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WO2025153011A1 - Antagoniste du récepteur de l'angiotensine ii et son utilisation dans le traitement de la douleur neuropathique induite en périphérie - Google Patents

Antagoniste du récepteur de l'angiotensine ii et son utilisation dans le traitement de la douleur neuropathique induite en périphérie

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Publication number
WO2025153011A1
WO2025153011A1 PCT/CN2025/072712 CN2025072712W WO2025153011A1 WO 2025153011 A1 WO2025153011 A1 WO 2025153011A1 CN 2025072712 W CN2025072712 W CN 2025072712W WO 2025153011 A1 WO2025153011 A1 WO 2025153011A1
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WIPO (PCT)
Prior art keywords
optionally substituted
alkylene
compound
stereoisomer
polymorph
Prior art date
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Pending
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PCT/CN2025/072712
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English (en)
Chinese (zh)
Inventor
王红军
梁会宁
王晓倩
赵焰平
兰洲
候思予
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Beijing Tide Pharmaceutical Co Ltd
Original Assignee
Beijing Tide Pharmaceutical Co Ltd
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Application filed by Beijing Tide Pharmaceutical Co Ltd filed Critical Beijing Tide Pharmaceutical Co Ltd
Publication of WO2025153011A1 publication Critical patent/WO2025153011A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to angiotensin II type 2 (AT 2 ) receptor antagonists and their use in preventing or treating peripheral neuropathic pain and related disorders.
  • AT 2 angiotensin II type 2
  • the renin-angiotensin system plays an important role in neuroprotection and neuroregeneration, regulating arterial blood pressure and ion homeostasis.
  • AT1R and AT2R are mainly AT 2 receptor subtypes.
  • AT 2 receptor-specific antagonists are valuable in the treatment of various cerebrovascular, cognitive and central nervous system (CNS) diseases.
  • AT 2 receptors are found in neuronal tumor cells and transformed human neural cells. AT 2 receptors are also involved in the differentiation and regeneration of neuronal tissue and the maintenance of bone.
  • AT2R is expressed in damaged nerves and invasive immune cells and is associated with neurological pain.
  • peripheral neuropathic pain refers to chronic pain caused by damage or disease of the peripheral sensory nervous system.
  • Peripheral neuropathic pain can be divided into five subtypes: trigeminal neuralgia, chronic neuropathic pain after peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. (Chronic neuropathic pain, Chinese Journal of Pain Medicine 2021, 27(7)).
  • peripheral nerve damage and lesions lead to pNP the course of the disease is long and the clinical manifestations are complex, such as sensory impairment, movement disorders, autonomic dysfunction, and pain symptoms in the corresponding nerve innervation area.
  • the pain can be spontaneous, persistent pain or paroxysmal pain.
  • patients may experience symptoms such as muscle spasms, stiffness, weakness and atrophy.
  • Physical examination can show decreased muscle tone, muscle atrophy, weakening, disappearance of tendon reflexes, and paresthesia. Even if the original cause is removed, the injury is healed or effectively controlled, the pain will still persist, seriously affecting the patient's quality of life and accompanied by emotional disorders (Editorial Committee of Chinese Expert Consensus on Peripheral Neuropathic Pain.
  • PDPN Painful diabetic peripheral neuropathy
  • Postherpetic neuralgia is also a common type of pNP, with an annual incidence of 3.9 to 42.0/100,000. 9% to 34% of herpes zoster patients will develop PHN.
  • patients aged ⁇ 40 years who visited the dermatology, neurology and pain departments of urban hospitals in my country the overall prevalence of herpes zoster was 7.7%, and the overall prevalence of PHN was 2.3%. Both prevalences tended to increase gradually with age.
  • Trigeminal neuralgia is a common cranial nerve disease in clinical practice, with a prevalence of 182 people per 100,000 and an annual incidence of 3 to 5 per 100,000. It mostly occurs in adults and the elderly, with a peak age of 48 to 59 years old.
  • peripheral neuropathic pain has a profound emotional and socioeconomic impact on patients, while existing therapeutic drugs and treatments have limited efficacy and relatively large side effects. Therefore, pNP has a significant unmet medical need.
  • the present invention particularly provides the use of AT2 receptor antagonist compounds in preventing or treating peripheral neuropathic pain (pNP).
  • pNP peripheral neuropathic pain
  • the mechanism of the present invention is that, due to the action of AngII on AT2 receptors, inflammatory factors such as reactive oxygen free radicals (ROS) are produced in the skin/peripheral macrophages of damaged nerves, and ROS act on the dorsal root ganglion, causing calcium ion influx in the neurons of the dorsal root ganglion to produce hypersensitive pain.
  • AT2 receptor antagonists can reduce the recruitment of macrophages at the pain site, inhibit the high expression of AT2 receptors in macrophages, inhibit the generation of reactive oxygen/nitrogen by inhibiting AT2 receptors, and then inhibit pain signal transmission.
  • the present invention exerts analgesic effects from the immune cells of the peripheral nervous system, rather than acting through the central nervous system, thereby avoiding the central side effects caused by previous drugs.
  • the present invention provides the use of compounds as AT2 receptor antagonists in preventing or treating peripheral neuropathic pain associated with macrophages, in particular preventing or treating peripheral neuropathic pain associated with the recruitment/aggregation of macrophages, peripheral neuropathic pain associated with high expression of AT2 receptors in macrophages and/or peripheral neuropathic pain associated with increased levels of reactive oxygen/nitrogen produced by macrophages.
  • the present application provides the following embodiments of AT2 receptor antagonist compounds:
  • U is a C 1-3 alkylene group
  • R 1a is selected from: C 2-8 alkenyl and C 2-8 alkynyl, wherein the C 2-8 alkenyl and C 2-8 alkynyl are each substituted with one C 6-10 aryl or 5-14 membered heteroaryl; C 6-10 aryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; -C 1-6 alkylene-saturated or partially unsaturated 3-10 membered heterocyclyl; -C 1-6 alkylene -C 6-10 aryl; and -C 1-6 alkylene-(5-14 membered heteroaryl);
  • R 1b is absent or is selected from: H; C 1-8 alkyl optionally substituted by 1, 2 , 3 or more R 13 ; saturated or partially unsaturated C 3-10 cycloalkyl; C 6-10 aryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; and -C 1-6 alkylene-C 6-10 aryl;
  • X 1 does not exist or is CR 10 or N;
  • R 2a is C 6-10 aryl
  • R 2b is C 6-10 aryl
  • X 2 is CR 10 or N
  • R4 is H
  • R 10 at each occurrence, is selected from H, -OR 11 , -SR 11 and C 1-6 alkyl;
  • R 11 and R 12 are each independently H or C 1-6 alkyl at each occurrence;
  • h and k are each independently 1;
  • alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1, 2, 3 or more R 13 at each occurrence;
  • Said R 13 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, -OR 11 , -SR 11 , -P(O)R 11 R 12 and -NR 11 R 12 , and wherein the alkyl, alkylene, aryl and heteroaryl described for the substituent R 13 are optionally further substituted with 1, 2, 3 or more substituents independently selected from halogen and C 1-6 alkyl.
  • R 13 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, -OR 11 , -SR 11 and -NR 11 R 12 , and wherein the alkyl, aryl and heteroaryl described for the substituent R 13 are optionally further substituted with 1, 2, 3 or more substituents independently selected from halogen and C 1-6 alkyl.
  • R 13 at each occurrence is independently selected from: F, Cl, Br, I, amino, cyano, nitro; C 1-4 alkyl optionally substituted with 1, 2, 3 or more substituents independently selected from halogen; C 5-7 cycloalkyl; phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl, each optionally substituted with 1, 2, 3 or more substituents independently selected from halogen, OH, amino, cyano and C 1-4 alkyl; wherein R 11 is -OR 11 of C 1-6 alkyl optionally substituted with 1, 2, 3 or more halogen; wherein R 11 is -SR 11 of C 1-6 alkyl optionally substituted with 1, 2, 3 or more halogen; and wherein R 11 and R 12 is independently at each occurrence -NR
  • R 13 at each occurrence is independently selected from: F, Cl, Br, I, amino, cyano, nitro; C 1-4 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R 11 is -OR 11 of C 1-3 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R 11 is -SR 11 of C 1-3 alkyl optionally substituted with 1, 2, 3 F or Cl; wherein R 11 and R 12 at each occurrence are independently -NR 11 R 12 or -P(O)R 11 R 12 of C 1-3 alkyl ; phenyl, 5-6 membered heteroaryl and 9-10 membered heteroaryl, each optionally substituted by 1, 2, 3 or more substituents independently selected from F, Cl, Br, I and methyl.
  • R 1a is selected from: C 2-6 alkenyl and C 2-6 alkynyl, wherein the C 2-6 alkenyl and C 2-6 alkynyl are each substituted with one phenyl or 5-10 membered heteroaryl; phenyl; -C 1-3 alkylene-C 3-7 cycloalkyl; -C 1-3 alkylene-(5-7 membered monocyclic heterocyclyl); -C 1-3 alkylene-(8-10 membered benzo-fused heterocyclyl); -C 1-3 alkylene-phenyl; and -C 1-3 alkylene-(5-10 membered heteroaryl);
  • R 1b is absent or is selected from: H; C 1-6 alkyl; C 3-7 cycloalkyl; phenyl; -C 1-3 alkylene-C 3-7 cycloalkyl; and -C 1-3 alkylene-phenyl; and
  • alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1, 2, 3 or more R 13 as defined in Embodiment 1 at each occurrence.
  • R 1b is a group selected from the group consisting of H, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted phenyl, -optionally substituted C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), and -optionally substituted C 1-3 alkylene-optionally substituted phenyl;
  • R 2a is optionally substituted phenyl
  • R 2b is optionally substituted phenyl
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R 1b is selected from: H, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted phenyl, -C 1-3 alkylene-(optionally substituted C 3-7 -cycloalkyl) and -C 1-3 alkylene optionally substituted phenyl.
  • U is ethylene
  • R 1a is selected from: -C 1-6 alkylene-C 6-10 aryl; and -C 1-6 alkylene-(5-14 membered heteroaryl);
  • R 1b is selected from: C 1-8 alkyl; saturated C 3-10 cycloalkyl; and -C 1-6 alkylene-saturated C 3-10 cycloalkyl;
  • R4 is H
  • h and k are each independently 1;
  • cycloalkyl, aryl and heteroaryl are each optionally substituted by 1 R 13 at each occurrence; said R 13 is C 1-6 alkyl;
  • the C 6-10 aryl group is phenyl
  • the saturated C 3-10 cycloalkyl group is cyclopropyl
  • the 5-14 membered heteroaryl group is thienyl or benzothienyl.
  • the present application provides the following embodiments, which relate to the use of the compound as described in the first aspect in the preparation of a drug for treating a disease.
  • the secondary neuropathy includes: diabetic neuropathy; herpes zoster-associated neuropathy; uremia-associated neuropathy; amyloid neuropathy; HIV sensory neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcerous lesions; nitrofurantoin neuropathy; sausage-like swelling neuropathy; neuropathy caused by nutritional deficiency; neuropathy and complex regional pain syndrome caused by renal failure; neuropathy caused by repetitive activities (such as typing or working on an assembly line); peripheral neuropathy caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapeutic drugs (such as vincristine), alcohol, lead, arsenic, mercury and organophosphate pesticides; and peripheral neuropathy associated with infectious processes (such as Guillain-Barré syndrome).
  • the secondary neuropathy includes: diabetic neuropathy; herpes zoster-associated
  • any one of embodiments 44-50, wherein the medicament is for preventing or treating a condition or symptoms associated therewith selected from the group consisting of trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.
  • any one of embodiments 44-50, wherein the medicament is for preventing or treating a condition or symptoms associated therewith selected from the group consisting of postoperative neuralgia, trigeminal neuralgia, chronic neuropathic pain following peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, or painful radiculopathy.
  • a condition or symptoms associated therewith selected from the following: painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.
  • a condition or symptoms associated therewith selected from the following: painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or post-traumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.
  • the present application provides the following embodiments, which relate to a method for treating a disease, comprising administering a therapeutically effective amount of the compound as described in the first aspect to a patient in need thereof.
  • a method for preventing or treating macrophage-associated peripheral neuropathic pain comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite or prodrug thereof.
  • the secondary neuropathy includes: diabetic neuropathy; herpes zoster-associated neuropathy; uremia-associated neuropathy; amyloid neuropathy; HIV sensory neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcerous lesions; nitrofurantoin neuropathy; sausage-like swelling neuropathy; neuropathy caused by nutritional deficiencies; neuropathy and complex regional pain syndrome caused by renal failure; neuropathy caused by repetitive activities (such as typing or working on an assembly line); peripheral neuropathy caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapeutic drugs (such as vincristine), alcohol, lead, arsenic, mercury and organophosphate pesticides; and peripheral neuropathy associated with infectious processes (such as Guillain-Barré syndrome).
  • antiretroviral drugs such as zalcitabine and didanosine
  • antibiotics such
  • any one of embodiments 53-59 wherein the disease is a condition or symptoms associated therewith selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.
  • the disease is a condition or symptoms associated therewith selected from the group consisting of painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or posttraumatic neuropathic pain, chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.
  • 61a The method of any one of embodiments 53-59, wherein the disease is a condition selected from the following or symptoms associated therewith: painful diabetic peripheral neuropathy, postherpetic neuralgia, peripheral nerve entrapment syndrome (carpal tunnel syndrome, etc.), cranial neuralgia, postoperative or post-traumatic neuropathic pain (including chronic postoperative neuralgia), chemotherapy-related neuropathic pain, and HIV (human immunodeficiency virus) painful sensory neuropathy.
  • alkylene refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12 carbon atoms, particularly 1 to 8 (“C 1-8 alkyl”), such as 1 to 6 carbon atoms (“C 1-6 alkyl”), 1 to 4 carbon atoms (“C 1-4 alkyl”), and more particularly 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • C1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2 to 8 carbon atoms (" C2-8 alkenyl", for example " C2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, heptenyl and octenyl.
  • the compound of the present invention contains an alkenylene group, the compound may be present in the pure E (ent ought) form, the pure Z (zusammen) form or any mixture thereof.
  • alkynyl means a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6, 7 or 8 carbon atoms, for example ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, etc.
  • cycloalkylene refers to saturated (i.e., “cycloalkylene” and “cycloalkyl") or unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6, such as 5-6 or 5-7) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.
  • heterocyclyl refers to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or bicyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6; or, suitably 8-10, more suitably 9 or 10) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C.
  • a “3-10 membered (sub)heterocyclyl” is a saturated or partially unsaturated monocyclic or bicyclic (sub)heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • Examples of monocyclic heterocyclylene and heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.
  • monocyclic heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl (e.g., pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl (e.g., morpholino), thiomorpholinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,3-oxazinane, 1,3-thiazinane, 1,3-thiazin ane), hexahydropyrimidinyl, 1,3-oxathiane, 1,4-oxathiane, 1,3-diazepane, 1,4-diazepane, 1,3
  • Bicyclic heterocyclylene and heterocycle include spiro systems, fused (e.g., benzofused) systems or bridged systems.
  • Benzo-fused heterocyclylene and heterocyclyl refer to the monocyclic heterocyclylene and heterocyclyl described above fused to benzo, such as benzo derivatives of saturated or partially unsaturated monocyclic groups having 3-6 (suitably 4-6, more suitably 5-6) ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms selected from N, O and S and the remaining ring atoms are C (i.e., "7-10 membered benzo-fused heterocyclyl"), including, for example, 2,3-dihydrobenzofuranyl.
  • (ylidene)aryl and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • C 6-10 (ylidene)aryl and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as (ylidene)phenyl (benzene ring) or (ylidene)naphthyl (naphthalene ring).
  • the (ylidene)aryl group and the aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • suitable substituents e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.
  • heteroaryl(ene) and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case additionally may be benzo-fused.
  • heteroaryl or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl), isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl (e.g., 1-tetrazolyl or 5-tetrazolyl), thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.
  • pyrazolyl e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl
  • isoxazolyl iso
  • heteroaryl or “heteroaromatic ring” include pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl and purinyl.
  • aralkyl preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl may have 6-14 carbon atoms
  • the heteroaryl may have 5-14 ring atoms
  • the alkyl may have 1-6 carbon atoms.
  • Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br, or I.
  • substituted means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H
  • Certain isotopically labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because they are easily incorporated and easily detected.
  • Substitution with positron emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or in the examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.
  • Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • stereoisomer means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc.
  • solid lines can be used Solid wedge Virtual wedge Carbon-carbon bonds of the compounds of the invention.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention” herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts.
  • bases include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.
  • esters means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • the amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.
  • peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane such as dimethyldioxirane
  • Mouse peritoneal macrophages express angiotensin II type 2 receptor (AT2R).
  • Angiotensin II (AngII) as a ligand of AT2R, can induce an increase in reactive oxygen free radicals (ROS) produced by mouse peritoneal macrophages by binding to AT2R receptors.
  • ROS reactive oxygen free radicals
  • mice After euthanasia of 6-week-old C57BL/6 male mice, primary peritoneal macrophages of mice were obtained by intraperitoneal injection of phenol red-free medium, centrifuged and suspended in RPMI1640+5% FBS (containing 50ng/ ⁇ l GM-CSF) medium, and cultured in a 37°C, 5% CO2 incubator for 2 days. The above macrophages were seeded in 96-well plates.
  • the macrophages were stained with the reactive oxygen species (ROS) indicator DCFH-DA and treated as follows: 1) blank solvent group; 2) AngII (0.2 ⁇ M) treatment group alone; 3) PD123319 combined with AngII group (PD (1 ⁇ M) + AngII (0.2 ⁇ M)): PD123319+AngII group 319 was co-treated with AngII for 0.5 h; 4) A1 combined with AngII group (A1 (0.5 ⁇ M) + AngII (0.2 ⁇ M)): A1 (0.5 ⁇ M) was co-treated with AngII for 0.5 h; 5) A1 combined with AngII group (A1 (5 ⁇ M) + AngII (0.2 ⁇ M)): A1 (5 ⁇ M) was co-treated with AngII for 0.5 h, and the production level of reactive oxygen species (ROS) in macrophages of each group was determined by real-time fluorescence scanning.
  • ROS reactive oxygen species
  • IACUC approval number IACUC-202104-r-001.
  • rats were subjected to plantar Von Frey fiber pain measurement once to screen out animals weighing more than 10g. After fasting but not water deprivation for 16 hours, a single intraperitoneal injection of 40mg/kg (animal body weight 220-250g) or 50mg/kg (animal body weight 180-220g) STZ was given. Random blood glucose levels were tested 72 hours later, and a blood glucose level ⁇ 16.7mmol/L indicated a successful diabetic model. Rats with successful diabetic modeling were trained with plantar Von Frey fiber pain measurement once a week. After 4 or 5 weeks, animals with 50% PWT values in the range of 1-6g were selected as diabetic foot pain animals.
  • the rats were randomly divided into 7 groups according to the pain threshold before administration: control solvent (ddH 2 O), gabapentin 100 mg/kg, A1 (12.5, 25, 50, 100 and 200 mg/kg), 10 rats/group, the administration volume was 10 mL/kg, and the drug was administered by oral gavage.
  • Von Frey fiber filament pain measurement was performed 2, 4 and 6 hours after administration, and the drug efficacy was evaluated based on the change of 50% PWT of rats.
  • SD rats were completely anesthetized by intraperitoneal injection of sodium pentobarbital (50 mg/kg).
  • the animal's lumbar surgical area was shaved, and the skin was disinfected three times with iodine and 70% ethanol.
  • the surgery began after the skin was dry, and the surgical procedure was performed aseptically.
  • the left sciatic nerve was separated, and four 4-0 chromic gut sutures were used to loosely ligate the sciatic nerve about 7 mm upstream of the bifurcation of the sciatic nerve, with a spacing of about 1 mm.
  • the wound was sutured to complete the rat CCI model.
  • the basal value of mechanical allodynia was measured in the rats.
  • the animals without mechanical allodynia (foot withdrawal threshold greater than 5g) and animals with foot withdrawal threshold less than 0.5g were eliminated and randomly divided into 5 groups according to the basal foot withdrawal threshold: vehicle control group (ddH2O), Olodanrigan 200mg/kg, A3 100mg/kg, A1 200mg/kg, 8 rats/group, 5mL/kg was administered by gavage.
  • vehicle control group ddH2O
  • Olodanrigan 200mg/kg A3 100mg/kg
  • A1 200mg/kg 8 rats/group
  • 5mL/kg was administered by gavage.
  • Figure 4 shows the efficacy evaluation of AT2R antagonists on the rat sciatic nerve chronic compression injury model.
  • A3 100 mg/kg 2h and 4h after administration A1 200 mg/kg 2h after administration, can significantly inhibit the mechanical allodynia caused by sciatic nerve compression in rats.
  • Olodanrigan 200 mg/kg 2h and 4h after administration did not inhibit the mechanical allodynia induced by sciatic nerve compression in rats.
  • the Von Frey electronic analgesia was used to evaluate the analgesic effect of AT2R antagonists on the sciatic nerve branch injury (SNI) model in mice, and to study the effects of AT2R antagonists on the co-staining of AT2R receptors and F4/80 on macrophages in the SNI model of mice, as well as the expression of transient receptor potential ion channel subunit 1 (TRPA1) in dorsal root ganglion (DRG) neurons.
  • SNI sciatic nerve branch injury
  • TRPA1 transient receptor potential ion channel subunit 1
  • mice were fully anesthetized by inhalation of isoflurane, and fixed on the operating table in a prone position to fully expose the lateral buttocks.
  • the left posterior branch was shaved and disinfected with alcohol.
  • the surgical procedure was performed aseptically.
  • SNI surgical group The mouse skin was cut in the direction of the femur parallel to the sciatic nerve to expose the sciatic nerve trunk until the tibial nerve, common peroneal nerve and sural nerve were exposed.
  • the tibial nerve and common peroneal nerve of the mouse were tightly ligated with medical absorbable sutures (8-0), and then a section of nerve (about 2-4mm) was cut from the ligation site of the tibial nerve and common peroneal nerve to the distal nerve to ensure the integrity of the sural nerve.
  • the muscles and epidermis were sutured layer by layer to complete the mouse SNI model.
  • mice were randomly divided into 5 groups (SNI model group) according to their body weight and PWT value: solvent control group (sterile water for injection), Gabapetin 50mg/kg, A1 50mg/kg, A1 100mg/kg, A1 200mg/kg, 12 mice/group, 10mL/kg was administered by gavage.
  • the paw withdrawal threshold was tested using a Von Frey electronic analgesic at 0 h before administration and 2 and 4 h after administration.
  • the animals were placed in a special multi-unit metal mesh cage for pain detection and adapted to the environment for 30 minutes.
  • an electronic analgesic Electric von Frey Anesthesiometer, IITC Life Science Inc.
  • the reading recorded by the electronic analgesic was the threshold of the mechanical pain reaction, with g as the detection unit, and the test was repeated 6 times. The average value was then taken as the final detection index.
  • mice in the Vehicle group A1 50 mg/kg, A1 100 mg/kg, and A1 200 mg/kg were anesthetized with isoflurane inhalation using a small animal anesthesia machine (R510-29) and then euthanized by cervical dislocation.
  • R510-29 small animal anesthesia machine
  • the sciatic nerves on the injured and non-injured sides of the animals and the DRG on the injured side were fixed in 4% paraformaldehyde solution.
  • tissue sections were washed 3 times with PBS, 5 min each time; incubated with 0.3% Triton-X100 PBS for 20 min; washed 3 times with PBS, 5 min each time; blocked with goat serum at room temperature for 1 h;
  • the secondary antibody Goat Anti-Rabbit (Alexa 594) (abcam, ab150080); Goat Anti-Rabbit (Alexa 594) (abcam, ab150080); Goat Anti-Rat ( 488)(abcam, ab150165)
  • antibody diluent New Saimei Biotechnology, Lot: 20220824
  • the sections were sealed with a sealing solution containing DAPI, and photographed with a confocal microscope (Leica Microsystems, DCM8).
  • the Find Maxima function of Image J was used to count the number of AT2R and F4/80 co-stained cells of macrophages in the sciatic nerve tissue, and Image J was used to count the TRPA1 fluorescence intensity of DRG neuronal cells.
  • the sections were removed from the ⁇ 80°C freezer, fixed with 4% paraformaldehyde at 4°C for 10 min, and rinsed three times with 1 ⁇ PBS. Endogenous peroxidase activity was blocked for 10 min using a specific blocking buffer, followed by three additional washes with 1 ⁇ PBS. Subsequently, the sections were blocked with normal goat serum solution for 30 min. The primary antibody was incubated overnight at 4°C, and the secondary antibody was incubated for 1 h at room temperature the next day. Finally, the sections were stained with AEC reagent and hematoxylin solution.
  • TRPA1 antibody orb374201, 1:2000, Biorbyt, UK
  • TRPV1 antibody orb645490, 1:2000, Biorbyt, UK
  • anti-rabbit antibody (1:1000) were used for immunohistochemical staining. Microscopic images were taken using a Leica Microsystems microscope and processed with Image-Pro Plus software.
  • Figure 7 shows the fluorescence intensity of AT2R and F4/80 co-stained macrophages on the injured side of the sciatic nerve of SNI mice.
  • the results show that compared with the solvent control group, A1 100mg/kg and A1 200mg/kg can significantly reduce the number of AT2R and F4/80 co-stained macrophages on the injured side of the sciatic nerve.
  • Figure 8 shows the fluorescence intensity of AT2R and F4/80 co-stained macrophages on the non-injured side of the sciatic nerve of SNI model mice.
  • the results show that on the non-injured side of the sciatic nerve, the number of AT2R and F4/80 co-stained macrophages in each experimental group was low and there was no significant difference in the number of AT2R and F4/80 co-stained cells among the groups.
  • the results show that the injured side of the sciatic nerve recruited more peripheral macrophages than the non-injured side.
  • the AT2R antagonist A1 was administered orally at 100mg/kg and 200mg/kg, it can significantly reduce the number of peripheral macrophages and the expression of AT2R.
  • the results indicate that compared with the vehicle control group, A1 100 mg/kg and A1 200 mg/kg can significantly reduce the expression of TRPA1 in DRG neurons.
  • Macrophages RAW264.7 were obtained from the Cell Resource Center of Peking Union Medical College, and mouse hippocampal neurons HT22 (CL-0697) were kindly provided by Procell Life Science Technology Co., Ltd.
  • RAW264.7 cells were cultured in DMEM medium supplemented with 10% FBS at 37°C, and experiments were performed when the cell density reached 70%. After RAW264.7 cells were treated with different groups, the supernatant was collected, centrifuged at 4°C and 1000 g to remove the cell precipitate, and the supernatant was added to HT22 cells in DMEM medium supplemented with 10% FBS and co-cultured at 37°C.
  • A1 inhibits AT2R receptors.
  • Experimental method When RAW264.7 cells reach 70% density, a certain concentration of AngII and a corresponding concentration of A1 (10, 30, 50, 100, and 200 nM) are added. An equal volume of saline (without AngII) is added to the negative control group. After 24 hours of treatment, cells are collected to extract protein and RNA to evaluate the expression level of AT2R. Further, a suitable concentration is selected. When RAW264.7 cells reach 70% density, a certain concentration of AngII and a certain concentration of A1, PD123319 and Olodanrigan are added. An equal volume of saline (without AngII) is added to the negative control group. After 24 hours of treatment, cells are collected to extract protein and RNA to evaluate the expression level of AT2R.
  • ELISA After RAW264.7 cells were treated with normal saline (negative control group), AngII, AngII+A1, AngII+PD123319 and AngII+Olodanrigan for 24 hours, the supernatant was collected and centrifuged at 4°C and 1000 g to remove the cell pellet. The sample concentration was determined using an ELISA kit at a wavelength of 450 nm. The supernatant after centrifugation was used to detect the concentrations of tumor necrosis factor TNF- ⁇ (cat. no. ml002095, Shanghai Enzyme-linked Biotechnology, China), IL-1 (cat. no.
  • the iQ5 TM multi-color real-time PCR detection system (Bio-Rad, Hercules, CA, USA) was used to determine the difference in mRNA levels using GAPDH as a standard gene.
  • RT-PCR system and conditions 10 ⁇ L 2X TransStart Green qPCR SuperMix (TransGen Biotech, Beijing, China), 3 ⁇ L cDNA template, 2 ⁇ L primers (1 ⁇ mol/L) and 5 ⁇ L ddH2O (nuclease-free).
  • the RT-PCR program first performed an initial denaturation at 95°C for 2 min, followed by 40 cycles of amplification: denaturation at 95°C for 15 s and annealing/extension at 60°C for 30 s.
  • Figure 12 shows the inhibitory effect of A1 on AT2R activated by AngII in R264.7 cells. It indicates that A1 can significantly inhibit the expression of AT2R.
  • WB and RT-PCR in Figures 12A, B, and C show that compared with the negative control, AngII at 10, 30, 50, 100, and 200 nM increases the AT2R protein expression level and mRNA level in RAW264.7 cells in a concentration-dependent manner.
  • WB and RT-PCR in Figures 12D, E, and F show that compared with the negative control, AngII treatment increases the expression of AT2R, but A1 at concentrations of 10, 30, 50, 100, and 200 nM dose-dependently inhibits the expression of AT2R in RAW264.7 cells.

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Abstract

La présente invention concerne un antagoniste du récepteur de l'angiotensine II et son utilisation dans le traitement de la douleur neuropathique induite en périphérie. En particulier, la présente invention concerne un composé de formule (IV) ou un sel pharmaceutiquement acceptable de celui-ci ou un stéréoisomère de celui-ci, et son utilisation dans le traitement de la douleur neuropathique induite en périphérie.
PCT/CN2025/072712 2024-01-17 2025-01-16 Antagoniste du récepteur de l'angiotensine ii et son utilisation dans le traitement de la douleur neuropathique induite en périphérie Pending WO2025153011A1 (fr)

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CN2024072719 2024-01-17
CNPCT/CN2024/072719 2024-01-17
CN2024135584 2024-11-29
CNPCT/CN2024/135584 2024-11-29

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019179515A1 (fr) * 2018-03-23 2019-09-26 北京泰德制药股份有限公司 Inhibiteur de récepteur, composition pharmaceutique le comprenant et son utilisation
CN112204006A (zh) * 2017-11-02 2021-01-08 卡里科生命科学有限责任公司 整合应激通路的调节剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112204006A (zh) * 2017-11-02 2021-01-08 卡里科生命科学有限责任公司 整合应激通路的调节剂
WO2019179515A1 (fr) * 2018-03-23 2019-09-26 北京泰德制药股份有限公司 Inhibiteur de récepteur, composition pharmaceutique le comprenant et son utilisation

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