WO2023160004A1 - 具有镇痛活性的稠环化合物及其制备方法与用途 - Google Patents

具有镇痛活性的稠环化合物及其制备方法与用途 Download PDF

Info

Publication number
WO2023160004A1
WO2023160004A1 PCT/CN2022/129152 CN2022129152W WO2023160004A1 WO 2023160004 A1 WO2023160004 A1 WO 2023160004A1 CN 2022129152 W CN2022129152 W CN 2022129152W WO 2023160004 A1 WO2023160004 A1 WO 2023160004A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkoxy
alkyl
alkylamino
hydrogen
aryl
Prior art date
Application number
PCT/CN2022/129152
Other languages
English (en)
French (fr)
Inventor
张哲峰
张爱琴
杨谋伟
Original Assignee
南京知和医药科技有限公司
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 南京知和医药科技有限公司 filed Critical 南京知和医药科技有限公司
Publication of WO2023160004A1 publication Critical patent/WO2023160004A1/zh

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 System
    • 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 System
    • 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 System
    • 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 System
    • 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

Definitions

  • the present application relates to the technical field of medicines, in particular to a class of condensed ring compounds and their compositions as active ingredients, and the use of such compounds and their compositions for preparing analgesic drugs.
  • Pain is a self-protective reaction caused by tissue damage or potential tissue damage, accompanied by physiological conditions such as emotional anxiety and tension, and is a common symptom or accompanying symptom of many clinical diseases. Pain is divided into acute pain and chronic pain. Acute pain is mainly caused by surgery, severe physical trauma, etc. Chronic pain is usually caused by nociceptive pain, inflammation, neuropathic pain, migraine, etc.
  • Analgesics are a class of drugs that act on the central nervous system and can effectively relieve or eliminate pain without affecting other sensations. They are of great significance in first aid.
  • opioid alkaloids Opioids
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Opioid receptors include the classical mu, delta, kappa and nonclassical nociceptin (NOP) receptors.
  • ⁇ receptor agonists have the strongest analgesic effect, but usually increase addiction and even cause respiratory depression; ⁇ receptor agonists are less addictive, but the analgesic effect is far less than ⁇ receptor agonists; The analgesic effect of receptor agonists is between the two, but it is easy to cause side effects such as hallucinations, mydriasis, and irritability.
  • the current mainstream opioid receptor agonists mainly include morphine, oxycodone, fentanyl, sufentanil, remifentanil, and methadone. Worryingly, the current abuse of opioids has also led researchers to expand into new research directions, but most of them are in the early clinical stage.
  • Antipyretic and analgesic drugs are a class of drugs that can relieve fever and relieve local pain. They exert antipyretic and analgesic effects by inhibiting the synthesis and release of prostaglandins (PGs) in the hypothalamus, and usually have anti-inflammatory effects. These drugs are better for local pain, neuralgia, joint pain, menstrual pain and other dull pain, but less effective for other kinds of pain. At present, the commonly used ones are: aspirin, ibuprofen, voltaren, and chinoli, etc., but the use of such drugs needs to be considered in different situations.
  • PGs prostaglandins
  • Analgesics currently have relatively large side effects. Therefore, the development of high-quality analgesics is still imminent.
  • the invention provides a novel condensed ring compound and its composition.
  • the compound has strong stability and significant analgesic activity, and is suitable for being developed into various dosage forms.
  • the compound provided by the present invention can overcome the deficiencies of the prior art, has high efficacy in vivo, has long-lasting analgesic effect, and has no obvious side effects.
  • the present invention provides a compound of formula I:
  • Y is selected from CH, or N;
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, Carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above-mentioned alkyl , alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by the following One or more groups A are substituted;
  • R4 is selected from
  • T is selected from O, or S;
  • n is selected from 1, 2, or 3;
  • R 5 and R 6 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 5 and R 6 are connected to form a ring ;
  • R 7 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2-8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above - mentioned alkyl , alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl
  • the group and the heteroaryl group can be further optionally substituted by one or more of the following groups A;
  • R 8 and R 9 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 8 and R 9 are connected to form a ring ;
  • R a and R b are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring;
  • R c and R d are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R c and R d are connected to form a ring;
  • X1 is selected from O, or N;
  • R 10 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2-8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above - mentioned alkyl , alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl
  • the group and the heteroaryl group can be further optionally substituted by one or more of the following groups A;
  • R 11 is selected from hydrogen, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl , C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl, heteroaryl can be further optionally substituted by one or more of the following groups A;
  • X 2 and X 3 are each independently selected from O, NH, or S;
  • R 12 and R 13 are each independently selected from hydrogen, Na, K, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, C 2-8 alkenyl, C 2-8 Alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl, or R 12 , R 13 are connected to form a ring; the above-mentioned alkyl, alkane Oxygen, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by one or more of the following hydrogen, halogen, hydroxy, hydroxymethyl, hydroxy Ethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, formalde
  • R 14 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino ;
  • R 15 selected from
  • Z is selected from CH, or N;
  • R 16 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy , C 1-8 alkylamino,
  • R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, methyl Thio, acetyl, methylsulfonyl, ethylsulfonyl;
  • R 18 is selected from C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above carbocyclyl, heterocyclyl, aryl, heteroaryl
  • the group can be further optionally substituted by one or more of the following groups A;
  • Group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, Methanesulfonyl, ethylsulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
  • the compound provided by the present invention has the following structure of formula II:
  • the compound provided by the present invention has the following structure of formula III:
  • the compound provided by the present invention has the structure of the following formula IV:
  • the compound provided by the present invention has the following structure of formula V:
  • Y is selected from CH, or N;
  • R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R 1 is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, cyano, trifluoromethyl , C 1-8 alkyl, C 1-8 alkoxy; more preferably, R 1 is hydrogen .
  • R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde Base, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
  • R2 is selected from F, Cl, hydroxyl, hydroxyethyl, methoxy, cyano, trifluoromethyl, methylsulfonyl.
  • R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde Base, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
  • R3 is selected from hydrogen, or methyl.
  • L is in
  • R 5 and R 6 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 5 and R 6 are connected to form a ring;
  • R 5 and R 6 are each independently selected from hydrogen, or C 1-8 alkyl ;
  • R and R are both hydrogen
  • R 7 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R 7 is C 1 - 8 alkyl
  • R 7 is selected from isopropyl or tert-butyl
  • L is in
  • R 8 and R 9 are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R 8 and R 9 are connected to form a ring;
  • R 8 and R 9 are each independently selected from hydrogen, or C 1-8 alkyl ;
  • R and R are both hydrogen
  • X 1 is selected from O, or N;
  • X 1 is O, at this time R 11 does not exist;
  • R 10 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R 10 is selected from C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino , C 2-8 alkenyl , C 2-8 alkynyl, C 3-8 carbocycle Base, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
  • R 10 is selected from methyl, or isopropyl
  • R 11 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A; in particular, X is N at this time;
  • L is in
  • R a and R b are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring ;
  • R a and R b are each independently selected from hydrogen, or C 1-8 alkyl ;
  • R a and R b are both hydrogen;
  • R c and R d are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring ;
  • R c and R d are each independently selected from hydrogen, or C 1-8 alkyl ;
  • both R a and R b are hydrogen, or one of R a and R b is hydrogen, and the other is methyl;
  • L is in
  • X 2 and X 3 are each independently selected from O, NH, or S;
  • X 2 and X 3 are each independently selected from O, or NH;
  • R 12 and R 13 are each independently selected from hydrogen, Na, K, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino , C 2-8 alkenyl , C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl, or R 12 and R 13 are connected to form a ring; wherein, the above-mentioned alkyl Alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by one or more of the following hydrogen, halogen, hydroxyl, methylol hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl
  • R 12 and R 13 are each independently selected from hydrogen, Na, C 1-8 alkyl, C 6-18 aryl, or R 12 and R 13 are connected to form a 5-6 membered ring;
  • R 16 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or
  • R 4 is in
  • T is selected from O, or S;
  • m is selected from 1, 2, or 3;
  • m is selected from 1, or 2;
  • R 14 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino;
  • R 14 is selected from hydrogen, or C 1-8 alkyl ;
  • R 14 is selected from hydrogen, methyl, or ethyl
  • the above Z is selected from CH, or N;
  • R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, Methylthio, acetyl, methylsulfonyl, ethylsulfonyl;
  • R 17 is selected from hydroxyl, methylthio, isopropoxy, acetyl;
  • R 18 is selected from C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above carbocyclyl, heterocyclyl, aryl, hetero
  • the aryl group can be further optionally substituted by one or more of the following groups A;
  • R 18 is selected from C 5 - 6 carbocyclyl, or C 2 - 5 heterocyclyl; wherein, the above-mentioned carbocyclyl and heterocyclyl can be further optionally replaced by one or more of the following groups A replace;
  • Group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, Methanesulfonyl, ethylsulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
  • the compound provided by the invention has the following structure:
  • the present invention provides compounds comprising the above compounds, or solvates, pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemic mixtures (as active compounds) Component) and the pharmaceutical composition of inert carrier.
  • composition the applicable composition form comprises: injection, powder, spray, inhalant, tablet, pill, capsule, lozenge, jelly, powder, granule, gel, cream, Ointments, patches, suppositories, suspensions, syrups.
  • composition wherein the active ingredient occupies a unit dose of 0.01 mg-1.0 g of the body weight of the individual in need of treatment.
  • the present invention provides the use of the above-mentioned pharmaceutical composition in the preparation of medicines for treating and/or preventing related diseases or conditions.
  • the related diseases or conditions include neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive decline, appetite disturbance, emotional disturbance, sunset syndrome, Alzheimer's disease.
  • a method of treating a disease or condition comprises administering to a subject in need thereof a therapeutically effective amount of said compound or said composition.
  • the compound disclosed in the invention has the function of inhibiting the deposition of ⁇ -amyloid protein.
  • the compound disclosed in the present invention has more significant analgesic effect.
  • the compounds disclosed in the present invention have stronger blood-brain barrier penetration and greater in vivo exposure, especially compound RE-33, which is the most excellent in the above aspects.
  • amino group herein refers to a functional group having 1 nitrogen atom and 0, 1, or 2 hydrogen atoms.
  • the halogen herein refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C1-8 alkyl refers to a straight chain, side chain or cyclic hydrocarbon group having 1 to 8 carbon atoms.
  • C1-8 alkoxy refers to a straight-chain, side-chain or cyclic hydrocarbon group having 1 to 8 carbon atoms inserted into an -OH or -O- group at any reasonable position.
  • C1-8 alkylamino refers to a group in which -N-, -NH-, -NH2 atomic groups are inserted at any reasonable position of "C1-8 alkyl". For example, methylamino, ethylamino, diisopropylamino, N-methyl-n-propylamino, di-n-propylamino, N-ethylisopropylamino, 2-(isopropylamino)ethyl and the like.
  • C2-8 alkenyl refers to a straight chain, branched chain or cyclic hydrocarbon group containing at least one carbon-carbon double bond in a molecule having 2 to 8 carbon atoms.
  • C2-8 alkynyl refers to a straight-chain, branched-chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond in a molecule having 2 to 8 carbon atoms.
  • C3-8 carbocyclyl refers to a saturated or unsaturated alicyclic hydrocarbon group having 3 to 8 carbon atoms.
  • the cyclic hydrocarbon group can be selected from one ring, or polycyclic fused, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, dicyclopentyl, methylcyclohexyl, ethyl Cyclohexyl, decalinyl, 3-cyclopentyl-1-propyl, 1,3-cyclohexadienyl, 1-methyl-1-cyclohexenyl, etc.
  • C2-8 heterocyclic group refers to a saturated or unsaturated monocyclic or polycyclic group with at least one ring containing heteroatoms with 2 to 8 carbon atoms.
  • Each ring of this type of polycyclic heterocycloalkyl group may have Different connection methods, such as fusion, bridging, spiro, etc.
  • pyrrolidinyl piperidinyl, morpholinyl, homopiperazinyl, 4-pyrrolidin-1-yl-piperidinyl, 3-methylpiperidinyl, N-methylpiperidinyl, N-ethyl Piperidinyl, furyl, thienyl, pyrazolyl, oxazolyl, tetrahydro-3-thiol, 4-methyl-1-piperazineethyl, etc.
  • C6-18 aryl refers to a group containing at least one aromatic ring with 6 to 18 carbon atoms.
  • each ring of the polycyclic aryl group can have different connection methods, such as fused , bridging, etc., and the fused rings may be saturated or unsaturated.
  • fused e.g., fused , bridging, etc.
  • the fused rings may be saturated or unsaturated.
  • C3-12 heteroaryl refers to a monocyclic or polycyclic aromatic heterocyclic group with 3 to 12 carbon atoms and containing at least one heteroatom, and each ring of the polycyclic heteroaryl group can have different connections , such as fused, bridged, etc., such as furyl, thienyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, indolyl, pyrazinyl, quinolinyl, pyridazinyl, indenyl, indanyl base, benzofuryl, etc.
  • the double bond-containing compounds of the present invention include all configurational isomers (such as cis and trans isomers).
  • hetero atom in the present invention includes nitrogen atom, oxygen atom, phosphorus atom, boron atom, sulfur atom, selenium atom and the like.
  • the compounds of the present invention possess one or more asymmetric centers and the present invention therefore relates to the use of all optical isomers and stereoisomers of these compounds and mixtures thereof. It also includes the use of compounds with tautomers and their mixtures.
  • the compounds of the present invention contain basic nitrogen atoms (heterocyclic or aliphatic amino groups, etc.), and are easily oxidized by oxidants such as oxygen in the air and hydrogen peroxide to be selected from N-oxides to generate other compounds of the present invention.
  • the converted N-oxide derivatives are therefore part of the group selected from the compounds of the present invention.
  • each instance of a substituent is selected from the available variable definitions independently of other selections to define the variable. Accordingly, each substituent may be the same as or different from the other substituents.
  • Treatment refers to the effect of significantly reversing, alleviating the symptoms of the individual's disease, or causing the reversal of the progress of the disease by administering a drug or a pharmaceutical composition to the individual.
  • “Individuals in need of treatment” in the present invention refer to warm-blooded animals or cold-blooded animals, such as humans, rats, mice, rabbits, dogs, pigs, sheep, chickens, ducks, geese, cats, cows, horses, etc.
  • the “compounds and their salts” mentioned in the present invention refer to the complexes formed by the combination of the compound and the corresponding acid. This property depends on the characteristics of the compound.
  • the addition salt of the compound and the 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, etc.
  • the “compounds and their salts” mentioned in the present invention also refer to the addition salts of the compounds and bases, salts of inorganic bases such as sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts and the like.
  • Salts of organic amines such as diethylamine salts, ethylenediamine salts, meglumine salts, tromethamine salts, arginine salts, lysine salts, histidine salts, piperidine salts, etc.
  • in the present invention refers to substances that help individuals to take or absorb the active substances in the pharmaceutical composition, and will not cause obvious adverse effects on patients or individuals, including glucose, disintegrants, fillers, Flavoring agent, lubricant, fatty acid ester, hydroxymethyl cellulose, stabilizer, emulsifier, colorant, starch, sodium saccharin, cellulose, etc.
  • the "disease or disease” in the present invention refers to neuropathic pain, joint pain, postoperative pain, obstetrical 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 “disease or disease” mentioned in the present invention also includes insomnia, Alzheimer's disease, sunset syndrome, Parkinson's disease, memory loss, inattention, mental retardation, addiction and the like.
  • composition refers to a specific amount of the compound provided by the present invention, or any product obtained directly or indirectly from the specific amount of the compound provided by the present invention.
  • the compounds of the present invention can be used alone or in combination with one or more other drugs for the treatment and prevention of diseases or symptoms described by the compounds of the present invention. Combined use can have more significant curative effect.
  • the compound of the present invention occupies a unit dose of 0.01 mg to 1.0 g, more preferably 0.1 mg to 0.5 g, of the body weight of an individual in need of treatment.
  • Figure 1 shows the results of the analgesic test of the compounds of the present invention and TM.
  • Fig. 2 shows the ⁇ -amyloid deposition inhibitory activity of the compounds of the present invention.
  • Embodiment one the preparation of intermediate E
  • Embodiment two the preparation of compound RE-01
  • intermediate H 2.5g, 0.01mol, 1.0eq
  • dichloromethane 100mL
  • HOBt 1.g, 0.01mol, 1.0eq
  • EDCI 1.9g , 0.01mol, 1.0eq
  • intermediate E stirred at room temperature for 6 hours
  • concentrated under reduced pressure washed with water (2*50mL)
  • Embodiment three the preparation of compound RE-22 and compound RE-23
  • Embodiment four the preparation of compound RE-24
  • Embodiment five the preparation of compound RE-25
  • Embodiment six the preparation of compound RE-28
  • Embodiment seven the synthesis of compound TM
  • Dissolve SM01 (7.5g, 45.28mmol) in a mixed solvent of acetonitrile (45mL) and water (75mL), add triethylamine (13.75g, 135.85mmol), the system exotherms, cool the reaction system to 10°C, add Boc Acetonitrile solution (15 mL) of acid anhydride (14.83 g, 67.93 mmol) was added dropwise, stirred at room temperature for 70 h, and the reaction was detected by TLC.
  • Dissolve IM01 (8.88g, 38.73mmol) in dichloromethane (60mL), add benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 14.69g, 38.73mmol) and N,N-diisopropylethylamine (DIPEA, 13.02g, 100.7mmol), stirred for 0.5h, then added DCM solution (40mL) dissolved in SM02 (10.00g, 63.85mmol), and reacted overnight at room temperature , TLC detected that the reaction was complete.
  • HBTU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • IM03 (6.0 g, 17.16 mmol) was dissolved in dioxane (50 mL), and trifluoroacetic acid (TFA, 9.78 g, 85.82 mmol) was added under ice cooling, stirred overnight, and the reaction was detected by TLC.
  • TFA trifluoroacetic acid
  • reaction solution was concentrated to dryness to obtain a brown oil, namely the crude compound IM04 (6.5 g), which was fed to the next step according to 100% without further treatment.
  • SM03 (8.08g, 29.06mmol) was dissolved in N,N-dimethylformamide (DMF, 70mL), the solution was khaki, and 1H-1,2,3-triazole (4.01g, 58.12mmol ) and cesium carbonate (18.94g, 58.12mmol), the temperature was raised to 40°C, a small amount of gas was released, and cuprous iodide (0.277g, 1.45mmol) was added, the solution gradually turned green, and the temperature rise was not obvious, and the temperature was raised to 70°C, and stirred After 1 h, TLC detected that the reaction was complete.
  • DMF N,N-dimethylformamide
  • IM04 (3.0g, 10.48mmol) was dissolved in dichloromethane (30mL), and IM05 (2.30g, 10.48mmol), DIPEA (6.77g, 52.40mmol), HBTU (3.98g, 10.48mmol) were added successively in an ice bath , start the reaction (as the reaction proceeds, the solution color gradually turns brownish red), the reaction is stirred overnight, and TLC detects that the reaction is complete.
  • Embodiment 8 Preparation of compound RE-31
  • Embodiment 9 Preparation of compound RE-32
  • Embodiment 10 Preparation of compound RE-33
  • Embodiment 11 Preparation of compound RE-37
  • Embodiment 12 Preparation of compound RE-38
  • Embodiment 14 The influence of acetic acid writhing method to measure the pain of mice
  • the concentrations of the above compounds were 0.26mg/mL, 0.33mg/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 ( The molar concentration of each compound is the same).
  • mice Sixty 18-22g female KM mice were divided into 20 groups with 3 mice in each group.
  • the administration group and the TM control group were injected intraperitoneally with 0.4 mL of the newly prepared compound solution, and the model group was injected with the same volume of water for injection intraperitoneally.
  • each mouse was intraperitoneally injected with 0.2 mL of 0.6% glacial acetic acid solution, and at the same time recorded the times of writhing in each mouse within 20 minutes, and calculated the average value. The result is shown in Figure 1.
  • Example 15 ⁇ -amyloid deposition inhibitory activity
  • Accelerated aging mice (SAMP8), 63 males (8 months old at the start of the study), were divided into 9 groups with 7 mice in each group.
  • the non-intervention group drank tap water normally; experimental group 1-experimental group 8 respectively drank tap water containing compounds (RE-01, RE-23, RE-31, RE-32, RE-33, RE-37, RE-45 , RE-47) solution, the dosage is 0.1mg/kg/day.
  • Sections were immunostained with streptavidin-biotin using the VECTASTATIN ABC kit. After incubation in 10% normal goat serum for one hour, the anti- ⁇ -amyloid (A ⁇ ) antibody was diluted 10-fold with PBS and incubated overnight at 4°C. The next day, wash with PBS, incubate with biotinylated anti-rabbit secondary antibody for 1.5 hours, wash with PBS, and incubate with peroxidase-labeled streptavidin for 1.5 hours. Immunoreactions were visualized and samples prepared with DAB.
  • Immunoreactive A ⁇ -like granules in the hippocampus were counted under a microscope. A ⁇ -like immunoreactive granules were observed as brown deposits in the hippocampus. Each individual was counted using one slice.
  • ⁇ -amyloid-like immunoreactivity in the hippocampus was observed in the untreated group of accelerated aging mice (SAMP8).
  • SAMP8 accelerated aging mice
  • SAM8 experimental groups 1 to 8 of accelerated aging mice
  • Embodiment 16 Compound Parallel Artificial Membrane Permeation Model (PAMPA) test disclosed by the present invention
  • the compound was diluted into a 25 ⁇ g/mL solution with a buffer solution with a pH of 7.4; the pig brain lipid extract (PBL) was dissolved in dodecane to form a 20 mg/mL solution as a phospholipid film; Add 4 ⁇ L of PBL solution dropwise on the vinyl fluoride membrane to form a phospholipid membrane simulating the environment in the brain; add 300 ⁇ L/well buffer solution above the phospholipid membrane as an acceptor tube, and add 150 ⁇ L/well of 25 ⁇ g/mL compound to another 96-well plate
  • the solution is used as a donor tube, and each drug has three parallel holes; the two plates are stacked so that the phospholipid membrane can contact the donor solution to form a sandwich structure, and placed in a constant temperature environment at 37°C for 18 hours; the 96-hole filter plate
  • the medium solution was taken out and transferred to a blank 96-well plate, and the OD value was measured at 340 nm.
  • the data show that the compounds disclosed in the present invention have stronger ability to penetrate the blood-brain barrier than the reference compound TM, wherein compounds RE-31, RE-32, RE-33, RE-35, RE-38 and RE-45 pass through the blood-brain barrier
  • the ability is 11 to 16 times that of TM. It shows that the compounds disclosed in the present invention can more advantageously pass through the blood-brain barrier and reach the brain, so as to more effectively play the role of treating brain diseases.
  • mice 12 male SD rats, 180g-220g, were fed adaptively for 3 days before the experiment.
  • Preparation of the test product Weigh the appropriate amount of the test product TM, RE-33, RE-37 and RE-38 respectively, place them in reagent bottles, add an appropriate amount of 0.5% carboxymethyl cellulose solution, and prepare TM, RE-33 , RE-37 and RE-38 concentrations are respectively 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (molar concentration of each compound is the same) of the test solution.
  • Test method Rats were randomly divided into 4 groups, including TM group, RE-33 group, RE-37 group and RE-38 group, with 3 rats in each group. Each animal was given the newly prepared corresponding test solution by gavage respectively. The dosage was 4 mg/kg in TM group, 4.8 mg/kg in RE-33 group, 5.0 mg/kg in RE-37 group and 5.2 mg/kg in RE-38 group. Fast for 16-17 hours before administration, and 4 hours after administration, and water is not allowed during the whole process.
  • Observation of general clinical symptoms During the whole process of the experiment, observe the general state of the experimental animals. The observation contents include: changes in food intake and water intake of rats, changes in body weight, abnormality in coat color, abnormality in behavior and mental state, eye, Whether there are abnormal secretions in the ears, mouth and nose, and whether there is any abnormality in urine and stool. If there is an abnormality, it will be recorded immediately and the cause of the abnormality will be analyzed.
  • the maximum blood drug concentration of the compounds disclosed in the present invention is more than 120%, and the exposure is more than 130% of it, especially RE-33, which is the best in terms of maximum blood drug concentration and in vivo exposure prominent, and there is no abnormality in the observation of general clinical symptoms, indicating that the compounds disclosed in the present invention have higher bioavailability.
  • Embodiment 18 Rat brain tissue distribution experiment
  • mice 12 male SD rats, 180g-220g, were fed adaptively for 3 days before the experiment.
  • Preparation of the test product Weigh the appropriate amount of the test product TM, RE-33, RE-37 and RE-38 respectively, place them in reagent bottles, add an appropriate amount of 0.5% carboxymethyl cellulose solution, and prepare TM, RE-33 , RE-37 and RE-38 concentrations are respectively 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (molar concentration of each compound is the same) of the test solution.
  • Test method Rats were randomly divided into 4 groups, including TM group, RE-33 group, RE-37 group and RE-38 group, with 3 rats in each group. Each animal was given the newly prepared corresponding test solution by gavage respectively. The dosage is 4 mg/kg in TM group, 4.8 mg/kg in RE-33 group, 5.0 mg/kg in RE-37 group and 5.2 mg/kg in RE-38 group; Eat for 4 hours, the whole process can not help water.
  • Sampling and detection Animals in each group were sacrificed 3.0 hours after intragastric administration, the brain tissue was separated, homogenized, and analyzed by LC-MS/MS to detect TM. The results are shown in the table below. The results are shown in Table 3.

Abstract

提供如式I所示的具有镇痛活性的稠环化合物及其制备方法与用途，该化合物具有显著的镇痛活性，可开发为治疗疼痛症状、阿尔茨海默症等多种疾病治疗药物，同时适合开发为多种剂型。

Description

具有镇痛活性的稠环化合物及其制备方法与用途 技术领域
本申请涉及药物技术领域，具体涉及一类稠环化合物以及其作为活性成分的组合物，以及该类化合物及其组合物用于制备治疗镇痛药物的用途。
背景技术
疼痛是一种因组织损伤或潜在的组织损伤产生的一种自我保护性反应，同时伴有情绪不安、紧张等生理情况，是临床多种疾病的常见症状或伴随症状。疼痛分为急性疼痛和慢性疼痛，急性疼痛主要是由手术、身体严重创伤等原因引起；慢性疼痛通常由伤害性疼痛、炎症、神经病理性疼痛偏头痛等原因引起。
镇痛药(Analgesics)是一类作用于中枢神经***，能有效缓解或消除痛觉又不影响其他感觉的药物，在急救中具有重要意义。目前申报上市的镇痛药物主要由阿片生物碱类(Opioids)、非甾体抗炎(Nonsteroidal Anti-inflammatory Drugs，NSAIDs)类等两大类，但阿片受体类药物仍占据主导地位。阿片受体包括经典受体μ、δ、κ和非经典痛敏肽(NOP)受体。μ受体激动剂的镇痛效果最强，但通常会增加瘾性，甚至引起呼吸抑制作用；δ受体激动剂的成瘾性较小，但镇痛效果远不及μ受体激动剂；κ受体激动剂的镇痛效果在两者之间，但容易引起幻觉、瞳孔散大、烦躁不安等副作用。目前主流的阿片受体激动剂主要有***、羟考酮、芬太尼、舒芬太尼、瑞芬太尼、***等。令人担忧的是，目前阿片类药物的滥用也使得研究人员扩展新的研究方向，但大多处于临床早期。解热镇痛药是一类能解热并减轻局部疼痛的药物，通过抑制下丘脑中的***素(PGs)的合成和释放，发挥解热和镇痛作用，通常兼有抗炎作用。 此类药物对局部疼痛、神经痛、关节痛、月经痛等钝痛效果较好，但对其他种类疼痛效果较差。目前临床常用的有：阿司匹林、布洛芬、扶他林和奇诺力等，但是此类药物的使用需分多种情况考虑。
镇痛药目前都有较大的副作用。因此，开发优质的镇痛药仍迫在眉睫。
发明内容
本发明提供了一种新型稠环化合物及其组合物，化合物稳定性强，具有显著的镇痛活性，适合开发为多种剂型。
本发明另一方面提供的化合物可克服现有技术的不足，在生物体内具有较高功效同时，镇痛效果持续时间长，并且没有明显的副作用。
本发明提供一种具有式I的化合物：
Figure PCTCN2022129152-appb-000001
或其溶剂化物、药学上可接受的盐、对映异构体、非对映异构体、以及外消旋混合物；
式I中：
Y选自CH、或N；
R 1、R 2、R 3各自独立地选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯甲基、吡啶甲基、C 1- 8烷基、C 1- 8烷氧基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的烷基、烷氧基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
L选自
Figure PCTCN2022129152-appb-000002
Figure PCTCN2022129152-appb-000003
R 4选自
Figure PCTCN2022129152-appb-000004
T选自O、或S；
m选自1、2、或3；
R 5、R 6各自独立地选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基，或R 5、R 6相连成环；
R 7选自C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
R 8、R 9各自独立地选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基，或R 8、R 9相连成环；
R a、R b各自独立地选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基，或R a、R b相连成环；
R c、R d各自独立地选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基，或R c、R d相连成环；
X 1选自O、或N；
X 1为O时，R 11不存在；
R 10选自C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
R 11选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
X 2、X 3各自独立地选自O、NH、或S；
R 12、R 13各自独立地选自氢、Na、K、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基、或R 12、R 13相连成环；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、甲氧基、乙氧基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯基、苯甲基、吡啶基、吡啶甲基、-(C＝O)OR 16、-(C＝S)NHR 16取代；
R 14选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基；
R 15选自
Figure PCTCN2022129152-appb-000005
Z选自CH、或N；
R 16选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、
Figure PCTCN2022129152-appb-000006
R 17选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氰基、三氟甲基、甲氧基、乙氧基、异丙氧基、甲硫基、乙酰基、甲磺酰基、乙磺酰基；
R 18选自C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
基团A为：氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯基、苯甲基、吡啶基、吡啶甲基、C1-8烷基、C1-8烷氧基、C1-8烷氨基。
本发明提供的化合物，其具有如下式Ⅱ的结构：
Figure PCTCN2022129152-appb-000007
式II中取代基的定义式I所定义的。
本发明提供的化合物，其具有如下式Ⅲ的结构：
Figure PCTCN2022129152-appb-000008
式III中取代基的定义如式I所定义的。
本发明提供的化合物，其具有如下式IV的结构：
Figure PCTCN2022129152-appb-000009
式IV中取代基的定义如式I所定义的。
本发明提供的化合物，其具有如下式V的结构：
Figure PCTCN2022129152-appb-000010
式V中取代基的定义如式I所定义的。
在一些实施方案中，上述式(I)-(V)中，Y选自CH、或N；
在一些实施方案中，上述式(I)-(V)中，R 1选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯甲基、吡啶甲基、C 1- 8烷基、C 1- 8烷氧基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；其中，上述的烷基、烷氧基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
优选地，R 1选自氢、卤素、羟基、羟甲基、氰基、三氟甲基、C 1- 8烷基、C 1- 8烷氧基；更优选的，R 1为氢。
在一些实施方案中，上述式(I)-(V)中，R 2选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯甲基、吡啶甲基、C 1- 8烷基、C 1- 8烷氧基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；其中，上述的烷基、烷氧基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
优选地，R 2选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯甲基、吡啶甲基、C 1- 8烷基、C 1- 8烷氧基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；
更优选地，R 2选自F、Cl、羟基、羟乙基、甲氧基、氰基、三氟甲基、甲磺酰基。
在一些实施方案中，上述式(I)-(V)中，R 3选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯甲基、吡啶甲基、C 1- 8烷基、C 1- 8烷氧基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；其中，上述的烷基、烷氧基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
优选地，R 3选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯甲基、吡啶甲基、C 1- 8烷基、C 1- 8烷氧基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；
更优选地，R 3选自氢、或甲基。
在一些实施方案中，上述式(I)-(Ⅱ)中，L为
Figure PCTCN2022129152-appb-000011
其中，
上述R 5、R 6各自独立地选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基，或R 5、R 6相连成环；
优选地，R 5、R 6各自独立地选自氢、或C 1- 8烷基；
更优选地，R 5和R 6均为氢；
上述R 7选自C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的烷基、烷氧基、烷 胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
优选地，R 7为C 1- 8烷基；
更优选地，R 7选自异丙基、或特丁基；
在一些实施方案中，上述式(I)和/或(Ⅲ)中，L为
Figure PCTCN2022129152-appb-000012
其中，
上述R 8、R 9各自独立地选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基，或R 8、R 9相连成环；
优选地，R 8、R 9各自独立地选自氢、或C 1- 8烷基；
更优选地，R 8和R 9均为氢；
上述X 1选自O、或N；
优选地，X 1为O，此时R 11不存在；
上述R 10选自C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
优选的，R 10选自C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；
更优选地，R 10选自甲基、或异丙基；
上述R 11选自C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；特别的，此时X 1为N；
在一些实施方案中，上述式(I)和/或(Ⅳ)中，L为
Figure PCTCN2022129152-appb-000013
其中，
上述R a、R b各自独立地选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基，或R a、R b相连成环；
优选的，R a、R b各自独立地选自氢、或C 1- 8烷基；
更优选地，R a和R b均为氢；
上述R c、R d各自独立地选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基，或R a、R b相连成环；
优选的，R c、R d各自独立地选自氢、或C 1- 8烷基；
更优选地，R a和R b均为氢、或R a和R b其中一个为氢，另一个为甲基；
上述X 1、R 10、和R 11如上述所定义的；
在一些实施方案中，上述式(I)和/或(Ⅴ)中，L为
Figure PCTCN2022129152-appb-000014
其中，
上述X 2、X 3各自独立地选自O、NH、或S；
优选地，X 2、X 3各自独立地选自O、或NH；
上述R 12、R 13各自独立地选自氢、Na、K、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、C 2- 8烯基、C 2- 8炔基、C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基、或R 12、R 13相连成环；其中，上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、甲氧基、乙氧基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯基、苯甲基、吡啶基、吡啶甲基、-(C＝O)OR 16、-(C＝S)NHR 16取代；
优选地，R 12、R 13各自独立地选自氢、Na、C 1- 8烷基、C 6- 18芳基，或R 12、R 13相连成环；其中，上述的烷基、烷氧基、芳基、可进一步任选地被下列的 一个或多个氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、甲氧基、乙氧基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯基、苯甲基、吡啶基、吡啶甲基、-(C＝O)OR 16、-(C＝S)NHR 16取代；
更优选地，R 12、R 13各自独立地选自氢、Na、C 1- 8烷基、C 6- 18芳基，或R 12、R 13相连成5～6元环；其中，上述烷基可进一步地被-(C＝O)OR 16取代；其中，
上述R 16选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基、或
Figure PCTCN2022129152-appb-000015
在一些实施方案中，上述式(I)-(V)中，R 4为
Figure PCTCN2022129152-appb-000016
其中，
上述T选自O、或S；
上述m选自1、2、或3；
优选地，m选自1、或2；
上述R 14选自氢、C 1- 8烷基、C 1- 8烷氧基、C 1- 8烷胺基；
优选地，R 14选自氢、或C 1- 8烷基；
更优选地，R 14选自氢、甲基、或乙基；
上述R 15为
Figure PCTCN2022129152-appb-000017
其中，
上述Z选自CH、或N；
上述R 17选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氰基、三氟甲基、甲氧基、乙氧基、异丙氧基、甲硫基、乙酰基、甲磺酰基、乙磺酰基；
优选地，R 17选自羟基、甲硫基、异丙氧基、乙酰基；
上述R 18选自C 3- 8碳环基、C 2- 8杂环基、C 6- 18芳基、C 3- 12杂芳基；上述的碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
优选地，R 18选自C 5- 6碳环基、或C 2- 5杂环基；其中，上述的碳环基、杂环基可进一步任选地被下列的一个或多个基团A取代；
基团A为：氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯基、苯甲基、吡啶基、吡啶甲基、C1-8烷基、C1-8烷氧基、C1-8烷氨基。
本发明提供的化合物，其具有以下结构：
Figure PCTCN2022129152-appb-000018
Figure PCTCN2022129152-appb-000019
Figure PCTCN2022129152-appb-000020
Figure PCTCN2022129152-appb-000021
Figure PCTCN2022129152-appb-000022
另一方面，在一些实施方案中，本发明提供了包含上述化合物、或其溶剂化物、药学上可接受的盐、对映异构体、非对映异构体、外消旋混合物(作为活性成分)以及惰性载体的药物组合物。
所述的组合物，可施用的组合物形式包括：注射剂、散剂、喷剂、吸入剂、片剂、丸剂、胶囊、锭剂、胶糖剂、粉剂、颗粒剂、凝胶剂、乳膏剂、软膏剂、贴剂、栓剂、悬浮液、糖浆剂。
所述的组合物，其中的活性成分占有治疗需求的个体体重的0.01mg～1.0g的单位剂量。
在一些实施方案中，本发明提供了上述药物组合物可用于在制备治疗和/或预防相关疾病或病症药物中的用途。
所述的相关疾病或病症包括神经病理性疼痛、口腔疼痛、面部疼痛、内部脏器疼痛、头痛、失眠、认知能力减退、食欲功能紊乱、情绪功能紊乱、日落综合征、阿尔茨海默症。
一种治疗疾病或病症的方法包括将治疗有效量的所述的化合物或所述的 组合物给予有治疗需求的个体。
本发明公开的化合物具有抑制β-淀粉样蛋白沉积作用。
本发明公开的化合物与TM相比，具有更显著的镇痛作用。
本发明公开的化合物与TM相比，具有穿透血脑屏障更强、体内暴露量更大，尤其化合物RE-33，在上述方面表现均最为优异。
本发明中，为使各技术人员更详尽的理解本发明，各术语具有如下定义。
本文中的“氨基”是指具有1个氮原子及0个、1个、至2个氢原子的官能团。
本文中的卤素指氟原子、氯原子、溴原子、或碘原子。
“C1-8烷基”是指碳原子数1～8的直链、侧链或环状的烃基基团。例如甲基、乙基、丙基、异丙基、异丁基、戊基、甲基戊烷基、2-甲基已烷基、异辛烷、环戊基、环己基等。
“C1-8烷氧基”是指碳原子数1～8的直链、侧链或环状的烃基基团在任意合理的位置***-OH、或-O-基团的基团。例如甲氧基、乙氧基、异丙氧基、异丁氧基、叔丁氧基、2-甲氧基丙基、(S)-(+)-1-甲氧基-2-丙基、1-丙氧基-2-丙基、乙二醇单丁基等。
“C1-8烷氨基”是指在“C1-8烷基”任意合理的位置***-N-、-NH-、-NH2原子团的基团。例如甲氨基、乙氨基、二异丙胺基、N-甲基正丙氨基、二正丙氨基、N-乙基异丙氨基、2-(异丙基氨)乙基等。
“C2-8烯基”是指碳原子数2～8的分子中含有至少一个碳碳双键的直链、支链或环状烃基。例如烯丙基、丁烯基、顺-2-戊烯基、反-2-已烯基、3,3-二甲基-1-丁烯基、2,5-二甲-3-己烯基、2,4,4-三甲基-2-戊烯基、顺-2-戊烯基、反-2-已烯基、环己烯基、3-甲基-1-环己烯基等。
“C2-8炔基”是指碳原子数2～8的分子中含有至少一个碳碳三键的直链、支链或环状烃基。例如2-丙炔基、3,3-二甲基-1-丁炔基、环丙乙炔基、2-戊炔基、4-甲基-2-己炔基、甲基異丙基乙炔基、环戊基乙炔基、环己乙炔基、3-环戊基-1-丙炔基、4-辛炔基、丙-1-炔基环丙烷基、1-乙炔基-1-甲基环己烷基等。
“C3-8碳环基”是指碳原子数3～8个的饱和或不饱和脂肪环烃基。其中的环烃基可以选自一个环，或多环稠合的，例如环丙基、环丁基、环戍基、环己基、甲基环戊基、双环戊烷基、甲基环己基、乙基环己基、萘烷基、3-环戊基-1-丙基、1,3-环己二烯基、1-甲基-1-环己烯基等。
“C2-8杂环基”是指碳原子数2～8个的至少一个环含有杂原子的饱和或不饱和单环或多环基团，此类多环杂环烷基的各个环可具有不同的连方式，比如稠合、桥连、螺环等。例如吡咯烷基、哌啶基、吗啉基、高哌嗪基、4-吡咯烷-1-基-哌啶基、3-甲基哌啶基、N-甲基哌啶基、N-乙基哌啶基、呋喃基、噻吩基、吡唑基、噁唑基、四氢-3-硫酚基、4-甲基-1-哌嗪乙基等。
“C6-18芳基”是指碳原子数6～18个的至少含一个芳香环的基团，除了共价基团外，多环芳基的各个环可具有不同的连方式，比如稠合、桥连等，并且稠合的环可以是饱和的或者不饱和的。例如苯基、茚满基、茚基、二苯基甲基、α-四氢萘基等。
“C3-12杂芳基”是指碳原子数3～12个的并且含有至少一个杂原子的单环或多环芳香族杂环基，多环杂芳基的各个环可具有不同的连方式，比如稠合、桥连等，例如呋喃基、噻吩基、咪唑基、惡唑基、吡啶基、嘧啶基、吲哚基、吡嗪基、喹啉基、哒嗪基、茚基、茚满基、苯并呋喃基等。
本发明含有双键的化合物包括所有的构型异构体(如顺式和反式异构体)。
本发明中的“杂原子”包括氮原子、氧原子、磷原子、硼原子、硫原子、硒原子等。
本发明化合物具有一个或多个非对称中心，因此本发明涉及所有这些化合物的光学异构体和立体异构体及它们的混合物的用途。同时包含具有互变异构体的化合物及它们的混合物的用途。
本发明的化合物含有碱性氮原子(杂环或者脂肪氨基等)，易被氧化剂如空气中的氧、过氧化氢氧化选自N-氧化物以生成本发明的其他化合物。因此，转化成的N-氧化物衍生物作选自本发明化合物的一部分。
本发明中的术语“任选地”指具有1个或多个变量，则取代基的每一实例从可用的变量定义中的选择与其他选择定义变量无关。因此，每一取代基可与其他取代基相同或不同。
“治疗”是指通过给予个体药物或者药物组合物达到明显逆转、缓解个体病症症状或引起逆转病症进展的作用。
本发明中的“有治疗需求的个体”是指温血动物或冷血动物，例如人、大鼠、小鼠、兔、狗、猪、羊、鸡、鸭、鹅、猫、牛、马等。
本发明所述的“化合物及其盐”指的是化合物与相应的酸结合成的络合物，此性质取决于化合物的特性，所述的化合物与酸的加成盐，例如无机酸盐如盐酸盐、硫酸盐、氢溴酸盐盐等。有机酸盐如马来酸盐、富马酸盐、乙酸盐、丙酸盐、苹果酸盐、酒石酸盐、丙二酸盐、琥珀酸盐、枸橼酸盐、肉桂酸盐、扁桃酸盐、甲磺酸盐、对甲苯磺酸盐、水杨酸盐等。
本发明所述的“化合物及其盐”同时指的是所述的化合物与碱的加成盐，无机碱的盐如钠盐、钾盐、铵盐、钙盐、镁盐等。有机胺的盐如二乙胺盐、乙二胺盐、葡甲胺盐、氨基丁三醇盐、精氨酸盐、赖氨酸盐、组氨酸盐、哌啶盐等。
本发明所述的“惰性载体”是指有助于个体服用或吸收药物组合物中的活性物质的物质，并且对患者或个体不会造成明显不良影响，包括葡萄糖、崩解剂、填充剂、调味剂、润滑剂、脂肪酸酯、羟甲基纤维素、稳定剂、乳化剂、 着色剂、淀粉﹑糖精钠、纤维素等。
本发明所述的“疾病或病症”是指神经病理性疼痛、关节疼痛、手术后疼痛、产科疼痛、带状疱疹疼痛、痛风、关节退变疼痛、椎间盘源性疼痛、三叉神经痛、顽固性头痛、肿瘤疼痛、心绞痛、特发性胸腹痛、口腔疼痛、面部疼痛、内部器官疼痛等。
本发明所述的“疾病或病症”同时包括失眠、阿尔茨海默症、日落综合征、帕金森氏病、记忆力减退、注意力不集中、智力障碍、成瘾性等。
本发明所述的“组合物”是指包含特定量的本发明提供的化合物，或者由特定量的本发明提供的化合物通过直接或间接手段得到的任何产品。
本发明的化合物可以单独使用或与一种或多种其它药物联合用于治疗、预防本发明的化合物所述的疾病或症状。联合使用可以由更显著的疗效。
本发明的化合物占有治疗需求的个体体重的0.01mg～1.0g的单位剂量，更优地占有治疗需求的个体体重的0.1mg～0.5g的单位剂量。
附图说明
图1表示的是本发明化合物与TM的镇痛试验结果。
图2表示的是本发明化合物β-淀粉样蛋白沉积抑制活性情况。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制性的。下述实施例中所用的实验溶剂或试剂如无特殊说明，均通过商业市场购得。
实施例一：中间体E的制备
Figure PCTCN2022129152-appb-000023
步骤1：中间体B的合成：
将(2S)-2-甲基-2-哌啶羧酸(14.3g，0.1mol，1.0eq)溶解在乙腈(200mL)溶液中，加入三乙胺(30.4g，0.3mol，3.0eq)。冷却反应体系至0～5℃，小心滴入Boc酸酐(21.8g，0.1mol，1.0eq)。加完后体系放置在室温反应15小时。减压除去乙腈，然后将残留物缓慢加入水(250mL)中。乙酸乙酯(2*250mL)萃取，有机相浓缩，柱层析分离得到11.9g中间体B，收率：49％，[M+H] +＝244.10。
步骤2：中间体D的合成：
将中间体B(24.3g，0.1mol，1.0eq)溶于乙酸乙酯(500mL)中，加入HOBt(13.5g，0.1mol，1.0eq)与EDCI(19.1g，0.1mol，1.0eq)，搅拌1小时后加入C(12.7g，0.1mol，1.0eq)。反应室温下搅拌6小时，水洗(2*300mL)，减压浓缩，柱层析分离得15.5g中间体D，收率：44％，[M+H] +＝353.19。
步骤3：中间体E的合成：
将中间体D(3.5g，10mmol，1.0eq)溶于醋酸(60mL)中，加热至100℃，反应3小时。浓缩除去醋酸，残留物溶于DCM(60mL)中，然后加入三氟乙酸(10mL)，继续搅拌3小时，水洗(2*300mL)，减压浓缩，柱层析分离得0.7g中间体E，收率：30％，[M+H] +＝235.11。
实施例二：化合物RE-01的制备
Figure PCTCN2022129152-appb-000024
步骤1：中间体G的合成：
将中间体F(21.7g，0.1mol，1.0eq)溶于四氢呋喃(THF，300mL)中，氮气保护下缓慢加入氢氧化钠(12.0g，0.3mol，3.0eq)与2-溴丙烷(12.3g，0.1mol，1.0eq)，加热至60℃反应3小时，水洗(2*200mL)，有机相用盐酸(2.0M)调节为酸性(pH值为2～3)，减压浓缩，柱层析分离得9.1g中间体G，收率：35％，[M+H] +＝259.16。
步骤2：中间体H的合成：
氮气保护下在三口烧瓶中，加入中间体G(25.9g，0.1mol，1.0eq)，1,4-二氧六环(500mL)与水(50mL)中，缓慢加入环戊基硼酸(11.4g，0.1mol，1.0eq)、二氯[1,1'-二(二苯基膦)二茂铁]钯(7.3g，0.01mol，0.1eq)与碳酸铯(32.6g，0.1mol，1.0eq)，加热至回流反应16小时，降温，盐酸(2.0M)调节pH为3～4，浓缩，加入水(300mL)，乙酸乙酯萃取(2*300mL)，有机相浓缩，柱层析分离得13.6g中间体H，收率：55％，[M+H] +＝249.14。
步骤3：中间体I的合成：
氮气保护下在三口烧瓶中，加入中间体H(2.5g，0.01mol，1.0eq)，溶于二氯甲烷(100mL)中，加入HOBt(1.4g，0.01mol，1.0eq)与EDCI(1.9g，0.01mol，1.0eq)，搅拌1小时后加入中间体E(2.4g，0.01mol，1.0eq)，室温下搅拌6小时，水洗(2*50mL)，减压浓缩，柱层析分离得1.6g中间体I，收率：35％，[M+H] +＝465.09。
步骤4：化合物RE-01的合成：
氮气保护下在三口烧瓶中，加入中间体I(4.6g，0.01mol，1.0eq)，溶于THF(100mL)中，加入钠氢(0.48g，0.02mol，2.0eq)与氯甲基异丁酸酯(1.4g，0.01mol，1.0eq)，室温下搅拌16小时，过滤，减压浓缩，柱层析分离得1.4g化合物RE-01，收率：25％，[M+H] +＝565.13。 1H 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)。
实施例三：化合物RE-22和化合物RE-23的制备
Figure PCTCN2022129152-appb-000025
化合物RE-22的合成：
氮气保护下在三口烧瓶中，加入中间体I(4.6g，0.01mol，1.0eq)，溶于THF(100mL)中，加入钠氢(1.4g，0.02mol，2.0eq)与氯磷酸二异丙酯(2.0g，0.01mol，1.0eq)，室温下搅拌16小时，过滤，加入盐酸(20mL)与水(20mL)，继续反应16小时，浓缩，制备液相分离得0.7g化合物RE-22，收率：12％，[M+H] +＝575.20。 1H 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)。
化合物RE-23的合成：
氮气保护下在三口烧瓶中，加入化合物RE-22(5.7g，0.01mol，1.0eq)，溶于无水THF(100mL)中，加入氯化亚砜(2.4g，0.02mol，2.0eq)，继续搅拌反应1小时，加入甲醇(10mL)与三乙胺(3.0g，0.03mol，3.0eq)，继续反应6小时，过滤，减压浓缩，制备液相分离得0.6g化合物RE-23，收率：10％，[M+H] +＝603.10。 1H 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)。
实施例四：化合物RE-24的制备
Figure PCTCN2022129152-appb-000026
氮气保护下在三口烧瓶中，加入化合物RE-22(5.7g，0.01mol，1.0eq)，溶于丙酮(100mL)与水(10mL)中，加入氢氧化钠(4.0g，0.1mol，10.0eq)，室温下搅拌16小时，过滤，浓缩，所得残留物用丙酮/水重结晶得1.3g化合物RE-24，收率：21％，[M+Na] +＝641.11。 1H 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)。
实施例五：化合物RE-25的制备
Figure PCTCN2022129152-appb-000027
氮气保护下在三口烧瓶中，加入化合物RE-22(5.7g，0.01mol，1.0eq)，溶 于无水THF(100mL)中，加入氯化亚砜(2.4g，0.02mol，2.0eq)，继续搅拌反应1小时，加入苯酚(1.0g，0.01mol，1.0eq)与三乙胺(4.0g，0.04mol，4.0eq)，继续反应6小时，加入L-丙氨酸异丙酯(1.7g，0.01mol，1.0eq)，继续反应6小时，过滤，减压浓缩，制备液相分离得0.8g化合物RE-25，收率：11％，[M+H] +＝764.19。 1H 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)。
实施例六：化合物RE-28的制备
Figure PCTCN2022129152-appb-000028
氮气保护下在三口烧瓶中，加入化合物RE-22(5.7g，0.01mol，1.0eq)，溶于无水THF(100mL)中，加入氯化亚砜(2.4g，0.02mol，2.0eq)，继续搅拌反应1小时，加入乙二醇(0.6g，0.01mol，1.0eq)与三乙胺(4.0g，0.04mol，4.0eq)，继续反应6小时，过滤，减压浓缩，制备液相分离得0.6g化合物RE-28，收率：10％，[M+H] +＝601.12。 1H 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)。
实施例七：化合物TM的合成
Figure PCTCN2022129152-appb-000029
步骤1：化合物IM01的制备
将SM01(7.5g，45.28mmol)溶解在乙腈(45mL)和水(75mL)的混合溶剂中，加入三乙胺(13.75g，135.85mmol)，体系放热，冷却反应体系至10℃，加入Boc酸酐(14.83g，67.93mmol)的乙腈溶液(15mL)，滴毕，室温下搅拌70h，TLC检测反应完毕。
浓缩出大部分乙腈，然后将浓缩残留物倒入2N氢氧化钠水溶液(40mL)中，用乙酸乙酯萃取三次后，水相用2N盐酸水溶液将pH调至1～2，有大量固体析出，过滤得类白色固体16g，将固体放入鼓风干燥中50℃干燥3h，得到类白色固体，即化合物IM01(8.88g)，收率84.78％。[M+H] +＝230.15。
步骤2：化合物IM02的制备
将IM01(8.88g，38.73mmol)溶于二氯甲烷(60mL)中，加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU，14.69g，38.73mmol)和N,N-二异丙基乙胺(DIPEA，13.02g，100.7mmol)，搅拌0.5h，随后加入溶有SM02(10.00g，63.85mmol)的DCM溶液(40mL)，室温反应过夜，TLC检测反 应完毕。
减压浓缩除去溶剂，将反应体系倒入水中，用DCM萃取，合并有机相，无水硫酸钠干燥，浓缩得棕色油状物，柱层析得白色固体，即化合物IM02(7.5g)，收率52.74％。[M+H] +＝368.18。
步骤3：化合物IM03的制备
将IM02(7.00g，19.03mmol)溶于乙酸中，加热至100℃，反应1h，TLC检测反应完毕。
浓缩除去大部分乙酸，后加入DCM稀释，加入碳酸氢钠水溶液中(冰水)，分液，水相用DCM萃取三次后，合并有机相，浓缩得米色泡沫状固体，即化合物IM03(6.0g)，收率90.10％。[M+H] +＝350.15。
步骤4：化合物IM04的制备
将IM03(6.0g，17.16mmol)溶于二氧六环(50mL)中，冰浴下加入三氟乙酸(TFA，9.78g，85.82mmol)，搅拌过夜，TLC检测反应完毕。
将反应液浓缩至干，得到褐色油状物，即化合物IM04粗品(6.5g)，不经进一步处理，按照100％计下一步投料。
步骤5：化合物IM05的制备
将SM03(8.08g，29.06mmol)溶于N,N-二甲基甲酰胺(DMF，70mL)中，溶液呈土黄色，加入1H-1,2,3-三氮唑(4.01g，58.12mmol)和碳酸铯(18.94g，58.12mmol)，升温至40℃，有少量气体放出，加入碘化亚铜(0.277g，1.45mmol)，溶液逐渐变绿，升温不明显，升温至70℃，搅拌1h，TLC检测反应完毕。
将反应液降至室温，倒入水中，用乙酸乙酯(EA)萃取一次，保留水相，水相用柠檬酸调至酸性，用EA萃取两次，有机相用无水硫酸钠干燥，浓缩得到黄褐色油状物，即化合物IM05(13.0g)，收率按100％计。[M+H] +＝220.06。
步骤6：化合物TM的制备
将IM04(3.0g，10.48mmol)溶于二氯甲烷(30mL)中，冰浴中依次加入 IM05(2.30g，10.48mmol)，DIPEA(6.77g，52.40mmol)，HBTU(3.98g，10.48mmol)，开始反应(随着反应进行，溶液颜色逐渐变成棕红色)，反应搅拌过夜，TLC检测反应完毕。
用水和二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥后浓缩得粗品(8.26g)，采用柱层析得化合物TM(1.05g)，收率22.20％。[M+H] +＝451.6。 1HNMR(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)。
实施例八：化合物RE-31的制备
Figure PCTCN2022129152-appb-000030
冰浴下化合物TM(400mg，0.887mmol)用DMF溶解，加入60％氢化钠(70.96mg，1.774mmol)搅拌30分钟后，加入氯甲基异丁酸酯(242.29mg，1.774mmol)，反应半小时，升至室温，反应过夜，TLC检测反应完毕。
用水进行淬灭后，用EA和水进行萃取3次，合并有机相，用无水硫酸钠进行干燥后，用层析法进行分离产物(PE：EA＝2：1)，浓缩后得粉状固体，即化合物RE-31(105mg)，收率21.47％。[M+H] +＝551.14。 1HNMR(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)。
实施例九：化合物RE-32的制备
Figure PCTCN2022129152-appb-000031
冰浴下TM(500mg，1.109mmol)用DMF(5mL)溶解，加入60％氢化钠(88.72mg，2.218mmol)搅拌30分钟后，加入特戊酸氯甲酯(334.03mg，2.218mmol)，反应半小时，TLC检测反应完毕。
后处理：用水进行淬灭后，用EA和水进行萃取3次，合并有机相，用无水硫酸钠进行干燥后，用层析法进行分离产物(PE：EA＝2：1)，浓缩后得化合物RE-32(100mg)产物，收率15.95％。[M+H] +＝565.18。 1HNMR(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)。
实施例十：化合物RE-33的制备
Figure PCTCN2022129152-appb-000032
冰浴下化合物TM(1.1g，2.44mmol)用DMF(5.5mL)溶解，加入60％氢化钠(0.195g，4.88mmol)搅拌30分钟后，加入氯甲基甲基碳酸酯(0.608g，4.88mmol)，反应半小时，升至室温，继续反应5小时，TLC检测，物料反应了大半，用水进行淬灭后，用EA和水进行萃取3次，合并有 机相，用无水硫酸钠进行干燥后，依次经层析分离，制备液相分离，得到产物化合物RE-33(15mg)，收率1.14％。[M+H] +＝539.17。
1HNMR(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)。
实施例十一：化合物RE-37的制备
Figure PCTCN2022129152-appb-000033
氮气保护下在三口烧瓶中，加入化合物TM(2.25g，5.00mmol)，溶于THF(35mL)中，加入60％氢化钠(0.4g，10.0mmol)与氯磷酸二异丙酯(1.0g，5.0mmol)，室温下搅拌20小时，过滤，加入盐酸(10mL)与水(10mL)，继续反应20小时，浓缩，制备液相分离得化合物RE-37(0.43g)，收率：15.4％，[M+H] +＝561.01。
实施例十二：化合物RE-38的制备
Figure PCTCN2022129152-appb-000034
氮气保护下在三口烧瓶中，加入化合物RE-37(1.12g，2.0mmol)，溶于无水THF(20mL)中，加入氯化亚砜(0.472g，4.0mmol)，继续搅拌反 应1小时，加入甲醇(3mL)与三乙胺(0.607g，6.0mmol)，继续反应6小时，过滤，减压浓缩，制备液相分离得化合物RE-38(0.13g)，收率：11.0％，[M+H] +＝589.19。
实施例十三：化合物RE-39的制备
Figure PCTCN2022129152-appb-000035
氮气保护下在三口烧瓶中，加入化合物RE-37(1.12g，2.0mmol)，溶于丙酮(20mL)与水(2mL)中，加入氢氧化钠(0.8g，20mmol)，室温下搅拌18小时，过滤，浓缩，所得残留物用丙酮/水重结晶得化合物RE-39(0.22g)，收率：18.2％，[M+H] +＝605.17。
采用类似的合成方法，通过合理的上保护基，脱保护基制备了下列实施例化合物：
Figure PCTCN2022129152-appb-000036
Figure PCTCN2022129152-appb-000037
Figure PCTCN2022129152-appb-000038
Figure PCTCN2022129152-appb-000039
Figure PCTCN2022129152-appb-000040
实施例十四：醋酸扭体法测定对小鼠疼痛的影响
分别配置化合物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和RE-47的水溶液，备用。上述化合物的浓度分别0.26mg/mL、0.33mg/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和0.36mg/mL(各化合物的摩尔浓度相同)。
60只18-22g雌性KM小鼠，分成20组，每组3只。给药组和TM对照组分别腹腔注射0.4mL新配置的化合物溶液，模型组腹腔注射等体积注射用水。
于给药30min后，每鼠腹腔注射0.6％冰醋酸溶液0.2mL，同时记录各小鼠20min内出现扭体的次数，计算平均值。结果如图1。
结果表明，各给药组和TM对照组的扭体次数均明显少于模型对照组；与TM对照组比较，各给药组的扭体次数也均明显减少，并且化合物RE-19、RE-33、RE-35、RE-37、RE-38和RE-45的扭体次数减少最为显著；综上说明，本发明公开的化合物具有更强的镇痛活性。
实施例十五：β-淀粉样蛋白沉积抑制活性
加速衰老的小鼠(SAMP8)63只，雄性(研究开始时为8个月大)，平均分成9组，每组7只。未干预组正常饮用自来水；实验组1-实验组8分别饮用用自来水溶解的含化合物(RE-01、RE-23、RE-31、RE-32、RE-33、RE-37、RE-45、RE-47)的溶液，给药剂量均为0.1mg/kg/日。给药八周后，取出鼠脑，用Methacarn(甲醇:氯仿:乙酸＝6:3:1)固定，并植入石蜡。然后，使用切片机制备8μm厚的切片。
使用VECTASTATIN ABC试剂盒对切片进行链霉抗生物素蛋白-生物素免疫染色。在10％的正常山羊血清中孵育一小时后，用PBS将抗β-淀粉样蛋白(Aβ)抗体稀释至10倍，并在4℃下孵育过夜。第二天，进行PBS清洗、用生物素化的抗兔二次抗体孵育1.5小时、PBS清洗，并用过氧化物酶标记的链霉抗生物素蛋白孵育1.5小时。用DAB使免疫反应可视化并制备样品。
在显微镜下对海马体中的免疫反应性Aβ样颗粒进行计数。Aβ样免疫反 应性颗粒在海马体中作为棕色沉积物被观察到。每个个体用一切片进行计数。
如图2所示，在加速衰老小鼠(SAMP8)的未干预组中观察到了海马体中的β-淀粉样蛋白样免疫反应性。以0.1mg/kg/日的给药剂量情况下，在加速衰老的小鼠(SAM8)的实验组1-实验组8中，β-淀粉样蛋白样免疫反应性减小。这表明，由于本发明公开的化合物的干预，使β-淀粉样蛋白-免疫反应性颗粒的数量显著减少，所以，本发明公开的化合物能够抑制β-淀粉样蛋白沉积。
实施例十六：本发明公开的化合物平行人工膜渗透模型(PAMPA)试验
化合物用pH为7.4的缓冲液稀释成25μg/mL的溶液；将猪脑脂质提取物(PBL)溶解在十二烷中配成20mg/mL的溶液作为磷脂膜；在96孔滤板的聚氟乙烯膜上滴加4μL PBL溶液以形成模拟脑内环境的磷脂膜；在磷脂膜上方加入300μL/孔缓冲液作为受体管，另一块96孔板中加入150μL/孔的25μg/mL的化合物溶液作为供体管，每个药物平行三个孔；将两块板叠合，使磷脂膜能接触到供体液，形成三明治结构，置于37℃恒温环境中放置18小时；将96孔滤板中溶液取出移至一空白96孔板中，在340nm处测定OD值。平行3次实验。根据文献(Kiyohiko S.,et al.Optimized conditions of bio-mimetic artificial membrane permeation assay[J].Int.J.Pharm.,2001,228,181-188)计算渗透率Pe值。结果见表1。
表1人工膜渗透模型(PAMPA)试验结果
化合物编号 Pe值(*10 -6cm/s) 化合物编号 Pe值(*10 -6cm/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
数据表明，本发明公开的化合物透过血脑屏障能力均强于对照化合物TM，其中化合物RE-31、RE-32、RE-33、RE-35、RE-38和RE-45通过血脑屏障能力是TM的11～16倍。说明本发明公开的化合物能够更有优势的透过血脑屏障到达脑部，从而更有效的发挥治疗脑部疾病的作用。
实施例十七：大鼠体内的药代动力学特征评价
实验动物：12只雄性SD大鼠，180g-220g，适应性饲养3天后进行试验。
供试品配制：分别称取供试品TM、RE-33、RE-37和RE-38适量，分别置于试剂瓶中，加入适量0.5％羧甲基纤维素溶液，配制TM、RE-33、RE-37和RE-38的浓度分别为2.0mg/mL、2.4mg/mL、2.5mg/mL和2.6mg/mL(各化合物的摩尔浓度相同)的供试品溶液。
试验方法：将大鼠随机分为4组，包括TM组、RE-33组、RE-37组和RE-38组，每组3只。每只动物分别灌胃给予新配制的相应供试品溶液。给药剂量为TM组4mg/kg、RE-33组4.8mg/kg、RE-37组5.0mg/kg和RE-38组5.2mg/kg。给药前禁食16-17h，给药后禁食4h，全过程不禁水。口服灌胃给药前0h、给药后0.083h、0.17h、0.33h、0.5h、1h、2h、4h、8h、24h大鼠眼球取静脉采血约300μL。
血样处理及检测：将大鼠静脉血置于含肝素钠的离心管中，并置于冰浴上，静置15分钟后离心(4000rpm，10min)，取血浆适量，-80℃保存待测。结果见表2。
一般临床症状观察：实验全过程中对实验动物进行一般状态观察，观察内容包括：大鼠的进食、进水变化情况，体重变化情况，毛色有无异常，行为和精神状态有无异常，眼、耳、口、鼻有无异常分泌物，大小便有无异常。如出现异常则马上进行记录，并分析出现异常的原因。
表2大鼠体内的药代动力学参数平均值结果
供试品 剂量(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
结果表明，本发明公开化合物与TM相比，最大血药浓度是其120％以上，且暴露量在其130％以上，尤其是RE-33，在最大血药浓度和体内暴露量方面表现的最为突出，且一般临床症状观察现象均无异常，说明本发明公开化合物具有更高的生物利用度。
实施例十八：大鼠脑组织分布实验
实验动物：12只雄性SD大鼠，180g-220g，适应性饲养3天后进行试验。
供试品配制：分别称取供试品TM、RE-33、RE-37和RE-38适量，分别置于试剂瓶中，加入适量0.5％羧甲基纤维素溶液，配制TM、RE-33、RE-37和RE-38的浓度分别为2.0mg/mL、2.4mg/mL、2.5mg/mL和2.6mg/mL(各化合物的摩尔浓度相同)的供试品溶液。
试验方法：将大鼠随机分为4组，包括TM组、RE-33组、RE-37组和RE-38组，每组3只。每只动物分别灌胃给予新配制的相应供试品溶液。给药剂量为TM组4mg/kg、RE-33组4.8mg/kg、RE-37组5.0mg/kg和RE-38组5.2mg/kg；给药前禁食16-17h，给药后禁食4h，全过程不禁水。取样和检测：每组均在灌胃给药后3.0h处死动物，分离脑部组织，经均质化处理后，用LC-MS/MS分析检测TM。结果见下表。结果见表3。
表3大鼠脑组织分布结果
供试品 剂量(mg/kg) 3h脑组织浓度(ng/g)
TM 4.0 1659
RE-33 4.8 4651
RE-37 5.0 3875
RE-38 5.2 3974
结果表明，本发明公开化合物3h的大鼠脑组织中的TM浓度均显著高于TM原型，其中RE-33的脑组织浓度达到TM的3倍以上。
通过以上具体对本专利的具体说明，本领域技术人员可以透彻地理解本本发明的特征，同时，对本发明的改良性结果也落在本申请所附权利要求范围内。

Claims (11)

  1. 具有式I所示的化合物：
    Figure PCTCN2022129152-appb-100001
    或其溶剂化物、药学上可接受的盐、对映异构体、非对映异构体、以及外消旋混合物；
    式I中：
    Y选自CH、或N；
    R 1、R 2、R 3各自独立地选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯甲基、吡啶甲基、C 1-8烷基、C 1-8烷氧基、C 3-8碳环基、C 2-8杂环基、C 6-18芳基、C 3-12杂芳基；上述的烷基、烷氧基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
    L选自
    Figure PCTCN2022129152-appb-100002
    Figure PCTCN2022129152-appb-100003
    R 4选自
    Figure PCTCN2022129152-appb-100004
    T选自O、或S；
    m选自1、2、或3；
    R 5、R 6各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基，或R 5、R 6相连成环；
    R 7选自C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、C 2-8杂环基、C 6-18芳基、C 3-12杂芳基；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
    R 8、R 9各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基，或R 8、R 9相连成环；
    R a、R b各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基，或R a、R b相连成环；
    R c、R d各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基，或R c、R d相连成环；
    X 1选自O、或N；
    X 1为O时，R 11不存在；
    R 10选自C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、C 2-8杂环基、C 6-18芳基、C 3-12杂芳基；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
    R 11选自氢、C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、C 2-8杂环基、C 6-18芳基、C 3-12杂芳基；上述的烷基、烷氧基、烷 胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
    X 2、X 3各自独立地选自O、NH、或S；
    R 12、R 13各自独立地选自氢、Na、K、C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、C 2-8杂环基、C 6-18芳基、C 3-12杂芳基、或R 12、R 13相连成环；上述的烷基、烷氧基、烷胺基、烯基、炔基、碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氨基、硝基、氰基、三氟甲基、甲氧基、乙氧基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯基、苯甲基、吡啶基、吡啶甲基、-(C＝O)OR 16、-(C＝S)NHR 16取代；
    R 14选自氢、C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基；
    R 15选自
    Figure PCTCN2022129152-appb-100005
    Z选自CH、或N；
    R 16选自氢、C 1-8烷基、C 1-8烷氧基、C 1-8烷胺基、
    Figure PCTCN2022129152-appb-100006
    R 17选自氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、氰基、三氟甲基、甲氧基、乙氧基、异丙氧基、甲硫基、乙酰基、甲磺酰基、乙磺酰基；
    R 18选自C 3-8碳环基、C 2-8杂环基、C 6-18芳基、C 3-12杂芳基；上述的碳环基、杂环基、芳基、杂芳基可进一步任选地被下列的一个或多个基团A取代；
    基团A为：氢、卤素、羟基、羟甲基、羟乙基、巯基、巯甲基、巯乙基、 氨基、硝基、氰基、三氟甲基、羧基、乙酰基、甲醛基、甲磺酰基、乙磺酰基、苯基、苯甲基、吡啶基、吡啶甲基、C1-8烷基、C1-8烷氧基、C1-8烷氨基。
  2. 根据权利要求1的化合物，其具有如下式Ⅱ的结构：
    Figure PCTCN2022129152-appb-100007
    式II中取代基的定义如权利要求1式I所定义的。
  3. 根据权利要求1的化合物，其具有如下式Ⅲ的结构：
    Figure PCTCN2022129152-appb-100008
    式III中取代基的定义如权利要求1式I所定义的。
  4. 根据权利要求1的化合物，其具有如下式IV的结构：
    Figure PCTCN2022129152-appb-100009
    式IV中取代基的定义如权利要求1式I所定义的。
  5. 根据权利要求1的化合物，其具有如下式V的结构：
    Figure PCTCN2022129152-appb-100010
    式V中取代基的定义如权利要求1式I所定义的。
  6. 根据权利要求1-5中任一项的化合物，其具有以下结构：
    Figure PCTCN2022129152-appb-100011
    Figure PCTCN2022129152-appb-100012
    Figure PCTCN2022129152-appb-100013
    Figure PCTCN2022129152-appb-100014
  7. 包含如权利要求1-6中任一项所述的化合物、或其溶剂化物、药学上可接受的盐、对映异构体、非对映异构体、外消旋混合物以及惰性载体的药物组合物。
  8. 根据权利要求7所述的组合物，可施用的组合物形式包括：注射剂、散剂、喷剂、吸入剂、片剂、丸剂、胶囊、锭剂、胶糖剂、粉剂、颗粒剂、凝胶剂、乳膏剂、软膏剂、贴剂、栓剂、悬浮液、糖浆剂。
  9. 根据权利要求7所述的组合物，其中的活性成分占有治疗需求的个体体重的0.01mg-1.0g的单位剂量，所述活性成分为权利要求1-6中任一项所述的化合物、或其溶剂化物、药学上可接受的盐、对映异构体、非对映异构体、外消旋混合物。
  10. 权利要求1至6中任一项所述的化合物、或其溶剂化物、药学上可接受的盐、对映异构体、非对映异构体、外消旋混合物，或者权利要求7至9中任一项所述的药物组合物在制备治疗和/或预防相关疾病或病症药物中的用途；其中，所述疾病或病症包括神经病理性疼痛、口腔疼痛、面部疼痛、内部脏器疼痛、头痛、失眠、认知能力减退、食欲功能紊乱、情绪功能紊乱、日落综合征、阿尔茨海默症。
  11. 一种治疗疾病或病症的方法，包括将治疗有效量的权利要求1～6中任一项所述的化合物，或者权利要求7-9中任一项所述的组合物给予有治疗需求的个体；其中，所述疾病或病症包括神经病理性疼痛、口腔疼痛、面部疼痛、内部脏器疼痛、头痛、失眠、认知能力减退、食欲功能紊乱、情绪功能紊乱、日落综合征、阿尔茨海默症。
PCT/CN2022/129152 2022-02-25 2022-11-02 具有镇痛活性的稠环化合物及其制备方法与用途 WO2023160004A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210176037 2022-02-25
CN202210176037.4 2022-02-25

Publications (1)

Publication Number Publication Date
WO2023160004A1 true WO2023160004A1 (zh) 2023-08-31

Family

ID=86647946

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/129152 WO2023160004A1 (zh) 2022-02-25 2022-11-02 具有镇痛活性的稠环化合物及其制备方法与用途

Country Status (2)

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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002028839A1 (en) * 2000-10-06 2002-04-11 Neurogen Corporation Benzimidazole and indole derivatives as crf receptor modulators
CN104334544A (zh) * 2012-06-04 2015-02-04 埃科特莱茵药品有限公司 苯并咪唑脯氨酸衍生物
CN105793258A (zh) * 2013-12-03 2016-07-20 埃科特莱茵药品有限公司 (S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯烷-1-基)(5-甲氧基-2-(2H-1,2,3-***-2-基)苯基)甲酮作为食欲素受体拮抗剂的结晶盐形式
CN105793257A (zh) * 2013-12-03 2016-07-20 埃科特莱茵药品有限公司 (S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯啶-1-基)(5-甲氧基-2-(2H-1,2,3-***-2-基)苯基)甲酮的晶形及其作为食欲素受体拮抗剂的用途
CN105873921A (zh) * 2013-12-04 2016-08-17 埃科特莱茵药品有限公司 苯并咪唑-脯氨酸衍生物的用途
WO2021213923A1 (en) * 2020-04-19 2021-10-28 Idorsia Pharmaceuticals Ltd Medical use of daridorexant

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100173941A1 (en) * 2006-06-09 2010-07-08 Astrazeneca Ab Muscarinic Receptor Agonists that are Effective in the Treatment of Pain, Alzheimer's Disease and Schizophrenia
CN106478502B (zh) * 2015-08-29 2021-04-27 上海翰森生物医药科技有限公司 1,2,3,4-四氢异喹啉衍生物、其制备方法和应用
WO2017043636A1 (ja) * 2015-09-11 2017-03-16 大日本住友製薬株式会社 新規ベンズイミダゾール化合物およびその医薬用途
WO2017171100A1 (en) * 2016-03-31 2017-10-05 Takeda Pharmaceutical Company Limited Heterocyclic compound
CN114349820A (zh) * 2016-06-07 2022-04-15 江苏恒瑞医药股份有限公司 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用
WO2018140648A1 (en) * 2017-01-25 2018-08-02 Eric Jon Jacobsen Pyrrolopyrimidine itk inhibitors for treating inflammation and cancer

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002028839A1 (en) * 2000-10-06 2002-04-11 Neurogen Corporation Benzimidazole and indole derivatives as crf receptor modulators
CN104334544A (zh) * 2012-06-04 2015-02-04 埃科特莱茵药品有限公司 苯并咪唑脯氨酸衍生物
CN105793258A (zh) * 2013-12-03 2016-07-20 埃科特莱茵药品有限公司 (S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯烷-1-基)(5-甲氧基-2-(2H-1,2,3-***-2-基)苯基)甲酮作为食欲素受体拮抗剂的结晶盐形式
CN105793257A (zh) * 2013-12-03 2016-07-20 埃科特莱茵药品有限公司 (S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯啶-1-基)(5-甲氧基-2-(2H-1,2,3-***-2-基)苯基)甲酮的晶形及其作为食欲素受体拮抗剂的用途
CN105873921A (zh) * 2013-12-04 2016-08-17 埃科特莱茵药品有限公司 苯并咪唑-脯氨酸衍生物的用途
WO2021213923A1 (en) * 2020-04-19 2021-10-28 Idorsia Pharmaceuticals Ltd Medical use of daridorexant

Also Published As

Publication number Publication date
CN115925699A (zh) 2023-04-07
CN115925699B (zh) 2023-10-03

Similar Documents

Publication Publication Date Title
US9861627B2 (en) 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5-C]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor
BRPI0805826B1 (pt) compostos espiro-substituídos, composição farmacêutica e uso
WO2014183520A1 (zh) 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用
US11453642B2 (en) Oxygenated amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use
JP6107650B2 (ja) テトラヒドロカルボリン誘導体
JP2021527112A (ja) ニューロキニン−１受容体アンタゴニストとしての化合物およびその使用
JP2020506878A (ja) Ｔｒｅｋ（ｔｗｉｋ関連ｋチャネル）チャネルのアクチベータ
TW201625620A (zh) 作為蛋白去乙醯酶抑制劑及雙蛋白去乙醯酶蛋白激酶抑制劑之雜環氧肟酸及其使用方法
WO2018103626A1 (zh) 一类水溶性别孕烯醇酮衍生物及其用途
JP2004501136A (ja) Ｎｍｄａ受容体の選択的拮抗薬としてのアミジン誘導体
WO2023160004A1 (zh) 具有镇痛活性的稠环化合物及其制备方法与用途
CN110256408B (zh) 一种二芳基吡唑化合物及包含该化合物的组合物及其用途
JP2023535692A (ja) 腸内分解性共薬、その調製及び使用
WO2019233366A1 (zh) 选择性a 2a受体拮抗剂
AU2020240301A1 (en) Crystalline and amorphous forms of N-(5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine and its salts, and preparation methods and therapeutic uses thereof
JP2022517396A (ja) Ｅｇｆｒ阻害剤の塩、結晶形及びその製造方法
US20170007610A1 (en) Novel heterobicyclic compounds as kappa opioid agonists
JPH08504441A (ja) アザノルアダマンタン
WO2019134510A1 (zh) 短肽季铵盐化合物及其用途
ES2672326T3 (es) Analogos de tiazolidinona deuterados como agonistas para el receptor de la hormona folículo estimulante
TW202328073A (zh) Ｅｐ４拮抗劑化合物及其鹽、多晶型及其製備方法和用途
JP2002155080A (ja) ヒドラジド誘導体を有効成分とする医薬

Legal Events

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

Ref document number: 22928266

Country of ref document: EP

Kind code of ref document: A1