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WO2023213198A1 - Utilisation d'un composé cyclique fusionné aromatique en tant qu'activateur de trek-1 et composition pharmaceutique et analgésique le contenant - Google Patents

Utilisation d'un composé cyclique fusionné aromatique en tant qu'activateur de trek-1 et composition pharmaceutique et analgésique le contenant Download PDF

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Publication number
WO2023213198A1
WO2023213198A1 PCT/CN2023/089862 CN2023089862W WO2023213198A1 WO 2023213198 A1 WO2023213198 A1 WO 2023213198A1 CN 2023089862 W CN2023089862 W CN 2023089862W WO 2023213198 A1 WO2023213198 A1 WO 2023213198A1
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pain
saturated
cancer
substituted
partially unsaturated
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PCT/CN2023/089862
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English (en)
Chinese (zh)
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阳怀宇
叶阳亮
李俊男
莫奕青
晏雨茜
梅良和
张乾森
沈菊文
钱林艺
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华东师范大学
苏州阿尔脉生物科技有限公司
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Publication of WO2023213198A1 publication Critical patent/WO2023213198A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically, relates to the use of aromatic fused ring compounds as TREK-1 activators, pharmaceutical compositions containing the same, and analgesics.
  • the clinical drugs used to treat pain mainly include opioid analgesics, nonsteroidal anti-inflammatory drugs, anticonvulsants, depressants and other drugs.
  • Opioids have good analgesic effects, but they have toxic side effects such as addiction and respiratory depression, which can cause great harm.
  • Nonsteroidal anti-inflammatory drugs are less effective and have stronger gastrointestinal and cardiovascular side effects.
  • Pregabalin is a drug used to treat neuropathic pain and herpes zoster. However, the treatment effect is not ideal, and only half of the patients who take the drug get partial relief. Therefore, the development of new drugs with new mechanisms is an urgent need for the treatment of pain.
  • TREK-1 potassium channel belongs to the dual-pore potassium channel family, mediates background potassium current, and participates in regulating neural excitability. After knocking out the gene corresponding to TREK-1, rodents have increased sensitivity to thermal pain and mechanical pain (Alloui et al. EMBO J. 2006, 25:2368-2376). TREK-1 plays an important role in the analgesic pathway of morphine and is not related to morphine's addiction, respiratory depression and constipation (Devarrii et al. Nat Commun. 2013, 4:2941). Therefore, activating TREK-1 channels is a new therapeutic strategy for treating pain such as neuralgia and inflammatory pain, and finding agonists of TREK-1 channels is a new direction for developing new analgesic (reducing and/or eliminating pain) drugs.
  • the inventors conducted in-depth research and found that the aromatic fused ring derivative compound represented by the following formula (I) has TREK-1 potassium ion channel activating activity, which means its analgesic use.
  • the present invention provides the following technical solutions:
  • the present invention provides the use of aromatic fused ring compounds represented by formula (I) or their pharmaceutically acceptable salts, esters, optical isomers, stereoisomers, and metabolites as potassium ion channel TREK-1 agonists,
  • L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from N or CR 4 ,
  • L 9 is selected from chemical bonds, saturated or partially unsaturated C1-6 alkylene groups, saturated or partially unsaturated C3-10 cycloalkylene groups, preferably C1-6 alkylene groups, further preferably methylene and ethylene groups , methylethylene, dimethylethylene, propylene;
  • L 7 is selected from chemical bond, S, O or CH 2 ;
  • Ar is selected from H, halogen, NH 2 , OH, SH, amino, substituted amino, amide, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, substituted or Unsubstituted saturated or partially unsaturated 3-10 membered heterocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-14 membered heteroaryl; here "substituted or unsubstituted”"Substituted” in means optionally substituted by 1-3 halogens, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkoxy or C1-C3 haloalkyl Substituted, cyano group, nitro group, hydroxyl group, amino group, phosphinyl group, sul
  • R 1 is selected from H, -C(O)CH 3 or -S(O) 2 CH 3 ;
  • R 2 is selected from H, halogen, cyano, nitro, hydroxymethyl, hydroxyl, amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy;
  • R 3 is selected from H or -OH
  • R 4 is selected from H, halogen or -NH 2 .
  • the compound has the structure of the following formula (II),
  • Ar, R 1 , R 2 , L 3 , L 4 , L 6 , L 8 and L 9 have the same meanings as described above.
  • the compound has a structure represented by the following formula (III),
  • Ar is selected from the following groups,
  • connection site is at any position on the ring structure that can form a bond.
  • L 8 and L 9 are each independently one of the following divalent groups
  • L 3 is N
  • L 4 is CR 4
  • both L 3 and L 4 are CR 4
  • both L 3 and L 4 are N.
  • the present invention also provides the use of the aromatic fused ring compound represented by formula (I) or its pharmaceutically acceptable salts, esters, optical isomers, stereoisomers, and metabolites for reducing and/or eliminating pain,
  • L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from N or CR 4 ,
  • acyl and sulfonyl preferably C1-6 alkylene, further preferably methylene, ethylene, methylethylene, dimethylethylene, propylene; here "substituted” ” means optionally substituted by 1-3 halogens, C1-C3 alky
  • L 9 is selected from chemical bonds, saturated or partially unsaturated C1-6 alkylene groups, saturated or partially unsaturated C3-10 cycloalkylene groups, preferably C1-6 alkylene groups, further preferably methylene and ethylene groups , methylethylene, dimethylethylene, propylene;
  • L 7 is selected from chemical bond, S, O or CH 2 ;
  • Ar is selected from H, halogen, NH 2 , OH, SH, amino, substituted amino, amide, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, substituted or Unsubstituted saturated or partially unsaturated 3-10 membered heterocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-14 membered heteroaryl; here "substituted or unsubstituted”"Substituted” in means optionally substituted by 1-3 halogens, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkoxy or C1-C3 haloalkyl Substituted, cyano group, nitro group, hydroxyl group, amino group, phosphinyl group, sul
  • R 1 is selected from H, -C(O)CH 3 or -S(O) 2 CH 3 ;
  • R 2 is selected from H, halogen, cyano, nitro, hydroxymethyl, hydroxyl, amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy;
  • R 3 is selected from H or -OH
  • R 4 is selected from H, halogen or -NH 2 .
  • the compound has the structure of the following formula (II),
  • Ar, R 1 , R 2 , L 3 , L 4 , L 6 , L 8 and L 9 have the same meanings as described above.
  • the compound has a structure represented by the following formula (III),
  • Ar is selected from the following groups,
  • L 8 and L 9 are each independently one of the following divalent groups
  • L 3 is N
  • L 4 is CR 4
  • both L 3 and L 4 are CR 4
  • both L 3 and L 4 are N.
  • analgesia Reducing and/or eliminating pain is commonly referred to as analgesia.
  • the analgesic effect of the compounds of the present invention is not limited to activation of the potassium ion channel TREK-1.
  • Preferred embodiments of the present invention when the compound is used to reduce and/or eliminate pain are the same as the preferred embodiments described above.
  • the pain includes chronic pain, acute pain, and cancer pain; wherein the chronic pain includes muscle and soft tissue pain, bone and joint pain, headache, visceral pain, and pathological neuralgia.
  • the muscle and soft tissue pain includes one or more of myofasciitis, tenosynovitis, frozen shoulder, muscle strain pain, fibromyalgia, cold pain, burn pain, and toothache; and/or, the described Bone and joint pain include knee pain, ankle pain, wrist pain, elbow pain, shoulder pain, patellofemoral joint pain, hip joint pain, femoral joint pain, ankylosing spondylitis, sacroiliitis, rheumatoid arthritis inflammation, rheumatoid arthritis, gouty arthritis, disc herniation, cervical pain, One or more types of lumbar pain.
  • Described headache includes primary headache, secondary headache, cranial neuralgia, central and primary facial pain and other headaches; Described primary headache includes migraine without aura, migraine with aura, hemiplegic migraine.
  • the secondary Headaches include headaches due to head and neck trauma, headaches due to non-vascular intracranial diseases, headaches due to substance or substance withdrawal, headaches due to head and neck vascular diseases, headaches due to internal environment disorders, Headache due to mental illness, one or more types of head and facial pain due to lesions of the head, neck, eyes, ears, nose, sinuses, teeth, mouth or other head and face structures;
  • Episodic facial pain and other headaches include one or more of trigeminal neuralgia, glossopharyngeal neuralgia, intermediary neuralgia, occipital
  • the visceral pain includes pain from internal organs, including the respiratory tract, gastrointestinal tract, pancreas, urethra, kidneys, gallbladder, bladder and genitals; and/or the pathological neuralgia includes post-herpetic nerves.
  • the acute pain includes one or more of acute traumatic pain, postoperative pain, labor pain, visceral pain, itching, and post-operative pain.
  • the cancers in cancer pain include adenocarcinoma in glandular tissue, blastoma in organ embryonic tissue, cancer in epithelial tissue, leukemia in blood cell-forming tissue, lymphoma in lymphoid tissue, and bone marrow in bone marrow.
  • tumors sarcomas in connective or supporting tissues
  • adrenal cancer AIDS-related lymphoma
  • bladder cancer bone cancer
  • brain cancer breast cancer
  • carcinoid tumor cervical cancer
  • colon cancer endometrial cancer
  • esophageal cancer gastric cancer , head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma
  • Hodgkin's disease non-Hodgkin's disease
  • nervous system tumors oral cancer, ovarian cancer
  • pancreatic cancer, prostate cancer rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, urinary tract cancer, bone marrow cancer, multiple myeloma, tumors that metastasize to bones, tumors that infiltrate nerves and hollow organs, and tumors near neural structures species or several species.
  • the dosage of the compound of formula (I) is 0.1-50 mg/kg.
  • the invention also provides an aromatic fused ring compound represented by formula (I) or its pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, and metabolite,
  • L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from N or CR 4 ,
  • acyl and sulfonyl preferably C1-6 alkylene, further preferably methylene, ethylene, methylethylene, dimethylethylene, propylene; here "substituted” ” means optionally substituted by 1-3 halogens, C1-C3 alky
  • L 9 is selected from chemical bonds, saturated or partially unsaturated C1-6 alkylene groups, saturated or partially unsaturated C3-10 cycloalkylene groups, preferably C1-6 alkylene groups, further preferably methylene and ethylene groups , methylethylene, dimethylethylene, propylene;
  • L 7 is selected from chemical bond, S, O or CH 2 ;
  • Ar is selected from H, halogen, NH 2 , OH, SH, amino, substituted amino, amide, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, substituted or Unsubstituted saturated or partially unsaturated 3-10 membered heterocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-14 membered heteroaryl; here "substituted or unsubstituted”"Substituted” in means optionally substituted by 1-3 halogens, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkoxy or C1-C3 haloalkyl Substituted, cyano group, nitro group, hydroxyl group, amino group, phosphinyl group, sul
  • R 1 is selected from H, -C(O)CH 3 or -S(O) 2 CH 3 ;
  • R 2 is selected from H, halogen, cyano, nitro, hydroxymethyl, hydroxyl, amino, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy;
  • R 3 is selected from H or -OH;
  • R 4 is selected from H, halogen or -NH 2 .
  • the compound has the structure of the following formula (II),
  • Ar, R 1 , R 2 , L 3 , L 4 , L 6 , L 8 and L 9 have the same meanings as described above.
  • the compound has a structure represented by the following formula (III),
  • Ar is selected from the following groups:
  • connection site is at any position on the ring structure that can form a bond.
  • L 8 and L 9 are each independently one of the following divalent groups
  • L 3 is N
  • L 4 is CR 4
  • both L 3 and L 4 are CR 4
  • both L 3 and L 4 are N.
  • the present invention also provides a pharmaceutical composition, which contains a preventive or therapeutically effective amount of the above-mentioned compound of the present invention or its pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, metabolite, and pharmaceutical
  • the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • the pharmaceutical composition also contains other active ingredients for treating chronic pain.
  • the dosage form of the pharmaceutical composition is an oral dosage form or an injection, and the oral dosage form includes tablets, capsules, films, and granules.
  • the present invention is a method for reducing and/or eliminating pain, comprising administering an effective amount of a compound of the present invention or its pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, Metabolites or the above-mentioned pharmaceutical compositions of the present invention.
  • the compounds of the present invention are structurally original.
  • the compound (I) of the present invention can be used in the preparation of drugs for diseases related to potassium ion channel TREK-1, and can also be used in the preparation of analgesic drugs.
  • alkylene refers to a saturated divalent hydrocarbon radical, preferably a saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • an alkyl group has 1 to 12, such as 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents
  • halogen substitution in this case, the group is called "haloalkyl" (for example, CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5
  • C1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2 -Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenyl group, the compound can be in the form of pure E (enthafen), pure Z (same as Chrysler) (zusammen)) form or any mixture thereof.
  • alkynyl means a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclo, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.)), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclonon
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl or cycloalkyl). hexyl), optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl-substituted cyclopropyl.
  • cycloalkylene As used herein, the terms “cycloalkylene”, “cycloalkyl” and “hydrocarbon ring” refer to having, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6) ring carbons.
  • heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean, for example, 3-10 (suitably 3-8, more suitably 3-6) Ring atoms, in which at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., have one or more double bond and/or triple bond) cyclic group.
  • 3-10 suitably 3-8, more suitably 3-6
  • Ring atoms in which at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., have one or more double bond and/or triple bond) cyclic group.
  • a “3-10 membered (ylidene)heterocycle(yl)” has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N , a saturated or partially unsaturated (sub)heterocyclic ring (base) with one or more (eg 1, 2, 3 or 4) heteroatoms of O and S.
  • heterocyclylene and heterocycl(yl) include, but are not limited to: ()oxirylene, ()aziridinyl, (azetidinyl), (ylidene) Heterocyclobutyl (oxetanyl), (ylidene) tetrahydrofuranyl, (ylidene) dioxolinyl (dioxolinyl), (ylidene) pyrrolidinyl, (ylidene) pyrrolidonyl, (ylidene) imidazolidinyl, (ylidene) )Pyrazolidinyl, (ylidene) pyrrolinyl, (ylidene) tetrahydropyranyl, (ylidene) piperidyl, (ylidene) morpholinyl, (ylidene) dithianyl (dithianyl), (ylidene) Thiomorpholinyl, (ylidene)piperazinyl
  • the groups also encompass bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[5.5]undecan, Heterobicyclo[2.2.2]octane, etc.).
  • Heterocyclylene and heterocycl(yl) groups may be optionally substituted with one or more (eg 1, 2, 3 or 4) suitable substituents.
  • (arylene) and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic radicals having a conjugated pi electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean aromatic groups containing 6 to 10 carbon atoms, such as ()phenylene (Benzene ring) or (phenylene) naphthyl (naphthalene ring).
  • the ()arylene groups and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • heteroarylene and “heteroaryl ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one heteroatom which may be the same or different (the heteroatoms are for example oxygen, nitrogen or sulfur), and, in each case, may additionally be benzo-fused.
  • (ylene)heteroaryl or “heteroaryl ring” is selected from (ylene)thienyl, (ylene)furyl, (ylene)pyrrolyl, (ylene)oxazolyl, (ylene)thiazolyl, (Imidazolyl), (pyrazolylene), (isoxazolyl), (isothiazolylene), (ylidene) oxadiazolyl, (ylidene) triazolyl, (ylidene) thiadiazolyl etc., as well as their benzo derivatives; or (pyridylidene), (pyridylene) pyridazinyl, (pyrimidinyl), (ylidene) pyrazinyl, (ylidene) triazinyl, etc., and their benzo derivatives derivative.
  • aralkyl preferably means an aryl- or heteroaryl-substituted alkyl group, wherein aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group may have 6 to 14 carbon atoms
  • the heteroaryl group may have 5 to 14 ring atoms
  • the alkyl group may have 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • Alkyl refers to a saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms , or a saturated linear or branched chain monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group can be independently optionally substituted by one or more substituents described in the present invention.
  • alkyl groups include, but are not limited to In methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-di Methylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl , 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one CC is sp 2 double bond, in which the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention. Specific examples include, but are not limited to, vinyl, allyl and alkenyl. Dinky and more. Alkenyl groups may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring includes 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called a spiro atom) with each other, and the ring contains 1 or more An aromatic system with double bonds but in which no ring has fully conjugated ⁇ electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is divided into single spiro, double spiro or polyspiral cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to:
  • Condensed cycloalkyl refers to an all-carbon polycyclic group with 5 to 18 members and containing two or more cyclic structures sharing a pair of carbon atoms with each other.
  • One or more rings may contain one or more double bonds.
  • aromatic systems in which none of the rings have fully conjugated ⁇ electrons are preferably 6 to 12 members, and more preferably 7 to 10 members.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl groups.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other.
  • One or more rings may contain one or more Aromatic systems with multiple double bonds but no ring having fully conjugated ⁇ electrons are preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • Non-limiting examples of "bridged cycloalkyl” include, but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetralin base, benzocycloheptyl, etc.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application. They are used interchangeably in this application and all refer to 3-12 A saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group with ring atoms, in which at least one ring atom is a heteroatom, such as oxygen, nitrogen, sulfur atom, etc. Preference is given to a 5- to 7-membered monocyclic ring or a 7 to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocyclyl.
  • Heterocyclyl groups may be optionally substituted or unsubstituted.
  • “Spiroheterocyclyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one atom with each other.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocyclic group.
  • spiroheterocyclyl include, but are not limited to:
  • Condensed heterocyclyl refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to:
  • “Bridged heterocyclyl” refers to a polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two atoms that are not directly connected to each other.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner.
  • aryl includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups may be substituted or unsubstituted.
  • the "aryl” can be fused with a heteroaryl, heterocyclyl or cycloalkyl group, where an aryl ring is attached to the parent structure. Non-limiting examples include, but are not limited to:
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzobis Oxolenyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl,
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring.
  • Non-limiting examples include, but are not limited to:
  • Alkoxy refers to the group (alkyl-O-). Among them, alkyl group is as defined in this article. C 1 -C 6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxy refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate group refers to -C(O)O (alkyl) or (cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present in the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the substituent lists, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Optional substituent substitutions of choice. If the nitrogen of a substituent is described as optionally substituted with one or more of the substituents listed, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected as optional. substitution of substituents.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms are substituted with the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature. or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ) ; Isotopes of chlorine (e.g. 36 Cl); Isotopes of fluorine (e.g.
  • Isotopes of iodine e.g. 123 I and 125 I
  • Isotopes of nitrogen e.g. 13 N and 15 N
  • Isotopes of oxygen e.g. 15 O , 17 O and 18 O
  • isotopes of phosphorus such as 32 P
  • isotopes of sulfur such as 35 S.
  • Certain isotopically labeled compounds of the invention eg, those incorporating radioactive isotopes
  • the radioactive isotopes tritium (i.e. 3H ) and carbon-14 (i.e. 14C) are particularly useful for this purpose because they are easy to incorporate and detect.
  • positron emitting isotopes eg 11 C, 18 F, 15 O and 13 N
  • PTT positron emission tomography
  • Isotopically labeled compounds of the invention may be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using appropriate isotopically labeled reagents in place of the previously employed non-labeled reagents.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O , acetone- d6 or DMSO- d6 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • the term "pediatric patient” as used herein refers to a patient who is under 16 years of age at the time of diagnosis or treatment.
  • the word "child” can also be divided into the following subcategories: newborn (from birth to the first month of life); infant (1 month to 2 years old); child (2 years to 12 years old); adolescent (12 years old) to 21 years of age (up to but not including the 22nd birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Edition. New York: McGrow-Hill, 2002; and Avery MD, 1st LR. Pediatric Medicine, 2nd ed. Baltimore: Williams &Wilkins; 1994.
  • an "effective amount" of a compound refers to an amount sufficient to negatively regulate or agonize TREK-1 potassium channels.
  • a "therapeutically effective dose" of a compound is one sufficient to ameliorate or in some way reduce symptoms, stop or reverse the disease. progression, or the amount of negative regulation or activation of TREK-1 potassium channels. This dose can be taken as a single dose or as part of a regimen to be effective.
  • treatment means to ameliorate or otherwise modify in any manner the symptoms or pathology of a patient's condition, disorder, or disease.
  • amelioration of the symptoms of a particular disease by the use of a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, attributable to or associated with the use of the composition sexual, permanent or temporary.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. part.
  • Diastereomers can be separated into individual diastereomers on the basis of their physical and chemical differences by methods such as chromatography, crystallization, distillation or sublimation.
  • Enantiomers can be converted into diastereomeric mixtures by separation of chiral isomeric mixtures by reaction with a suitable optically active compound, such as a chiral auxiliary agent such as a chiral alcohol or Mosher's acid chloride. , separate diastereomers, and convert individual diastereomers into the corresponding pure enantiomers.
  • a suitable optically active compound such as a chiral auxiliary agent such as a chiral alcohol or Mosher's acid chloride.
  • the intermediates and compounds of the invention may also exist in different tautomeric forms, and all such forms are included within the scope of the invention.
  • racemic mixture A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomers that lacks optical activity.
  • Tautomers or “tautomeric forms” refer to isomers of structures with different energies that can be converted into each other through a low energy barrier.
  • proton tautomers i.e., proton-shifting tautomers
  • tautomers by proton migration such as keto-enol and imine-enamine isomerizations.
  • Valence (valency) tautomers include recombination of bonding electrons.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, the R, S configuration containing an asymmetric center, Double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers or mixtures of enantiomers, diastereomers, or geometric isomers of the compounds of the present invention are within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present invention that are safe and effective when administered to humans or animals. Salts of the compounds can be obtained by using a sufficient amount of base or acid in pure solution or in a suitable inert solution to obtain the corresponding addition salts.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, etc.
  • Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts.
  • the inorganic acids and organic acids include Hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, butadione, Phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, etc. (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).
  • Solid lines may be used in this article solid wedge or virtual wedge Draw the chemical bonds of the compounds of the invention.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, a racemic mixture, etc.).
  • the use of solid or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to demonstrate that the stereoisomers shown exist. When present in a racemic mixture, solid and imaginary wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the present invention are intended to exist as stereoisomers (which includes cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, They exist in the form of geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism, and Composed of mixtures thereof (such as racemic mixtures and pairs of diastereomers).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present invention may exist in free form for therapeutic use, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, clathrates or Prodrugs, upon their administration to a patient in need thereof, can directly or indirectly provide a compound of the invention or a metabolite or residue thereof. Therefore, when reference is made herein to "a compound of the invention", it is also intended to encompass the various derivative forms of the compound described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordination bonds.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphoric acid Salt, hypobenate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmi
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.
  • esters means esters derived from compounds of each general formula herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention). compound).
  • the compounds of the present invention may themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural elements of the crystal lattice of the compounds a polar solvent, in particular such as water, methanol or ethanol.
  • a polar solvent in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides; those skilled in the art will recognize that nitrogen-containing heterocycles are capable of forming N-oxides. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocyclic and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyldioxirane are used to oxidize heterocyclic and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • hydrogen peroxide alkyl Hydroperoxides
  • alkyl Hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the invention ie substances formed in the body upon administration of the compounds of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce metabolites thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity when administered into or onto the body. can be transformed by, for example, hydrolytic cleavage into a compound of the invention having the desired activity. Typically such prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the present invention may be prepared, for example, by using certain moieties known to those skilled in the art as “pro-moiety” (eg as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)) Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming chemically protected forms of the compounds of the invention. This can be accomplished by conventional protecting groups, for example, those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • the protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • Typical compounds of the present invention include but are not limited to the compounds in the table above.
  • the naming of the compounds in the present invention follows systematic naming, or is named using ChemDraw software.
  • the aromatic fused ring compound represented by the general formula 1 of the present invention can be obtained by a known method, for example, synthesized by a known organic synthesis method.
  • An exemplary synthetic route is given below, but those in the art can also obtain it through other known methods.
  • the synthesis method of the compound is briefly explained.
  • the representative synthesis route of the compound of general formula 1 is as follows. It should be noted that here, the synthesis method of the same type of compound as compound 2 in the above table is selected to briefly introduce the synthesis route. .
  • Ar, R 1 , R 2 , L 3 , L 4 , L 6 , L 8 and L 9 are other parallel technical solutions.
  • the synthesis of compounds can be achieved by replacing the corresponding raw materials. L 3 and L 4 are different.
  • the construction method of the fused heterocycle can be realized by known methods.
  • the reagent for alkaline conditions can be selected from organic bases or inorganic bases.
  • the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, bis One or more of lithium trimethylsilylamide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide.
  • the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate and potassium acetate. , one or more of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;
  • the reagent that provides acidic conditions may be one of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a methanol solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid, or variety;
  • the metal catalyst is palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( Pd(dppf)Cl 2 ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bistriphenylphosphine palladium dichloride (Pd(PPh 3 ) One or more of Cl 2 ) and tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 );
  • the ligands are 2-bicyclohexylphosphine-2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (XantPhos), 2- Dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl (DavePhos), one or more of 1,1'-bis(diphenylphosphine)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP) , preferably 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP);
  • the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and lithium aluminum tetrahydride;
  • the oxidizing agent is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmate;
  • the above reaction is preferably carried out in a solvent, and the solvents used are N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • solvents used are N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • compositions and methods of treatment are provided.
  • the present invention provides a pharmaceutical composition, which contains an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, metabolite thereof, and a pharmaceutically acceptable carrier, so
  • the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered with a therapeutic agent and is suitable for contact with humans and/or within the scope of reasonable medical judgment. Tissues from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous glucose and glycerol solutions may also be used as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol etc.
  • the compositions may also, if desired, contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.
  • compositions of the present invention can be administered in suitable dosage forms.
  • the dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, and aqueous suspensions. , injectable solutions, elixirs, syrups.
  • the pharmaceutical composition of the present invention can be used to prevent and/or treat pain disorders.
  • other pain treatment agents such as fluoxetine, opioid analgesics, non-opioid analgesics, etc., can also be used simultaneously.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient include (but are not limited to): one or more of saline, buffer, glucose, water, glycerol, ethanol, powder, etc.
  • the drug formulation should match the mode of administration.
  • the pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, prepared by conventional methods using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions, such as tablets and capsules can be prepared by conventional methods.
  • Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under sterile conditions.
  • the pharmaceutical composition of the present invention can also be made into powder for aerosol inhalation.
  • the dosage of the active ingredient is a therapeutically effective amount, for example, about 1 microgram/kg body weight to about 50 mg/kg body weight per day; preferably, about 5 micrograms/kg body weight to about 10 mg/kg body weight; further preferably, About 10 micrograms/kg body weight - about 5 mg/kg body weight. Additionally, the compounds of the present invention may be used with other therapeutic agents.
  • composition of the present invention can be administered to desired subjects (such as humans and non-human mammals) by conventional means.
  • desired administration methods include (but are not limited to): oral administration, injection, aerosol inhalation, etc.
  • a safe and effective amount of the drug is administered to the mammal, where the safe and effective amount is usually at least about 10 micrograms/kg of body weight, and in most cases no more than about 50 mg/kg of body weight, preferably the dose is about 10 micrograms/kg of body weight to about 20 mg/kg of body weight.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • an "effective amount” of a compound refers to an amount of a compound that, when administered, alleviates to a certain extent one or more symptoms of the condition being treated.
  • an "effective amount” of a compound refers to an amount sufficient to negatively regulate or agonize TREK-1 potassium channels.
  • a “therapeutically effective dose” of a compound refers to an amount sufficient to ameliorate or reduce symptoms in some manner, stop or reverse disease progression, or negatively regulate or agonize TREK-1 potassium channels. This dose can be taken as a single dose or as part of a regimen to be effective.
  • Dosage regimens can be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as the exigencies of the therapeutic situation indicate. It is noted that dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that, for any particular individual, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
  • treatment means to ameliorate or otherwise modify in any manner the symptoms or pathology of a patient's condition, disorder, or disease.
  • aboration of the symptoms of a particular disease by the use of a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, attributable to or associated with the use of the composition sexual, permanent or temporary.
  • “Individual” as used herein includes humans or non-human animals.
  • Exemplary human subjects include human subjects (referred to as patients) suffering from a disease, such as those described herein, or normal subjects.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs , cats, cows, pigs, etc.).
  • compositions of the present invention may also include one or more additional therapeutic or prophylactic agents.
  • the mass spectrum was measured using an LC/MS instrument, and the ionization method was ESI.
  • High performance liquid chromatography model Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150mm, 3.5 ⁇ m); mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); Flow rate: 1.0mL/min; Gradient: 5%A for 1min, increase to 20%A within 4min, increase to 80%A within 8min, 80%A for 2min, back to 5%A within 0.1min; Wavelength: 220nm; Column temperature oven: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the thin layer chromatography (TLC) uses silica gel.
  • the specifications used for plates are 0.2mm-0.3mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm.
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C-30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent used in the reaction, the column chromatography eluent system or the thin layer chromatography developing agent system used to purify the compound include: A: Petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents can also be added Adjust, such as acetic acid or triethylamine, etc.
  • the first step is (1S,2S,3S,5R)-3-(2-bromoethoxy)-5-(7-(((1R,2S)-2-(3,4-difluorophenyl)) ring Propyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2-diol 1b
  • Triphenylphosphine (166 mg, 0.63 mmol) was dispersed in dichloromethane (5 mL), cooled to 0°C in an ice bath, and stirred for 20 minutes. Then bromine (101 mg, 0.63 mmol) was dissolved in dichloromethane (2 mL) and slowly added dropwise to the reaction solution, controlling the temperature change to about 2°C. After the dropping is completed, continue stirring at 0°C for 30 minutes.
  • the reaction solution was cooled to room temperature and concentrated to obtain crude product.
  • Step 4 2-(((3aR,4S,6R,6aS)-6-((6-chloro-2-((cyclopropylmethyl)thio)-5-nitropyrimidin-4-yl)amino )-2,2-dimethyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)ethan-1-ol 2f
  • Step 5 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-((cyclopropylmethyl)thio)pyrimidin-4-yl)amino) -2,2-Dimethyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)ethan-1-ol 2g
  • Step 6 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-((cyclopropylmethyl)thio)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy) Ethyl-1-ol 2h
  • Step 7 2-(((3aR,4S,6R,6aS)-6-(5-((cyclopropylmethyl)thio)-7-(((1R,2S)-2-(3,4 -Difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H -Cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)ethan-1-ol 2j
  • Step 8 (1S,2S,3R,5S)-3-(5-((cyclopropylmethyl)thio)-7-(((1R,2S)-2-(3,4-difluorobenzene) yl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol 2
  • Example 3-11 The compounds of Example 3-11 were synthesized with reference to the synthesis method of Example 2:
  • Step 5 2-(((3aR,4S,6R,6aS)-6-((6-chloro-2-((2-cyclopentylethyl)thio))-5-nitropyrimidine-4-yl )Amino)-2,2-dimethyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)ethan-1-ol 12f
  • Step 6 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-((2-cyclopentylethyl)thio)pyrimidin-4-yl) Amino)-2,2-dimethyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)ethan-1-ol 12g
  • Dissolve compound 12f (0.33g, 0.66mmol) in methanol (5mL), add reduced iron powder (0.37g, 6.62mmol) and acetic acid (1.19g, 19.83mmol) at room temperature, complete the addition, stir at room temperature for 3 hours, and perform TLC It shows that the reaction is complete.
  • Step 7 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-((2-cyclopentylethyl)thio)-3H-[1,2,3]tri Azolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy ) Ethyl-1-ol 12h
  • Step 8 2-(((3aR,4S,6R,6aS)-6-(5-((2-cyclopentylethyl)thio)-7-(((1R,2S)-2-(3) ,4-difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro -4H-Cyclopent[d][1,3]dioxolane-4-yl)oxy)ethan-1-ol 12i
  • the third step is 4,6-dichloro-2-(methylsulfanyl)-5-nitropyrimidine 15d
  • Step 4 N-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro -4H-Cyclopentadiene[d][1,3]dioxolane-4-yl)-6-chloro-2-(methylthio)-5-nitropyrimidine-4-amine 15e
  • Dissolve compound 15e (311 mg, 0.58 mmol) in methanol (2 mL), add iron powder (324 mg, 5.8 mmol) and acetic acid (1.04 g, 17.4 mmol), react at room temperature for 16 hours, TLC detects that the reaction is complete, filter, and collect the mother liquor Add water (10mL) to dilute, extract with ethyl acetate (10mL to the next step.
  • Step 6 3-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro -4H-Cyclopentadiene[d][1,3]dioxolane-4-yl)-7-chloro-5-(methylthio)-3H-[1,2,3]triazolo[ 4,5-d]pyrimidine 15g
  • Step 7 3-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro -4H-Cyclopentadiene[d][1,3]dioxolane-4-yl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl) -5-(Methylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine 15h
  • Step 8 3-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro -4H-Cyclopentadiene[d][1,3]dioxolane-4-yl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl) -5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine 15i
  • Step 9 3-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro -4H-Cyclopentadiene[d][1,3]dioxolane-4-yl)-N 7 -((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl )-N 5 -propyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7-diamine 15j
  • Step 4 2-(4-(((3aR,4S,6R,6aS)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-di Methyltetrahydro-4H-cyclopentadiene[d][1,3])dioxolane-4-yl)amino)-6-chloro-2-(isopentylthio)pyrimidin-5-yl) Ethyl-1-ol 16e
  • Step 5 7-((3aR,4S,6R,6aS)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro -4H-cyclopentadien[d][1,3]dioxolane-4-yl)-4-chloro-2-(isopentylthio)-7H-pyrrolo[2,3-d]pyrimidine 16f
  • Step 6 7-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro -4H-Cyclopentadiene[d][1,3]dioxolane-4-yl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl) -2-(isopentylthio)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 16g
  • Example 17-28 The compounds of Examples 17-28 were synthesized with reference to the synthesis methods of Example 12 and Example 16:
  • 4,6-Dichloro-5-nitro-2-propylthiopyrimidine 30a (1.0g, 3.73mmol) was dissolved in tetrahydrofuran (10mL), and compound 2e (1.37g, 3.73mmol) and N, N were added at room temperature.
  • -Diisopropylethylamine (0.96g, 7.46mmol).
  • TLC TLC detected that the reaction was complete.
  • Step 2 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-di Methyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)-ethanol 30c
  • Step 4 9-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro -4H-Cyclopentadiene[d][1,3]dioxolane-4-yl)-6-chloro-2-(propylthio)-9H-purine 30e
  • Step 5 2-(((3aR,4S,6R,6aS)-6-(6-chloro-2-(propylthio)-9H-purin-9-yl)-2,2-dimethyltetrahydro -4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)-ethanol 30f
  • Step 6 2-(((3aR,4S,6R,6aS)-6-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2 -(propylthio)-9H-purin-9-yl)-2,2-dimethyltetrahydro-4H-cyclopentadien[d][1,3]dioxolane-4-yl) Oxygen)-ethanol 30g
  • Step 7 (1S,2S,3R,5S)-3-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2-(propylthio) (yl)-9H-purin-9-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol 30
  • Step 6 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-propoxypyrimidin-4-yl)amino)-2,2-dimethyl Tetrahydro-4H-cyclopenta[d][1,3]dioxolane-4-yl)oxy)-ethan-1-ol 31g
  • Step 7 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-propoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidine -3-yl)-2,2-dimethyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)-ethan-1-ol 31h
  • Step 8 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5 -Propoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopentadiene[d] [1,3]dioxolane-4-yl)oxy)-eth-1-ol 31i
  • the cDNA of human TREK-1 was subcloned into the pEGFP-N1 expression vector.
  • the constructed plasmid was transfected into CHO-K1 cells using Lipofectamine3000.
  • the cell culture medium used in the experiment was DMEM/F12 and contained 10% FBS and 1% penicillin-streptomycin.
  • the culture conditions were a constant temperature of 37°C and a 5% CO2 gas environment.
  • the detection adopts Whole-Cell Recording whole-cell patch-clamp recording mode.
  • the experiment used HEKA EPC10 amplifier, Sutter Instrument MP-225 microscope operating system, Nikon fluorescence microscope, and Bio-Logic RSC-200 drug delivery system.
  • the glass electrode was drawn with a Sutter Instrument P-97 electrode drawing instrument, and the liquid entry resistance was 3-7M ⁇ .
  • TREK-1 intracellular fluid components include: 140mM KCl, 2mM MgCl 2 , 10mM EGTA, 1mM CaCl 2 , 10mM HEPES, and adjust the pH to 7.3 with KOH; extracellular fluid components include: 150mM NaCl, 5mM KCl, 0.5mM CaCl 2 , 1.2mM MgCl 2 , 10mM HEPES, and adjust the pH to 7.3 with NaOH.
  • the detected current signal is filtered using a low-frequency filter with a frequency of 2kHz, and the sampling frequency is 10kHz.
  • the test concentration of the compound is 1 ⁇ M, 5 ⁇ M or 10 ⁇ M.
  • the specific test concentration is indicated in parentheses.
  • the activation multiple greater than 1 indicates that the compound has TREK-1 agonistic activity. The larger the value, the better the agonistic activity.
  • the compounds of the present invention have significant activating ability on TREK-1 channel and are agonists of TREK-1.
  • Test Example 2 HTRF cAMP method to determine the inhibitory activity of compounds on P2Y12 receptors
  • the detection concentration of the positive control substance Ticagrelor was starting from 10 ⁇ M, 5-fold dilution, 10 concentrations, and 2 replicates.
  • the control substance is 0.2% DMSO.
  • CHO cell culture Use a CHO cell line that stably expresses the P2Y12 receptor (constructed for Beijing Aisiyipu Biotechnology Co., Ltd. and expresses the human P2Y12 gene).
  • the CHO cell line stably expressing P2Y12 was cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg/mL Hygromycin B at a culture temperature of 37°C and a carbon dioxide concentration of 5%.
  • Cell passage Remove the old culture medium and wash once with PBS, then add 1mL TrypLE TM Express solution and incubate at 37°C for about 2 minutes. When the cells detach from the bottom of the dish, add approximately 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect cells for experiments or subculture.
  • the experimental cell fusion was controlled at about 80%.
  • the present invention uses the above examples to illustrate the use of an aromatic fused ring compound as a TREK-1 activator, pharmaceutical compositions and analgesics containing the same, but the present invention is not limited to the above embodiments. Examples do not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent replacement of raw materials of the product of the present invention, addition of auxiliary ingredients, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

La présente invention concerne le composé (I) suivant ou un sel, ester, isomère optique, stéréoisomère ou métabolite pharmaceutiquement acceptable de celui-ci, et une composition pharmaceutique contenant le composé selon la présente invention. L'invention concerne en outre une utilisation du composé selon la présente invention en tant qu'activateur d'un canal ionique potassique TREK-1, et une utilisation dans la réduction et/ou l'élimination de la douleur, et une utilisation du composé selon la présente invention dans la préparation de médicaments analgésiques. La présente invention concerne également une méthode de traitement de maladies associées au canal ionique potassique TREK-1.
PCT/CN2023/089862 2022-05-04 2023-04-21 Utilisation d'un composé cyclique fusionné aromatique en tant qu'activateur de trek-1 et composition pharmaceutique et analgésique le contenant WO2023213198A1 (fr)

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DATABASE Registry 22 December 2021 (2021-12-22), ANONYMOUS: "1,2-Cyclopentanediol, 3-[7-[[(1R,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-iodoethoxy)-, (1S,2S,3R,5S)- (CA INDEX NAME)", XP093105720, retrieved from STNext Database accession no. 2750168-80-8 *
DATABASE Registry 26 June 2020 (2020-06-26), ANONYMOUS: "1,2,3-Cyclopentanetriol, 4-[7-[[(1R)-2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5- d]pyrimidin-3-yl]-, (1S,2S,3R,4R)-rel- (CA INDEX NAME)", XP093105721, retrieved from STNext Database accession no. 2434860-97-4 *
DATABASE Registry. 21 February 2019 (2019-02-21), ANONYMOUS: "1,2-Cyclopentanediol, 3-[7-[[(1R,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(2-propen-1-ylthio)-3H-1,2,3- triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-, (1S,2S,3R,5S)- (CA INDEX NAME)", XP093105722, Database accession no. 2271293-30-0 *
ERIC GOFFIN ET AL.: "Synthesis of Ticagrelor Analogues Belonging to 1,2,3-triazolo[4,5-d]pyrimidines and Study of Their Antiplatelet and Antibacterial Activity", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 208, 23 August 2020 (2020-08-23), XP086345788, DOI: 10.1016/j.ejmech.2020.112767 *
HASSANE SADOU YAYE ET AL.: "Identification of the Major Degradation Pathways of Ticagrelor", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 105, 4 December 2014 (2014-12-04), XP029130906, DOI: 10.1016/j.jpba.2014.11.046 *
ZHONG WANPING, WANG XIPEI, TANG LAN, MAI LIPING, CHEN XIAO-PING, HE GUODONG, ZHENG ZHIJIE, ZHONG SHILONG: "Simultaneous Determination of Ticagrelor and Its Metabolites in Human Plasma and Urine Using Liquid Chromatography–Tandem Mass Spectrometry", JOURNAL OF ANALYTICAL TOXICOLOGY, PRESTON PUBLICATIONS, INC., US, vol. 40, no. 6, 1 July 2016 (2016-07-01), US , pages 445 - 453, XP093105672, ISSN: 0146-4760, DOI: 10.1093/jat/bkw039 *

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