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WO2025162194A1 - Nouveau composé modulateur de canal sodique et son utilisation - Google Patents

Nouveau composé modulateur de canal sodique et son utilisation

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Publication number
WO2025162194A1
WO2025162194A1 PCT/CN2025/074442 CN2025074442W WO2025162194A1 WO 2025162194 A1 WO2025162194 A1 WO 2025162194A1 CN 2025074442 W CN2025074442 W CN 2025074442W WO 2025162194 A1 WO2025162194 A1 WO 2025162194A1
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WIPO (PCT)
Prior art keywords
compound
mmol
lcms
reaction
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/074442
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English (en)
Chinese (zh)
Inventor
段书冬
杜书奇
秦继红
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Huilun Pharmaceutical Co Ltd
Original Assignee
Shanghai Huilun Pharmaceutical Co Ltd
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Application filed by Shanghai Huilun Pharmaceutical Co Ltd filed Critical Shanghai Huilun Pharmaceutical Co Ltd
Publication of WO2025162194A1 publication Critical patent/WO2025162194A1/fr
Pending legal-status Critical Current
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    • 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
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    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • 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
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    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—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 sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
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    • 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
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Definitions

  • the present invention relates to the field of medicine, and in particular to a new sodium channel modulator compound, a preparation method thereof, and therapeutic use thereof in treating diseases.
  • Pain is a complex sensation, usually an uncomfortable feeling caused by physical injury, illness or adverse external stimuli.
  • the International Association for the Study of Pain (ISAP) defines pain as "an unpleasant sensory and emotional experience, often accompanied by actual or potential tissue damage.” Pain, as a warning signal, can alert the body to potential dangers and plays an indispensable protective role in normal life activities. Pain is also a common clinical symptom. After the external stimulus that causes pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the living organism. Data show that about one in five people worldwide suffers from moderate or severe chronic pain.
  • action potentials nerve impulses
  • DRG dorsal root ganglia
  • the generation and conduction of action potentials in neurons rely on voltage-gated sodium channels (VGSCs) on the cell membrane. When the cell membrane depolarizes, sodium channels activate and open, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and relieve pain.
  • VGSCs voltage-gated sodium channels
  • Voltage-gated sodium channels are widely present on the cell membranes of excitable cells, such as neurons and skeletal muscle cells. They are transmembrane glycoprotein complexes composed of an ⁇ subunit and several ⁇ subunits.
  • the ⁇ subunit is the functional carrier of the sodium channel and consists of 1700 to 2000 amino acids.
  • the ⁇ subunit plays a primarily auxiliary role, modifying the kinetics and voltage-gating dependence of the ion channel.
  • Sodium channels can be classified based on the differences in the ⁇ subunit.
  • nine sodium channel isoforms namely Na v 1 (Na v 1.1 to Na v 1.9), have been identified in mammals. Different isoforms exhibit distinct tissue distributions and electrophysiological and pharmacological characteristics.
  • TTX-S TTX-sensitive
  • TTX-R TTX-resistant
  • Na v 1.5, Na v 1.8, and Na v 1.9 are of the TTX-R type, with their encoding genes located on human chromosomes 3p21-24.
  • Na v 1.5 is primarily found in cardiomyocytes
  • Na v 1.8 and Na v 1.9 are found in the peripheral nervous system (PNS).
  • PNS peripheral nervous system
  • Nav1.8 is a key ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, making it a highly selective target for pain treatment. It has been shown to act as a carrier of sodium current, sustaining action potential firing in neurons of the small dorsal root ganglion. It also participates in the spontaneous electrical signaling of damaged neurons, driving neuropathic pain.
  • Currently reported small molecule inhibitors of Nav1.8 include PF-01247324, A-803467, PF-06305591, VX-150, HRS-4800, JMKX-000623, HBW-004, and VX-548.
  • PF-01247324, A-803467, and PF-06305591 suffer from poor selectivity, poor pharmacokinetic data, and low bioavailability.
  • the compound further includes stereoisomers and racemates thereof.
  • the above compound is further represented by Formula IA or IB:
  • R a1 and R a3 are each independently selected from hydrogen, halogen, hydroxyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, -N(R c3 R c4 )m, and the alkyl, alkoxy, cycloalkyl, and cycloalkoxy are optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, and amino; R a2 is selected from one or more deuterium- or fluorine-substituted C 1 -C 6 alkyl.
  • any two adjacent Ra1 and Ra3 are linked to form a 5-7 membered ring
  • the 5-7 membered ring may be a saturated or unsaturated carbocyclic ring or heterocyclic ring
  • the 5-7 membered ring may be optionally substituted with one or more halogen, hydroxyl, cyano, C1 - C5 alkyl, C1 - C5 alkoxy, or amino.
  • Ra1 and Ra3 are each independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, and amino.
  • R a2 is arbitrarily selected from 1, 2, or 3 methyl groups substituted with deuterium or fluorine.
  • any two adjacent R a1 and R a3 are linked to form a 5- or 6-membered carbocyclic or heterocyclic ring.
  • the 5-membered or 6-membered heterocyclic ring contains one or two N, O, or S( ⁇ O)m heteroatoms.
  • the 5-membered or 6-membered carbocyclic or heterocyclic ring is optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • R b1 , R b2 , R b3 and R b4 are each independently selected from hydrogen, halogen, hydroxy, C 1 -C 5 alkyl and C 1 -C 5 alkoxy, and the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy and amino groups.
  • R b1 , R b2 , R b3 and R b4 are each independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy and ethoxy.
  • R b1 and R b2 are each independently selected from hydrogen, methyl, and trifluoromethyl;
  • any two of R b1 , R b2 , R b3 , and R b4 are linked to form a 3- to 7-membered ring;
  • the 3- to 7-membered ring may be a saturated or unsaturated carbocyclic ring or heterocyclic ring;
  • the heterocyclic ring may optionally contain one or more N, O, or S( ⁇ O)m heteroatoms;
  • the 3- to 7-membered ring may be further optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • R b1 and R b2 are linked to form a 3-7 membered saturated carbon ring, and the 3-7 membered ring may be optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • R b1 and R b2 are linked to form a three-membered saturated carbon ring, and the three-membered ring may be optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • R b3 and R b4 are linked to form a 3-7 membered saturated carbocyclic ring, and the 3-7 membered ring may be optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • any two of R b1 , R b2 , R b3 , and R b4 are linked to form a 3-7 membered ring, which may be optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • any two of R b1 , R b2 and R b3 , R b4 are linked to form a 3-7 membered saturated carbocyclic ring, which may be optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • any two of R b1 , R b2 , R b3 , and R b4 are linked to form a 3-6 membered saturated carbocyclic ring, which may be optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • any two of R b1 , R b2 and R b3 , and R b4 can be connected by R b1 and R b3 , R b1 and R b4 , R b2 and R b3 , or R b2 and R b4 .
  • M 1 and M 2 are independently selected from C, O, S( ⁇ O) m and NR n , wherein R n is selected from hydrogen and C 1 -C 5 alkyl. In a specific embodiment, R n is selected from hydrogen, methyl or ethyl.
  • ring A has the structure of A1:
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from a bond, C, N, O, C ⁇ O and S( ⁇ O) m ;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are selected from a “bond” to indicate that they are directly connected in the form of a bond, provided that this does not violate the principles of chemical bonding.
  • X 1 is directly connected to X 3 via a bond, and in this case, Ring A is a five-membered ring;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from a bond, C, N, C ⁇ O, and S( ⁇ O) 2 ;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are all selected from C atoms;
  • any of X 1 , X 2 , X 3 , X 4 and X 5 contains one or two N atoms;
  • any of X 1 , X 2 , X 3 , X 4 and X 5 contains a C ⁇ O;
  • any of X 1 , X 2 , X 3 , X 4 and X 5 contains one S( ⁇ O) 2 ;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are arbitrarily selected from a bond, C, S, or O;
  • Ring A has the following structure:
  • X1 , X2 , X3 , and X4 have the same definitions as in Formula A1.
  • X1 , X2 , X3 , and X4 being selected from "bond” means being directly connected in the form of a bond.
  • X3 is selected from a bond
  • X2 is directly connected to X4 via a bond to form a five-membered ring
  • Y1 and Y2 can be the same or different and can be selected from C atoms or N atoms.
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from a bond, C, N, and C ⁇ O;
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from a bond, C, N, and O;
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from a bond, C, N, or S( ⁇ O) m ;
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, N, and C ⁇ O;
  • Ring A has the following structure:
  • R c1 and R c2 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -S( ⁇ O) m -R c3 R c4 , -C( ⁇ O)-NR c3 R c4 , -C( ⁇ S)-NR c3 R c4 , -N(R c3 R c4 ) m , -P( ⁇ O) m -R c3 R c4 , -C( ⁇ N)-NR c3 R c4 , -S( ⁇ O) 2 NR c3 R c4 , -CH 2 NR c3 R c4 , -S( ⁇ O)( ⁇ NR c3 )R c4 ; and the C 1 -C 5 alkyl and C 1 -C 5 alkoxy may be further substituted by one or more substituents selected from the
  • R c1 and R c2 are substituted at any substitutable position on ring A, including substitution on X 1 , X 2 , X 3 , X 4 , Y 1 and Y 2 ; in some embodiments of the present invention, R c1 and R c2 are substituted on a carbon atom; in some embodiments of the present invention, R c1 and R c2 are substituted on a heteroatom.
  • R c3 and R c4 are each independently selected from hydrogen, hydroxyl, amino, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or a 3-7 membered ring, or R c3 and R c4 are linked to form a 3-7 membered ring;
  • the 3-7 membered ring may be a saturated or unsaturated carbocyclic ring or heterocyclic ring;
  • the heterocyclic ring may optionally contain one or more N, O, or S( ⁇ O) m heteroatoms;
  • the 3-7 membered ring may be further optionally substituted with one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • M 1 , Ring A, Ra1 , Ra2 , Ra3 , Rb1 , Rb2 , Rb3 , Rb4 , Rc1 and Rc2 are as defined above.
  • m and n are 0, 1 or 2.
  • the specific compound of the present invention has the following structure:
  • the present invention provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting a voltage-gated sodium channel, wherein the voltage-gated sodium channel is Nav1.8.
  • the present invention provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing or alleviating voltage-gated sodium channel-related diseases, wherein the related diseases include but are not limited to pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia.
  • the pain includes: acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain. Therefore, the present invention further provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing, or alleviating pain.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Pharmaceutically acceptable excipients include fillers, disintegrants, surfactants, and solubilizers.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention can be administered in various known ways, such as oral, topical, rectal, parenteral, inhalation or implantation.
  • the pharmaceutical composition can be prepared into the form of tablets, capsules, bagged granules, dragees, powders, granules, lozenges, powder injections, liquid preparations or suppositories.
  • the present invention provides a use of a compound of formula I or a pharmaceutically acceptable pharmaceutical composition thereof in the preparation of a medicament for treating, preventing or alleviating voltage-gated sodium channel-related diseases, wherein the voltage-gated sodium channel-related diseases include but are not limited to pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia.
  • the pain includes: acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain. Therefore, the present invention further provides a pharmaceutical combination containing a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating, preventing, or alleviating pain.
  • Halogen or "halogen atom” includes fluorine, chlorine, bromine and iodine; in the present invention, preferred halogen is fluorine or chlorine.
  • C 1 -C 5 alkyl refers to a straight or branched chain alkyl group containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, etc.; preferably, C 1 -C 5 alkyl is C 1 -C 3 alkyl, including methyl, ethyl, propyl, isopropyl.
  • C1 - C5 alkoxy refers to a straight-chain or branched alkoxy group containing 1-5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.
  • Preferred C1 - C5 alkoxy groups are C1 - C3 alkoxy groups, including methoxy, ethoxy, propoxy, and isopropoxy.
  • C3 - C6 cycloalkyl refers to a cycloalkyl group containing 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. These cycloalkyl groups may be further substituted with one or more of the following substituents: halogen, hydroxyl, cyano, C1 - C5 alkyl, C1 - C5 alkoxy, and amino.
  • C 3 -C 6 cycloalkoxy refers to a cycloalkoxy group containing 3-6 carbon atoms, including cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
  • the cycloalkoxy group may be further substituted with one or more of the following substituents: halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, and amino.
  • 3-7 membered ring refers to a saturated or unsaturated ring containing 3-7 carbon atoms, such as a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, or a seven-membered ring.
  • the 3-7 membered ring may be further optionally substituted by one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino, where m is 0, 1, or 2.
  • 5-7 membered ring refers to a saturated or unsaturated ring containing 5-7 carbon atoms, such as a 5-membered ring, a 6-membered ring, or a 7-membered ring.
  • the 5-7 membered ring may be further optionally substituted by one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino, where m is 0, 1, or 2.
  • Multiple can be two, three, four or more.
  • multiple halogen substitutions can be trifluoromethyl, difluoromethyl.
  • alkyl, alkoxy, cycloalkyl, cycloalkoxy, 5-7 membered ring, 3-7 membered ring described in the present invention may be optionally substituted with one or more deuterium, halogen, hydroxyl, cyano, oxo, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or amino.
  • a bold or hashed wedge-shaped bond (respectively, ), such as in
  • the prefix "rel-" when used in conjunction with a chiral compound refers to a single enantiomer of unknown absolute configuration.
  • the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound.
  • the compound of formula (A) reacts with the compound of formula (B) to obtain the compound of formula (IB-1) of the present invention, wherein ring A, M1 , Ra1 , Ra2 , Ra3 , Rb1 , Rb2 , Rb3 , Rb4 , Rc1 , Rc2 and n are as defined above.
  • the present invention further prepares specific compounds by the following method. Unless otherwise specified, the compounds, reagents, etc. used in the examples of the present invention were purchased from qualified suppliers or synthesized with reference to methods disclosed in the prior art. The synthesis of some intermediate compounds can refer to the method described in WO2022256660A1, such as the preparation of intermediate 1a with reference to the method of the prior art.
  • Bis(4-methoxybenzyl)amine (4 g, 1.8 mmol, 1.0 eq), methyl 4-bromopicolinate (6.2 g, 2.4 mmol, 1.3 eq), 1,1′-[1,1′-dinaphthyl]-2,2′-diylbis[1,1-diphenyl-(ACI)phosphine (580 mg, 0.09 mmol, 0.05 eq), palladium acetate (210 mg, 0.09 mmol, 0.05 eq), cesium carbonate (12.06 g, 3.7 mmol, 2.0 eq), and toluene (40 mL) were added sequentially to a microwave tube and stirred at 100° C. for 4 hours.
  • Methyl 2-bromo-3-fluoro-5-nitrobenzoate 20b 400 mg, 1.43 mmol, 1.0 eq was dissolved in methanol (10 mL), and Pd(dppf) Cl2 (32 mg, 0.143 mmol, 0.1 eq) and Et3N (437 mg, 4.32 mmol, 3.0 eq) were added. The reaction mixture was stirred at 80°C for 16 hours in the presence of carbon monoxide (0.1 MPa).
  • Step 1 (3Z)-4-(3,4-difluoro-2-methoxyphenyl)-1,1,1-trifluoro-3-methylbut-3-en-2-one (25a)
  • Step 2 rac-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxylic acid ethyl ester (25b)
  • Step 3 rac-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxamide (25c)
  • Step 4 rac-(1R,3R,4R,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-6-(trimethylsilyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (25d)
  • Step 5 rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (25e)
  • Step 6 rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxylic acid (25f)
  • Step 1 Benzyl (2-(S-methylsulfonylimino)pyridin-4-yl)carbamate (34b)
  • Step 1 Benzyl (2-(N,S-dimethylsulfonyl imide)pyridin-4-yl)carbamate (35a)
  • Step 2 (4-aminopyridin-2-yl)(methyl)(methylimino)-1-6-sulfonic acid ketone (35b)
  • 2-bromopyridin-4-amine 43a 200 mg, 1.16 mmol, 1.0 eq was dissolved in 1,4-dioxane (3 mL).
  • Dimethylphosphine oxide 180 mg, 2.31 mmol, 2.0 eq
  • 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene 67 mg, 0.12 mmol, 0.1 eq
  • tris(dibenzylideneacetone)palladium 106 mg, 0.12 mmol, 0.1 eq
  • potassium carbonate 320 mg, 2.3 mmol, 2.0 eq
  • Step 1 Synthesis of (2R,3S,4S,5R)-3- ⁇ (3,4-difluoro-2-[(fluoromethyl)oxy]phenyl) ⁇ -4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid fluoromethyl ester (54a)
  • Step 2 Synthesis of compound (2R,3S,4S,5R)-3- ⁇ (3,4-difluoro-2-[(fluoromethyl)oxy]phenyl) ⁇ -4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (54b)
  • Step 1 (2R,3S,4S,5R)-3-(3,4-difluoro-2-difluoromethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid difluoromethyl ester (55a)
  • Step 2 (2R,3S,4S,5R)-3-(3,4-difluoro-2-difluoromethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (55b)
  • Example 1 (0.22 g, 94% yield).
  • 1 H NMR 400MHz, CD 3 OD
  • 7.157.09 m, 1H
  • Example 54 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(fluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)phthalamide
  • Example 54 was prepared by a method similar to Example 1, using Intermediate 54b instead of 1d.
  • ESI-MS m/z 534.1 (M+1) + .
  • Example 55 was prepared by a synthetic method similar to Example 1, substituting Intermediate 55b for 1d.
  • ESI-MS m/z 552.1 (M+1).
  • Table 1 The following compounds were prepared using the corresponding reagents as starting materials and following procedures similar to those described in Example 1.
  • Step 1 4-( ⁇ [(2R,3S,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteromethyl)oxy]phenyl ⁇ -4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl ⁇ amino)pyridine-2-carboxamide (12a)
  • Step 2 2-Formamido-4-( ⁇ [(2R,3S,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl ⁇ amino)-1-methylpyridinium-1-ol ion (Example 12)
  • Step 5 tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(methyl-d3)carbamate (22f)
  • Step 7 2-Methylpropan-2-yl( ⁇ [4-( ⁇ [(2R,3S,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl ⁇ amino)pyridin-2-yl]dioxylidene- ⁇ 6 -thio ⁇ (trideuteriomethyl)amino)methanoate (22h)
  • Step 8 (2R,3S,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -N-(2- ⁇ dioxyylidene[(trideuteriomethyl)amino]- ⁇ 6 -sulfanyl ⁇ pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide
  • Step 1 tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(ethyl)carbamate (23a)
  • Step 2 2-Methylpropane-2-yl(ethyl ⁇ [4-( ⁇ [(2R,3S,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl ⁇ amino)pyridin-2-yl]dioxyylidene- ⁇ 6 -sulfanyl ⁇ amino)methanoate (23b)
  • Step 2 tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamate (24c)
  • Step 3 2-Methylpropan-2-yl( ⁇ [4-( ⁇ [(2R,3S,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl ⁇ amino)pyridin-2-yl]dioxyylidene- ⁇ 6 -thio ⁇ (2,2,2-trifluoroethyl)amino)methanoate (24d)
  • Step 4 (2R,3S,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -N-(2- ⁇ dioxyylidene[(2,2,2-trifluoroethyl)amino]- ⁇ 6 -sulfanyl ⁇ pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 24)
  • Step 6 rac-(2R,3R,4S,5R)-N-[2-(aminodioxyylidene- ⁇ 6 -sulfanyl)pyridin-4-yl]-3- ⁇ 3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl ⁇ -3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 28)
  • Step 1 Compound ((4-bromopyridin-2-yl)sulfonyl)(methyl)carbamic acid tert-butyl ester (29a)
  • Step 2 rac-(3aR,3S,5aR)-3- ⁇ 3,4-difluoro-2-[(trideuteromethyl)oxy]phenyl ⁇ -3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[1,2-b]furan-2-carboxamide (29b)
  • Step 3 rac-(2R,3R,4S,5R)- ⁇ [(4- ⁇ [(3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutano[2,1-b]furan-2-yl)carbonyl]amino ⁇ pyridin-2-yl)dioxyylidene- ⁇ 6 -thio](methyl)amino ⁇ methanoic acid-2-methylpropan-2-yl ester (29c)
  • Step 4 rac-(2R,3R,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -3a-methyl-N- ⁇ 2-[(methylamino)dioxyylidene- ⁇ 6 -thio]pyridin-4-yl ⁇ -5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 29)
  • compound 1-(4-bromopyridin-2-yl)ethane-1-one 30a 300 mg, 1.50 mmol, 1.00 eq
  • toluene 3 mL
  • tert-butyldimethylsilyl trifluoromethanesulfonate 595 mg, 2.25 mmol, 1.50 eq
  • triethylamine 326 mg, 3.22 mmol, 2.15 eq
  • the reaction solution was stirred at 80°C for 2 hours.
  • the reaction solution was concentrated, and acetonitrile (3 mL) and a selective fluorine reagent (537 mg, 1.51 mmol, 1.01 eq) were added.
  • Step 3 4-Bromo-2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridine (30d)
  • Step 4 rac-(2R,3R,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl ⁇ -N-[2-(1-fluoro-4,4,5,5-tetramethyl-3-oxa-4-silan-2-yl)pyridin-4-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (30e)
  • Step 5 rac-(2R,3R,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl ⁇ -N-[2-(2-fluoro-1-hydroxyethyl)pyridin-4-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 30)
  • reaction mixture was stirred at 25°C for 0.5 hours.
  • LCMS monitored the reaction completion of the starting material reaction.
  • Step 2 rac-(4-(2R,3R,4S,5R)- ⁇ [(4- ⁇ [(3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-yl)carbonyl]amino ⁇ pyridin-2-yl)methyl][(3S)-tetrahydrofuran-3-yl]amino ⁇ methanoic acid-2-methylpropan-2-yl ester (31d)
  • Step 3 rac-(2R,3R,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl ⁇ -N-[2-( ⁇ [(3S)-tetrahydrofuran-3-yl]amino ⁇ methyl)pyridin-4-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 31)
  • Example 32 rac-(2R,3R,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -3a-methyl-5a-(trifluoromethyl)-N-[2-(5-aza-2-oxahex-6-yl)pyridin-4-yl]hexahydrocyclobutane[2,1-b]furan-2-carboxamide
  • Step 4 rac-(1R,3R,4S,5R)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -N-[6-(2,2-dimethyl-1,3-dioxolane-4-yl)pyridin-3-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (36e)
  • Step 5 rac-(1R,3R,4S,5R)-03- ⁇ 3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl ⁇ -N-[6-(1,2-dihydroxyethyl)pyridin-3-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 36)
  • Example 40 rac-(2R,3R,4S,5R)-N-[6-(aminodioxyylidene- ⁇ 6 -sulfanyl)pyridin-3-yl]-3- ⁇ 3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl ⁇ -3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide
  • tert-Butyl 3-oxo-1-piperazinecarboxylate (1.37 g, 6.82 mmol, 1.2 eq) was dissolved in DMF (15 mL), cooled to 0°C, and sodium hydride (341 mg, 8.52 mmol, 1.5 eq) was added. The mixture was stirred for 30 minutes.
  • 2-Fluoro-5-bromopyridine 100a (1.0 g, 5.68 mmol, 1.0 eq) was added, and the temperature was raised to 60°C and stirred for 16 hours. Water was added and the mixture was extracted with ethyl acetate (50 mL*3).
  • Step 2 rac-tert-butyl 4-(4-((1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteromethoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamido)pyridin-2-yl)-3-oxopiperazine-1-carboxylate (41c)
  • Step 3 rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteromethoxyphenyl)-5-methyl-N-(2-(2-oxopiperazin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (41d)
  • Step 4 rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteriomethoxyphenyl)-5-methyl-N-(2-(4-methyl-2-oxopiperazin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 41)
  • Step 3 rac-(2R,3S,4S,5R)-N-(2-acetoxy-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl)-3- ⁇ 3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl ⁇ -4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (45d)
  • the experimental test was performed using a CHO cell line stably expressing the Nav1.8 sodium channel.
  • Gene information Sodium channel, voltage-gated, type 8, alpha (SCN10A), cDNA strictly similar to GenBank accession number: NM_006514.
  • Electrophysiological recording solutions Extracellular solution: K-007-1, 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2 ⁇ 6H2O , 2 mM CaCl2 ⁇ 2H2O, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH2PO4 ⁇ 2H2O , pH adjusted to 7.4 with NaOH.
  • Intracellular solution Nav- 001-2 , 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH adjusted to 7.2 with CsOH.
  • the extracellular solution has a shelf life of 2 weeks.
  • intracellular solution was aliquoted into 1 mL tubes and stored frozen at -20°C. Freshly thawed intracellular solution was used daily for each experiment. All intracellular solutions were used within 3 months. If the intracellular solution is older than three months, discard it and prepare a new one.
  • Patch clamp assay The voltage stimulation protocol for whole-cell patch clamp recording of Nav1.8 sodium currents is as follows: After the whole-cell seal is formed, the cell voltage is clamped at -120 mV for 30 ms. The clamping voltage is depolarized to 0 mV for 50 ms, and then the voltage is restored to -50 mV (the specific voltage refers to the half-inactivation voltage of the IV test) and maintained for 5 s. The cell membrane potential is then restored to -120 mV and maintained for 20 ms, then depolarized to 0 mV again for 50 ms, and finally restored to the clamping voltage of -120 mV and maintained for 30 ms. Data are collected repeatedly every 20 ms. The effect of drugs on the peak sodium current is observed. The experimental data are collected by an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.
  • HEKA EPC 10 amplifier
  • HEKA PatchMaster
  • Electrodes are drawn from capillary glass tubes using a microelectrode puller.
  • the electrodes, filled with intracellular fluid, are placed in an electrode holder.
  • the microelectrode manipulator is used to immerse the electrodes in extracellular fluid and record the electrode resistance (Rpip).
  • the electrodes are placed in contact with the cell surface and negative pressure is applied to create a high-resistance seal (G ⁇ ).
  • Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode.
  • Slow capacitance compensation is then performed, and experimental parameters such as membrane capacitance (Cm) and series resistance (Rs) are recorded. No leakage compensation is performed.
  • the drug is administered. After each drug concentration is applied for 5 minutes (or the current is stable), the next concentration is detected. Multiple concentrations are detected for each test compound.
  • the coverslip with cells is placed in a recording bath under an inverted microscope.
  • the blank control external solution and the working solution of the test compound are passed through the recording bath from low concentration to high concentration by gravity perfusion to act on the cells.
  • a peristaltic pump is used for liquid exchange during recording.
  • the current detected for each cell in the external solution without the compound serves as its own control group. At least three cells are used for each concentration and the test is repeated three times independently. All electrophysiological experiments were performed at room temperature.
  • IC50 value of each compound was calculated using the above equation, and a nonlinear fit was performed on the dose-dependent effect, where IC50 is the half-inhibitory concentration. IC50 calculations and curve fitting were performed using GraphPad Prism software.
  • Step 1 Preparation of working solutions of test compounds and control compounds: 5 ⁇ L of stock solution (10 mM in DMSO) was added to 495 ⁇ L of acetonitrile solution (i.e., 100 ⁇ M, 99% acetonitrile). Testosterone, diclofenac, and propafenone were used as controls in this experiment.
  • Step 2 Prepare NADPH coenzyme working solution: ⁇ -nicotinamide adenine dinucleotide phosphate (reduced form), tetrasodium salt (supplier: BONTAC, catalog number: BT04). Weigh an appropriate amount of NADPH powder and dilute it to a 10 mM MgCl2 solution.
  • Step 3 Prepare liver microsomes: Use 100 mM potassium phosphate buffer to prepare liver microsomes into a 0.56 mg/mL working solution.
  • Step 4 Preparation of stop solution: cold (4°C) acetonitrile to which 250 nM toluene butanamide and 250 nM labetalol as internal standards were added was used as the stop solution.
  • liver microsome working solution (0.56 mg/mL) to the preheated T60 and NCF60 plates and stir thoroughly.
  • Step 6 Data analysis: Calculate T1/2 and CLint(mic) ( ⁇ L/min/mg) using the first-order kinetic equation.
  • Example 1 of the present invention has better metabolic stability than Reference Compound 1, and may have better pharmacokinetics, safety and efficacy.
  • Preparation method Weigh appropriate amounts of each compound and add DMSO, Solutol HS 15, Tween 80, and saline in that order to obtain a final concentration of 0.5 mg/mL for oral administration to animals.
  • mice Male SD rats (sourced from Weitong Lihua Laboratory Animal Technology Co., Ltd.) were fasted for at least 12 hours (with free access to water) and then gavage administered with a dose of 10 mL/kg.
  • Approximately 0.2 mL of blood was collected from the jugular sinus before dosing, i.e., 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 10 h, and 24 h after dosing.
  • the collected 0.2 mL of whole blood was placed in a pre-chilled EDTA-K2 anticoagulant tube and centrifuged at 4°C (1500-1600 g) for 10 min. Plasma was separated and stored at -90 to -60°C for analysis.
  • the pharmacokinetic parameters of rats are shown in Table 5. Compared with the control compound 1, the compound of the present invention has a higher peak blood concentration and a higher plasma exposure, indicating that the compound provided by the present invention has better pharmacokinetic properties and has a better application prospect in the treatment of pain.

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Abstract

L'invention concerne un nouveau composé modulateur de canal sodique et son utilisation. Le modulateur de canal sodique a une structure complètement nouvelle telle que représentée dans la formule I, et présente d'excellents effets inhibiteurs in vitro contre Nav 1.8. Le composé ou un sel pharmaceutiquement acceptable de celui-ci peut être utilisé pour traiter des maladies liées au canal sodique, y compris des maladies telles que la douleur, la sclérose en plaques, la maladie de Charcot-Marie-Tooth, l'incontinence, la toux pathologique ou l'arythmie.
PCT/CN2025/074442 2024-01-31 2025-01-23 Nouveau composé modulateur de canal sodique et son utilisation Pending WO2025162194A1 (fr)

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CN114945566A (zh) * 2019-12-06 2022-08-26 沃泰克斯药物股份有限公司 作为钠通道调节剂的取代四氢呋喃
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WO2022256679A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2022256660A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Procédé de synthèse de modulateurs de tétrahydrofurane substitués de canaux sodiques
WO2022256676A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de tétrahydrofurane substitués utiles en tant que modulateurs de canaux sodiques
WO2024146632A1 (fr) * 2023-01-06 2024-07-11 西藏海思科制药有限公司 Dérivé de tétrahydrothiophène et son utilisation en médecine
CN118388466A (zh) * 2024-04-23 2024-07-26 安润医药科技（苏州）有限公司 作钠通道调节剂的酰胺衍生物及其用途
WO2024217557A1 (fr) * 2023-04-19 2024-10-24 武汉人福创新药物研发中心有限公司 Tétrahydrofuranes substitués en tant qu'inhibiteurs de nav1.8
CN119143737A (zh) * 2024-11-18 2024-12-17 嘉兴安帝康生物科技有限公司 四氢呋喃甲酰胺类钠通道调节剂及其在医药上的应用
CN119371405A (zh) * 2023-07-26 2025-01-28 上海闻耐医药科技有限公司 多取代吡咯烷类衍生物、其制备方法及用途

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1073161A (zh) * 1991-11-05 1993-06-16 史密丝克莱恩比彻姆公司 Et(endothelin)受体拮抗物
CN114945566A (zh) * 2019-12-06 2022-08-26 沃泰克斯药物股份有限公司 作为钠通道调节剂的取代四氢呋喃
WO2022256660A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Procédé de synthèse de modulateurs de tétrahydrofurane substitués de canaux sodiques
WO2022256842A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuranes à substitution hydroxy et (halo)alkoxy utiles en tant que modulateurs de canaux sodiques
WO2022256702A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuran-2-carboxamides substitués utiles en tant que modulateurs de canaux sodiques
WO2022256679A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2022256622A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hétéro)aryl) tétrahydrofuran carboxamides utilisés en tant que modulateurs de canaux sodiques
WO2022256676A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de tétrahydrofurane substitués utiles en tant que modulateurs de canaux sodiques
WO2024146632A1 (fr) * 2023-01-06 2024-07-11 西藏海思科制药有限公司 Dérivé de tétrahydrothiophène et son utilisation en médecine
WO2024217557A1 (fr) * 2023-04-19 2024-10-24 武汉人福创新药物研发中心有限公司 Tétrahydrofuranes substitués en tant qu'inhibiteurs de nav1.8
CN119371405A (zh) * 2023-07-26 2025-01-28 上海闻耐医药科技有限公司 多取代吡咯烷类衍生物、其制备方法及用途
CN118388466A (zh) * 2024-04-23 2024-07-26 安润医药科技（苏州）有限公司 作钠通道调节剂的酰胺衍生物及其用途
CN119143737A (zh) * 2024-11-18 2024-12-17 嘉兴安帝康生物科技有限公司 四氢呋喃甲酰胺类钠通道调节剂及其在医药上的应用

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