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WO2025223193A1 - Dérivé d'amide utilisé en tant que modulateur de canal sodique et son utilisation - Google Patents

Dérivé d'amide utilisé en tant que modulateur de canal sodique et son utilisation

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Publication number
WO2025223193A1
WO2025223193A1 PCT/CN2025/087765 CN2025087765W WO2025223193A1 WO 2025223193 A1 WO2025223193 A1 WO 2025223193A1 CN 2025087765 W CN2025087765 W CN 2025087765W WO 2025223193 A1 WO2025223193 A1 WO 2025223193A1
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Prior art keywords
deuterated
cycloalkyl
derivative
halogen
amide
Prior art date
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Application number
PCT/CN2025/087765
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English (en)
Chinese (zh)
Inventor
洪健
迪达斯
曹予曦
王晓华
崔浩
吴依蒙
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ARROMAX PHARMATECH Co Ltd
Original Assignee
ARROMAX PHARMATECH Co Ltd
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Publication of WO2025223193A1 publication Critical patent/WO2025223193A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no 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
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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

Definitions

  • This invention relates to the field of biomedical technology, specifically to an amide derivative or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof used as a sodium channel modulator, and its application in the treatment of sodium channel-related diseases.
  • Pain is a sensation produced when the human body is subjected to various noxious stimuli. It is a complex physiological and psychological activity, as well as a defensive mechanism to protect the body from harm. Clinically, it is one of the most common symptoms.
  • the International Association for the Study of Pain (IASP) classifies pain into nociceptive pain (caused by the activation of corresponding pain receptors in inflamed or damaged tissues, further divided into somatic and visceral pain), neuropathic pain (caused by damage or disease of the nervous system, divided into peripheral and central pain), and psychogenic pain (caused by mental and psychological factors, psychological conflicts, emotional disorders, or mental illnesses, resulting in unpleasant feelings and exaggerated language and behavior to describe pain).
  • neuropathic pain typically includes pain caused by systemic metabolic damage (postherpetic neuralgia, diabetic neuropathy, and drug-induced neuralgia) and pain caused by discrete nerve damage (post-amputation pain, postoperative nerve damage pain, etc.).
  • Voltage-gated sodium channels are mainly distributed in the nervous system and excitable cells (such as neurons), playing an important biophysical role in the transmission of pain-related signals. They transmit electrical signals through the generation and propagation of action potentials (APs) in the peripheral (PNS) and central nervous systems (CNS).
  • APs action potentials
  • PNS peripheral
  • CNS central nervous systems
  • Humans have nine types of sodium ion channels, Nav1.1 to Nav1.9, each composed of one ⁇ subunit and one or more ⁇ subunits.
  • different subtypes of Nav channels not only have specific tissue distributions, but also have different voltage dependencies and activation, inactivation and recovery kinetics (Xiaoshuang H, Xueqin J, Gaoxingyu H, et al.
  • Nav1.8 is a tetrodotoxin (TTX)-insensitive sodium channel encoded by SCN10A, primarily expressed in sensory neurons, located in the 3p21-22 region of human chromosome, and mainly encoding the ⁇ subunit.
  • TTX tetrodotoxin
  • NaV1.8 blockers lack isotype selectivity. Since not all NaV1.8 positive neurons are nociceptive sensory neurons, some NaV1.8 blockers may act on non-nociceptive sensory neurons, thus limiting their therapeutic efficacy and safety. Therefore, there is an urgent need to develop an effective and highly selective NaV1.8 blocker.
  • this invention provides an amide derivative or its pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex that can be used as a sodium channel modulator.
  • This derivative exhibits high selectivity, favorable pharmacokinetic properties, high bioavailability, and low side effects, and shows promising application prospects in the treatment of sodium channel-related diseases.
  • the first aspect of this invention provides an amide derivative of Formula I or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex thereof:
  • A is selected from aryl or heteroaryl containing one or more heteroatoms of N, O, and S;
  • G1 , G2 , and G3 are independently selected from hydrogen, deuterium, oxygen, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or G1 and/or G2 form a ring with an imide linked to tetrahydrofuran and pyridine.
  • R is selected from C1-C10 alkyl, halogenated and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogenated and/or deuterated C3-C10 cycloalkyl;
  • Y1 , Y2 , Y3 , and Y4 are independently selected from hydrogen, deuterium, and halogens;
  • R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;
  • R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;
  • R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.
  • A is selected from phenyl, pyridine, thiazole, furan, oxazole, isoxazole, and quinoline.
  • Equation I Choose from one of the following structures:
  • R is preferably trifluoromethyl.
  • the C5-C10 fused heterocycle is preferably one of the following structures:
  • G1 , G2 , and G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or G1 and/or G2 form a ring with an imide linked to tetrahydrofuran and pyridine;
  • Y1 , Y2 , Y3 , and Y4 are independently selected from hydrogen, deuterium, and halogens;
  • R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;
  • R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;
  • R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.
  • Q is either N or CH
  • G1 , G2 , and G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, and N-hydroxyimide;
  • Y1 , Y2 , Y3 , and Y4 are independently selected from hydrogen, deuterium, and halogens;
  • R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;
  • R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;
  • R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.
  • G1 , G2 , and G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or G1 and/or G2 form a ring with an imide linked to tetrahydrofuran and pyridine;
  • Y1 , Y2 , Y3 , and Y4 are independently selected from hydrogen, deuterium, and halogens;
  • R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;
  • R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;
  • R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.
  • Q is either N or CH
  • M is O, S, or N
  • G1 is selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or G1 forms a ring with an imide linked to tetrahydrofuran and pyridine;
  • Y1 , Y2 , Y3 , and Y4 are independently selected from hydrogen, deuterium, and halogens;
  • R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;
  • R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;
  • R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.
  • Q is either N or CH
  • M is O, S, or N
  • G1 is selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or G1 forms a ring with an imide linked to tetrahydrofuran and pyridine;
  • Y1 , Y2 , Y3 , and Y4 are independently selected from hydrogen, deuterium, and halogens;
  • R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;
  • R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;
  • R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.
  • R1X is preferably one of the following structures:
  • the amide derivative is preferably one of the compounds shown in the following structures:
  • the second aspect of the present invention provides the use of the amide derivative described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof in the preparation of a medicament for treating, alleviating or preventing sodium channel modulation-related diseases.
  • the sodium channel is Nav 1.8.
  • the diseases mentioned include pain, multiple sclerosis, pathological cough, but are not limited to the types of diseases listed above.
  • the drug may be administered alone or in combination with other therapeutic agents.
  • the drug can be administered orally, parenterally, intravenously, or transdermally.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the amide derivative described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof, and a pharmaceutically acceptable carrier or excipient.
  • the fourth aspect of the present invention provides the use of the pharmaceutical composition described in the third aspect in the preparation of a medicament for treating, alleviating or preventing sodium channel modulation-related diseases.
  • the sodium channel is Nav 1.8.
  • the diseases include pain, multiple sclerosis, and pathological cough, but are not limited to the types of diseases listed above; the pain includes acute pain and chronic pain; the acute pain includes, but is not limited to, surgical pain, bone pain, and toothache; and the chronic pain includes, but is not limited to, diabetic neuropathy and herpes zoster neuropathy.
  • the drug may be administered alone or in combination with other therapeutic agents.
  • the drug can be administered orally, parenterally, intravenously, or transdermally.
  • R and S are terms used to describe isomers and are descriptors of the stereochemical configuration of asymmetrically substituted carbon atoms. Naming an asymmetrically substituted carbon atom “R” or “S” is accomplished by applying the Cahn-Ingold-Prelog priority rule, which is well known to those skilled in the art and described in Section E, Stereochemistry, of the International Union of Pure and Applied Chemistry (IUPAC) Rules of Nomenclature for Organic Chemistry.
  • Cahn-Ingold-Prelog priority rule which is well known to those skilled in the art and described in Section E, Stereochemistry, of the International Union of Pure and Applied Chemistry (IUPAC) Rules of Nomenclature for Organic Chemistry.
  • aryl refers to a monocyclic, bicyclic, or tricyclic system having a total of 5-14 ring carbon atoms, wherein at least one ring in the system is aromatic, and each ring in the system contains 3-7 ring carbon atoms.
  • heteroaryl refers to a monocyclic, bicyclic, or tricyclic system having a total of 5-14 ring carbon atoms, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms, such as N, O, or S, and each ring contains 3-7 ring members, such as pyridine, thiazole, furan, oxazole, isoxazole, quinoline, etc.
  • halogen refers to F, Cl, Br, or I.
  • esters group refers to -COOR, where R is an alkyl or other non-hydrogen group.
  • Ci-Cj refers to the number of carbon atoms i-j in the moiety.
  • C1-C10 alkyl means that the alkyl unit has any number of carbon atoms between 1 and 10.
  • alkyl refers to a fully saturated straight-chain, branched alkane group. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. Non-limiting examples of exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-heptyl, n-octyl, etc. Additionally, the term "cycloalkyl” refers to a monocyclic or bicyclic saturated carbon ring, each ring having 3 to 10 carbon atoms.
  • substitution refers to replacing a hydrogen group in a given structure with a specific substituent group.
  • the optionally substituted group may have a substituent at each substitution position of the group, and when more than one position in any given structure is substituted by a substituent selected from a specified group, the substituents at each position may be the same or different.
  • all three hydrogens in the methyl group are substituted by F to form -CF3 , or the three hydrogens are substituted by two F and one deuterium to form -CF2D .
  • carbon heterocycle refers to a monocycle containing at least one heteroatom, including but not limited to N, O, and S.
  • the ring may be saturated or contain one or more unsaturated bonds.
  • dialkylamine is R-NH- R1 , where R and R1 are the same or different alkyl groups.
  • fused heterocycle contains at least two rings that share an edge, and at least one ring contains one or more heteroatoms.
  • alkynyl refers to a carbon chain containing at least one carbon-carbon triple bond, which can be straight-chain or branched, or a combination thereof.
  • the aforementioned C2-C3 alkynyl groups include ethynyl and propynyl.
  • alkenyl refers to a carbon chain containing at least one carbon-carbon double bond, which can be straight-chain or branched, or a combination thereof.
  • the aforementioned C2-C3 alkenyl groups include vinyl, propenyl, 2-methyl-1-propenyl, etc.
  • Some Formula I compounds may contain one or more ring systems, and therefore may have cis and trans isomers. This invention is intended to cover all such cis and trans isomers.
  • Any enantiomer of a compound of general formula I can be obtained by stereo-oriented synthesis using optically pure starting materials or reagents with known configurations.
  • compounds of formula I may also include a series of stable isotope-labeled analogs.
  • one or more protons in a compound of formula I may be substituted with deuterium atoms, thereby providing deuterated analogs with improved pharmacological activity.
  • “Pharmaceutically acceptable salt” refers to the acid salt or base salt of the compounds of this invention, which has the desired pharmacological activity and is neither biologically desirable nor otherwise desirable.
  • the salt can form with acids, including but not limited to acetic acid, adipic acid, benzoate, citric acid, camphoric acid, camphor sulfonate, dicarboxylate, dodecyl sulfate, ethanesulfonate, fumarate, glucono-heptate, glycerol phosphate, hemisulfate, heptanate, hexanoate, hydrobromide hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, and oxalate.
  • the present invention has at least the following advantages:
  • This invention provides a novel class of amide derivatives that can serve as sodium channel modulators. These compounds exhibit high inhibitory activity and selectivity against Nav.18, with minimal impact on other sodium ion channels, reducing side effects on the cardiovascular and central nervous systems. This improves the therapeutic efficacy and safety for Nav.18-mediated diseases, facilitating the expansion of clinical applications. Furthermore, the amide derivatives provided by this invention possess superior pharmacokinetic properties, enabling effective absorption, distribution to the target site, and maintenance of appropriate concentrations in vivo for sustained therapeutic effects. They also exhibit high bioavailability, ensuring sufficient drug delivery to and action on target neurons, thereby enhancing therapeutic efficacy. Therefore, these novel amide derivatives show promising application prospects in the preparation of drugs for treating, alleviating, or preventing sodium channel modulation-related diseases.
  • This embodiment relates to the preparation of compounds I-1, 1F1(4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide), and 1F2(4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide).
  • the reaction process is as follows:
  • reaction solution was extracted with ethyl acetate, and the combined organic layers were washed with sodium chloride aqueous solution, dried over anhydrous sodium sulfate and evaporated to obtain the crude product.
  • the crude product was purified by silica gel column chromatography to obtain 1b (400 mg).
  • Mobile phase A supercritical CO2
  • mobile phase B ethanol
  • gradient ratio: A:B 3:1
  • flow rate 120 mL/min.
  • This embodiment involves compounds I-2, 2F1(4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-5-fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide, and 2F2(4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy-d)-5-fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide.
  • Triethylamine (52.6 g, 0.52 mol) and 4-acetaminobenzenesulfonyl azide 2b 50 g, 0.20 mol
  • Triethylamine 52.6 g, 0.52 mol
  • 4-acetaminobenzenesulfonyl azide 2b 50 g, 0.20 mol
  • the mixture was stirred at room temperature for 4 hours.
  • the solvent was removed from the mixture under reduced pressure.
  • petroleum ether (500 mL) was added and stirred for 30 minutes.
  • the filtrate was collected and the solvent was removed under reduced pressure.
  • the crude mixture was purified by silica gel column chromatography to obtain ethyl 2-diazo-3-oxovalerate 2c (27 g, yield: 91.5%).
  • Titanium tetrachloride 25 g, 0.13 mol was slowly added to a mixture of trifluoroacetone (19.8 g, 0.18 mol) and dichloromethane (300 mL) at -78 °C, followed by the crude mixture obtained above.
  • the reaction was maintained at -78 °C for 3 hours, quenched with water, and extracted with dichloromethane (300 mL ⁇ 2).
  • the combined organic layers were washed with NaCl aqueous solution, dried over anhydrous Na2SO4 and evaporated to obtain a crude mixture.
  • Chiral HPLC analysis results: retention time 2.965 min, purity 100% (column: Cellulose-2, 150 ⁇ 4.6mm ID, 3 ⁇ m, mobile phase A: supercritical CO2 , mobile phase B: isopropanol, gradient ratio: B 5-40%, flow rate: 2.5 mL/min).
  • This embodiment relates to the preparation of compounds I-3, 3F1(2R,3S,4S,5R)-N-(2-(1H-tetrazol-5-yl)pyridin-4-yl)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, and 3F2(2S,3R,4R,5S)-N-(2-(1H-tetrazol-5-yl)pyridin-4-yl)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide.
  • the reaction process is as follows:
  • the aqueous phase was extracted with ethyl acetate, the organic phases were combined, and dried over anhydrous sodium sulfate or anhydrous magnesium sulfate. Purification by column chromatography yielded 260 mg of the target product I-3, in a yield of 35.4%.
  • Chromatographic column ChiralPak IH, 100 ⁇ 4.6mm I.D., 3 ⁇ m;
  • Mobile phase A supercritical CO2
  • mobile phase B ethanol
  • gradient ratio: B 5-40%
  • flow rate 2.5 mL/min.
  • Chromatographic column ChiralPak IH, 100 ⁇ 4.6mm I.D., 3 ⁇ m;
  • Mobile phase A supercritical CO2
  • mobile phase B ethanol
  • gradient ratio: B 5-40%
  • flow rate 2.5 mL/min.
  • This embodiment relates to the preparation of compounds I-24, 24F14-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid, and 24F24-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid.
  • the reaction process is as follows:
  • This embodiment relates to the preparation of compounds I-25, 25F14-((2R,3S,4S,5R)-3-(2-(deuterated difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid, and 25F24-((2S,3R,4R,5S)-3-(2-(deuterated difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid.
  • the reaction process is as follows:
  • This embodiment relates to the preparation of compounds I-38, 38F1 2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(deuterated methoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine 1-oxide, and 38F2 2-carbamoyl-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(deuterated methoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine 1-oxide.
  • the reaction process is as follows:
  • Chromatographic column ChiralPak IH, 100 ⁇ 4.6mm I.D., 3 ⁇ m;
  • This embodiment relates to the preparation of compounds I-39, 39F14-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide-5-deuterium, and 39F24-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide-5-deuterium.
  • the reaction process is as follows:
  • Chromatographic column ChiralPak AD, 150 ⁇ 4.6mm I.D., 3 ⁇ m;
  • This embodiment relates to the preparation of compounds I-40, 40F15-bromo-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxycarboxamide)pyridinecarboxamide, and 40F25-bromo-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxycarboxamide)pyridinecarboxamide.
  • the reaction process is as follows:
  • Chromatographic column ChiralPak AD, 150 ⁇ 4.6mm I.D., 3 ⁇ m;
  • This embodiment relates to the preparation of compounds I-41 and 41F1 2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(deuteromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine-1-oxide-5-deuterium and 41F2 2-carbamoyl-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(deuteromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine-1-oxide-5-deuterium.
  • the reaction process is as follows:
  • Chromatographic column ChiralPak IH, 100 ⁇ 4.6mm I.D., 3 ⁇ m;
  • Nav1.8 current measured in normal extracellular fluid was used as the baseline. After the Nav1.8 current remained stable for at least 5 minutes, the solution containing the test compound was sequentially perfused around the cells from low to high concentration. After the recorded current tended to stabilize, the last 5 Nav1.8 current values were recorded, and their average value was taken as the final current value at the specific concentration.
  • Peak current inhibition rate [1 - (peak current size compound - peak current size positive control) / (peak current size blank control - peak current size positive control)] ⁇ 100%;
  • the dose-response curve was fitted using Graphpad Prism 8.0 software and the IC50 value was calculated.
  • the inhibitory activity test results for Nav1.8 show that the novel amide derivatives provided by this invention have good inhibitory activity against Nav1.8, and compounds 1F1, 1F2, and 2F1 exhibit significantly better inhibitory activity against Nav1.8 than A-803467. Among them, compound 1F1 has an IC50 value of less than 0.0016 ⁇ M, demonstrating extremely high inhibitory activity against Nav1.8.
  • mice Male SD rats (purchased from SPF Laboratory Animal Technology Co., Ltd.), age: 6-8 weeks, weight: 180-300 grams.
  • IV Intravenous
  • PO Oral
  • IV (0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24h); PO (0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24h).
  • the novel amide derivatives provided by this invention not only exhibit high selectivity for Nav.18, but also possess advantages such as better pharmacokinetic properties and high bioavailability, which are beneficial for improving the therapeutic efficacy and safety of Nav.18-mediated diseases and expanding the clinical application scope of the drug.

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Abstract

La présente invention concerne un dérivé d'amide représenté par la formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère, un dérivé deutéré, un hydrate, un solvate ou un complexe de solvant de celui-ci, utilisé en tant que modulateur de canal de sodique. La présente invention concerne en outre une composition pharmaceutiquement acceptable comprenant le dérivé d'amide selon la présente invention, et l'utilisation du dérivé d'amide ou de la composition dans le traitement de maladies liées au canal sodique, y compris la douleur, la sclérose en plaques, les toux pathologiques, etc.
PCT/CN2025/087765 2024-04-23 2025-04-08 Dérivé d'amide utilisé en tant que modulateur de canal sodique et son utilisation Pending WO2025223193A1 (fr)

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CN120192286A (zh) * 2023-12-21 2025-06-24 武汉熙瑞医药科技有限公司 一种含苯环的多环化合物、其药物组合物及其应用
WO2025162194A1 (fr) * 2024-01-31 2025-08-07 上海汇伦医药股份有限公司 Nouveau composé modulateur de canal sodique et son utilisation
WO2025218764A1 (fr) * 2024-04-19 2025-10-23 广州市联瑞制药有限公司 Composé utilisé en tant qu'inhibiteur de canal sodique dépendant de la tension et son utilisation
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