 0.6% glacial acetic acid solution was injected intraperitoneally into each mouse, and the number of writhing occurred in each mouse within 20min was recorded, and the average value was calculated. The results are shown in FIG. 1.
The results show that the times of twisting the body of each administration group and the TM control group are obviously less than those of the model control group; compared with the TM control group, the twisting times of each administration group are also obviously reduced, and the twisting times of the compounds RE-19, RE-33, RE-35, RE-37, RE-38 and RE-45 are most obviously reduced; in conclusion, the compounds disclosed by the invention have stronger analgesic activity.
Example fifteen: amyloid beta deposition inhibitory Activity
Aging accelerated mice (SAMP 8) 63, males (8 months old at the beginning of the study), were evenly divided into 9 groups of 7 mice each. Running water is normally drunk in a non-dried group; experimental groups 1 to 8 solutions containing the compounds (RE-01, RE-23, RE-31, RE-32, RE-33, RE-37, RE-45, RE-47) dissolved in tap water were each administered at a dose of 0.1 mg/kg/day. Eight weeks after administration, rat brains were removed, fixed with Methacarn (methanol: chloroform: acetic acid = 6. Then, a 8 μm thick section was prepared using a microtome.
Sections were immunostained for streptavidin-biotin using the VECTASTATIN ABC kit. After one hour incubation in 10% normal goat serum, anti-beta-amyloid (a β) antibody was diluted 10-fold with PBS and incubated overnight at 4 ℃. The next day, PBS washes, incubation with biotinylated anti-rabbit secondary antibody for 1.5 hours, PBS washes, and incubation with peroxidase-labeled streptavidin for 1.5 hours were performed. The immunoreactions were visualized with DAB and samples were prepared.
Immunoreactive Α β -like particles in hippocampus were counted under microscope. A β -like immunoreactive particles were observed as brown deposits in hippocampus. Each individual was counted in one slice.
As shown in fig. 2, β -amyloid-like immunoreactivity in hippocampus was observed in the non-primed group of aging-accelerated mice (SAMP 8). In the case of the administration dose of 0.1 mg/kg/day, the β -amyloid-like immunoreactivity was decreased in experimental group 1 to experimental group 8 of aging-accelerated mice (SAM 8). This indicates that the disclosed compounds are capable of inhibiting beta-amyloid deposition due to a significant reduction in the number of beta-amyloid-immunoreactive particles resulting from the intervention of the disclosed compounds.
Example sixteen: the compound parallel artificial membrane permeation model (PAMPA) test compound disclosed by the invention is diluted into a solution of 25 mu g/mL by using a buffer solution with the pH value of 7.4; dissolving pig brain lipid extract (PBL) in dodecane to obtain 20mg/mL solution as phospholipid membrane; dripping 4 mu L of PBL solution on a polyfluortetraethylene membrane of a 96-hole filter plate to form a phospholipid membrane simulating the environment in the brain; adding 300 μ L/well buffer solution as receptor tube above phospholipid membrane, adding 150 μ L/well 25 μ g/mL compound solution as donor tube into another 96-well plate, each drug being in parallel with three wells; superposing the two plates to enable the phospholipid membrane to contact donor liquid to form a sandwich structure, and placing the sandwich structure in a constant temperature environment of 37 ℃ for 18 hours; the solution in the 96-well filter plate was removed to a blank 96-well plate and the OD was measured at 340 nm. Experiments were performed in parallel for 3 times. The permeability Pe value is calculated according to the literature (Kiyohiko S., et al. Optimized conditions of bio-electrochemical characterization evaluation [ J ]. Int. J. Pharm.,2001,228, 181-188). The results are shown in Table 1.
TABLE 1 Artificial Membrane permeation model (PAMPA) test results
Compound number Pe value (. About.10) -6 cm/s) Compound numbering Pe value (. About.10) -6 cm/s)
RE-01 3.32 RE-35 10.45
RE-23 5.29 RE-37 1.98
RE-24 1.85 RE-38 11.59
RE-25 4.79 RE-40 3.56
RE-28 7.23 RE-41 3.26
RE-31 9.36 RE-45 11.59
RE-32 9.88 RE-47 4.57
RE-33 13.65 TM 0.85
The data show that the blood-brain barrier penetrating capacity of the compounds disclosed by the invention is stronger than that of a control compound TM, wherein the blood-brain barrier penetrating capacity of the compounds RE-31, RE-32, RE-33, RE-35, RE-38 and RE-45 is 11-16 times that of the TM. The compound disclosed by the invention can advantageously permeate the blood brain barrier to reach the brain, so that the effect of treating brain diseases can be more effectively exerted.
Example seventeen: evaluation of pharmacokinetic profiles in rats
Experimental animals: 12 male SD rats, 180-220 g, were tested after 3 days of acclimatization.
Preparing a test article: respectively weighing appropriate amounts of test articles TM, RE-33, RE-37 and RE-38, respectively placing the test articles in reagent bottles, adding appropriate amounts of 0.5% carboxymethyl cellulose solution, and preparing test article solutions with TM, RE-33, RE-37 and RE-38 concentrations of 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (the molar concentrations of the compounds are the same).
The test method comprises the following steps: rats were randomly divided into 4 groups, including TM, RE-33, RE-37 and RE-38 groups, with 3 animals per group. Each animal was separately administered the newly prepared test solution by gavage. The dose was 4mg/kg for TM group, 4.8mg/kg for RE-33 group, 5.0mg/kg for RE-37 group, and 5.2mg/kg for RE-38 group. Fasting is carried out for 16-17h before administration and 4h after administration, and water is not forbidden in the whole process. Blood is collected from rat eyeballs at about 300 mu L before oral administration for intragastric administration, 0.083h, 0.17h, 0.33h, 0.5h, 1h, 2h, 4h, 8h and 24 h.
Blood sample treatment and detection: placing rat venous blood into a centrifuge tube containing heparin sodium, placing the centrifuge tube on an ice bath, standing for 15 minutes, centrifuging (4000rpm, 10min), taking a proper amount of plasma, and storing at-80 ℃ to be detected. The results are shown in Table 2.
General clinical symptom observations: the general state observation is carried out on the experimental animals in the whole experimental process, and the observation contents comprise: the change of the food intake and water intake, the change of the body weight, the hair color, the behavior and the mental state of the rat, the eyes, the ears, the mouth and the nose of the rat, and the stool and the urine are abnormal. If the abnormity occurs, recording immediately, and analyzing the reason of the abnormity.
TABLE 2 mean results of pharmacokinetic parameters in rats
Test article Dosage of (A)mg/kg) Tmax(h) Cmax(ng/ml) AUClast(h*ng/ml)
TM 4.0 1 14.5 38.6
RE-33 4.8 1 20.5 58.1
RE-37 5.0 1 18.1 50.9
RE-38 5.2 1 17.6 50.1
The results show that compared with TM, the maximum blood concentration of the compound disclosed by the invention is more than 120%, the exposure amount is more than 130%, especially RE-33, the maximum blood concentration and the in vivo exposure amount are most prominent, and the observation phenomenon of common clinical symptoms is not abnormal, which indicates that the compound disclosed by the invention has higher bioavailability.
Example eighteen: rat brain tissue distribution experiment
Experimental animals: 12 male SD rats, 180-220 g, were tested after 3 days of acclimatization.
Preparing a test article: respectively weighing appropriate amounts of test articles TM, RE-33, RE-37 and RE-38, respectively placing the test articles in reagent bottles, adding appropriate amounts of 0.5% carboxymethyl cellulose solution, and preparing test article solutions with TM, RE-33, RE-37 and RE-38 concentrations of 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (the molar concentrations of the compounds are the same).
The test method comprises the following steps: rats were randomly divided into 4 groups, including TM, RE-33, RE-37 and RE-38 groups, with 3 per group. Each animal was separately administered the newly prepared test solution by gavage. The administration dose is 4mg/kg for TM group, 4.8mg/kg for RE-33 group, 5.0mg/kg for RE-37 group and 5.2mg/kg for RE-38 group; fasting is carried out for 16-17h before administration and 4h after administration, and water is not forbidden in the whole process. Sampling and detecting: animals were sacrificed 3.0h after gavage for each group, brain tissue was isolated, homogenized, and TM was detected by LC-MS/MS analysis. The results are shown in the following table. The results are shown in Table 3.
TABLE 3 rat brain tissue distribution results
Test article Dosage (mg/kg) 3h brain tissue concentration (ng/g)
TM 4.0 1659
RE-33 4.8 4651
RE-37 5.0 3875
RE-38 5.2 3974
The results show that the concentration of TM in rat brain tissue of compound 3h disclosed by the invention is significantly higher than that of the TM prototype, wherein the brain tissue concentration of RE-33 reaches more than 3 times of TM.
From the above detailed description of the present patent, those skilled in the art will be able to fully appreciate the features of the present invention while still obtaining improved results within the scope of the appended claims.

Claims (11)

1. A compound having the formula I:
Figure FDA0003921880730000011
or solvates, pharmaceutically acceptable salts, enantiomers, diastereomers, and racemic mixtures thereof;
in formula I:
y is selected from CH or N;
R 1 、R 2 、R 3 each independently selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxy, acetyl, carboxaldehyde, mesyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Carbocyclyl, C 2 - 8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl may be further optionally substitutedOptionally substituted with one or more groups A;
l is selected from
Figure FDA0003921880730000012
Figure FDA0003921880730000013
R 4 Is selected from
Figure FDA0003921880730000014
T is selected from O or S;
m is selected from 1,2, or 3;
R 5 、R 6 each independently selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R 5 、R 6 Connecting to form a ring;
R 7 is selected from C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as set forth below;
R 8 、R 9 each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R 8 、R 9 Connecting to form a ring;
R a 、R b each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R a 、R b Connecting to form a ring;
R c 、R d each independently selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino, or R c 、R d Connecting to form a ring;
X 1 selected from O, or N;
X 1 when is O, R 11 Is absent;
R 10 is selected from C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as set forth below;
R 11 selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more groups a as set forth below;
X 2 、X 3 each independently selected from O, NH, or S;
R 12 、R 13 each independently selected from hydrogen, na, K, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 Alkylamino radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 Heteroaryl, or R 12 、R 13 Connecting to form a ring; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may further optionally be substituted with one OR more hydrogens, halogens, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, - (C = O) OR 16 、-(C＝S)NHR 16 Substitution;
R 14 selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 An alkylamino group;
R 15 is selected from
Figure FDA0003921880730000031
Z is selected from CH or N;
R 16 selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 1-8 An alkylamino group,
Figure FDA0003921880730000032
R 17 Selected from the group consisting of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, methylthio, acetyl, methylsulfonyl, ethylsulfonyl;
R 18 is selected from C 3-8 Carbocyclyl, C 2-8 Heterocyclic group, C 6-18 Aryl radical, C 3-12 A heteroaryl group; the above-mentioned carbocyclyl, heterocyclyl, aryl, heteroaryl may be further optionally substituted with one or more groups a as follows;
the group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, carboxaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
2. The compound according to claim 1, having the structure of formula ii:
Figure FDA0003921880730000041
the substituents of formula II are as defined for formula I in claim 1.
3. The compound according to claim 1, having the structure of formula iii:
Figure FDA0003921880730000042
/>
the substituents in formula III are as defined for formula I in claim 1.
4. The compound according to claim 1, having the structure of formula IV:
Figure FDA0003921880730000043
the substituents of formula IV are as defined for formula I in claim 1.
5. The compound according to claim 1, having the structure of formula V:
Figure FDA0003921880730000044
the substituents in formula V are as defined for formula I in claim 1.
6. The compound according to any one of claims 1-5, having the structure:
Figure FDA0003921880730000051
/>
Figure FDA0003921880730000061
/>
Figure FDA0003921880730000071
/>
Figure FDA0003921880730000081
7. a pharmaceutical composition comprising a compound of any one of claims 1-6, or a solvate, pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, and inert carrier thereof.
8. The composition of claim 7, in an administrable composition form comprising: injection, powder, spray, inhalant, tablet, pill, capsule, lozenge, gum sugar, powder, granule, gel, cream, ointment, patch, suppository, suspension, syrup.
9. The composition according to claim 7, wherein the active ingredient is a compound according to any one of claims 1 to 6, or a solvate, pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture thereof, in a unit dose of 0.01mg to 1.0g of the body weight of an individual in need of treatment.
10. Use of a compound of any one of claims 1 to 6, or a solvate, pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture thereof, or a pharmaceutical composition of any one of claims 7 to 9, in the manufacture of a medicament for the treatment and/or prevention of a related disease or condition; wherein the disease or condition comprises neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive decline, appetite dysfunction, mood dysfunction, sunset syndrome, alzheimer's disease.
11. A method of treating a disease or disorder comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of any one of claims 1-6, or a composition of any one of claims 7-9; wherein the disease or condition comprises neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive decline, appetite dysfunction, mood dysfunction, sunset syndrome, and Alzheimer's disease.
CN202211366859.5A 2022-02-25 2022-11-02 Fused ring compound with analgesic activity and preparation method and application thereof Active CN115925699B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2022101760374 2022-02-25
CN202210176037 2022-02-25

Publications (2)

Publication Number Publication Date
CN115925699A true CN115925699A (en) 2023-04-07
CN115925699B CN115925699B (en) 2023-10-03

Family

ID=86647946

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211366859.5A Active CN115925699B (en) 2022-02-25 2022-11-02 Fused ring compound with analgesic activity and preparation method and application thereof

Country Status (2)

Country Link
CN (1) CN115925699B (en)
WO (1) WO2023160004A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117736193A (en) * 2023-12-19 2024-03-22 南京知和医药科技有限公司 Deuterated condensed ring compound and preparation method and application thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101501021A (en) * 2006-06-09 2009-08-05 阿斯利康(瑞典)有限公司 Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia
CN106478502A (en) * 2015-08-29 2017-03-08 上海翰森生物医药科技有限公司 1,2,3,4- tetrahydro isoquinoline derivative, its preparation method and application
CN107922350A (en) * 2015-09-11 2018-04-17 大日本住友制药株式会社 New benzimidazole compound and its medical usage
CN108290926A (en) * 2016-06-07 2018-07-17 江苏恒瑞医药股份有限公司 Phenylpropionyl amine derivant, preparation method and its application in medicine
US20180208594A1 (en) * 2017-01-25 2018-07-26 Eric Jon Jacobsen Pyrrolopyrimidine itk inhibitors for treating inflammation and cancer
CN109715613A (en) * 2016-03-31 2019-05-03 武田药品工业株式会社 Heterocyclic compound

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2425185A1 (en) * 2000-10-06 2002-04-11 Stephane De Lombaert Benzimidazole and indole derivatives as crf receptor modulators
CN104334544B (en) * 2012-06-04 2016-10-19 埃科特莱茵药品有限公司 Benzimidazole proline derivative
TWI664177B (en) * 2013-12-03 2019-07-01 瑞士商愛杜西亞製藥有限公司 Crystalline forms
UA119151C2 (en) * 2013-12-03 2019-05-10 Ідорсія Фармасьютікалз Лтд Crystalline salt form of (s)-(2-(6-chloro-7-methyl-1 h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
UA116053C2 (en) * 2013-12-04 2018-01-25 Ідорсія Фармасьютікалз Лтд Use of benzimidazole-proline derivatives
BR112022020924A2 (en) * 2020-04-19 2023-02-14 Idorsia Pharmaceuticals Ltd METHODS OF TREATMENT OF A SLEEP DISORDER, DAYTIME DREAMINESS IN AN INDIVIDUAL, INSOMNIA, AND, DARIDOXANT IN FREE OR PHARMACEUTICALLY ACCEPTABLE SALT FORM

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101501021A (en) * 2006-06-09 2009-08-05 阿斯利康(瑞典)有限公司 Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia
CN106478502A (en) * 2015-08-29 2017-03-08 上海翰森生物医药科技有限公司 1,2,3,4- tetrahydro isoquinoline derivative, its preparation method and application
CN107922350A (en) * 2015-09-11 2018-04-17 大日本住友制药株式会社 New benzimidazole compound and its medical usage
CN109715613A (en) * 2016-03-31 2019-05-03 武田药品工业株式会社 Heterocyclic compound
CN108290926A (en) * 2016-06-07 2018-07-17 江苏恒瑞医药股份有限公司 Phenylpropionyl amine derivant, preparation method and its application in medicine
US20180208594A1 (en) * 2017-01-25 2018-07-26 Eric Jon Jacobsen Pyrrolopyrimidine itk inhibitors for treating inflammation and cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117736193A (en) * 2023-12-19 2024-03-22 南京知和医药科技有限公司 Deuterated condensed ring compound and preparation method and application thereof

Also Published As

Publication number Publication date
CN115925699B (en) 2023-10-03
WO2023160004A1 (en) 2023-08-31

Similar Documents

Publication Publication Date Title
ES2314931T3 (en) USE OF 3,11B-CIS-DIHIDROTETRABENAZINE FOR THE TREATMENT OF SYMPTOMS OF HUNTINGTON'S DISEASE.
EP3766882B1 (en) Phthalazine isoxazole alkoxy derivatives, preparation method thereof, pharmaceutical composition and use thereof
HUE032948T2 (en) Opioid receptor ligands and methods of using and making same
US20200345700A1 (en) Lsd1 inhibitor and preparation method and application thereof
TW202116767A (en) Beta adrenergic agonist and methods of using the same
TW201215611A (en) Tetrahydrocarboline derivative
WO2019205983A1 (en) Oxa-spiro compound and preparation method therefor and uses thereof
CN111344290A (en) Macrocyclic compound as Wee1 inhibitor and application thereof
IL223515A (en) Triazaspirodecanyl compounds and uses thereof
EA023751B1 (en) Kit, composition, product or medicament for treating cognitive impairment
HUE031999T2 (en) Cyclic n,n'-diarylthioureas and n,n'-diarylureas as androgen receptor antagonists, anti-cancer agent, method for producing and using same
CA3064004A1 (en) Methods of making and using pde9 inhibitors
CN113164475A (en) Macrocyclic inhibitors of DYRK1A
TW200810752A (en) Modulators of muscarinic receptors
WO1995011894A1 (en) Histamine h3-receptor antagonists and therapeutic uses thereof
CN115925699A (en) Condensed ring compound with analgesic activity and preparation method and application thereof
EP3700895B1 (en) Polycyclic amides as muscarinic m1 receptor positive allosteric modulators
CN114126615A (en) Opioid receptor antagonist prodrugs
WO2017105881A1 (en) Deuterated compounds for treating pain
CN111148515A (en) 2, 6-dioxaspiro [4,5] decane derivative, preparation method and medical application thereof
BRPI0707089A2 (en) camptothecin derivatives and their uses
CN110372557B (en) Cyclohexanamines D3/D2Partial receptor agonists
NZ248776A (en) Imidazole-substituted piperidine derivatives; pharmaceutical compositions and preparatory methods
EP1736474A1 (en) Piperidine derivative
US9242935B2 (en) (-)-(2R,3S)-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan-1-one (L)-(+) tartrate salt, its method of production and use

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant