WO2023174138A1 - Composé amide, son procédé de préparation et son utilisation - Google Patents

Composé amide, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2023174138A1
WO2023174138A1 PCT/CN2023/080381 CN2023080381W WO2023174138A1 WO 2023174138 A1 WO2023174138 A1 WO 2023174138A1 CN 2023080381 W CN2023080381 W CN 2023080381W WO 2023174138 A1 WO2023174138 A1 WO 2023174138A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pain
alkyl
reaction
synthesis
Prior art date
Application number
PCT/CN2023/080381
Other languages
English (en)
Chinese (zh)
Inventor
高召兵
胡有洪
魏爱环
郑月明
杨春皓
熊兵
陈笑艳
秦慧
谭村
许海燕
周雷
Original Assignee
中国科学院上海药物研究所
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 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Publication of WO2023174138A1 publication Critical patent/WO2023174138A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • 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
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00

Definitions

  • the present invention relates to the technical field of inhibitor synthesis, and in particular to a class of amide compounds and their preparation methods and uses for treating pain-related diseases related to Nav1.8 target.
  • Pain serves as a protective mechanism that alerts and protects tissue from further injury.
  • the generation of pain is mainly caused by the nociceptors converting the stimulation received into nerve impulses (action potentials) and transmitting them to the nerve center via afferent nerve fibers, causing pain sensation.
  • the generation and conduction of action potentials in neurons depend on the voltage on the cell membrane.
  • Gated sodium channels voltage-gated sodium channels, Nav).
  • Voltage-gated sodium channels mediate the selective transmembrane flow of sodium ions and play a key role in mediating the initiation, conduction, and transmission of action potentials in excitable cells such as neurons (Catterall et al., Pharmacol Rev. 2005 ,57(4):397-409.).
  • Nav channel is an important drug target, and Nav channel inhibitors are used for the treatment of pain, arrhythmia, epilepsy, anesthesia, pruritus and other diseases (Black et al., Neuron. 2013, 80(2):280-91; Catterall et al., Annu Rev Pharmacol Toxicol.2014,54:317-38; Bennett et al., Physiol Rev.2019,99(2):1079-1151.).
  • TTX-R TTX-resistant channels
  • TTX-S TTX-sensitive channels
  • the voltage-gated Nav1.8 channel subtype (TTX-R type) is mainly distributed in the peripheral nervous system, such as 75% of dorsal root neurons expressing Nav1.8 channels. Because the Nav1.8 channel has high activation and inactivation voltages, it becomes the main component of the ascending branch of the action potential (other Nav channel subtypes are already in a non-functional inactivated state) (Goodwin et al., Nat Rev Neurosci. 2021, 22(5):263-274.). Due to the characteristics of slow inactivation and fast reactivation of Nav1.8 channel, it is involved in the physiological and pathological processes of membrane potential depolarization and high-frequency neuron discharge such as pain (Alsaloum et al., Nat Rev Neurol.
  • Nav1.8 gene mutations cause small fiber neuralgia and erythroalgesia (Faber et al., Proc Natl Acad Sci U S A. 2012, 109(47):19444-9; Kaluza et al., Pflugers Arch. 2018,470(12):1787-1801.).
  • genetic knockout or knockdown of the Nav1.8 channel gene can alleviate a variety of inflammatory pain and neuralgia; while giving Nav1.8 channel inhibitors such as A-803467 can effectively alleviate the pain response (Jarvis et al., Proc. Natl Acad Sci U S A. 2007,104(20):8520-5.).
  • Diabetic neuralgia is one of the most common neuropathic pain diseases. About 60% to 70% of diabetic patients suffer from this disease, and more than 70% of patients have not received effective treatment (Jensen et al., Brain. 2021, 144(6) :1632-1645.). Pyruvaldehyde directly enhances Nav1.8 in patients with diabetic neuralgia Channel function, genetic knockout or knockdown of the Nav1.8 channel can effectively alleviate neuralgia (Bierhaus et al., Nat Med. 2012, 18(6):926-33.).
  • intraperitoneal or plantar administration of the Nav1.8 channel inhibitor A-803467 can dose-dependently alleviate the animals' pain behavioral responses (Mert et al., J Am Assoc Lab Anim Sci. 2012, 51 (5):579-85.).
  • Nav1.8 channels have been implicated in diseases such as multiple sclerosis, cardiac arrhythmias, coughing, itching, and epilepsy.
  • Multiple sclerosis is an inflammatory demyelinating disease originating in the central nervous system, and its exact pathogenesis remains to be elucidated.
  • the cerebellar Purkinje fibers of normal people do not express the Nav1.8 channel.
  • the expression of Nav1.8 in the cerebellum of patients with multiple sclerosis is up-regulated, and the expression of the channel increases in a dependent manner with the development of the disease.
  • the single nucleus of the Nav1.8 encoding gene SNPs are also related to the severity of MS (Craner et al., J Neuropathol Exp Neurol.
  • CREB Phosphorylated cAMP response element binding protein
  • Nav1.8 channel is expressed in the cough-related vagus nerve plexus.
  • the phosphorylation level and expression of Nav1.8 increase and participate in the cough reflex (Muroi et al., Lung. 2014, 192(1):15-20. ).
  • histamine and other itch factors released by lymphocytes, mast cells, etc. can activate the Nav1.8 channel.
  • Knocking out Nav1.8 in mice can effectively alleviate the itch behavior induced by histamine and endothelin (Riol -Blanco et al., 2014, 510(7503):157-61.).
  • congenital mutations in human Nav1.8 have been reported to cause epilepsy and convulsive diseases (Kambouris et al., Ann Clin Transl Neurol. 2016, 4(1):26-35.).
  • the Nav1.8 selective inhibitor includes VERTEX's VX-150. This compound has completed Phase II clinical trials in patients with osteoarthritis, acute pain, and pain caused by small fiber neuropathy, and has achieved positive results.
  • the Nav1.8 selective inhibitor that has entered clinical trials in China is Hengrui's HRS-4800, which is currently undergoing Phase I clinical trials; multiple other selective inhibitors are in the preclinical development stage; therefore, the development activity is better and the selectivity is better.
  • Nav1.8 inhibitors with higher efficacy and fewer side effects have important clinical applications and innovative drug value.
  • One of the objects of the present invention is to provide an amide compound with Nav1.8 selective inhibitory activity.
  • the second object of the present invention is to provide a method for preparing amide compounds.
  • the third object of the present invention is to provide a pharmaceutical composition containing the amide compound.
  • the fourth object of the present invention is to provide the use of the amide compound or pharmaceutical composition in preparing Nav1.8 inhibitors or preparing drugs for treating, preventing or controlling diseases or symptoms related to Nav1.8 channels. .
  • One aspect of the invention provides a compound of formula I, its isomer, racemate, prodrug or pharmaceutically acceptable salt thereof,
  • X is selected from N or CH; Y is selected from N or CR 3 ;
  • V and G are each independently selected from N or CH, Q and T are each independently selected from N or C;
  • R a is independently selected at each occurrence from hydrogen, amino, hydroxyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 Alkylamino, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, S, C6-C12 aryl or 1 selected from N, O, S 5-10 membered heteroaryl groups with 4 heteroatoms;
  • R b at each occurrence is independently selected from hydrogen, halogen, nitro, amino, cyano, hydroxyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1- C6 alkoxy, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, S, C6-C12 aryl or containing selected 5-10 membered heteroaryl group with 1 to 4 heteroatoms from N, O, and S;
  • n is selected from 0, 1 or 2; especially 2;
  • R 1 is selected from hydrogen, hydroxyl, halogen, cyano, nitro or amino; preferably hydrogen, fluorine, chlorine, bromine, amino or hydroxyl;
  • R 2 is selected from halogen, hydroxyl, cyano, nitro or halogenated C1-C6 alkyl; preferably chlorine, bromine, iodine, trifluoromethyl;
  • R 3 is selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 alkenyloxy, halogenated C2-C6 alkenyloxy, C2-C6 alkynyl, halogenated C1-C6 alkynyl, C2-C6 alkynyloxy, halogenated C1-C6 alkynyloxy, C1-C6 alkoxy, halogenated C1-C6 alkane Oxygen, C1-C6 alkylamino, halogenated C1-C6 alkylamino, C3-C6 cycloalkylamino, C1-C6 alkoxyamino, C3-C6 cycloalkyl, C3-C6 cycloalkoxy or containing selected from N , 3-8 membered heterocycl
  • R 6 and R 7 are each independently selected from hydrogen, fluorine, chlorine, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy; preferably each is independently hydrogen , fluorine, chlorine, methyl, ethyl or isopropyl;
  • R 5 , R 8 and R 9 are each independently selected from hydrogen, fluorine, chlorine, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy, C3-C8 cycloalkyl; preferably each independently hydrogen, methyl, ethyl, isopropyl or cyclopropyl;
  • the compound of Formula I is selected from the following compounds of Formula II:
  • R 3 , A, Z, W, Q, T, V and G are the same as mentioned above.
  • the compound of formula I is selected from the following compounds:
  • Halogen can be fluorine, chlorine, bromine or iodine.
  • C1-C6 alkyl refers to a chain alkyl group with 1-6 carbon atoms; specific examples thereof may include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl , isobutyl, tert-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1 -Methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl and similar groups; "haloalkyl” means A group obtained by substituting at least one hydrogen of the alkyl group with a halogen as described above; specific examples thereof include trifluoromethyl and the like.
  • C2-C6 alkenyl refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond; specific examples thereof may include vinyl, propenyl, 2-propenyl, (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl, 2,3-Dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (E)-2-pentenyl, (Z)-2- Hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2-hexenyl, (Z)-3-hexenyl, (E)-3- Hexenyl, (E)-1,3-hexadienyl, 4-methyl-3-pentenyl or norbornene.
  • C2-C6 alkynyl refers to a linear or branched chain containing 2-6 carbon atoms and at least one carbon-carbon double bond; specific examples thereof may include ethynyl, 1-propynyl, 2- Proparnyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl.
  • C1-C6 alkoxy refers to an RO- group, wherein R is a C1-C6 alkyl group as described above; specific examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropyl Oxygen, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methyl Pentyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, etc.
  • Hydroalkoxy refers to a group in which at least one hydrogen of the alkoxy group as described above is substituted by a halogen; specific examples thereof include trifluoromethoxy and the like.
  • C2-C6 alkenyloxy refers to an RO- group, where R is a C2-C6 alkenyl group as described above; specific examples of alkenyloxy include vinyloxy and propyleneoxy.
  • C2-C6 alkynyloxy refers to an RO- group, where R is a C2-C6 alkynyl group as described above; specific examples of the alkynyloxy group include ethynyloxy and propynyloxy.
  • Amino refers to -NH2 .
  • C1-C6 alkylamino refers to a group obtained by replacing one or two hydrogens of -NH2 with C1-C6 alkyl as mentioned above, which can be expressed as R 1 R 2 N-, where R 1 and R 2 is each independently H or C1-C6 alkyl, and R 1 and R 2 are at most one One is H.
  • C1-C6 alkylamino groups include methylamino group, dimethylamino group, ethylamine group, n-propylamine group, isopropylamine group, n-butylamine group, isobutylamine group, tert-butylamine group, sec-butylamine group, n-pentylamine group Amino, isopentylamine, neopentylamine, n-hexylamine, isohexylamine, 3-methylpentylamine, 3,3-dimethylbutylamine, 2-ethylbutylamine, etc.
  • C1-C6 alkoxyamino group refers to a group in which two hydrogens of -NH2 are respectively substituted by C1-C6 alkyl group and oxygen as described above; specific examples of C1-C6 alkoxyamino groups include methoxyamine base, dimethoxyamine group, ethoxyamine group, n-propoxyamine group, isopropoxyamine group.
  • C3-C8 cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group containing 3-8 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C3-C6 cycloalkylamino refers to a group obtained by replacing one or two hydrogens of -NH 2 with a C3-C6 cycloalkyl group as described above, which can be expressed as R 1 R 2 N-, where R 1 and R 2 are each independently H or C3-C6 cycloalkyl, and at most one of R 1 and R 2 is H.
  • Specific examples of the C3-C6 cycloalkylamino group include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, and the like.
  • 3-8-membered heterocyclyl refers to a 3-8-membered non-aromatic cyclic alkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur on the ring; specific examples thereof include piperazine, piperidine, and morpholine wait.
  • C6-C12 aryl refers to a monocyclic or polycyclic aryl group having 6 to 12 carbon atoms; specific examples thereof include phenyl and naphthyl.
  • 5-10-membered heteroaryl refers to a 5-10-membered aromatic group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur on the ring; specific examples include pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazine-3 -base, indolyl base, isoindolyl base, etc.
  • “Pharmaceutically acceptable salts” include salts formed by the compound of formula I with acids or bases; the acids include inorganic acids and organic acids; preferably, the inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, Sulfuric acid, nitric acid, phosphoric acid, carbonic acid; preferably, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citron Acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, pamoic acid; the base includes sodium, potassium, calcium, aluminum, lithium and ammonium hydroxides , carbonate, bicarbonate, etc.
  • the compounds involved in this application and their pharmaceutically acceptable salts may have isomers or racemates, such as optical isomers (including diastereomers and enantiomers), atropisomers , geometric isomers (cis-trans isomers), conformational isomers, tautomers and their mixtures, etc., but are not limited to these. These isomers are also included in the scope defined by the claims of the present invention.
  • the present invention provides a preparation method of the above-mentioned compound of formula I, which method is realized through the following reaction route:
  • the base is selected from pyridine, sodium carbonate, and sodium bicarbonate.
  • compositions which includes one or more selected from the group consisting of a compound of formula I and its isomers, racemates, pharmaceutically acceptable salts and prodrugs, and optionally of pharmaceutically acceptable excipients.
  • Another aspect of the present invention provides compounds of formula I or their isomers, racemates, pharmaceutically acceptable salts, and prodrugs for preparing Nav1.8 inhibitors or for treating, preventing, or controlling Nav1.8 channels. Use of medicines related to diseases or conditions.
  • Yet another aspect of the present invention provides a method for treating, preventing or controlling diseases or symptoms associated with Nav1.8, the method comprising administering to a subject in need thereof a compound selected from the group consisting of a compound of formula I, an isomer thereof, and an antibiotic.
  • a compound selected from the group consisting of a compound of formula I, an isomer thereof, and an antibiotic comprising administering to a subject in need thereof a compound selected from the group consisting of a compound of formula I, an isomer thereof, and an antibiotic.
  • spinners, pharmaceutically acceptable salts and prodrugs, or the above pharmaceutical compositions are examples of spinners, pharmaceutically acceptable salts and prodrugs, or the above pharmaceutical compositions.
  • the diseases or symptoms related to the Nav1.8 channel include but are not limited to nociceptive pain, inflammatory pain, neuropathic pain, functional pain, muscle or bone injury-related pain, pelvic pain, abdominal pain, chest pain, lumbosacral pain Neuralgia, preoperative pain, interoperative pain, postoperative pain, acute or chronic pain, migraine, trigeminal neuralgia, pancreatitis, renal colic, cancer pain, pain due to chemical or drug therapy, diabetic neuralgia, band Postherpetic neuralgia, back pain, phantom limb pain, sciatica, small fiber neuralgia, erythromelalgia, arthritis, pruritus, acute or chronic pruritus, asthma, multiple sclerosis, cardiac arrhythmias, atrial fibrillation , heart failure, Brugada syndrome, kidney stones, epilepsy, convulsions.
  • the amide compound of the structure of the present invention has Nav1.8 selective inhibitory activity and can be used as a Nav1.8 selective inhibitor. It has better activity, higher selectivity and fewer side effects, and can be used to treat, prevent or control problems with Nav1. .8 channel involvement or dysfunction-related diseases have important clinical application value.
  • the raw materials, reagents, methods, etc. used in the examples are all conventional raw materials, reagents, and methods in this field.
  • reagents represented by chemical formulas or English abbreviations are as follows: °C represents degrees Celsius; g represents grams; s represents singlet, d represents doublet, t represents triplet, m represents multiplet; min represents minutes; ml represents milliliter; mmol stands for millimoles; h stands for hours; TLC stands for thin layer chromatography.
  • Thin layer chromatography uses GF254 high-efficiency plates, produced by Yantai Chemical Industry Research Institute.
  • the organic solvent was evaporated under reduced pressure in a rotary evaporator.
  • intermediate 1-6 was replaced with intermediate 5-4 to obtain intermediate 5-5.
  • TFA trifluoroacetic acid
  • step 9 of Example 1 intermediate 1-6 was replaced with 4-aminophthalic hydrazide (purchased by Leyan) to obtain compound 10 (8.0 mg, 22.5%).
  • 1 H NMR 400MHz, MeOD
  • ⁇ 8.60 s, 1H
  • 7.76 s, 1H
  • intermediate 1-6 was replaced with compound 11-1 to obtain intermediate 11-2 (0.48g, 69.1%).
  • 1 H NMR 400MHz, DMSO
  • ⁇ 10.77(s,1H),8.20–8.16(m,1H),7.94(s,1H),7.79(s,1H),7.55(t,J 9.1Hz,1H ),3.60(m,2H),3.40–3.35(m,2H),2.44(s,3H),2.25-2.35(m,2H),1.91-1.98(m,2H),1.80-1.87(m,2H ).
  • Compound 13-1 (0.5g, 1.72mmol) was dissolved in anhydrous dichloromethane (40ml) and placed in an ice bath. Add oxalyl chloride (0.18ml, 2.1mmol) dropwise under nitrogen protection, and add a catalytic amount of DMF. React in an ice bath for about 2 hours. Spin the reaction liquid directly to dryness to obtain a crude product and place it in a reaction bottle; Add 5-amino-2-fluorobenzonitrile to the reaction bottle, and add anhydrous pyridine (5ml) dropwise under nitrogen protection and ice bath conditions. After 2 hours, TLC detects that the reaction is basically complete. Extract with EA and water.
  • intermediate 13-3 was replaced with 14-1 to obtain intermediate 14-2 (0.06g, 64%).
  • intermediate 11-1 was replaced with 4-amino-2 fluorobenzonitrile (purchased by Bid) to obtain intermediate 15-1.
  • step (2) of Example 11 intermediate 11-2 was replaced with intermediate 15-1 to obtain compound 15.
  • step (1) of Example 11 intermediate 11-1 was replaced with intermediate 17-2 to obtain intermediate 17-3 (0.11g, 29.6%).
  • intermediate 11-1 was replaced with intermediate 6-amino-2-chlorocyanopyridine to obtain intermediate 19-1.
  • 1 H NMR 400MHz, DMSO
  • step (2) of Example 11 intermediate 11-2 was replaced with intermediate 19-1 to obtain compound 19.
  • step (9) of Example 1 intermediate 1-6 was replaced with intermediate 21-5 to obtain compound 21.
  • intermediate 1-6 was replaced with intermediate 26-3 to obtain intermediate 26-4.
  • Detection method whole-cell manual patch-clamp technique to detect the effect of compounds on voltage-gated Nav1.8 channel current
  • Negative control electrophysiology extracellular fluid containing 0.5% DMSO
  • VX-150 is the positive control drug
  • Test compound Weigh a certain mass of the compound and dissolve it in DMSO to prepare a 20mM DMSO stock solution. On the day of the test, dilute the 20mM compound stock solution with extracellular fluid to the final concentration to be detected, ensuring that the DMSO content in the test drug solution does not exceed 0.5%. This concentration of DMSO has no effect on the detected Nav1.8 channel current.
  • the gradient dilution method is as follows: first add 5 ⁇ L of DMSO stock solution to 10 mL of extracellular fluid, dissolve evenly, and obtain a 10 ⁇ M compound solution; then take 1 mL of 10 ⁇ M compound and add it to 9 mL of cells. Dissolve evenly in the extracellular fluid to obtain a 1 ⁇ M compound solution; then absorb 1 mL of the 1 ⁇ M compound, add it to 9 mL of extracellular fluid, and dissolve evenly to obtain a 100 nM compound solution.
  • Nav1.8 cell line HEK293 (Flp-In T-Rex-293) cells stably expressing human Nav1.8 sodium channel.
  • the encoding gene information is as follows: NM_001293306.2.
  • the whole-cell voltage clamp recording experiment uses Axon patch 700B patch clamp amplifier (Molecular Devices Company), the digital-to-analog converter is Digidata 1440A (Molecular Devices Company), and the glass microelectrode is made of glass electrode blank (World Precision Instruments Company) It is drawn by a drawing instrument (P97, Sutter Company). The tip resistance after filling the electrode internal liquid is about 1.5-2.5 M ⁇ .
  • the glass microelectrode can be connected to the patch clamp amplifier by inserting it into the amplifier probe.
  • the clamping voltage and data recording were controlled and recorded via computer by pClamp 10 software (Molecular Devices), with a sampling frequency of 20kHz and a filtering frequency of 2kHz.
  • Extracellular fluid formula 140mM NaCl, 3mM KCl, 1mM CaCl 2 , 1mM MgCl 2 , 10mM HEPES and 20mM glucose, adjust pH to 7.3 with NaOH.
  • Intracellular solution formula 140mM CsF, 10mM NaCl, 10mM HEPES, 1.1mM EGTA and 20mM glucose, adjust pH to 7.3 with CsOH.
  • HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid);
  • EGTA ethylene glycol Alcohol bis(2-aminoethyl ether)tetraacetic acid; all drugs were purchased from Sigma.
  • Electrophysiological stimulation plan After obtaining whole-cell recording, wait 4-5 minutes under a clamp voltage of -80mV until the fluid in the electrode and the intracellular fluid are balanced, and then start electrophysiological recording (to achieve high-impedance G ⁇ sealing conditions ).
  • Current stimulation and compound activity detection protocol Cells were clamped at -80mV, given a 20ms, +10mV depolarizing voltage stimulus, and then repolarized to -80mV, with a stimulation frequency of 0.5Hz. After confirming that the Nav1.8 sodium channel current is stable (about 1 minute), start the administration process until the cell current no longer changes (compound inhibition reaches steady state). Compounds were tested on at least 3 cells per concentration (n ⁇ 3). After all tested compounds, a single concentration of 100nM VX-150 was given as a positive control.
  • Inhibition rate (%) [1-the magnitude of the current after adding the drug (I Drug )/the magnitude of the current before adding the drug (I Control )] ⁇ 100.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)

Abstract

L'invention concerne un composé amide tel que représenté par la formule I, son procédé de préparation et son utilisation. Le composé amide selon l'invention a une activité inhibitrice sélective sur Nav1.8 et peut être utilisé en tant qu'inhibiteur sélectif pour Nav1.8. Le composé présente une meilleure activité, une sélectivité plus élevée et moins d'effets secondaires. Le composé peut être utilisé pour traiter, prévenir ou lutter contre des maladies associées à une implication ou un dysfonctionnement de canal Nav1.8, et a une valeur d'application clinique significative.
PCT/CN2023/080381 2022-03-17 2023-03-09 Composé amide, son procédé de préparation et son utilisation WO2023174138A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210267217.3A CN116789644A (zh) 2022-03-17 2022-03-17 酰胺类化合物及其制备方法和用途
CN202210267217.3 2022-03-17

Publications (1)

Publication Number Publication Date
WO2023174138A1 true WO2023174138A1 (fr) 2023-09-21

Family

ID=88022228

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/080381 WO2023174138A1 (fr) 2022-03-17 2023-03-09 Composé amide, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN116789644A (fr)
WO (1) WO2023174138A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006050476A2 (fr) * 2004-11-03 2006-05-11 Vertex Pharmaceuticals Incorporated Modulateurs de canaux ioniques et leurs methodes d'utilisation
CN101883760A (zh) * 2007-10-11 2010-11-10 沃泰克斯药物股份有限公司 用作电压-门控钠通道抑制剂的杂芳基酰胺类
WO2020092187A1 (fr) * 2018-11-02 2020-05-07 Merck Sharp & Dohme Corp. 2-amino-n-phényl-nicotinamides utilisés en tant qu'inhibiteurs de nav1.8

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006050476A2 (fr) * 2004-11-03 2006-05-11 Vertex Pharmaceuticals Incorporated Modulateurs de canaux ioniques et leurs methodes d'utilisation
CN101883760A (zh) * 2007-10-11 2010-11-10 沃泰克斯药物股份有限公司 用作电压-门控钠通道抑制剂的杂芳基酰胺类
WO2020092187A1 (fr) * 2018-11-02 2020-05-07 Merck Sharp & Dohme Corp. 2-amino-n-phényl-nicotinamides utilisés en tant qu'inhibiteurs de nav1.8

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY ANONYMOUS : "- Benzamide, N-(2-cyclopropyl-2,3-dihydro-5-benzoxazolyl)-5-nitro-2-(1- pyrrolidinyl)- (CA INDEX NAME)", XP093092674, retrieved from STN *

Also Published As

Publication number Publication date
CN116789644A (zh) 2023-09-22

Similar Documents

Publication Publication Date Title
CN101842361B (zh) 吡嗪酮衍生物及其在治疗肺病中的用途
CN106103422B (zh) 异喹啉衍生物及其用途
CN102414177B (zh) 作为缓激肽b1拮抗剂的化合物
CN100567293C (zh) N-取代的非芳基-杂环nmda/nr2b拮抗剂
KR101722898B1 (ko) 칼슘 통로 차단제로서 ｎ-피페리디닐 아세트아미드 유도체
EP3766882B1 (fr) Dérivés alcoxy de phtalazine isoxazole, procédé de préparation associé, composition pharmaceutique et utilisation correspondantes
KR20130095772A (ko) 나트륨 채널 차단제로서 퀴나졸린 화합물
US20060235065A1 (en) Aminopyrazole derivatives
KR20130010078A (ko) Ｃｆ의 치료를 위한 피리딘 및 피라진 유도체
WO2016039408A1 (fr) Composé hétérocyclique
DE602004011515T2 (de) Furazanobenzimidazole
CN102781916B (zh) 作为缓激肽b1拮抗剂的化合物
KR102556482B1 (ko) 테트라히드로이소퀴놀린계 화합물, 이의 제조 방법, 테트라히드로이소퀴놀린계 화합물을 포함하는 약물 조성물 및 이의 용도
EP2119704A1 (fr) Dérivé d'acylguanidine
AU2015269449B2 (en) 2-acylaminothiazole derivative or salt thereof
EP3388433B1 (fr) Dérivé de phthalazine et procédé de préparation, composition pharmaceutique et utilisation associées
BR112015030095B1 (pt) Moduladores do receptor de cxcr7
WO2020156312A1 (fr) Modulateur de dérivé polycyclique, son procédé de préparation et son application
CN101679275A (zh) 新化合物707及其应用
WO2023174138A1 (fr) Composé amide, son procédé de préparation et son utilisation
JP6693520B2 (ja) ピペラジン誘導体
CN112851583B (zh) 新型苯并氮杂䓬类化合物、组合物及其用途
DK3024825T3 (en) IMIDAZOLE CARBOXAMIDES AND THEIR USE AS FAAH INHIBITORS
WO2021083246A1 (fr) Modificateur de dérivé cyclique à quatre chaînons, procédé de préparation et application de celui-ci
CN107344936A (zh) 三唑哒嗪类衍生物、其制备方法、药物组合物和用途

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: 23769644

Country of ref document: EP

Kind code of ref document: A1