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WO2020119616A1 - Dérivés de benzène substitués par sulfonamide, leur procédé de préparation et d'utilisation - Google Patents

Dérivés de benzène substitués par sulfonamide, leur procédé de préparation et d'utilisation Download PDF

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Publication number
WO2020119616A1
WO2020119616A1 PCT/CN2019/123940 CN2019123940W WO2020119616A1 WO 2020119616 A1 WO2020119616 A1 WO 2020119616A1 CN 2019123940 W CN2019123940 W CN 2019123940W WO 2020119616 A1 WO2020119616 A1 WO 2020119616A1
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group
alkyl
substituted
compound
unsubstituted
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Chinese (zh)
Inventor
南发俊
高召兵
王锦涛
郑月明
张仰明
许海燕
顾民
詹丽
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • 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 relates to a class of benzenesulfonamide substituted derivatives, its preparation method and use.
  • Voltage-gated ion channels are the key to the generation of electrical signals in mammalian cell membranes.
  • voltage-gated sodium ion channels play an important role in the generation and conduction of voltage-sensitive cell electrical signals.
  • Navs is a very important type of transmembrane protein in the cell that transmits electrical signals.
  • the activity of Navs is regulated by the potential difference on the surface of the cell membrane. The opening of the channel can cause a strong inward current in the cell.
  • Nav channels voltage-gated sodium ion channels
  • the Nav1.7 channel is currently the most advantageous target of the nine sodium channel subtypes (Nav1.1-Nav1.9) that have been discovered in pain research:
  • the Nav1.7 channel is an “amplifier for the occurrence of pain and other stimuli. ", which is mainly distributed in the somatosensory and sympathetic nerves, more than 85% of the pain sensory nerves have the expression of this channel, and the refined tissue distribution shows that the Nav1.7 channel is expressed on the periphery of the sensory nerves and the central terminal, which is It plays an important role in the occurrence and transmission of pain and provides a material basis.
  • Nav1.7 channels leads to congenital pain and lack of effective treatment drugs, including erythematous limb pain (Inherited erythromelalgia), paroxysmal severe pain (Paroxysmal extreme pain) and small fiber neuralgia (Small fiber neuropathy)
  • erythematous limb pain Inherited erythromelalgia
  • paroxysmal severe pain Paroxysmal extreme pain
  • small fiber neuralgia Small fiber neuropathy
  • analgesic drugs such as aspirin, non-steroidal anti-inflammatory drugs, lidocaine, etc.
  • the found Nav1.7 inhibitors such as Funapide are only effective for some patients.
  • the loss of Nav1.7 function leads to analgesia and does not affect other physiological functions. The complete loss of Nav1.7 function produces congenital painlessness (Complete Insensitivity to Pain, CIP).
  • Nav1.7 channel function directly participates in the clinical analgesic effects of traditional analgesics such as local anesthetics and antidepressants.
  • Nav1.7 dysfunction and respiratory diseases such as epilepsy, pruritus, weight regulation, cough, etc.
  • Nav1.7 channel inhibitors can be used not only to treat pain, including acute pain, inflammatory pain and neuropathic pain induced by trauma, but also for epilepsy, itching, weight regulation, Intervention and treatment of coughing and other respiratory diseases. So many companies have developed drugs for Nav1.7 so far.
  • Xenon Funapide mentioned above for the treatment of erythematous limb pain, it is in clinical phase II; GDC-0276, a collaboration between Xenon and Genentech, is used to treat pain.
  • AstraZeneca's AZD-3161 is used in the treatment of neuropathic pain and is currently in clinical Phase I; Pfizer's series of compounds PF-05150122, PF-05186462 and PF-05241328 as new non-opioid analgesics are currently in clinical In the first phase of development.
  • the object of the present invention is to provide a class of benzenesulfonamide substituted derivatives, their preparation and use, the benzenesulfonamide substituted derivatives can be used as selective inhibitors of Nav1.7, targeting Nav1.7
  • the development of drugs for the treatment of pain opens up new ways.
  • Z 2 is a 4-6 membered heteroaryl
  • L 1 is a bond or -(CH 2 ) n -;
  • X is O, S or -NR a -;
  • L 2 is a bond, substituted or unsubstituted -(CH 2 ) n -, substituted or unsubstituted -(CH 2 ) n -X 1 -(CH 2 ) m -;
  • W is substituted or unsubstituted -(CH 2 ) s -(6-22 membered carbocycle); the substitution refers to being substituted by one or more substituents selected from the following group: halogenated C1-C20 alkyl (such as CF 3 ), C1-C20 alkyl, C1-C20 alkoxy, F, Cl, Br, -(CH 2 ) n NR a R b , OH, CN, NO 2 ;
  • Y is H, O, S or -NR a -;
  • L 3 does not exist or is substituted or unsubstituted -(CH 2 ) n -; the substitution refers to being substituted by one or more substituents selected from the following group: C1-C20 alkyl, OH, CN, F, Cl, Br, NO 2 , CF 3 , C1-C20 alkoxy;
  • Z 1 does not exist or is a substituted or unsubstituted 4-8 membered heterocyclic ring, -NR a R b , substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C6-C10 aryl, C1-C20 Alkyl group, C2-C20 alkynyl group, C2-C20 alkenyl group, PMB, the substitution means one or more substituents selected from the following group: C1-C20 alkyl group, F, Cl, Br , Halogenated C1-C20 alkyl (such as CF 3 ), C1-C20 alkoxy, OH, CN, NO 2 ;
  • Each of R a, each R b each independently H, Bn, a substituted or unsubstituted C1-C20 alkyl;
  • n and m are independently integers of 1-20;
  • s is an integer from 0-20.
  • Z 2 is a 5-membered heteroaryl group.
  • Z2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 and R 4 are each independently H, F, and Cl.
  • R 2 and R 3 are each independently H, CN, F, and Cl.
  • L 1 is a bond
  • L 2 and L 3 are each independently a bond, wherein, R 5 is a C1-C6 alkyl group or a C2-C6 alkenyl group; n is an integer of 1-10.
  • L 2 is a bond, substituted or unsubstituted -(CH 2 ) n -, substituted or unsubstituted -(CH 2 ) n -X 1 -(CH 2 ) m -;
  • Z 1 is absent or a substituted or unsubstituted 4-7 membered heterocyclic ring, -NR a R b , substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted phenyl , C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, PMB;
  • substitution means being substituted by one or more substituents selected from the following group: C1-C6 alkyl, F, Cl, Br, halogenated C1-C6 alkyl (eg CF 3 ), C1-C6 alkoxy Base, OH, CN, NO 2 ;
  • R a and R b are each independently H, Bn, a substituted or unsubstituted C1-C4 alkyl group.
  • the 4-7 membered heterocyclic ring contains one N atom (cycloalkylamine), or contains N and O two heterocycles Atom (oxetanamine).
  • the group W is a substituted or unsubstituted group selected from :-( CH 2) s -C6-C14 aryl, - (CH 2) s -C8 -C12 bridged cycloalkyl , -(CH 2 ) s -C14-C22 aromatic bridge ring group;
  • substitution means being substituted by one or more substituents selected from the group consisting of halogenated C1-C6 alkyl (eg CF 3 ), C1-C6 alkyl, C1-C6 alkoxy, F, Cl, Br, -(CH 2 ) n NR a R b , OH, CN, NO 2 ;
  • substituents selected from the group consisting of halogenated C1-C6 alkyl (eg CF 3 ), C1-C6 alkyl, C1-C6 alkoxy, F, Cl, Br, -(CH 2 ) n NR a R b , OH, CN, NO 2 ;
  • R a and R b are each independently H, Bn, substituted or unsubstituted C1-C4 alkyl;
  • s is an integer from 0-6.
  • W is a substituted or unsubstituted group selected from the group consisting of: Each s is an integer of 0-6, and the substitution means being substituted by one or more substituents selected from the group consisting of halogenated C1-C6 alkyl groups (such as CF 3 ), C1-C6 alkyl groups, C1- C6 alkoxy, F, Cl, Br.
  • Z 2 is a 5-membered heteroaryl
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, CN, F, Cl and Br;
  • L 1 is the key
  • X is O or S-
  • L 2 is -(CH 2 ) n -;
  • Y is O or S
  • L 3 is -(CH 2 ) n -;
  • Z 1 substituted or unsubstituted 4-8 membered nitrogen-containing heterocyclic ring or -NR a R b , the substitution means being substituted by one or more substituents selected from the following group: C1-C4 alkyl, F, Cl , Br, halogenated C1-C4 alkyl, C1-C4 alkoxy, OH, CN, NO 2 ;
  • W is a substituted or unsubstituted -(CH 2 ) s -C8-C12 bridged cycloalkyl group, or a substituted or unsubstituted -(CH 2 ) s -C14-C22 aromatic bridged ring group; said substitution means choose one or more substituents in the following group: halogenated C1-C4 alkyl (such as CF 3 ), C1-C4 alkyl, C1-C20 alkoxy, F, Cl, Br, -(CH 2 ) n NR a R b , OH, CN, NO 2 ;
  • R a and R b are each independently H, Bn, C1-C4 alkyl
  • n is an integer of 1-6;
  • s is an integer of 1-6.
  • W is a substituted or unsubstituted group selected from the group consisting of: Each s is an integer of 1-6, and the substitution means being substituted by one or more substituents selected from the group consisting of halogenated C1-C6 alkyl (eg CF 3 ), C1-C6 alkyl, C1- C6 alkoxy, F, Cl, Br.
  • Z 2 is a 5-membered heteroaryl group, preferably R 1 and R 4 are each independently H; R 2 and R 3 are each independently CN; L 1 is a bond; X is O-; L 2 is -(CH 2 ) n -; Y is H, O or S; L 3 is -(CH 2 ) na -; n is an integer of 1-4; na is an integer of 1-6; Z 1 is absent, 5-7 membered nitrogen-containing heterocyclic ring, C1-C4 alkoxy or -NR a R b ; W is -(CH 2 ) s -C8-C12 bridged cycloalkyl group, or -(CH 2 ) s -C14-C22 aromatic bridged ring group; R a and R b are each independently H, C1- C4 alkyl; n is an integer of 1-4; na is an integer of 1-6; s is an integer of 1-4.
  • the compound is:
  • a pharmaceutical composition comprising:
  • pharmaceutically acceptable ingredients are substances that are suitable for humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergies), that is, they have a reasonable benefit/risk ratio.
  • a "pharmaceutically acceptable carrier” is a pharmaceutical or pharmaceutical used to deliver the compound of the present invention, its isomer, racemate, pharmaceutically acceptable salt, or a mixture thereof to animals or humans.
  • the carrier may be liquid or solid.
  • the composition contains 1-200 parts by weight of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and 10-5000 parts by weight of a pharmaceutically acceptable carrier or excipient Agent.
  • the pharmaceutical composition contains 5-150 parts by weight of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and 30-2000 parts by weight of a pharmaceutically acceptable carrier or excipient .
  • the dosage form of the pharmaceutical composition according to the present invention may be various, as long as it can effectively bring the active ingredient into the mammal.
  • it can be selected from: tablets, capsules, powders, granules, syrups, solutions, suspensions, or aerosols.
  • the compound may be present in a suitable solid or liquid carrier or diluent.
  • the preferred pharmaceutical compositions are solid compositions, especially tablets and solid or liquid filled capsules. Oral administration of pharmaceutical compositions is preferred.
  • the use of the compound according to the first aspect or a pharmaceutically acceptable salt thereof is provided for the preparation of a medicament for treating pain.
  • a method for treating pain comprising administering to a subject in need thereof the compound of the first aspect or a pharmaceutically acceptable salt thereof.
  • the object in need is a mammal.
  • the required object is a human.
  • halogen in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. Fluorine atoms and chlorine atoms are preferred.
  • halogenated in the present invention refers to any one of the atoms in the group that can be substituted is replaced by halogen, which can be fully halogenated, that is, all positions in the halogen atom substitution group that can be substituted.
  • C1-10 means 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms
  • C1-6 means 1, 2, 3, 4, 5, 6 carbon atoms
  • a 4-6 member means that the ring vertex has 4-6 atoms.
  • the "C1-20 alkyl group” in the present invention means a linear or branched alkyl group containing 1-20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl Base, sec-butyl, tert-butyl, etc. C1-10 alkyl, C1-6 alkyl, and C1-3 alkyl are preferred.
  • the "C1-4 alkyl group” in the present invention refers to the above-mentioned embodiment containing 1-4 carbon atoms.
  • C2-20 alkenyl group in the present invention refers to a linear or branched or cyclic alkenyl group having a double bond of 2-20 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl , 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl -2-propenyl and so on.
  • the double bond can optionally be cis and trans.
  • C2-20 alkynyl group in the present invention refers to a straight-chain or branched-chain alkynyl group having 2-6 carbon atoms containing a triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, etc.
  • C1-20 alkoxy refers to a group where "C1-20 alkyl” is connected to other structures through an oxygen atom, such as methoxy, ethoxy, propoxy, 1-methyl ethyl Oxygen, butoxy, 1-methylpropoxy, etc.
  • C1-6 alkoxy refers to a specific example containing 1-6 carbon atoms in the above examples.
  • 6-22 membered carbocyclic ring refers to a saturated or unsaturated carbocyclic ring containing 6-22 carbon atoms, including monocyclic cycloalkyl, fused ring cycloalkyl, bridged ring cycloalkyl, carbocycle may also have aromatic Sex, such as benzene ring, anthracene ring, phenanthrene ring, or a structure obtained by fusing aromatic ring with the above saturated ring, such as
  • the "4-8 membered heterocyclic group” in the present invention refers to a 4-8 membered cyclic group containing one or more heteroatoms, and the "heteroatom” refers to N, S, or O. Including saturated, partially saturated, unsaturated heterocyclic group. Also included are the heteroaryl groups mentioned above and their dihydro and tetrahydro analogs.
  • the "6--14-membered aryl group" in the present invention refers to a cyclic aromatic group having a ring atom of 6-14-membered carbon atoms, such as phenyl, anthracenyl, and phenanthrenyl.
  • the ring atoms of the "heteroaryl group” include one or more heteroatoms.
  • the “heteroatoms” include, but are not limited to, oxygen atoms, nitrogen atoms, and sulfur atoms.
  • the compound of the present invention has the structure shown in Formula I.
  • the compound has the structure represented by the general formula II:
  • W is preferably R7 (number of 1-4), R8 (number of 1-4), R9 are each C1-C20 alkoxy, C1-C20 alkyl, halogen, H.
  • R1, R2, R3, and R4 are as described above.
  • the definition of Het ring is the same as Z 2 .
  • the compound has the structure represented by the general formula III:
  • X is preferably O, S, R6 is H, C1-C20 alkyl substituent or branched chain substituent.
  • the compound has the structure represented by the general formula IV:
  • X is preferably O, S, N.
  • L2 is preferably R5 is a C1-C20 linear or branched alkyl group, a C2-C20 alkenyl substituent.
  • W is preferably Containing mono- or poly-substituted benzene rings, the definition of each substituent which is not explicitly shown is the same as above.
  • the invention also isomers, racemates, pharmaceutically acceptable salts, hydrates or precursors of the compounds.
  • pharmaceutically acceptable salt refers to a salt formed by the reaction of a compound with an inorganic acid, an organic acid, an alkali metal or an alkaline earth metal.
  • These salts include (but are not limited to): (1) salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) salts with organic acids such as acetic acid, oxalic acid, succinic acid, tartaric acid , Methanesulfonic acid, maleic acid, or arginine.
  • salts include salts with alkali metals or alkaline earth metals (such as sodium, potassium, calcium, or magnesium) in the form of esters, carbamates, or other conventional "prodrugs".
  • alkali metals or alkaline earth metals such as sodium, potassium, calcium, or magnesium
  • the compound has one or more asymmetric centers. Therefore, these compounds can exist as racemic mixtures, individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans isomers.
  • the "precursor of the compound” refers to a compound that is converted into the formula (I) by the metabolism or chemical reaction of the compound precursor in the patient's body after being taken by an appropriate method, or the chemical formula (I) A salt or solution composed of a compound.
  • the compound of the present invention that can be used as a Nav1.7 inhibitor can be prepared and synthesized by the following route.
  • R1a is the same as the definition of W in the general formula II
  • R1, R2, R3, R4, het is the same as the definition in the general formula II
  • n 0-10.
  • Het ring is the same as Z 2 .
  • compound 1 was dissolved in methanol and added NaBH4 at room temperature for 3 hours, and column chromatography was used to separate compound 2.
  • Compound 2 was dissolved in THF, NaHMDS was added at room temperature for 1 hour, then compound 3 in THF solution was added, and room temperature was reacted at 10 hours. After adding hydrochloric acid to quench and extracting, the compound 4 was isolated by column chromatography.
  • R3a is the same as the definition of W in the general formula III
  • R1, R2, R3, R4, het is the same as the definition in the general formula II
  • DMSO or DMF is used to mix trimethyl sulfoxide, and then NaH is added. After reaction at room temperature for 1 h, a solution of compound 5 in DMSO or DMF is added. After reaction at room temperature for 2 h, the mixture is extracted after quenching, and the compound is separated by column chromatography. 6,.
  • Dissolve R3bOH in DMSO or DMF add NaH, react at room temperature for 1h, then add compound 6 in DMSO or DMF, react at 60°C for 10h, extract after quenching, and separate compound 7 by column chromatography, dissolve compound 7 in THF After adding NaHMDS for 1 h at room temperature and then adding compound 3 in THF, reacting at room temperature for 10 h, adding hydrochloric acid to quench and extracting, and separating by column chromatography to obtain compound 8.
  • R3c is the sum of Z and L3 in the general formula III
  • R8 is as described in the general formula III
  • R1, R2, R3, R4, het are the same as defined in the general formula II
  • n 0-10.
  • Dissolve R3cOH with DMSO or DMF add NaH and react at room temperature for 1 h, then add compound 13 in DMSO or DMF solution, react at 60°C for 10 h, and extract the column chromatography to separate compound 14 after quenching.
  • Dissolve compound 14 in THF add NaHMDS to react at room temperature for 1 h, then add compound 3 in THF, react at room temperature for 10 h, add hydrochloric acid to quench, extract after extraction and column chromatography to obtain compound 15.
  • compound 16 was dissolved in DMF, water was added, and sodium dithionite was added, and the reaction was carried out at 90°C for 5 hours. After extraction, compound 17 was isolated by column chromatography. Compound 17 was dissolved in methylene chloride, and DBU and III were added under ice bath. Fluoromethanesulfonic anhydride, and react at 0 °C for 1h, extracted after quenching, column chromatography to obtain compound 18. Dissolve compound 18 with DMF, then add Pd(PPh3)4, Zn(CN)2, and react at 120°C for 10h. After quenching, extract column chromatography to isolate compound 19.
  • Compound 19 was dissolved in toluene, DIBAL-H was added in an ice bath, and reacted at room temperature for 10 h. After quenching, compound 20 was extracted. Compound 20 was dissolved in DMF and added to the autoclave, and ethylene was introduced. The reaction was carried out at 180°C and 90 atmospheric pressure for three days. Most of the DMF was distilled off under reduced pressure. Compound 21 was isolated by column chromatography. twenty two.
  • NMR was measured with a Mercury Vx300M instrument produced by Varian. NMR calibration: ⁇ H 7.26ppm (CDC13), 2.50ppm (DMSO-d6), 2.05ppm (Acetone-d6): the reagent was mainly produced by Shanghai Chemical Reagent Company Provided by: TLC thin layer chromatography silica gel plate produced by Shandong Yantai Huiyou Silica Gel Development Co., Ltd. Model HSGF254: Normal phase column chromatography silica gel used for compound purification is produced by Shandong Qingdao Ocean Chemical Plant Branch, model zcx-11,200-300 mesh .
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • DBU 1,8-diazabicycloundec-7-ene
  • DCM dichloro Methane
  • DPPA diphenyl azide phosphate
  • THF tetrahydrofuran
  • NaHMDS sodium bistrimethylsilylamino
  • LiHNDS lithium bistrimethylsilylamino
  • PMP 4-methoxyphenyl
  • PMB 4-methoxybenzyl
  • DMSO dimethylsulfoxide
  • (Ph)3PMOMCl methoxymethyltriphenylphosphine chloride
  • DME ethylene glycol dimethyl ether
  • PE petroleum ether
  • EA ethyl acetate Ester
  • DMF N, N-dimethylformamide
  • DIBAL-H diisobutylaluminum hydride.
  • N3 (720 mg, 1.82 mmol), zinc cyanide (430 mg, 3.64 mmol), palladium tetrakistriphenylphosphine (105 mg, 0.091 mmol) were mixed with DMF (20 ml), protected with nitrogen, and reacted at 120° C. overnight. Dilute with ethyl acetate (30ml), wash with water (10ml ⁇ 2), stand still and separate the layers. Retain the ethyl acetate phase. The ethyl acetate phase is washed with saturated brine (10ml) and dried over anhydrous sodium sulfate.
  • methoxymethyltriphenylphosphine chloride (6g, 17.5mmol) with dry THF (50ml), cool to 0°C under ice bath, then add potassium tert-butoxide (3.94g, 35.1mmol) to it, And react at 0 °C for 1h, dissolve compound M6 (2.9g, 11.7mmol) with 20ml of dry THF, slowly drop it into the reaction system, after the completion of the dropwise addition, move the reaction from ice bath to room temperature for 2h Then, 6N HCl (55ml) was added to continue the reaction for 2h.
  • methoxymethyltriphenylphosphonium chloride (2.6mg, 7.54mmol) with dry THF (20ml), cool to 0°C under an ice bath, and then add potassium t-butoxide (846mg, 7.54mmol) to it. And react at 0 °C for 1h, dissolve compound F1 (990mg, 3.77mmol) with 20ml of dry THF, slowly drop it into the reaction system, after the dropwise addition was completed, the reaction was moved from ice bath to room temperature for 2h, 6N HCl (18ml) was added again to continue the reaction for 2h.
  • HEK293 cell culture medium formulation stably expressing human Nav1.7 channels 90% high-sugar DMEM (V/V, Gibco, Carlsbad, USA), 10% FBS (V/V, Gibco, Australia) and 300 ⁇ g/ml antibiotic Hygromycin B (Invitrogen, Carlsbad, USA), placed in a 25 cm 2 culture flask, at 37° C., 5% CO 2 incubator.
  • the stable transfected cells HEK293 cells stably expressing the human Nav1.7 channel
  • the stable transfected cells have reached a stable state before they can be used for electrophysiological detection.
  • Using a 6-well plate spread the digested cells evenly on a glass slide coated with poly-L-Lysine. After 6 hours of cultivation, electrophysiological recording was started.
  • Extracellular fluid formulation 140 NaCl (Sigma), 3 KCl (Sigma), 1 CaCl2 (Sigma), 1 MgCl2 (Sigma), 10 HEPES (Sigma) and 20 Glucose (Sigma), adjusted with NaOH (Sigma) pH to 7.3.
  • the series resistance compensation is 60-80%.
  • the clamping voltage and data recording are controlled and recorded by the PC through the PC10 software.
  • the sampling frequency is 10kHz and the filtering frequency is 2kHz.
  • Compound human-derived Nav1.7 action effect detection scheme Clamp the cells at -40mV (>95% Nav1.7 channel inactivation); first give 20ms, -150mV hyperpolarization voltage to make hNav1.7 not combined with the drug The channel recovers from rapid inactivation; a test voltage of 0 mV and 10 ms is given to detect the effect of the compound on the hNav1.7 current; the stimulation frequency is 1 Hz. Test at least 3 cells at each concentration (n ⁇ 3).
  • Bottom and Top represent the minimum and maximum values of inhibition
  • X represents the logarithm of the sample concentration
  • k represents the Hill coefficient
  • Y represents the I Drug /I Control value.
  • WJT-572 29.76 ⁇ 5.54 3 WJT-516a 31.53 ⁇ 5.51 4 WJT-671 33.52 ⁇ 5.24 4 WJT-602 45.12 ⁇ 11.69 3 WJT-600b 52.67 ⁇ 13.81 3 WJT-628 88.24 ⁇ 23.14 3 WJT-648 103.7 ⁇ 19.5 4 WJT-600a 129.1 ⁇ 28.3 3 WJT-514 154.8 ⁇ 27.4 3 WJT-500b 228.1 ⁇ 83.8 3 WJT-599 307.6 ⁇ 100.2 6 WJT-585c 309.0 ⁇ 105.1 3 WJT-570 309.6 ⁇ 91.9 4 WJT-516 393.5 ⁇ 56.3 4 WJT-679 412.6 ⁇ 92.6 3 WJT-609 489.2 ⁇ 49.1 4 WJT-641 741.2 ⁇ 206.8 4 WJT-532 767.4 ⁇ 250.4 3 WJT-657a 972.8 ⁇ 283.5 3 WJT-488 989.6 ⁇ 290.6 3 WJT
  • n is the number of cells detected by (compound inhibitory effect)
  • the Nav1.5 I Drug /I Control of the compounds of the present invention at a concentration of 10 ⁇ M are basically greater than or close to 0.5, indicating that the inhibition rate of Nav1.5 at this concentration is less than 50% That is to say, the inhibitory activity against Nav1.5 (IC 50 ) is greater than 10 ⁇ M, indicating that the representative compounds of the present invention are more selective for Nav1.7/Nav1.5.

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Abstract

L'invention concerne une classe de composés substitués par sulfonamide et leur utilisation. En particulier, l'invention concerne des composés tels que représentés dans la formule générale (I) ci-dessous. Les composés de la présente invention ont un effet inhibiteur sélectif sur Nav1.7, et peuvent inhiber efficacement et sélectivement le canal Nav1.7 sur une membrane cellulaire.
PCT/CN2019/123940 2018-12-10 2019-12-09 Dérivés de benzène substitués par sulfonamide, leur procédé de préparation et d'utilisation Ceased WO2020119616A1 (fr)

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WO2018081384A1 (fr) * 2016-10-27 2018-05-03 Bristol-Myers Squibb Company Inhibiteurs de nav1.7 de type acyl-sulfonamide
WO2018093694A1 (fr) * 2016-11-17 2018-05-24 Merck Sharp & Dohme Corp. Composés d'arylsulfonamide à liaisons diamino-alkylamino présentant une activité sélective dans les canaux sodiques sensibles à la tension
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