WO2025193980A2 - Méthode de traitement de la douleur neuropathique utilisant un inhibiteur anti-cgrp - Google Patents

Méthode de traitement de la douleur neuropathique utilisant un inhibiteur anti-cgrp

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Publication number
WO2025193980A2
WO2025193980A2 PCT/US2025/019825 US2025019825W WO2025193980A2 WO 2025193980 A2 WO2025193980 A2 WO 2025193980A2 US 2025019825 W US2025019825 W US 2025019825W WO 2025193980 A2 WO2025193980 A2 WO 2025193980A2
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Prior art keywords
pain
cgrp
patient
inhibitor
formula
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WO2025193980A3 (fr
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Scott P. Falci
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CNS Biosciences Inc
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CNS Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the BBB and BSCB have several common structures.
  • the meninges separate the cerebrospinal fluid (CSF) from both the brain and spinal cord.
  • the meninges include the dura mater, arachnoid and pia mater, dural border cells, arachnoid cells, pial cells, basement membrane, and glial limitans and has a common structure in both the BBB and BSCB.
  • the arachnoid cell layer contains tight junctions that prevent molecules from exiting the fenestrated blood vessels in the dural layers and accessing the CSF. Tight junctions between the blood vessels and pial cell layer prevent paracellular transfer into the arachnoid CSF.
  • Endothelial cells of blood vessels are held together by tight junctions preventing paracellular transfer in both the BBB and BSCB.
  • the central canal of the spinal cord is lined with ependymal cells that separate the CSF from spinal tissue.
  • CGRP-r Neither small molecule nor therapeutic antibody molecule that target CGRP or the CGRP receptor (CGRP-r) are believed to cross the blood brain barrier in therapeutically effective amounts.
  • CGRP receptor antagonists do not cross the blood–brain barrier and therefore are not found in brain tissue.
  • known FDA approved gepants have been measured not to cross the BBB.
  • Nurtec rimegepant is an FDA approved orally administered pharmaceutical approved for acute treatment of migraine with or without aura and preventative treatment of episodic migraine.
  • the CGRP inhibitor can be a CGRP receptor (CGRP-r) antagonist.
  • the CGRP inhibitor is selected from the group consisting of Formula (I), Formula (V), and Formula (VII), or a salt, solvate, hydrate, ester, or combination thereof, as described herein.
  • the CGRP inhibitor is selected from the group consisting of Formula (III), Formula (IV), Formula (VI), Formula (VIII), and Formula (IX) , or a salt, solvate, hydrate, ester, or combination thereof, as described herein. 3 4897-2147-5622.1 [00015]
  • the CGRP inhibitor is an antibody.
  • the antibody can be: [00016] a heavy chain sequence of SEQ ID NO: 1 and a light chain sequence of SEQ ID NO:2; [00017] a heavy chain sequence of SEQ ID NO: 3 and a light chain sequence of SEQ ID NO:4; [00018] a heavy chain sequence of SEQ ID NO: 5 and a light chain sequence of SEQ ID NO:6; and [00019] a heavy chain sequence of SEQ ID NO: 7 and a light chain sequence of SEQ ID NO:8.
  • DETAILED DESCRIPTION [00020] The following detailed description is provided to aid those skilled in the art in practicing the present disclosure.
  • CGRP calcitonin gene-related peptide
  • administer refers to the physical introduction of a composition comprising a therapeutic agent to a patient, using any of the various methods and delivery systems known to those skilled in the art. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods and can be a therapeutically effective dose or a subtherapeutic dose.
  • antibody means monoclonal antibodies, including any isotype, such as, IgG, IgM, IgA, IgD and IgE.
  • An IgG antibody is comprised of two identical heavy chains and two identical light chains that are joined by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called “complementarity-determining regions" ("CDRs") or “hypervariable regions", which are primarily responsible for binding an epitope of an antigen. They are referred to as CDR1 , CDR2, and CDR3, numbered sequentially from the N-terminus.
  • CDRs complementarity-determining regions
  • CDRs are defined by either Chothia et al or Kabat et al. See Chothia C, Lesk AM. (1987) Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol., 196(4):901 -17, which is incorporated by reference in its entirety.
  • CGRP inhibitor also referred to herein as “CGRP inhibitor compound”, “CGRP inhibitor agent”, or “CGRP inhibitor drug”, refers to a compound that reduces binding of a CGRP to a CGRP receptor (CGRP-r).
  • the compound can be a CGRP antagonist or a CGRP-r antagonist.
  • CGRP inhibitor includes any compounds encompassed by chemical formulae or amino acid sequences described herein.
  • CGRP inhibitors include, by way of example but not limitation, rimegepant (Nurtec) (Biohaven Pharmaceutical Holding Company Ltd./Pfizer), zavegepant (Zavzpret) (Pfizer), atogepant (Qulipta) (AbbVie), ubrogepant (Ubrelvy) (Abbvie), galcanezumab (Emgality) Eli Lilly and Company, Ajovy (fremanezumab) (Teva Pharmaceutical Industries), erenumab (Aimovig) (Amgen, Inc.) eptinezumab (Vyepti) (Lundbeck).
  • CGRP inhibitor compounds may be identified either by their chemical structure, amino acid sequence, therapeutic name, and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers.
  • the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated 5 4897-2147-5622.1 compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • the stereoisomerically pure form e.g., geometrically pure, enantiomerically pure or diastereomerically pure
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • Compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof.
  • the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • Compounds described herein also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
  • isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, 2 H, 3 H, ⁇ C, 13 C, 14 C, I5 N, 18 0, 17 O, etc.
  • the compounds can include pharmaceutically acceptable salts, hydrates, solvates, esters, N-oxides, or combinations thereof.
  • Certain compounds may exist in multiple crystalline or amorphous forms. All physical forms are equivalent for the uses contemplated herein. Further, when partial structures of the compounds are illustrated, that brackets indicate the point of attachment of the partial structure to the rest of the molecule.
  • the term “decrease severity of pain” refers to reducing pain by at least 1 point on the 0 to 10-point scale, with 0 being “no pain” and 10 “pain as bad as it could be” or “the worst pain imaginable,” as described by Farrar et al., Clinical importance of changes in chronic pain intensity measured on an 11 -point numerical pain rating scale, Pain 94 (2001 ) 149 - 158, and Hawker et al., Measures of Adult Pain, Arthritis Care & Research Vol.63 No. S11, November 2011 (S240 - S252), incorporated herein by reference in its entirety.
  • Dosing frequency refers to the number of times a dose can be given in a specific period of time. Dosing frequency can be indicated as the number of doses per a given time, e.g., once a week or once in two weeks.
  • fast-dispersing dosage form refers to compositions that disintegrate or disperse within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably 1 to 10 seconds and particularly 2 to 8 seconds, after being placed in contact with a fluid.
  • the fluid is preferably that found in the oral cavity, i.e., saliva, as with oral administration.
  • neurodeal pain refers to pain caused by a lesion or disease of the somatosensory nervous system, as defined by International Association for the Study of Pain (IASP) on March 13, 2024. 6 4897-2147-5622.1
  • patient refers to a mammal. The patient can be a human mammal.
  • subject refers to a human mammal.
  • patient can be a human mammal.
  • pharmaceutically acceptable salt refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- aphfhalenesulfonic acid, 4-toluenesulf
  • anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • salts can be made according to common organic techniques employing commercially available reagents.
  • pharmaceutically acceptable vehicle refers to a diluent, an adjuvant, an excipient, a carrier, or a combination of any of the foregoing with which a compound provided by the disclosure may be administered to a patient and which does not destroy the pharmacological activity thereof and which is non-toxic when administered in doses sufficient to provide a therapeutically effective amount of the compound. 7 4897-2147-5622.1 [00038]
  • pharmaceutical composition refers to the combination of therapeutic amount of a compound and at least one pharmaceutically acceptable vehicle with which the compound is administered to a patient.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries, which facilitate processing of the compounds and one or more pharmaceutically acceptable vehicles into formulations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • Pharmaceutical compositions provided by the disclosure may take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for administration to an individual. [00039]
  • Pharmaceutical compositions provided by the disclosure may be formulated in a unit dosage form.
  • a unit dosage form refers to a physically discrete unit suitable as a unitary dose for individuals undergoing treatment, with each unit containing a predetermined quantity of the compound calculated to produce an intended therapeutic effect.
  • a unit dosage form may be for a single daily dose, for administration 2 times per day, or one of multiple daily doses, e.g., 3 or more times per day. When multiple daily doses are used, an example unit dosage form may be the same or different for each dose.
  • One or more dosage forms may comprise a dose, which may be administered to an individual at a single point in time or during a time interval. [00040] In some variations, the pharmaceutical compositions can be administered as recommended by FDA guidance.
  • systemic administration refers to administration by any method excluding intrathecal administration.
  • System administration includes any methods of administration including p.o. (by mouth), IV (intravenously), SC (subcutaneously), intranasally, sublingually, and PR (per rectum).
  • therapeutically effective amount refers to the amount of a compound that, when administered to a patient for treating neuropathic pain or symptom of neuropathic pain, is sufficient to reduce neuropathic pain or the symptom of neuropathic pain.
  • therapeutically effective dose refers to a dose that provides an effective treatment of neuropathic pain or a symptom thereof in a patient.
  • a therapeutically effective dose may vary based on compound or patient, and may depend upon factors such as the condition of the patient and the route of delivery.
  • a therapeutically effective dose may be determined in accordance with routine pharmacological procedures known to those skilled in 8 4897-2147-5622.1 the art. Such as in human patients during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • a therapeutically effective does excludes amounts that do not cross the blood brain barrier or blood spinal cord barrier in sufficient quantities to have a therapeutic effect (e.g., Moreno-Ajona et al., J Clin Med.2022 Mar; 11(6): 1656 and Altamura et al., Neurol Sci.
  • the terms “treat”, “treatment”, or “therapy” refers to reduction in neuropathic pain in an SCI patient and may include decreasing severity of pain (based on the 11 point scale), decreasing frequency of pain, decreasing duration of pain, and increasing frequency and/or duration of pain-free periods.
  • Spinal Cord and Spinal Cord Injury [00045] All vertebrate animals have a central axis of the body that consists of the spinal or vertebral column.
  • the vertebral column consists of a number of connected irregular bones, termed the vertebrae, which surround and thereby protect a spinal cord.
  • the vertebrae are grouped according to the region in which they lie — cervical, thoracic, lumbar, sacral, and coccygeal or caudal. Each vertebra has a ventral and dorsal side. In series with each vertebra are a number of spinal nerves. Each nerve is formed by the union of an anterior (motor) and posterior (sensory) nerve-root. The posterior or dorsal nerve-roots are the central branches of the axons of the pseudounipolar cells of the spinal ganglia. There are thirty-one pairs of spinal nerves: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral and 1 coccygeal.
  • Central pain refers to persistent or chronic pain caused by injury to nervous tissue within the CNS. Often central pain is described as severe, diffuse, and/or continuous, with periods of exacerbation. Injury to nervous tissue within the CNS often results in the abnormal up-regulation of neuronal activity, and this plays a key role in central pain associated with the injury. Several electrophysiological studies have suggested that neurons in injured CNS tissue show abnormal changes in their firing patterns, including spontaneous activity, reduced thresholds and increased responsiveness to peripheral stimulation. Eide, Spinal Cord, 36:601-612 (1998). [00047] Central pain has proven notoriously difficult to treat, often proving recalcitrant to modern medical and surgical pain treatment procedures.
  • DREZ dorsal root entry zone
  • DREZ dorsal root entry zone
  • Surgical destruction of a central pain-generating DREZ is believed to disrupt the neural (i.e., electrical) communication and/or generation of aberrant pain signals that result 9 4897-2147-5622.1 from the injury.
  • empiric techniques have been used to target DREZ sites for surgical treatment, resulting in modest outcomes for the patient, i.e., DREZ sites at the site of injury targeted for treatment.
  • a somatotopic map of specific DREZs to perceived regions of pain may be found in Falci et al., J. Neurosurg. Spine 2), 97:193-200, 2002, expressly incorporated herein by reference in its 10 4897-2147-5622.1 entirety, and a somatotopic map for neuropathic pain is provided by US 2007/0016264, which is expressly incorporated herein by reference in its entirety.
  • Using data provided by the illustrative somatotopic map it is believed that pain occurring distal from an injury site (below-level pain) is mediated significantly by the sympathetic nervous system. It is also believed that anatomic regions of perceived pain are somatotopically mapped to specific DREZ segments of the spinal cord.
  • lumbar segments (L1 in particular) mediate pain from the feet, T11 and T12 segments, the leg, and T8-T10 segments, the gluteal, rectal and perirectal regions. More cephalad segments would mediate pain in the truncal region. It is also believed that cephalad segments could mediate pain subtended by those in more caudal segments by way of the sympathetic chain or interneuronal pathways.
  • CGRP2 Calcitonin Gene-Related Peptide
  • CGRP is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA.
  • CGRP is widely distributed in the central nervous system and peripheral nervous system.
  • CGRP is a potent vasodilatory neurotransmitter believed to play a key role in migraine pathophysiology.
  • neuropathic pain in spinal cord individuals can be mediated by the sympathetic nervous system.
  • hyperactive electrical neuronal signals originating below the level of spinal cord injury can be routed around the injury site by way of the sympathetic chain to reach brain pain centers and/or ascend the spinal cord via intact afferent pathways, inclusive of sympathetic afferent pathways.
  • DREZ pain generators originate above the level of injury, signals can ascend via the sympathetic chain and/or ascend via spinal cord sensory tracts, inclusive of sympathetic afferent tracts.
  • Sympathetically mediated spinal cord injury pain is perceived by the patient to be below the neurological level of spinal cord injury (referred to herein as “below-level pain”).
  • CGRP inhibitor can be as described herein for each CGRP inhibitor.
  • CGRP inhibitor compounds and pharmaceutical compositions described herein can be administered to provide neuroprotection and/or regeneration in SCI patients to preserve or restore function.
  • Electrically hyperactive areas as described herein are found at the borders of spinal cord contusions two weeks after spinal cord injury. The hyperactive tissue can be identified within weeks of the injury. The front of hyperactivity ascends and descends the cord over years as cord function is lost.
  • the CGRP inhibitor compounds or pharmaceutical compositions can be administered soon after injury.
  • a CGRP inhibitor compound or pharmaceutical composition can be administered immediately after injury or in the ensuing hours or days following injury.
  • a CGRP inhibitor compound or pharmaceutical composition can be administered within one hour after injury.
  • a CGRP inhibitor compound or pharmaceutical composition can be administered within six hours after injury.
  • a CGRP inhibitor compound or pharmaceutical composition can be administered within 12 hours after injury.
  • a CGRP inhibitor compound or pharmaceutical composition can be administered within a day after injury.
  • a CGRP inhibitor compound or pharmaceutical composition can be administered within three days after injury.
  • a CGRP inhibitor compound or pharmaceutical composition can be administered within one week after injury.
  • administration can be systemic administration, or can be non- systemic administration (e.g., by intrathecal administration).
  • Administration of a CGRP inhibitor can proceed at hourly, daily, or weekly intervals following injury.
  • the CGRP inhibitor is administered each hour, every two hours, every three hours, or every four hours to the site of injury.
  • the CGRP inhibitor is administered each day to the site of injury.
  • the CGRP inhibitor can be administered daily, every other day, every three days, or every four days to the site of injury.
  • the CGRP inhibitor can be administered weekly. In some variations, the CGRP inhibitor is administered every week, every other week, ever three weeks, or every four weeks to the site of injury.
  • CGRP inhibitor administration can terminate after a period of time, or can continue indefinitely.
  • CGRP Inhibitors 13 4897-2147-5622.1 the CGRP inhibitor includes any molecular or biological agent that binds CGRP or the CGRP receptor thereby inhibiting binding of CGRP to the CGRP receptor.
  • the compound includes any compounds encompassed by chemical formulae or amino acid sequences described herein.
  • the methods encompass reducing the pain level as described herein.
  • the patient is a mammal, and in many variations a human.
  • the patient may be female or male of any age.
  • the patient has pain at a level.
  • Examples of CGRP inhibitor compounds are described in more detail below.
  • the disclosure is directed to treating neuropathic pain in a patient by administering the CGRP inhibitor having the compound of formula (I), or a pharmaceutically acceptable salt, ester, hydrate, solvate, N-oxide, or combination thereof, to a patient in need of such treatment.
  • the compound can be any compound described in U.S. Patent Nos.8,314,117, 8,759,372, and 11,083,724, all of which are hereby incorporated by reference in their entirety.
  • the compound is a compound of Formula (I)
  • R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl
  • R 2 is piperidinyl substituted with 1 substituent selected from the group consisting of 14 4897-2147-5622.1
  • R 3 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy
  • R 4 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy
  • R 5 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
  • R 6 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
  • R 7 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
  • R 8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino
  • R 8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino
  • the CGRP inhibitor is a compound of Formula (I) where: [00087] R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl; [00088] R 2 is piperidinyl substituted with 1 substituent selected from the group consisting of 16 4897-2147-5622.1
  • R 2 is [00090] [00091] alkoxy, or haloalkoxy; [00092] R 4 is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; [00093] R 5 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; 17 4897-2147-5622.1 [00094] R 6 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; [00095] R 7 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; [00096] R 8 is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; [00097] R 9 is hydrogen, hydroxy, hydroxy,
  • R 1 is hydrogen, halo, cyano, amino, alkylamino, or dialkylamino;
  • R 2 is piperidinyl substituted with 1 substituent selected from the group consisting of 18 4897-2147-5622.1
  • R 5 is hydrogen or hydroxy
  • R 6 is hydrogen
  • R 7 is hydrogen
  • R 8 is hydrogen
  • R 9 is hydrogen or hydroxy
  • R 10 is hydroxy, azido, or amino
  • R 11 is hydrogen; or R 10 and R 11 taken together is oxo; provided that at least one of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , or R 11 is not hydrogen
  • Ar 1 is phenyl or difluorophenyl
  • X is O, CH 2 , or NH
  • Y is O; or a pharmaceutically acceptable salt thereof.
  • the CGRP inhibitor is a compound of formula I where R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl.
  • the CGRP inhibitor is a compound of formula I where R 2 is N-piperidinyl and is 4-substituted.
  • the CGRP inhibitor is a compound of formula I where the substituent is [000132] [000133]
  • the CGRP inhibitor is a compound of formula I where R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydrogen, R 10 is hydroxy, azido, or amino, and R 11 is hydrogen; or where R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydrogen or hydroxy, and R 10 and R 11 taken together is oxo; or where R 5 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydroxy, R 10 is hydrogen or hydroxy, and R 11 is hydrogen; or where R 5 is hydroxy, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydrogen, R 10 is hydrogen, and R 11 is hydrogen.
  • the CGRP inhibitor is a compound of formula I where Ar 1 is phenyl substituted with 2 halo substituents. [000135] In another variation, the CGRP inhibitor is a compound of formula I where Ar 1 is 2,3-difluorophenyl. 20 4897-2147-5622.1 [000136] In another variation, the CGRP inhibitor is a compound of formula I where X is O.
  • any instance of a variable including R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , Ar 1 , X and Y, can be used independently with the scope of any other instance of a variable substituent.
  • the disclosure includes combinations of the different aspects.
  • Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons, preferably 1 to 3 carbons.
  • Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
  • Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
  • Hydroalkyl alkoxy
  • alkoxy alkoxy
  • other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety.
  • Haloalkyl and “haloalkoxy” include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl.
  • Aryl includes carbocyclic and heterocyclic aromatic ring systems.
  • Amino includes primary, secondary, and tertiary amine moieties.
  • Carbonyl means CO.
  • Olety means —O—.
  • Aminocarbonyl means —N(R)C( ⁇ O)—.
  • Oxycarbonyl means —OC( ⁇ O)—.
  • Methylenecarbonyl means —CHYDROGENC( ⁇ O)—.
  • Amino(cyano)iminomethyl means —NHC( ⁇ NCN)—.
  • Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R. [000139] In some variations, the compound is rimegepant. Rimegepant has the chemical structure of Formula (III), and is described, for example, in WO 2011/046997 published Apr.
  • the compound has rimegepant hemisulfate sesquihydrate is (5S,6S,9R)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9- yl 4-(2-oxo-2,3-dihydro-1Himidazo[4,5-b]pyridin-1-yl)-1-piperidinecarbxylate hemisulfate sesquihydrate and has the chemical structure of Formula (IV): [000141] [000142]
  • the pharmaceutical composition and methods of administering can be any pharmaceutical composition described in one of U.S.
  • the pharmaceutical composition is described in the prescribing information for NURTEC, revised 5/2021, and incorporated herein by reference in its entirety.
  • the pharmaceutical composition can be administered as described therein at 75 mg taken orally every other day.
  • Zavegepant (Zavzpret) [000144]
  • the disclosure is directed to treating neuropathic pain in a patient by administering the CGRP inhibitor having the compound of Formula (V), or a pharmaceutically acceptable salt, ester, hydrate, solvate, N-oxide, or combination thereof, to a patient in need of such treatment.
  • the compound can be a compound disclosed in U.S. Patent Nos.7,220,862, 7,314,883, or 8,481,546, each of which is incorporated by reference in its entirety.
  • the compound can be a compound formula ((V): 22 4897-2147-5622.1 (V) [000146] or a pharmaceutically acceptable salt and/or solvate thereof [000147] wherein [000148] V is —N(R 1 )(R 2 ) or OR 4 ; [000149] R 4 is H, C1-6alkyl, C1-4haloalkyl or (C1-4alkylene)0-1R 4′ R 4′ is C 3-7 cycloalkyl, phenyl, adamantyl, quinuclidyl, azabicyclo[2.2.1]heptyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrol
  • the compound is a compound disclosed in U.S. Patent No.7,314,883, which is incorporated herein by reference in its entirety.
  • the compound can be a compound formula (VI): (VI).
  • the pharmaceutical composition and methods of administering can be any pharmaceutical composition described in one of U.S. Patent Nos.7,220,862, 7,314,883, or 8,481,546, incorporated by reference herein in its entirety.
  • the pharmaceutical composition is described in the prescribing information for the Zavegepant (Zavzpret) product insert published by the FDA, revised 3/2023, and incorporated herein by reference in its entirety.
  • the pharmaceutical composition can be administered as described therein administered 10 mg nasally in a single dose per day.
  • the disclosure is directed to treating neuropathic pain in a patient by administering the CGRP inhibitor having the compound of Formula (VII), or a pharmaceutically acceptable salt, ester, hydrate, solvate, N-oxide, or combination thereof, to a patient in need of such treatment.
  • the compound can be a compound disclosed in U.S. Patent Nos. USPN 8,754,096 USPN 9,499,545, 9,850,246, and 10,117,836, each of which is incorporated by reference in its entirety.
  • the compound can be a compound Formula (VII): [000214] or a pharmaceutically acceptable salt thereof, wherein: [000215] X is selected from —C(R 8 ) ⁇ or —N ⁇ , wherein R 8 is hydrogen, F or CN; [000216] R 1 is selected from the group consisting of: C1-4alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and hydroxy; [000217] R 2 is selected from hydrogen and methyl; [000218] when R 2 is hydrogen then [000219] R 3 is selected from hydrogen, F or Cl; [000220] R 4 is selected from hydrogen, F or Cl; [000221] R 5 is hydrogen; [000222] R 6 is selected from hydrogen or F; and [000223] R 7 is selected from hydrogen, F, F
  • the compound can be a compound of Formula (VII), wherein [000232] X is selected from —C(R 8 ) ⁇ or —N ⁇ , wherein R 8 is hydrogen, F or CN; [000233] R 1 is selected from the group consisting of: C1-4alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and hydroxy; [000234] R 2 is selected from hydrogen and methyl; [000235] when R 2 is hydrogen then [000236] R 3 is selected from hydrogen, F or Cl; [000237] R 4 is selected from hydrogen, F or Cl; [000238] R 5 is hydrogen; [000239] R 6 is selected from hydrogen or F; and [000240] R 7 is selected from hydrogen, F or Cl; [000241] except
  • the compound is a compound according to Formula (IX) [000294]
  • the pharmaceutical composition and methods of administering can be any pharmaceutical composition described in one of U.S. Patent Nos.. USPN 8,754,096, 8,912,210, 9,499,545, 9,833,448 and 10,117,836, each of which is incorporated by reference herein in its entirety.
  • the pharmaceutical composition is described in the prescribing information for the UBRELVY (Ubrogepant) product insert published by the FDA, revised 9/2021, and incorporated herein by reference in its entirety.
  • the pharmaceutical composition can be administered as described therein orally administered in 50 mg or 100 mg, additional doses after the first dose, to a maximum of 200mg.
  • Therapeutic Antibodies [000309]
  • the CGRP inhibitor is an antibody.
  • Ajovy includes a heavy chain and a light chain amino acid sequence of the Fc regions of Ajovy.
  • the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:3 and the light chain amino acid sequence of SEQ ID NO: 4.
  • Aimovig includes a heavy chain and a light chain amino acid sequence of the Fc regions of Aimovig.
  • the 35 4897-2147-5622.1 antibody comprises the heavy chain amino acid sequence of SEQ ID NO:5 and the light chain amino acid sequence of SEQ ID NO: 6.
  • Vyepti includes a heavy chain and a light chain amino acid sequence of the Fc regions of Vyepti.
  • the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:7 and the light chain amino acid sequence of SEQ ID NO: 8.
  • CGRP inhibitor is administered at a lower daily dosage, reduced dosage schedule, and/or lower reduced dosage over a time course.
  • the combination therapy of CGRP inhibitor and opioid results in reduced dose requirements for the opioid.
  • Opioids are relatively ineffective at relieving neuropathic pain. These same opioid receptors, which normally decrease the hyperexcitability of the pain producing neurons in the dorsal horn Rexed Layers 1 -3 in normal pain states, fail to do so in neuropathic pain states. This effect is observed in both clinical data and the ineffectiveness of opioids in having an effect on hyperactive DREZ recordings in patients taking high doses of narcotics or with opioid administration during general anesthesia.
  • the opioid can be any opioid known in the art.
  • the opioid can be used to treat acute pain or chronic pain, and more specifically neuropathic pain.
  • the opioid is administered at a lower daily dosage, reduced dosage schedule, and/or lower reduced dosage over a time course.
  • the combination therapy surprisingly results in a reduced drug load to the patient.
  • the CGRP inhibitor can be administered to reduce opioid addiction by administering to a patient in need thereof.
  • the CGRP inhibitor can be administered alone to a patient to whom opioid has been administered, or the opioid can be administered at a lower 37 4897-2147-5622.1 dose than when administered alone.
  • the dose of the opioid can be reduced over a period of time until a lower dosage plateau is reached.
  • CGRP inhibitors can be used to reduce neuropathic pain in a patient on an opioid therapeutic regimen.
  • the regimen adapted to treat chronic pain. Due to the chronic nature of pain treatment, the amount of opioid administered to such patients can in some cases be substantially greater than the amounts approved for administration on various product labels.
  • the CGRP inhibitor is administered, and an opioid is also administered.
  • the patient has a decrease in pain of at least 1 on a 0-10 pain scale as compared to administration of the opioid in the absence of the CGRP inhibitor. In various aspects, the opioid dose is maintained.
  • the pain scale is generally known in the art, for example as described by Farrar et al., Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale, Pain 94 (2001 ) 149 - 158, and Hawker et al., Measures of Adult Pain, Arthritis Care & Research Vol.63 No. S11, November 2011 (S240 - S252). [000322] Without wishing to be limited to a particular mechanism or mode of action, the CGRP inhibitor may potentiate the effect of narcotics, allowing a substantial reduction in opioid dose and a substantial decrease in neuronal excitability.
  • CGRP inhibitors may potentiate the effect of narcotics, resulting in a decrease in required narcotic dose. This can be true for any kind of pain, including acute pain, chronic pain, neuropathic pain, pain resulting from SCI, and post-surgical pain.
  • Central pain can result from spontaneous neuronal hyperexcitability in the dorsal grey matter of the spinal cord.
  • opioids can act on the opioid receptors of hyperexcitable neurons in the dorsal grey matter to relieve pain (e.g., post- surgical pain, broken leg, etc.) by decreasing neuronal hyperexcitability.
  • Hyperexcitable neurons in the dorsal grey matter layers are caused by the firing of injured peripheral neurons (e.g., from a broken leg) in these normal pain states.
  • Different opioids can be administered in different doses depending on the opioid, mode of administration, and whether the patient is opioid-exposed. The dose of opioid can depend on the specific opioid used. In some variations, the opioid dose of a particular opioid can be determined relative to morphine equivalent. Table 1 depicts conversion of representative opioids in terms of morphine equivalents. Table 1 38 4897-2147-5622.1 Opioid Morphine Potency Equivalent Codeine 0.15 ive conventional dosages for different administration and formulations.
  • the CGRP inhibitor alone, or when combined with opioid, can be used to reduce the dose of opioid administered to a patient, while retaining the same or better decrease in the severity of pain.
  • the initial opioid dose when a CGRP inhibitor is administered, can be reduced by a percentage compared to the recommended dose.
  • the initial opioid dose can be reduced by at least 10% of the conventional initial dose described in Table 2.
  • the initial opioid dose can be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% as compared to the conventional initial dose described in Table 2.
  • the method is directed to reducing the maintenance dose of opioid by administering the CGRP inhibitor.
  • the maintenance dose of opioid can be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% as compared to the conventional initial dose described in Table 2.
  • the reduced dose is relative to morphine as described in Table 1.
  • combination therapy that includes a reduced opioid dose results in no increase in pain on a 0-10 pain scale.
  • the combination therapy that included a reduced opioid dose results in reduced pain on a 0-10 pain scale.
  • the reduced pain is at least 1 point. In some instances, the reduced pain is at least 2 points.
  • the reduced pain is at least 3 points. In some instances, the reduced pain is at least 4 points. In some instances, the reduced pain is at least 5 points. In some instances, the reduced pain is at least 6. In some variations, the reduction can be by a percent. In some variations, the pain can be reduced by a percentage. In some variations, the reduction of pain is at least 10%. In some variations, the reduction of pain is at least 20%. In some variations, the reduction of pain is at least 30%. In some variations, the reduction of pain is at least 40%. In some variations, the reduction of pain is at least 50%. In some variations, the reduction of pain is at least 60%.
  • the dose of opioid administered can be reduced from the conventionally administered dose by a particular percentage per given time period following the beginning of CGRP inhibitor administration. In some instances, the opioid dose is reduced by at least 10% per month. In some instances, the dose of opioid is reduced by at least 20% per month. Additional variations are possible. In some further variations, the opioid dose administered to the patient is reduced by at least 30%. In some further variations, the opioid dose administered to the patient is reduced by at least 40%. In some further variations, the opioid dose administered to the patient is reduced by at least 50%. In some further variations, the opioid dose administered to the patient is reduced by at least 60%. In some 40 4897-2147-5622.1 further variations, the opioid dose administered to the patient is reduced by at least 70%.
  • the opioid dose administered to the patient is reduced by at least 80% per month.
  • combination therapy that includes a reduced opioid dose results in no increase in pain on a 0-10 pain scale.
  • the initial dose of opioid is far above initial and maintenance doses for opioids.
  • the reductions in dose of opioid as described herein can be relative to the elevated dose for chronic pain.
  • Example 1 Tissues from Spinal Cord Injured Individuals
  • Tissue was acquired both from hyperactive (i.e., pain generating) and non- hyperactive (i.e., non-pain generating) DREZ sites to determine the in the abundance of specific proteins. Differentially abundant proteins may be markers of spinal cord injury pain and/or targets for drug discovery and development.
  • Tissues implicated in spinal cord injury central pain were acquired and fast frozen. Methods of acquiring tissues that exhibit spinal cord injury central pain have been described, for example, in U.S. Patent No.8,694,107, incorporated herein by reference in its entirety.
  • DREZ tissue generating CNS pain was acquired surgically. First, the DREZs that are potentially implicated in perceived pain were determined by comparing the anatomical location of perceived pain to a somatotopic map. [000334] Areas of specific DREZ tissue displaying hyperactive electrical signals were then identified by measuring their electrical hyperactivity. Non-electrically hyperactive, non- pain generating DREZ sites were identified in the same individual. Samples of both the hyperactive, pain generating DREZ spinal cord tissue and non-hyperactive, non-pain generating DREZ spinal cord tissue were surgically excised from the individual.
  • Tissues were obtained surgically exposing the DREZ tissue inclusive of the substantia gelatinosa tissue above (cephalad), below (caudal), and at the level of injury.
  • a recording electrode was inserted approximately 2 mm deep into the dorsal grey matter of the spinal cord, entering at the dorsal root entry zone (DREZ). Recordings of spontaneous electrical activity were recorded for one second. DREZ tissue was removed to a 2mm depth.
  • Recordings were performed bilaterally along the DREZs cephalad at and caudal to the level of the injury approximately 1 mm apart.
  • the recordings were analyzed using fast Fourier transform (FFT) root Mean Square analysis and "spindle” analysis (as disclosed in U.S. Patent Publication Nos.2010/0203022 and 2007/0016264, both of which are incorporated herein by reference) to identify regions of neuroelectrical hyperactivity.
  • the regions recorded correspond to at least Rexed layers 1, 2, and 3 within the dorsal grey matter.
  • the recordings were guided by a somatotopic map and made both cephalad and caudal to the level of injury as well as at the level of the injury until no additional electrical hyperactivity was detected.
  • Example 2 Tissues from hyperactive and non-hyperactive DREZ in Example 1 were then tested against a 4,000 marker panel, including CGRP2 according to methods at SomaLogic.
  • “Hot” and “cold” DREZ tissues were obtained from 10 patients (107 samples) and analyzed on the SomaScan 5K plex, which measures 4981 human proteins.
  • Hyperactive tissue was extracted from spinal cord injured patients. Per tissue protein extraction agent (Thermo Scientific) per the manufacturer's recommendation, 200 ⁇ L of buffer plus Halt protease inhibitor cocktail (Pierce Part# 78430) was added. The tissue was homogenized in a tube on ice with a rotary pestle for 30 seconds until no tissue fragments were visible. The sample was centrifuged at >14,000x g for 10 minutes while at 4°C.
  • the supernatant was filtered through a 0.2 micron filter into a sterile tube or plate while at 0°C Millipore Multiscreen GV filter plate, 0.22 ⁇ , sterile, Part # MSGV2210 or similar).
  • the amount of total protein was determined using Micro BCA Protein Assay Kit (Thermo Scientific). Aliquots were stored at - 81 °C. 42 4897-2147-5622.1 [000341] Of the approximate ninety proteins having increased abundance in the hyperactive DREZ tissue, twenty-one found literature support for relevance in neuronal and glial function in the DREZ leading to neuronal depolarization, and relevance in epilepsy and/or neuropathic pain rodent models.
  • CGRP was chosen from these twenty-one based on high hot/cold ratio of protein abundance, strong neurobiological relevance to neuronal and glial causation of DREZ neuronal hyperactivity involving multiple pathways, and strong rodent model validation.
  • the tissues were tested by SOMAscan ® analysis. SOMAscan tests tissue against a protein panel (including CGRP2), and a range of concentrations. SOMAscan ® and related methods and reagents are described, for example, at U.S.
  • the hyperactive DREZ tissue showed an increase in CGRP2 abundance over non-hyperactive DREZ tissue. Surgical destruction of this hyperactive DREZ tissue resulted in complete or near-complete relief of below-level neuropathic pain. CGRP is therefore a target for treating neuropathic pain in spinal cord injured individuals.
  • Example 3. [000347] A compound of one of Formulae (I), (II), (III), or (IV), or a pharmaceutical salt, hydrate, solvate, ester, N-oxide, or combination thereof, is administered to a male patient 43 4897-2147-5622.1 having severe below-level neuropathic pain. The patient experiences severe pain continuously, or with bursts in intensity occurring at least once daily.
  • the patient rates his pain as a 10 on a scale of 0 to 10, 10 considered near suicidal-level pain.
  • the compound is administered as directed in the product label of the compound, as described and incorporated herein by reference.
  • Administering the compound as described herein results in a reduction of central pain in the patient.
  • Opioid Dosing A patient is treated with a combination of opioid and rimegepant. During administration, the patient voluntarily lowered the opioid dose. The patient further had increased opioid efficacy with absence of withdrawal symptoms. The combination therapy demonstrated the effectiveness of combination therapy as well as the effectiveness of rimegepant in opioid withdrawal.
  • the patient additionally begins a course of rimegepant at 25mg once a day (qD) for two weeks. This is increased to 50mg/day BID, i.e., 100mg/day and remains at this dose for a six month period.
  • qD 25mg once a day
  • BID 50mg/day BID
  • the patient By one to two months after the initial rimegepant administration, the patient voluntarily decreases his breakthrough dosing of oxycodone to 20 mg/day. Pain decreases from 9-10 (near suicidal) to 6, without severe episodes. By 4-5 months the patient’s breakthrough dosing continued to decrease to at times not needing it at all.
  • breakthrough dose is completely eliminated.

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Abstract

L'invention concerne des méthodes de traitement systémique de la douleur neuropathique chez un patient souffrant d'une lésion de la moelle épinière par l'administration d'un inhibiteur du peptide lié au gène de la calcitonine (CGRP). Dans certaines variantes, des tissus engendrant de la douleur en lien avec une douleur neuropathique centrale à médiation sympathique chez des patients souffrant d'une lésion de la moelle épinière (SCI), ont été acquis.
PCT/US2025/019825 2024-03-13 2025-03-13 Méthode de traitement de la douleur neuropathique utilisant un inhibiteur anti-cgrp Pending WO2025193980A2 (fr)

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US8314117B2 (en) * 2009-10-14 2012-11-20 Bristol-Myers Squibb Company CGRP receptor antagonists
ES2746031T3 (es) * 2012-02-27 2020-03-04 Bristol Myers Squibb Co Sal de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[B]piridin-9-IL-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-B]piridin-1-il)piperidina-1-carboxilato
ES2972849T3 (es) * 2016-10-14 2024-06-17 Cns Biosciences Inc Tratamiento del dolor neuropático en personas con lesión de la médula espinal
SI4088720T1 (sl) * 2018-03-25 2026-01-30 Pfizer Ireland Pharmaceuticals Unlimited Company Rimegepant za motnje, povezane s cgrp
US20250044306A1 (en) * 2021-11-30 2025-02-06 East Carolina University Methods for Determining Opioid Responsiveness in the Treatment of Pain

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