WO2020199683A1 - Dérivé de sulfonylbenzamide substitué par un hétérocycle azoté, son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé de sulfonylbenzamide substitué par un hétérocycle azoté, son procédé de préparation et son utilisation en médecine Download PDF

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WO2020199683A1
WO2020199683A1 PCT/CN2019/128925 CN2019128925W WO2020199683A1 WO 2020199683 A1 WO2020199683 A1 WO 2020199683A1 CN 2019128925 W CN2019128925 W CN 2019128925W WO 2020199683 A1 WO2020199683 A1 WO 2020199683A1
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alkyl
compound
ring
pharmaceutically acceptable
stereoisomer
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周福生
谢婧
赵金柱
黄栋
许峰
沈思达
兰炯
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Shanghai Haiyan Pharmaceutical Technology Co Ltd
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/44—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medical technology. Specifically, the present invention particularly relates to a sulfonyl benzamide derivative substituted by a nitrogen heterocycle, a preparation method thereof, and application as a sodium ion channel (especially Nav1.7) inhibitor, and a pharmaceutical composition prepared therefrom And medicinal composition.
  • Nav1.7 (PN1, SCN9A) VGSC is sensitive to the blocking of tetrodotoxin, which is mainly expressed in peripheral sympathetic neurons and sensory neurons.
  • the SCN9A gene has been replicated in a variety of species (including humans, rats, and rabbits), and shows that the amino acids between human and rat genes have about 90% identity.
  • Nav1.7 plays an important role in a variety of pain states (including acute, chronic, inflammatory and/or neuropathic pain).
  • Nav1.7 protein accumulates in neuromas, Especially neuromas that cause pain.
  • Mutations that increase the function of Nav1.7 have been thought to involve primary erythematous limb pain (a disease characterized by burning and inflammation of the limbs), and sudden extreme pain.
  • the reported results of non-selective sodium channel blockers lidocaine and mexiletine can alleviate the symptoms of hereditary erythematous limb pain, and carbamazepine can effectively reduce the number and severity of PEPD attacks are consistent with the above observations .
  • Nav1.7 is specifically expressed in DRG sensory neurons but not in other tissues such as cardiomyocytes and central nervous system, the development of its specific blocker for the treatment of chronic pain may not only improve the efficacy, but also greatly reduce side effects. And the selective inhibitor of Nav1.7 ion channel can be used for almost all kinds of pain treatment.
  • NaV1.5 and Nav1.2 which are members of the protein family, are also important ion-type channels.
  • NaV1.5 is mainly expressed in cardiomyocytes (Raymond, CK, etc., op.cit.), including atria, The ventricle, sinoatrial node, atrioventricular node and heart Purkinje fibers.
  • the rapid ascent of the action potential of the heart and the rapid pulse conduction through the heart tissue are due to the opening of NaV1.5.
  • Abnormal function of NaV1.5 can lead to the formation of a variety of arrhythmias.
  • Human NaV1.5 mutations cause a variety of arrhythmia syndromes, including, for example, long QT3 (LQT3), Brugada syndrome (BS), inherited cardiac conduction defects, sudden death syndrome (SUNDS), and sudden infant death Syndrome (SIDS) (Liu, H. et al., Am. J. Pharmacogenomics (2003), 3(3): 173-9).
  • LQT3 long QT3
  • BS Brugada syndrome
  • SUNDS sudden death syndrome
  • SIDS sudden infant death Syndrome
  • NaV1.2 is highly expressed in the brain (Raymond, C.K. et al., J. Biol. Chem. (2004), 279(44): 46234-41) and is important for normal brain function. Therefore, inhibiting the Nav1.2 channel will produce inhibitory toxicity to the brain.
  • the Nav1.7 ion channel is an important target for the development of non-addictive analgesics. It is necessary to develop an inhibitor with the Nav1.7 ion channel highly selective and with good pharmacokinetic characteristics.
  • the purpose of the present invention is to provide a selective inhibitor of Nav1.7 ion channel and its application in medicine.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
  • R 0 is C 1-10 alkyl or NR a0 R b0 ;
  • R 1 is an optionally substituted 5- to 6-membered monocyclic heteroaryl group or a C 6-10 aryl group; wherein the optional substitution refers to unsubstituted or substituted by 1, 2 or 3 substituents selected from the following group Substitution: halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkoxy, C 3-10 cycloalkyl or -O-( CH 2) q -R a; wherein R a is hydrogen, C 1-10 alkyl, halo C 1-10 alkyl, substituted NR a0 R b0, C 3-8 cycloalkyl or optionally 4 to 6 Saturated single heterocyclic ring;
  • R 2 is hydrogen, hydroxyl, cyano or C 1-10 alkyl
  • R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy or C 3-8 cycloalkyl ;
  • L is a bond, O, NH, -(CH 2 ) p -or -O-(CH 2 ) p ;
  • n 0, 1 or 2;
  • n 1, 2 or 3;
  • p and q are each independently 1, 2 or 3;
  • R a0 and R b0 are each independently hydrogen or C 1-8 alkyl
  • the 4- to 6-membered saturated monocyclic heterocycle is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine , Piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 5- to 6-membered monocyclic heteroaryl group is selected from: thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, Pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring.
  • the C 6-10 aryl group is a phenyl group.
  • R 2 is hydrogen or C 1-10 alkyl.
  • R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen (preferably fluorine or chlorine) or C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl).
  • R 3 and R 6 are hydrogen.
  • R 3 and R 6 are hydrogen, and R 4 and R 5 are each independently hydrogen, halogen (preferably fluorine or chlorine) or C 3-8 cycloalkyl ( Preferably, it is C 3-6 cycloalkyl).
  • R 1 is optionally substituted pyridine or phenyl; wherein said optionally substituted refers to unsubstituted or substituted by 1, 2 or 3 selected from the following group Group substitution: halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkoxy, C 3-10 cycloalkyl or -O- (CH 2 ) q -R a ; wherein Ra is a C 1-10 alkyl group or a halogenated C 1-10 alkyl group, and q is 1, 2 or 3.
  • L is O or -O-(CH 2 ) p , and p is 1, 2 or 3.
  • R 1 and R 2 are as defined above.
  • the compound in formula (I), is a compound selected from Examples 1-35.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; and pharmacy Acceptable carrier.
  • the third aspect of the present invention provides the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition according to the second aspect of the present invention.
  • the disease or condition is selected from pain, depression, cardiovascular disease, respiratory system disease, mental disease or a combination thereof.
  • the disease or condition is selected from HIV-related pain, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, bowel disease Acute syndrome, g-Rohn's disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, bone and joint Inflammation, atherosclerosis, sudden dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudo-aldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety , Schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, local and general tonic seizures, restless legs syndrome, Arrhythmia,
  • the pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, postoperative pain, birth pain, childbirth pain, toothache, chronic pain, Persistent pain, peripheral-mediated pain, central-mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, trigeminal neuralgia, postherpetic neuralgia, acute Pain, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain or fibromyalgia or a combination thereof.
  • the fourth aspect of the present invention provides a method for treating a mammalian disease or condition, the method comprising administering to a subject in need (such as a mammal) a therapeutically effective amount of the compound according to the first aspect of the present invention, or a pharmacologically Acceptable salts, solvates, stereoisomers or prodrugs, or the pharmaceutical composition according to the second aspect of the invention.
  • the inventors unexpectedly discovered that the nitrogen heterocyclic ring substituted sulfonyl benzamide derivative of the present invention has a high inhibitory activity on Nav1.7, and is expected to be developed into a wide range of pain treatments. drug. On this basis, the inventor completed the present invention.
  • C 1-10 alkyl refers to linear and branched saturated aliphatic hydrocarbon groups containing 1 to 10 carbon atoms, as defined below; more preferably C 1-8 alkyl, non-limiting Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-
  • C 1-10 alkoxy refers to -O-(C 1-10 alkyl), where the definition of alkyl is as described above.
  • a C 1-8 alkoxy group is preferred, a C 1-6 alkoxy group is more preferred, and a C 1-3 alkoxy group is most preferred.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy and the like.
  • C 3-8 cycloalkoxy refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is defined as described above. Preferred is C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo refers to the replacement of one or more (eg, 1, 2, 3, 4, or 5) hydrogens in a group with halogen.
  • halo C 1-10 alkyl means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above. It is preferably a halogenated C 1-8 alkyl group, more preferably a halogenated C 1-6 alkyl group, and most preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-10 alkyl groups include (but are not limited to) monochloroethyl, dichloromethyl, 1,2-dichloroethyl, monobromoethyl, monofluoroethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, etc.
  • halogenated C 1-10 alkoxy means that the alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above. It is preferably a halogenated C 1-8 alkoxy group, more preferably a halogenated C 1-6 alkoxy group, and most preferably a halogenated C 1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
  • halo C 3-8 cycloalkyl refers to a cycloalkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. Preferably, it is a halogenated C 3-6 cycloalkyl group. Including (but not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl and the like.
  • deuterated C 1-8 alkyl refers to an alkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) deuterium atoms, where the definition of the alkyl group is as described above. It is preferably a deuterated C 1-6 alkyl group, and more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include (but are not limited to) mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl Base etc.
  • a bond means that two groups connected by it are connected by a covalent bond.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group
  • C 3-8 cycloalkyl refers to a cyclic hydrocarbon group containing 3 to 8 carbon atoms, which may preferably be C 3-6 Cycloalkyl, similar in definition; non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl Group, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, and cyclohexenyl.
  • spirocyclic ring refers to a polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system. According to the number of rings, spiro rings are classified into double spiro rings or multi spiro rings, preferably double spiro rings. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro ring. E.g:
  • spiro heterocyclic ring refers to a polycyclic hydrocarbon sharing one atom (called a spiro atom) between single rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer 0 to 2) of heteroatoms, the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. According to the number of rings, spiro heterocycles are classified into dispiro heterocycles or polyspiro heterocycles, and dispiro heterocycles are preferred. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro heterocyclic ring. E.g:
  • bridged ring refers to a polycyclic group that shares two or more carbon atoms.
  • the shared carbon atoms are called bridgehead carbons.
  • the two bridgehead carbons can be a carbon chain or a bond. , Called the bridge. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. Preferably it is a double ring or a triple ring bridged ring.
  • bridged heterocycle refers to a polycyclic group that shares two or more atoms, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2 ), the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably a bicyclic or tricyclic bridged heterocyclic ring. E.g:
  • 8 to 10 membered bicyclic ring refers to a bridged ring containing two rings containing 8 to 10 ring atoms.
  • the bicyclic ring may be a saturated full carbon bicyclic ring or a partially unsaturated full carbon bicyclic ring, and an 8 to 10 membered bicyclic ring Examples include (but are not limited to):
  • 8 to 10 membered bi-heterocyclic ring refers to a bridged heterocyclic ring containing two rings containing 8 to 10 ring atoms, in which 1, 2, 3, 4 or 5 ring carbon atoms are selected from nitrogen , Oxygen or sulfur heteroatoms.
  • 8- to 10-membered biheterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.
  • C 6-10 aryl and C 6-10 aryl ring are used interchangeably, and both refer to all-carbon monocyclic or fused polycyclic rings with a conjugated ⁇ -electron system (that is, sharing adjacent The ring) group of a carbon atom pair refers to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
  • amino refers to NH 2
  • cyano refers to the CN
  • Niro refers to NO 2
  • benzyl refers to -CH 2 - phenyl
  • carboxy Refers to -C(O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • Hydroxy refers to -OH
  • thiol refers to SH
  • the structure of "cyclopropylene” is:
  • heteroaryl ring and “heteroaryl” are used interchangeably and refer to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl ;
  • the ring array shares 6, 10 or 14 ⁇ electrons; and in addition to carbon atoms, there are groups with 1 to 5 heteroatoms.
  • Heteroatom refers to nitrogen, oxygen, or sulfur.
  • 3 to 7-membered (4 to 7-membered) saturated or partially unsaturated monocyclic ring refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing 3 to 7 ring atoms.
  • 3 to 7-membered saturated or partially unsaturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, ring Hexadienyl ring, cycloheptyl ring, cycloheptatrienyl ring, cyclooctyl ring, etc.
  • 5- to 6-membered monocyclic heteroaryl ring and “5- to 6-membered monocyclic heteroaryl” are used interchangeably, and both refer to a mono-heteroaryl ring containing 5 to 6 ring atoms
  • Examples include (but are not limited to): thiophene ring, N-alkane pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole
  • 8 to 10 membered bicyclic heteroaryl ring and “8 to 10 membered bicyclic heteroaryl ring” are used interchangeably, and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, for example including (But not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, Phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8 -Naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphth
  • 4- to 6-membered saturated monocyclic heterocyclic ring means that 1, 2, or 3 carbon atoms in a 4- to 6-membered monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer 0
  • the heteroatom to 2 is substituted, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members.
  • Examples of 4- to 6-membered saturated monocyclic heterocycles include (but are not limited to) azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine , Dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, etc.
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently substituted with each other Ground is substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort.
  • an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 or less groups independently selected from CN, halogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, amino, halogenated C 1-8 alkyl substituted amino, acetyl Group, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, nitro, C 6-10 ary
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like.
  • solvate refers to a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate or crystallize out of the solvent. For example, a complex formed with water is called a "hydrate”. Solvates of compounds of formula (I) fall within the scope of the present invention.
  • the compound represented by formula (I) of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • a compound contains a chiral center
  • the compound contains enantiomers.
  • the present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • diastereomers may exist.
  • the present invention includes the resolved optically pure specific isomers and mixtures of diastereomers. Diastereoisomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the present invention includes prodrugs of the aforementioned compounds.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released through enzymatic reactions to obtain the parent compound.
  • Specific preparation methods of prodrugs please refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMBioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or prodrug can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (for example, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
  • the above-mentioned dosage forms can be prepared from the active compound and one or more carriers or excipients through general pharmaceutical methods.
  • the above-mentioned carrier needs to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or a suspension with the aforementioned carriers.
  • composition of the present invention is formulated, quantified and administered in a manner that conforms to medical practice standards.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual to be treated, the cause of the condition, the target of the drug, and the mode of administration.
  • therapeutically effective amount refers to the amount of the compound of the present invention that will cause an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc. the amount.
  • the therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).
  • pharmaceutically acceptable carrier refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient, which is compatible with the patient and most It is preferably a mammal, more preferably a human, which is suitable for delivering the active agent to the target target without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded spinal mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.
  • the compound of formula (I) of the present invention can be easily prepared by various synthetic operations according to the specific compound structure with reference to the exemplary preparation methods in the following examples, and these operations are well mastered by those skilled in the art.
  • the reagents and raw material compounds used in the preparation process are all commercially available, or those skilled in the art can prepare them by referring to known methods according to different compound structures designed.
  • the series of compounds of the invention have novel structures and high Nav1.7 inhibitory activity and Nav1.7 selective inhibitory activity.
  • the series of compounds of the invention have statistically significant effects of inhibiting cold stimulation hyperalgesia.
  • the series of compounds of the present invention not only have obvious pharmacokinetic absorption effect and good bioavailability, but also have obvious metabolic stability, so they are expected to be developed into drugs for extensive pain treatment.
  • DMB 2,4-dimethoxybenzyl
  • THF tetrahydrofuran
  • EA ethyl acetate
  • PE petroleum ether
  • Ac 2 O acetic anhydride
  • NBS N-bromosuccinimide
  • DCM dichloromethane
  • AIBN azobisisobutyronitrile
  • Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphorferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl Is tert-butyldimethylchlorosilane
  • NCS N-chlorosuccinimide
  • DHP dihydropyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB p-methoxybenzyl
  • LiHMDS is di(tri Methylsilyl) lithium amide
  • Pd 2 (dba) 3 is tris(dibenzylideneacetone)
  • room temperature refers to about 20-25°C.
  • Step 1 Add z-1-1 (614mg, 3.05mmol, 1.0eq), 7mL 1,4-dioxane to a 50mL round bottom flask, add 4M HCl/1,4-dioxane dropwise at room temperature The ring solution (3 mL, 12 mmol, 3.93 eq) was stirred at room temperature overnight, and the solvent was removed by rotary evaporation to obtain a white solid z-1-2 (414 mg, 98.6%), which was directly used in the next reaction. MS m/z(ESI): N/A.
  • Step 2 Add 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (206mg, 0.748mmol, 1.0eq), z-1-2 (152mg, 1.105mmol, 1.48eq) to the 50mL sealed tube ), Pd 2 dba 3 (66mg, 0.072mmol, 0.1eq), binap (90mg, 0.145mmol, 0.19eq), potassium tert-butoxide (253mg, 2.255mmol, 3.01eq) and 10mL 1,4-dioxane , Degas by bubbling with Ar 2 for 5 min, heating the oil bath to 90° C., stirring and reacting for 15 h.
  • Step 3 Add z-1-3 (54mg, 0.183mmol, 1.2eq), 3mL THF to a 50mL round bottom flask, place it in an ice bath to cool, add NaH (18mg, 60%, 0.45mmol, 2.96eq), After stirring for 0.5h, 1-a (41mg, 0.152mmol, 1.0eq) was added and stirred at room temperature overnight.
  • Add 20mL of water, adjust pH 5 to 6 with 1M HCl, extract with ethyl acetate (20mL x 2), combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate, and purify the residue with preparative high performance liquid chromatography to obtain white Solid Z-1 (16 mg, 19.3%).
  • Step 1 Add 3,4-dichlorobromobenzene (1g, 4.46mmol, 1.0eq), z-2-1 (977mg, 8.92mmol, 2eq), Pd 2 dba 3 (259mg, 0.45 mmol, 0.1eq), binap (280mg, 0.45mmol, 0.1eq), potassium tert-butoxide (1g, 8.92mmol, 2.0eq) and 20mL 1,4-dioxane, replaced with Ar 2 balloon three times and protected, The oil bath was heated to 100°C, and the reaction was stirred for 15h.
  • Step 2 Add z-2-2 (350mg, 1.6mmol), 15mL THF to a 100mL round bottom flask, place it in an ice bath to cool, slowly add NaH (200mg, 60%, 4.8mmol, 3eq), after the addition is complete The reaction was stirred under ice bath for 10 min, then z-2-3 (500 mg, 1.6 mmol, 1.0 eq) was added, and the reaction was stirred under ice bath for 1 h.
  • Step 3 Add z-2-4 (200mg, 0.39mmol, 1.0eq), cyclopropylboronic acid (67mg, 0.78mmol, 2eq), Pd 2 (dppf)Cl 2 (29mg, 0.04mmol) to a 100mL round bottom flask , 0.1eq), cesium carbonate (254mg, 0.78mmol, 2eq), 10mL 1,4-dioxane and 1mL water, replaced with Ar 2 balloon three times and protected, the oil bath was heated to 100°C, and the reaction was stirred for 15h.
  • Compounds Z-5 to Z-32 can be prepared according to the method in Example 2.
  • Step 1 Combine (R)-pyrrolidin-2-yl methanol (275mg, 2.723mmol), 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (500mg, 1.815mmol), Pd2(dba )3 (164.8mg, 0.180mmol), BINAP (224.2mg, 0.36mmol), t-BuOK (407.3mg, 3.63mmol) were added to dry 1,4-dioxane (15ml), and the mixture was heated to 90°C After stirring overnight, the mixture was detected by LC-MS and concentrated under reduced pressure.
  • Step 2 Add (R)-(1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidin-2-yl)methanol (150mg, 0.508mmol) to DMF (5ml), Then NaH (61 mg, 1.524 mmol) was added, after stirring for a few minutes, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (137 mg, 0.508 mmol) was added, and the mixture was stirred overnight.
  • Compounds Z-34 and Z-35 can be prepared according to the method in Example 33.
  • Patch voltage clamp electrophysiology can directly measure and quantify the current blocking of voltage-gated sodium channels (various Navs) and determine the time and voltage dependence of the blocking. It has been interpreted as the resting, opening and The binding difference of the inactivation state reflects the inhibitory or activating effect of the compound (Hille, B., Journal of General Physiology (1977), 69:497-515).
  • the representative compounds of the present invention are carried out using manual patch clamp experiments.
  • the purpose of this study is to use the manual patch clamp method to test the effect of compounds on the ion channel currents on stable cell lines transfected with specific ion channels.
  • the stable cell line CHO-hNav1.7 used was from Genionics.
  • the manual patch clamp experiment protocol is as follows:
  • the positive control drug and the test compound are first dissolved in 100% DMSO (Sigma-Aldrich, D2650, and configured as a stock solution of a certain concentration (100nM, 1000nM). Before the experiment, the above-mentioned stock solution is serially diluted with DMSO, and then extracellular The solution is further diluted to obtain a test solution of the required concentration. The final concentration of DMSO in the extracellular solution does not exceed 0.30%.
  • the clamping potential is set at V 1/2 of the corresponding channel, that is, about 50% of the channels are in an inactive state. Then apply voltage to -120mV for 50ms. Then it depolarizes to -10mV, draws sodium current for 20ms, and finally returns to the clamping potential.
  • This kind of stimulation program can also be called a channel state-dependent voltage stimulation program.
  • the other is a non-inactivation stimulation program, which keeps the clamping potential at -120mV, gives a voltage stimulation to -10mV, and elicits a sodium current for 20ms, and finally returns to the clamping potential. That is to say, under the condition of this kind of stimulation program, all the channels have not experienced inactivation state, but directly activated from the resting state.
  • the time interval of the above two voltage stimulation procedures is 10s.
  • the inhibitory effect of the compound is calculated by the current change before and after the addition of the drug, and the IC 50 value is obtained by fitting the Hill equation. If the compound shows a certain multiple difference in the channel effect under the above two different voltage stimuli, then the compound is state-dependent on the channel.

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Abstract

L'invention concerne un dérivé de sulfonylbenzamide substitué par un hétérocycle azoté, son procédé de préparation et son utilisation en médecine. De façon spécifique, l'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère, un composé de solvant ou un promédicament de celui-ci, ainsi que son procédé de préparation et son utilisation.
PCT/CN2019/128925 2019-04-04 2019-12-27 Dérivé de sulfonylbenzamide substitué par un hétérocycle azoté, son procédé de préparation et son utilisation en médecine Ceased WO2020199683A1 (fr)

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PCT/CN2020/074731 Ceased WO2020199757A1 (fr) 2019-04-04 2020-02-11 Dérivé de sulfonylbenzamide, son procédé de préparation et son utilisation médicale
PCT/CN2020/083320 Ceased WO2020200317A1 (fr) 2019-04-04 2020-04-03 Dérivé de tétrahydroisoquinoline sulfonylamide, son procédé de préparation et son utilisation médicale

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PCT/CN2020/083320 Ceased WO2020200317A1 (fr) 2019-04-04 2020-04-03 Dérivé de tétrahydroisoquinoline sulfonylamide, son procédé de préparation et son utilisation médicale

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2012007877A2 (fr) * 2010-07-12 2012-01-19 Pfizer Limited Composés chimiques
WO2015051043A1 (fr) * 2013-10-01 2015-04-09 Amgen Inc. Composés d'acylsulfonamide de biaryle en tant qu'inhibiteurs des canaux sodiques
US20170002017A1 (en) * 2012-05-22 2017-01-05 Genentech, Inc. N-substituted benzamides and methods of use thereof
WO2017133591A1 (fr) * 2016-02-03 2017-08-10 上海海雁医药科技有限公司 Dérivé n-sulfonyle benzamide à substituant hétérocyclique, son procédé de préparation et son application pharmaceutique
CN107108517A (zh) * 2015-02-11 2017-08-29 株式会社大熊制药 钠通道阻断剂
CN107835805A (zh) * 2015-05-22 2018-03-23 基因泰克公司 被取代的苯甲酰胺和其使用方法
WO2018081384A1 (fr) * 2016-10-27 2018-05-03 Bristol-Myers Squibb Company Inhibiteurs de nav1.7 de type acyl-sulfonamide
CN109574927A (zh) * 2017-09-29 2019-04-05 浙江海正药业股份有限公司 N-(取代磺酰基)苯甲酰胺类衍生物及其制备方法和医药用途

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2007014180A (es) * 2005-05-10 2008-01-14 Vertex Pharma Derivados biciclicos como moduladores de canales de iones.
CA2625039A1 (fr) * 2005-10-19 2007-04-26 F. Hoffmann-La Roche Ag N-phenylphenylacetamides en tant qu'inhibiteurs de transcriptases inverses non-nucleosides
TW200817319A (en) * 2006-08-10 2008-04-16 Astellas Pharma Inc Sulfonamide compound or salt thereof
EP2565191B1 (fr) * 2008-05-14 2014-10-08 Astellas Pharma Inc. Dérivés d'acide 4-(indol-7-ylcarbonylaminométhyl)cyclohexanecarboxylique comme antagonistes du récepteur EP4 utilisables pour le traitement de l'insuffisance rénale chronique ou de la néphropathie diabétique
WO2013122897A1 (fr) * 2012-02-13 2013-08-22 Amgen Inc. Inhibiteurs des canaux sodiques de type dihydrobenzoxazine et tétrahydroquinoxaline
WO2013134518A1 (fr) * 2012-03-09 2013-09-12 Amgen Inc. Inhibiteurs sulfamides des canaux de sodium
US9776995B2 (en) * 2013-06-12 2017-10-03 Amgen Inc. Bicyclic sulfonamide compounds as sodium channel inhibitors
EA032928B1 (ru) * 2015-03-02 2019-08-30 Эмджен Инк. Бициклические кетосульфонамидные соединения
WO2018205948A1 (fr) * 2017-05-11 2018-11-15 Glaxosmithkline Intellectual Property Development Limited Composés

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2012007877A2 (fr) * 2010-07-12 2012-01-19 Pfizer Limited Composés chimiques
US20170002017A1 (en) * 2012-05-22 2017-01-05 Genentech, Inc. N-substituted benzamides and methods of use thereof
WO2015051043A1 (fr) * 2013-10-01 2015-04-09 Amgen Inc. Composés d'acylsulfonamide de biaryle en tant qu'inhibiteurs des canaux sodiques
CN107108517A (zh) * 2015-02-11 2017-08-29 株式会社大熊制药 钠通道阻断剂
CN107835805A (zh) * 2015-05-22 2018-03-23 基因泰克公司 被取代的苯甲酰胺和其使用方法
WO2017133591A1 (fr) * 2016-02-03 2017-08-10 上海海雁医药科技有限公司 Dérivé n-sulfonyle benzamide à substituant hétérocyclique, son procédé de préparation et son application pharmaceutique
WO2018081384A1 (fr) * 2016-10-27 2018-05-03 Bristol-Myers Squibb Company Inhibiteurs de nav1.7 de type acyl-sulfonamide
CN109574927A (zh) * 2017-09-29 2019-04-05 浙江海正药业股份有限公司 N-(取代磺酰基)苯甲酰胺类衍生物及其制备方法和医药用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DIMAURO, E. F. ET AL.: "Application of a Parallel Synthetic Strategy in the Discovery of Biaryl Acyl Sulfonamides as Efficient and Selective NaV1.7 Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, 21 July 2016 (2016-07-21), XP055739695, DOI: 20200316211532Y *

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