WO2025224601A1 - Antagonistes de trpm3 pour le traitement de la migraine et de la douleur - Google Patents

Antagonistes de trpm3 pour le traitement de la migraine et de la douleur

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Publication number
WO2025224601A1
WO2025224601A1 PCT/IB2025/054157 IB2025054157W WO2025224601A1 WO 2025224601 A1 WO2025224601 A1 WO 2025224601A1 IB 2025054157 W IB2025054157 W IB 2025054157W WO 2025224601 A1 WO2025224601 A1 WO 2025224601A1
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Prior art keywords
amino
oxopropan
carboxamide
hydroxy
methyl
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English (en)
Inventor
Richard BERTZ
Beth L. EMERSON
Volkan GRANIT
Arnaud Marchand
Stuart Murray
Irfan QURESHI
Jean-Christophe VANHERCK
Thomas VOETS
Joris VRIENS
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Katholieke Universiteit Leuven
Biohaven Therapeutics Ltd
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Katholieke Universiteit Leuven
Biohaven Therapeutics Ltd
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Publication of WO2025224601A1 publication Critical patent/WO2025224601A1/fr
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Anticipated expiration legal-status Critical

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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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • 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
    • A61P25/06—Antimigraine agents

Definitions

  • the present disclosure is related to TRPM3 antagonists for the treatment of migraine and pain as supported by pharmacokinetics and clinical studies in humans.
  • migraine Despite substantial progress in therapy, migraine remains a leading cause of disability on a global scale and afflicts more than 1 billion people worldwide. Many people with migraine have inadequate symptom relief or face tolerability and safety issues with existing acute therapies. Approximately 96% of people with migraine report at least one unmet acute treatment need, and about 74% describe inadequate treatment response. New treatments are needed to meet the needs of individual patients and to address the public health burden of this highly prevalent disorder. Effective treatments have the potential to give patients more headache-free days, an outcome associated with improved work and household activity participation, as well as a reduction in associated indirect costs. In addition, suboptimal acute treatment is associated with an increased risk of migraine progression.
  • a migraine attack is commonly preceded by an aura, which usually includes impairment in vision as well as a tingling sensation on the face and limbs.
  • An aura may occur a few minutes before pain begins.
  • the patient typically suffers from moderate to severe pulsing or throbbing pain, on the sides of their head and behind the eyes. The pain intensifies for patients with any movement of the head, including actions like sneezing and coughing. Pain symptoms are often accompanied by nausea and vomiting as well as sensitivity to light, noise, and odors.
  • Migraines can cause patients to lose the ability to perform daily tasks like driving or working, and in most cases prevent the patient from undergoing any physical activity without feeling intense pain.
  • Triptans serotonin 5-HT receptor agonists
  • Triptans are the anti-migraine agents that are the most effective and commonly prescribed agents.
  • Triptans bind to three serotonin receptors, 5HT1B, 5HT1D, and 5HT1F, causing the constriction of blood vessels in cranial arteries which become dilated during a migraine, thus inhibiting the neurotransmission of pain sensation.
  • triptans do not provide relief to all patients and due the effect triptans have in the cranial arteries, they can cause problems in patients with cardiovascular disease, cerebrovascular disease, and the like.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • these drugs can be slow acting and inconsistent in alleviating pain symptoms.
  • Calcitonin gene-related peptide (CGRP) inhibitors are a more recently developed option for the treatment and prevention of migraines. These agents modulate the CGRP ligand or its receptor that is located within pain signaling pathways, intracranial arteries, and mast cells. With the discovery that serum levels of CGRP are elevated during a migraine attack, many CGRP inhibitors have been developed such as olcegepant, telcagepant, ubrogepant, rimegepant, and others. Despite this welcome addition to the therapeutics, not all migraine sufferers respond to the CGRP antagonists. (See, Raffaelli B, Fitzek M, Overeem LH, Storch E, Terhart M, Reuter U.
  • TRP Transient receptor potential
  • TRPM3 Transient receptor potential melastatin-3
  • TRP Transient receptor potential
  • TRPM3 is a non-selective calcium permeable ion channel expressed in the meninges and trigeminal ganglion, which is sensitive to heat and ligand stimulation.
  • TRPM3 promotes neurogenic inflammation (which plays a key role in migraine pathophysiology) through its effects on CGRP release as well as mechanisms that are CGRP -independent.
  • TRPM3 sensitizes and activates nociceptors in the trigeminovascular system, and importantly, TRPM3 antagonism normalizes nociceptor function in preclinical models.
  • TRPM3 In nociceptors innervating inflamed tissues, antagonisms of TRPM3 also dampens the responsiveness of TRPV1 and TRPA1 which are both TRP channels that are expressed in nociceptors implicated in migraine, suggesting that TRPM3 is an upstream target for reducing inflammatory nociception.
  • Human transcriptomic data demonstrate TRPM3 co-expression with a spectrum of migraine-relevant genes in the human trigeminal ganglion. Further genetic analyses suggest a strong association between TRPM3 genetic variants and the risk of migraine. While there is a suggestion in the art as to the potential use of TRPM3 inhibitors to treat various pain-related disorders, no human clinical data or pharmacokinetics have been provided.
  • a method of treating migraine, headache, neuropathic pain, and/or nociceptive pain in a human patient in need thereof comprises orally administering to the patient a pharmaceutical composition for oral administration comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a TRPM3 antagonist, or a physiologically acceptable salt thereof, wherein the TRPM3 antagonist is a molecule of Formula (I) wherein
  • R 1 is CH3 optionally substituted with F
  • R 3 is H
  • T is -O-, U is -CH2-; R 6 , R 7 and R 8 are each H;
  • V is a 5-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, and imidazolyl, or a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein the 5- membered heteroaryl and 6-membered heteroaryl are optionally substituted with -F, -Cl, Ci- C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F.
  • FIG. 1 shows the pharmacokinetic profile for single oral doses of BHV-2100 in healthy subjects presented as mean concentration vs. time profiles.
  • FIG. 2 shows the mean concentration vs. time profiles of single oral doses of BHV-2100 with and without a high fat meal.
  • FIG. 3 shows the mean concentration vs. time profiles of single oral doses of BHV-2100 with and without famotidine.
  • FIG. 4 shows the mean concentration vs. nominal time at steady state profiles after multiple doses of BHV-2100.
  • the dashed line represents the theoretical concentrationtime profile of a second dose on a BID schedule (determined by superposition of steady-state data).
  • the parameter activity is expressed in arbitrary units (a.u.), corresponding to the number of automatically detected activity counts per second.
  • FIG. 6 shows the average ( ⁇ SEM) area under the curve and the average ( ⁇ SEM) peak increase in BCT during the three hour-period post oral dosing of vehicle, BHV- 2100 (100 mg/kg) or AMG517 (10 mg/kg).
  • Statistical comparison was performed using oneway ANOVA with Sidak-Holm post-hoc test.
  • FIG. 7. provides the time course for the oxaliplatin-induced peripheral neuropathy study in mice.
  • FIG. 8 shows results for the chemotherapy-induced neuropathic pain model.
  • the plot shows the reversal of cold-induced pain (%) when vehicle, tramadol or BHV-2100 (1, 5, or 24 mg/kg) were administered 6 days after oxaliplatin treatment in mice.
  • FIG. 9 shows results for animals investigated for mechano-sensitivity using the electronic von Frey test in the chemotherapy induced neuropathic pain model.
  • the mechanical threshold was calculated per animal at the start of the experiment (baseline), at day 6 post oxaliplatin injection (Day 6 pre-treatment) and 30 min post dosing of the different test conditions (Day 6 post-treatment).
  • N 8 male B16C57J mice.
  • FIG. 10 shows results for the diabetic neuropathy model in rats.
  • the plot shows the mechanical threshold (g) for vehicle, pregabalin or BHV-2100 (1, 5, or 24 mg/kg) administered 7 days after streptozoticin (STZ) administration.
  • FIG. 11 shows results for the pregnenolone sulfate (TRPM 3 agonist)-induced pain model in rats. Drug was administered 30 minutes prior to TRPM3 agonist injection into the hind paw of rats. The plot shows time spent licking/lifting (Sec) for vehicle or BHV- 2100 (2, 6, or 20 mg/kg).
  • FIG. 12 shows results for spared nerve injury of tactile allodynia in rats.
  • the plot shows threshold force (g) vs. time for vehicle, pregabalin (30 mg/kg) or BHV-2100 (1, 5, or 25 mg/kg).
  • FIG. 13 shows results for the partial sciatic nerve ligation model in rats. Drug was administered 14 days after unilateral sciatic nerve injury. The plot shows mechanical threshold (% of concentrated paw) vs. time for vehicle, pregabalin (30 mg/kg) or BHV-2100 (1, 5, or 25 mg/kg).
  • FIG. 14 also shows results for the partial sciatic nerve ligation model in rats. Drug was administered 14 days after unilateral sciatic nerve injury in rats. The plot shows 50% paw withdrawal threshold for ipsilateral paw and contralateral paw vs. time for pregabalin and BHV-2100 (1, 5, or 25 mg/kg).
  • FIG. 15 shows a protocol for a Phase 2 clinical study in the acute treatment of migraine.
  • BHV-2100 (1, 5, or 25 mg/kg p.o.) reduced the rodents’ nociceptive response (licks/lifts) in a dose-dependent manner.
  • BHV-2100 (1, 5, and 25 mg/kg, p.o.) induced a reduction of the oxaliplatin-induced cold allodynia and mechanical hypersensitivity.
  • the analgesic effect of BHV-2100 was comparable to the analgesic effect of tramadol (5 mg/kg), without the concomitant sedative effects associated with tramadol.
  • BHV-2100 at 25 mg/kg p.o. showed significant alleviation of mechanical allodynia at 1 and 2h post-treatment.
  • BHV-2100 (1, 5, 25 mg/kg p.o.) was tested in the tactile allodynia in the rat spared nerve injury model.
  • BHV-2100 25 mg/kg p.o.
  • BHV-2100 In the streptozotocin (STZ)-induced diabetic neuropathy model in Lewis rats, BHV-2100 dosed at 5 mg/kg or 25 mg/kg demonstrated statistically significant beneficial effects on tactile allodynia as determined using the von Frey assay. In view of these results, BHV-2100 is also expected to be useful in the treatment of various forms of migraine as well as neuropathic pain, including diabetes-related neuropathic pain, chemotherapy -induced peripheral neuropathy, peripheral neuropathy as a result of injury or trauma, postherpetic neuralgia, carpal tunnel syndrome, sciatica, HIV-related neuropathy, and others.
  • TRPM3 activation can trigger vasodilation via CGRP release.
  • Preclinical data suggest TRPM3 leads to neurogenic inflammation in part through the release of CGRP.
  • TRPM3 activation on the CGRP axis has been observed in isolated human tissues.
  • isolated human dermal arteries from subcutaneous fat the addition of the TRPM3 agonist pregnenolone sulfate led to a significant release of CGRP.
  • TRPM3 is present and functional in anatomically relevant sites that may initiate and propagate migraine, including the meninges and the TG. In mice, TRPM3 ligands evoke trigeminally-mediated pain.
  • TRPM3 is coexpressed with known migraine-relevant genes in both neuronal and non-neuronal cells within the human TG. Genetic substitutions in the S4-5 loop of TRPM3 have been shown to increase TRPM3 channel activity (Zhao S, Yudin Y, Rohacs T. “Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms”. Elife. 2020;9 (2020).) UK Biobank participants with variants in the S4-5 Loop and participants with CADDhi TRPM3 genetic variants have a significant risk of migraine and/or migraine with aura.
  • PK pharmacokinetics
  • BHV-2100 has been shown to potently inhibit human, rat, and mouse TRPM3.
  • BHV-2100 inhibits TRPM3 -mediated calcium responses in human embryonic stem cell-derived sensory neurons with a half-maximal inhibitory concentration of 3 nM.
  • dose-dependent pain reduction Vriens J, Vanherck J-C, Marchand A, Carr B, Dubowchik G, Caldwell R, et al. “BHV-2100, a first- in-class TRPM3 antagonist for the treatment of pain (S13.002)”. Neurology. 2024;102(2024):6059).
  • Described herein are methods of treating migraine, neuropathic pain, or nociceptive pain in a patient in need thereof, comprising orally administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a TRPM3 antagonist, or a physiologically acceptable salt thereof, wherein the pharmaceutical composition is a composition for oral administration.
  • the pharmaceutical composition is an immediate-release composition.
  • immediate-release means the composition includes no components meant to delay or prolong dissolution of the oral dosage form. That is, the composition is meant to be dissolved quickly to allow rapid absorption of the active agent.
  • the TRPM3 antagonist is a molecule of Formula (I) as described in U.S. Patent No. 12,209,081 : wherein
  • R 1 is QU optionally substituted with F
  • R 3 is H
  • T is -O-
  • U is -CH 2 -;
  • R 6 , R 7 and R 8 are each H;
  • V is a 5-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, and imidazolyl, or a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein the 5- membered heteroaryl and 6-membered heteroaryl are optionally substituted with -F, -Cl, Ci- C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F.
  • R 1 is -CH3.
  • V is 5-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, and imidazolyl, wherein the 5-membered heteroaryl is optionally substituted with -F, -Cl, C1-C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F.
  • V is 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein the 6-membered heteroaryl is optionally substituted with -F, -Cl, C1-C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F.
  • Exemplary compounds of Formula (I) include the following:
  • heteroatom(s) as used herein means an atom selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • alkyl, saturated or unsaturated encompasses saturated alkyl as well as unsaturated alkyl such as alkenyl, alkynyl, and the like.
  • alkyl as used herein means normal, secondary, or tertiary, linear or branched hydrocarbon with no site of unsaturation.
  • Examples are methyl, ethyl, 1 -propyl (n-propyl), 2-propyl (iPr), 1 -butyl, 2-methyl-l-propyl(i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1 -pentyl (n- pentyl), 2-pentyl, 3 -pentyl, 2-methyl-2 -butyl, 3-methyl-2-butyl, 3 -methyl- 1 -butyl, 2-methyl- 1 -butyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3 -methyl-3 -pentyl, 2-methyl-3 -pentyl, 2,3 -dimethyl-2 -butyl, and 3,3-dimethyl-2-butyl.
  • alkenyl as used herein means normal, secondary or tertiary, linear or branched hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond.
  • sites usually 1 to 3, preferably 1 of unsaturation, namely a carbon-carbon, sp2 double bond.
  • the double bond may be in the cis or trans configuration.
  • aryl as used herein means an aromatic hydrocarbon.
  • Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like.
  • Fused systems of an aryl ring with a cycloalkyl ring are considered as aryl irrespective of the ring that is bound to the core structure.
  • Fused systems of an aryl ring with a heterocycloalkyl ring are considered as heterocycloalkyl irrespective of the ring that is bound to the core structure.
  • indoline, dihydrobenzofuran, dihydrobenzo-thiophene and the like are considered as heterocycloalkyl.
  • Fused systems of an aryl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.
  • heteroaryl as used herein means an aromatic ring system including at least one heteroatom, i.e., N, O, or S as ring member of the aromatic ring system.
  • heteroaryl include but are not limited to benzimidazole, benzisoxazole, benzoazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furane, furazane, imidazole, imidazopyridine, indazole, indole, indolizine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxindole, phthalazine, purine, pyrazine, pyrazole, pyridazine
  • carbon bonded heterocyclic rings are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • Preferred carbon bonded heterocycles include 2-pyridyl, 3 -pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5- pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3 -pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H- indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or B-carboline.
  • Preferred nitrogen bonded heterocycles include 1-aziridyl, 1- azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Further heteroaryls in the meaning of the invention are described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.
  • the terms “monosubstituted”, “disubstituted”, “tri substituted”, “polysubstituted” and the like means chemical structures defined herein, wherein the respective moiety is substituted with one or more substituents, meaning that one or more hydrogen atoms of said moiety are each independently replaced with a substituent.
  • -Ci-6-alkyl that may be polysubstituted with -F covers -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.
  • -Ci-6-alkyl that may be polysubstituted with substituents independently of one another selected from -F and -Cl covers -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, -CH2CI, - CHCh, -CCh, -CH2CCI3, CCI2CCI3, -CHC1F, -CCIF2, -CCI2CF3, -CF2CCI3, -CCIFCCLF, and the like. Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.
  • solvate includes any combination which may be formed by a derivative of this invention with a suitable inorganic solvent (e.g., hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like.
  • a suitable inorganic solvent e.g., hydrates
  • organic solvent such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like.
  • physiologically acceptable salts means the therapeutically active non-toxic salt forms which the compounds of formulae herein are able to form. Therefore, the compounds described herein optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + , Ca 2+ and Mg 2+ .
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds may bear multiple positive or negative charges. The net charge of the compounds may be either positive or negative.
  • any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
  • Exemplary counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature, and that the compounds may be associated with any type of counter ion.
  • the compounds can exist in a variety of different forms, encompassed herein are not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such acids include, for instance, inorganic acids such as hydrohalogen acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e.
  • compositions herein comprise the compounds in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • physiologically acceptable salts examples include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4 + (wherein X is -Ci-6-alkyl).
  • an alkali metal for example, sodium
  • an alkaline earth for example, magnesium
  • ammonium and NX4 + (wherein X is -Ci-6-alkyl).
  • Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX4 + (wherein X typically is independently selected from -H or a -Ci-4-alkyl group).
  • a suitable cation such as Na + and NX4 + (wherein X typically is independently selected from -H or a -Ci-4-alkyl group).
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the disclosure.
  • enantiomer means each individual optically active form of the compounds described herein, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • isomers as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomers.
  • the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.
  • the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formulae herein may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or transconfiguration.
  • stereoisomerically pure or “chirally pure” relates to compounds having a stereoisomeric excess of at least about 80% (i.e., at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%.
  • enantiomerically pure and “diastereomerically pure” should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.
  • Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compound.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a- methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers can be separated and isolated by normal- and reversephase chromatography following methods for separation of atropisomeric naphthylisoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase.
  • Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives.
  • Commercially available polysaccharide based chiral stationary phases are ChiralCel® CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak® AD, AS, OP(+) and OT(+).
  • Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like.
  • compositions can be prepared in a dosage form such as, for example, tablets, capsules, nasal sprays, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • a dosage form such as, for example, tablets, capsules, nasal sprays, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • a preferred dosage form is an oral dosage form such as a tablet or a capsule or an oral liquid dosage form.
  • compositions comprising a TRPM3 antagonist of Formula (I) typically also include pharmaceutically acceptable carriers (also referred to as excipients) such as, for example, binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents, flavorants, preservatives and mixtures thereof.
  • pharmaceutically acceptable carriers also referred to as excipients
  • excipients such as, for example, binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents, flavorants, preservatives and mixtures thereof.
  • Examples of pharmaceutically acceptable carriers that may be used in preparing the pharmaceutical compositions include, but are not limited to, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methyl-cellulose, sodium carboxymethylcellulose, polyvinyl-pyrrolidone (PVP), talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen-free water and combinations thereof.
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
  • disintegrating agents may be employed such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the flavoring agent is selected from mint, peppermint, berries, cherries, menthol, sodium chloride flavoring agents, and combinations thereof.
  • the sweetener is selected from sugar, sucralose, aspartame, acesulfame, neotame, and combinations thereof.
  • the pharmaceutical compositions may be manufactured by conventional methods known in the art, for example, by means of mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilization processes, and the like.
  • the oral pharmaceutical composition is a fast-dispersing dosage form.
  • fast-dispersing dosage form refers to compositions which 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.
  • the oral pharmaceutical compositions are prepared in oral solid molded fast-dispersing dosage form, such as described in U.S. Pat. No. 9,192,580.
  • the pharmaceutical compositions are oral solid molded fast-dispersing dosage forms comprising a solid network of the active ingredient, a TRPM3 antagonist, and a water-soluble or water-dispersible carrier, for example a carrier containing a gelatin such as fish gelatin. Accordingly, the carrier is inert towards the active ingredient.
  • the network is obtained by subliming solvent from a composition in the solid state, the composition comprising the active ingredient and a solution of the carrier in the solvent.
  • the dosage forms can be prepared according to the process disclosed in Gregory et al., U.K. Patent No. 1,548,022, using fish gelatin as the carrier.
  • an initial composition comprising the active ingredient and a solution of the fish gelatin carrier in a solvent is prepared, followed by sublimation.
  • the sublimation is preferably carried out by freeze-drying the composition.
  • the composition can be contained in a mold during the freeze-drying process to produce a solid form in any desired shape.
  • the mold can be cooled using liquid nitrogen or solid carbon dioxide in a preliminary step prior to the deposition of the composition therein. After freezing the mold and composition, they are next subjected to reduced pressure and, if desired, controlled application of heat to aid in sublimation of solvent.
  • the reduced pressure applied in the process can be below about 4 mm Hg, preferably below about 0.3 mm Hg.
  • the freeze-dried compositions can then be removed from the mold if desired or stored therein until later use.
  • a solid fast-dispersing dosage form is produced having the advantages associated with the use of fish gelatin described herein.
  • fish gelatin is categorized as being from cold water and warm water fish sources and as being of the gelling or non-gelling variety.
  • the non-gelling variety of fish gelatin in comparison to gelling fish gelatin and bovine gelatin, contains lower proline and hydroxyproline amino acid content, which are known to be associated with cross-linking properties and gelling ability.
  • Non-gelling fish gelatin can remain at solution concentrations of up to about 40% as well as in temperatures as low as 20°C.
  • the fish gelatin is preferably obtained from cold water fish sources and is the non-gelling type of fish gelatin. More preferably, the non-hydrolyzed form of non-gelling fish gelatin is used. In an alternative embodiment, spray-dried non-hydrolyzed non-gelling fish gelatin can be used. Fish gelatins are commercially available, for example, from Croda Healthcare.
  • the solid fast-dispersing dosage forms can also contain, in addition to the active ingredient and fish gelatin carrier, other matrix forming agents and secondary components.
  • matrix forming agents include materials derived from animal or vegetable proteins, such as other gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatinacacia complexes.
  • Other materials which may also be incorporated into the solid fast-dispersing dosage forms include sugars such as mannitol, dextrose, lactose, galactose, and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L- phenylalanine.
  • One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification (freezing).
  • the matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant.
  • the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution of suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.
  • Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the fast-dissolving compositions.
  • Exemplary coloring agents include red, black and yellow iron oxides and FD & C dyes such as FD&C Blue No. 2 and FD&C Red No.
  • Exemplary flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations of these.
  • Exemplary pH modifiers include edible acids and bases, such as citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide.
  • Exemplary sweeteners include, for example, sucralose, aspartame, acesulfame K, and thaumatin.
  • Exemplary taste-masking agents include, for example, sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbates, and microencapsulated actives.
  • the pharmaceutical composition is provided in the form of an oral solid molded fast-dispersing dosage form.
  • the pharmaceutical composition comprises from about 70-80 percent by weight (“wt %”) of a TRPM3 antagonist of Formula (I), about 10-20 wt % of a fish gelatin, about 10-20 wt % of a filler, and 0.1-5.0 wt % of a flavorant.
  • the filler is mannitol.
  • Solid compositions are normally formulated in dosage units providing from about 1 to about 1000 mg of the TRPM3 antagonist of Formula (I) per dose.
  • Some examples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, 500 mg, 600 mg and 1000 mg.
  • Typical dose ranges in include from about 10-600 mg, 25-300 mg, 25-150 mg, 50-100 mg, 60-90 mg, and 70-80 mg.
  • Liquid compositions are generally in a unit dosage range of 1-100 mg/mL.
  • Some examples of liquid dosage units are 0.1 mg/mL, 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
  • administering refers to the physical introduction of a composition comprising a therapeutic agent to a subject, 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.
  • Described herein are methods of treating patients in need of treatment for migraine, headache, neuropathic pain, and/or nociceptive pain.
  • Migraine is a neurological condition characterized by moderate to severe headaches. Migraine is often accompanied by symptoms such as nausea, vomiting and/or sensitivity to light and sound.
  • Peripheral neuropathic pain also called peripheral nerve pain, occurs when peripheral nerves (outside of the brain and spinal cord) are damaged.
  • Peripheral neuropathy causes weakness, numbness and pain, especially in the hands and feet.
  • Neuropathic pain includes diabetes-related neuropathic pain and other metabolic neuropathies, chemotherapy- induced peripheral neuropathy and other toxic neuropathies, peripheral neuropathy as a result of injury, trauma, or surgery, or other diseases, including but not limited to, postherpetic neuralgia (pain following a shingles infection) and other infections, entrapment neuropathies such as carpal tunnel syndrome (nerve compression in the wrist), mononeuropathy multiplex, small fiber neuropathy, neuropathic pain associated with Charcot-Marie-Tooth Disease and other genetic neuropathies, sciatica (pain radiating down the leg due to nerve irritation) and other painful nerve root disorders, HIV-related neuropathy, neuropathies due to cancer, and others.
  • postherpetic neuralgia pain following a shingles infection
  • Nociceptive pain is pain arising from signals from nociceptors, generally as a result of tissue damage such as from physical or chemical agents. Nociceptive pain is most often localized to the area of tissue damage.
  • the terms “subject” and “patient” refer any human or nonhuman animal. In the methods described herein, the patient is preferably a human patient.
  • the term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In some embodiments, the subject is a human.
  • the terms, “subject” and “patient” are used interchangeably herein.
  • an agent also sometimes referred to herein as a “drug” refers to any amount of the agent that, when used alone or in combination with another agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or relief from impairment or disability due to the disease affliction.
  • the therapeutically effective amount of an agent can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • treatment refers to treatment of a condition or disease in a subject and may include: (i) preventing the disease or condition from occurring in the subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e., arresting its development; relieving the disease or condition, i.e., causing regression of the condition; or (iii) ameliorating or relieving the conditions caused by the disease, i.e., symptoms of the disease. Treatment could be used in combination with other standard therapies or alone.
  • Treatment or “therapy” of a subject also includes any type of intervention or process performed on, or the administration of an agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of a symptom, complication or condition, or biochemical indicia associated with a disease.
  • treatment is an approach for obtaining beneficial or desired results with a subject.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: improvement in any aspect of a headache including lessening severity, alleviation of pain intensity, and other associated symptoms, reducing frequency of recurrence, increasing the quality of life of those suffering from the headache, decreasing dose of other medications required to treat the headache and reducing the number of headache days per month.
  • other associated symptoms include, but are not limited to, nausea, vomiting, and sensitivity to light, sound, and/or movement.
  • other associated symptoms include, but are not limited to swelling under or around the eyes, excessive tears, red eye, rhinorrhea or nasal congestion, and red flushed face.
  • “preventing” can include reversing, alleviating, ameliorating, inhibiting, slowing down the progression, development, severity, or recurrence of a symptom, complication or condition.
  • T ma x refers to a time or period after administration of a drug when the maximum concentration (Cmax) is reached in blood, serum, a specified compartment or test area of a subject.
  • T1/2 or half-life is the time for the plasma concentration of a drug to decrease to half of its initial value.
  • AUC area under the curve refers to a total amount of drug absorbed or exposed to a subject. Generally, AUC may be obtained from mathematical method in a plot of drug concentration in the subject over time until the concentration is negligible. The term “AUC” could also refer to partial AUC at specified time intervals.
  • Cmax refers to a maximum concentration of a drug in blood, serum, a specified compartment or test area of a subject between administration of a first dose and administration of a second dose.
  • the term Cmax could also refer to dose normalized ratios, if specified.
  • Dosing interval refers to the amount of time that elapses between multiple doses of a formulation disclosed herein being administered to a subject. Dosing interval can thus be indicated as ranges.
  • Dosing frequency refers to the frequency of administering doses of a formulation disclosed herein in a given time. Dosing frequency can be indicated as the number of doses per a given time, e.g., twice a day, once a day, once every other day, once a week or once in two weeks, and the like.
  • the orally administered TRPM3 antagonist of Formula (I) is administered at a dose of 25 to 250 mg, such as 25, 50, 75, 150 mg, 250 mg, or higher, either once or twice daily.
  • the human patient is not responsive to CGRP inhibition, not responsive to triptan therapy, or a combination thereof.
  • Exemplary CGRP medications include erenumab (Aimovig®), galcanezumab (Emgality®), fremanezumab (Ajovy®), rimegepant (Nurtec®), eptinezumab (Vyepti®), ubrogepant (Ubrelvy®), and atogepant (Qulipta®).
  • a human patient not responsive to triptan therapy can be a patient who has previously been prescribed triptan therapy, and found it to lack efficacy, and additionally encompasses individuals that have not previously been prescribed triptan therapy, but whose migraines or pain would nonetheless not respond to such treatment options.
  • the triptan is a triptan selected from the group consisting of almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan.
  • the triptan is sumatriptan.
  • the human patient has a mutated TRPM3 with one or more of the following amino acid substitutions: R1670Q, A1645V, V990M and P1090Q (numbering based on SEQ ID NO: 1).
  • BHV-2100 and by analogy the TRPM3 antagonists of Formula (I), are particularly useful for the treatment of migraines and pain.
  • the PK data suggests a number of features of such treatment that could not have been predicted based upon the prior art.
  • orally administering an oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) (e.g., BHV-2100) provides a T ma x of 1-2 hours and a Ti/2 from 8-12 hours after a single dose.
  • the fast T ma x can be important for the acute treatment of migraine as rapid relief of migraine pain and other symptoms is a critical treatment goal.
  • the long T1/2 can be important to maintain symptom relief as well as to control symptom recurrence.
  • the TRPM3 antagonist of Formula (I) may be taken as needed for symptom relief, such as once or twice per day, or more frequently.
  • Treatment for acute migraine attacks can be intermittent treatment, short term treatment such as treatment over 1 day, 2 days, or up to 3 days, or ongoing treatment, e.g., preventative treatment.
  • Acute migraine may or may not be accompanied by aura.
  • Treatment of acute migraine attacks is critical due to the severe and disabling nature of migraine attacks which can be accompanied by sensory disturbances.
  • Goals of treatment of acute migraine attacks include rapid and consistent pain and symptom relief without recurrence; restored ability to function; minimal need for repeat dosing or rescue medication; optimizing self-care to reduce use of medical resources; minimizing or eliminating adverse events; reduced cost of treatment; and effective acute treatment to reduce pain, symptoms and disability associated with migraine attacks.
  • Efficacy in the treatment of acute migraine attacks can be defined as pain freedom and most bothersome symptom (MBS) freedom at two hours after dosing, compared to placebo.
  • Pain freedom can be defined as a reduction of moderate or severe headache pain to no headache pain, and MBS freedom was defined as the absence of MBS as identified by the patient.
  • Typical MBS include photophobia, phonophobia, and/or nausea.
  • orally administering pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) (e.g., BHV-2100) for a plurality of doses provides a T1/2 from 8-10 hours at steady-state.
  • a favorable T1/2 at steady state is important for the treatment and prevention of episodic migraine (less than 15 headache days per month), and could also be useful to treat patients with chronic migraine (15 or more headache days per month).
  • a clinical endpoint for the preventative treatment of episodic migraine includes the change from baseline in the mean number of monthly migraine days.
  • the TRPM3 antagonist of Formula (I) should be taken chronically, such as daily, twice a day, once every other day, once every 3 days, or once per week.
  • Administration chronically means administration over a long period of time, such as a week, several weeks, months or even years.
  • TRPM3 antagonists of Formula (I) described herein will be more favorable in the treatment and prevention of chronic migraine than the current standard of care.
  • TRPM3 antagonists of Formula (I) described herein due to their favorable mechanism of action and PK, will be able to prevent the progression from episodic to chronic migraine which occurs in a significant fraction of the population.
  • the oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) is dose proportional across a dose of 25 to 150 mg.
  • dose proportional means increases in the administered dose are accompanied by proportional increases in the PK profile, such as the AUC or Cmax.
  • the composition is dose proportional by a factor of about 1 to about 1.3 with respect to plasma concentration. Dose proportionality is important to provide a consistent and predictable outcome with increasing and decreasing doses.
  • the SAD and MAD studies for BHV-2100 also provide information on the EC50 and EC90 for single and multiple dosing of the TRPM3 antagonists of Formula (I) in a rat PS pain model.
  • the EC50 is the half maximal effective concentration of a drug, that is, the concentration where 50% of the maximal effect is observed.
  • the EC90 is 90% of the effective concentration of a drug, that is, the concentration where 90% of the maximal effect is observed.
  • orally administering the oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) provides rapid and sustained analgesic effects in the treatment of migraine and pain, wherein administering a single dose of the pharmaceutical composition provides a plasma concentration above the EC90 within 30 minutes and maintains a plasma concentration above the EC50 for at least 6 hours.
  • the EC90 and the EC50 are achieved across a dose of 25 to 150 mg.
  • orally administering the oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) provides sustained analgesic effects in the treatment of migraine and pain, wherein chronically administering a plurality of doses of the pharmaceutical composition maintains a plasma concentration above the EC90 for at least 7 hours, preferably at least 16 hours, more preferably at least 21 hours.
  • chronically administering a plurality of doses of the pharmaceutical composition maintains a plasma concentration above the EC90 for 24 hours.
  • orally administering the oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) provides sustained analgesic effects in the treatment of migraine, wherein chronically administering a plurality of doses of the pharmaceutical composition maintains the EC50 for at least 17 hours, preferably for 24 hours.
  • the TRPM3 antagonist of Formula (I) when administered twice daily, the chronically administering a plurality of doses of the pharmaceutical composition maintains the EC50 for 24 hours.
  • the immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) can be administered immediately after a high fat meal, wherein the T ma x is delayed by approximately 1.5 hr and the Cmax is increased by less than 15%.
  • a high-fat meal is defined as a meal which includes 500- 600 kcal derived from fat.
  • the immediate- release TRPM3 antagonist composition can be administered without regard to consumption of food, e.g., a high fat meal.
  • food-active agent interactions can influence the safety and efficacy of an orally administered drug. Depending on the active agent, an increase or decrease in potency/efficacy can be observed. Food effect studies are important to determine proper labeling for an active agent and to determine whether clinical studies should take into account the diet of the subject.
  • the immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) can be administered with a gastric acidreducing agent such as famotidine, wherein the T ma x and C max are not substantially affected by the acid reducing agent.
  • Acid reducing agents can affect pharmacokinetics by changing gastric pH. Without being held to theory, based on the data provided herein, it is believed that the immediate-release TRPM3 antagonist composition can be administered without regard to administration of acid-reducing agents.
  • Exemplary gastric acid-reducing agents include proton pump inhibitors (PPI), histamine 2 receptor antagonists (H2RA), and/or an antacid.
  • PPIs include omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole, and dexlansoprazole.
  • H2RAs include cimetidine, famotidine, nizatidine, and ranitidine.
  • Exemplary antacids include aluminum hydroxide/carbonate, calcium hydroxide/carbonate, and bismuth subsalicylate.
  • the TRPM3 antagonist of Formula (I) may be coadministered with second agent for the treatment of migraine or pain.
  • second agents for the treatment of migraine and pain include a CGRP inhibitor, a triptan agent, an ergot alkaloid, a non-steroidal anti-inflammatory drug, acetaminophen, butalbital, caffeine, aspirin, dexamethasone, lasmiditan, and combinations thereof.
  • CGRP inhibitors and triptan agents are listed above.
  • exemplary ergot alkaloids include dihydroergotamine and ergotamine.
  • exemplary non-steroidal antiinflammatory drugs include ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, and indomethacin.
  • SAD sequential single-ascending dose
  • MAD multiple ascending dose
  • AE adverse events
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • BHV-2100 shows rapid absorption and sustained concentrations after administration of a single dose. Also as shown in FIG. 1 and Table 1, the PK of BHV-2100 was approximately dose-proportional at doses up to 150 mg.
  • Table 1 BHV-2100 Pharmacokinetic parameters following single oral doses in healthy participants.
  • Table 3 Time above EC50 and EC90 with multiple doses of BHV-2100.
  • Table 4 BHV-2100 Pharmacokinetic parameters following multiple oral doses.
  • BHV-2100 is a first in class, orally administered, selective antagonist of TRPM3, a target for the treatment of migraine and pain.
  • Single doses demonstrated rapid absorption and sustained concentrations above the predicted efficacious levels at all doses tested after 20 minutes, an ideal PK profile for the treatment of migraine and pain.
  • Daily dosing achieved plasma concentrations predicted to have sustained analgesic effects.
  • BHV-2100 is a non-opioid candidate for the treatment of migraine and pain.
  • EXAMPLE 2 BHV-2100 Pharmacokinetic parameters following single serial oral doses [00117] Pharmacokinetic data after serial single oral doses of 150 mg BHV- 2100 administered as either an oral liquid suspension, an immediate-release tablet, an immediate-release tablet after a high fat meal, or an immediate-release tablet after the use of proton pump inhibitors (omeprazole) are provided in Tables 5-7. Table 5: BHV-2100 Pharmacokinetic parameters following single oral doses in healthy participants.
  • Table 6 BHV-2100 Pharmacokinetic parameters following single oral doses with and without food in in healthy participants.
  • Table 7 BHV-2100 Pharmacokinetic parameters following single oral doses with and without omeprazole in in healthy participants.
  • TEAEs Treatment-emergent adverse events
  • the BHV2100-102 study enrolled 18 participants, including 15 males and 3 non-childbearing potential females. Eligible participants were randomized to 1 of 6 treatment sequences based on a Williams design for the first 3 periods and a fixed fourth period and received each of the following treatments according to the randomization scheme:
  • Treatment A A single dose of 150 mg BHV-2100 administered as a suspension in the fasted state (reference)
  • Treatment B A single dose of 150 mg BHV-2100 administered as an IR tablet in the fasted state
  • Treatment C A single dose of 150 mg BHV-2100 administered as an IR tablet after consumption of a high-fat breakfast
  • Treatment D A single dose of 150 mg BHV-2100 administered as an IR tablet in the fasted state with 40 mg of omeprazole
  • FIG. 5 shows the time course of BCT, activity and heart rate in rats following p.o. treatment with vehicle, AMG517, or BHV-2100.
  • vehicle AMG517
  • BHV-2100 BHV-2100-treated animals did not show such an effect on BCT.
  • FIG. 6 provides the statistical analysis for the effects of the treatments on BCT. Compared to vehicle, both the AUC and the maximal change in BCT (max AT) were significantly higher in animals treated with AMG517. No significant differences were observed between animals treated with BHV-2100 or vehicle.
  • Table 9 provides the plasma concentrations of BHV-2100 and AMG517 at 45, 90, and 180 minutes post oral dosing of BHV-2100 (100 mg/kg) or AMG517 (10 mg/kg). These data were obtained from the rats in the satellite group.
  • Table 9 Plasma Concentrations of BHV-2100 and AMG517.
  • BHV-2100 100 mg/kg, p.o.
  • AMG517 10 mg/kg, p.o.
  • sustained hyperthermia in line with the literature on this and other TRPV1 antagonists (Gavva NR, “Body -temperature maintenance as the predominant function of the vanilloid receptor TRPV1”. Trends Pharmacol Sci., 2008, 29: 550-557).
  • EXAMPLE 5 BHV-2100 reverses established pain states in oxaliplatin-induced peripheral neuropathy in mice
  • CIPNP Chemotherapy-induced peripheral neuropathic pain
  • mice Forty male B16C57J mice were included in the study. Five different groups of eight male animals each (total of 40 mice) received a single dose (i.p.) of oxaliplatin (6 mg/kg) at the start of the study. All animals were tested for cold sensitivity and mechanosensitivity before (baseline), at day 6 post oxaliplatin injection (pre-treatment) and 30 min post dosing of vehicle/ BHV-2100 (1, 5, 25 mg/kg) (post-treatment) via the acetone spray test and the electronic von Frey filament, respectively. Tramadol (5 mg/kg) treatment was included as positive reference control. Blood sampling was done at the end of the experiment to quantify plasma exposure levels used to assess the drug's PK/PD parameters.
  • oxaliplatin 6 mg/kg
  • All animals were tested for cold sensitivity and mechanosensitivity before (baseline), at day 6 post oxaliplatin injection (pre-treatment) and 30 min post dosing of vehicle/ BHV-2100 (1, 5, 25 mg/
  • Cold sensitivity was tested by the acetone spray test. Briefly, thirty minutes prior to the start of the experiments, all the animals were placed in a testing apparatus consisting of eight chambers with a mesh floor in order to acclimatize the mice with the environment. After the acclimation, a volume of 50 pl of acetone was applied to one hind paw and the responses were monitored for 60 seconds post application. Responses to a cold stimulation were graded according to the following 5-point scale: 0-no response; 1 -brief lift, sniff, flick, or startle; 2-jumping, paw shaking; 3-multiple lifts, paw lick; 4- prolonged paw lifting, licking, shaking, or jumping; 5-paw guarding. Pain scores were determined by two independent researchers based on post-hoc analysis of video-recorded behavioral experiments, without knowledge of genotype or treatment.
  • FIG. 9 illustrates that oxaliplatin injection induced a strong reduction in the von Frey threshold in mice 6 days after dosing (day 6 pretreatment).
  • Treatment with BHV-2100 induced a dose dependent increase in the mechanical hypersensitivity, which was comparable to Tramadol (5 mg/kg) treatment (day 6 post treatment).
  • vehicle treated animals showed a similar von Frey threshold compared to pre-test conditions.
  • BHV-2100 Oral dosing of BHV-2100 induced a dose-dependent reduction of the oxaliplatin-induced cold allodynia and mechanical hypersensitivity.
  • the effects of BHV- 2100 were significant (compared to vehicle) at doses of 5 mg/kg and 25 mg/kg for cold allodynia and at a dose of 25 mg/kg for mechanical allodynia.
  • the effect of BHV-2100 was comparable to the analgesic effect obtained with Tramadol (5 mg/kg).
  • the STZ-induced diabetic neuropathy (i.e., peripheral nerve pain) model is a screen used to identify potential analgesics to treat diabetes-related neuropathic pain and possibly other types of peripheral nerve pain.
  • EXAMPLE 7 Evidence of efficacy of BHV-2100 in the pregnenolone sulfate (PS; TRPM 3 agonist)-induced pain model
  • BHV-2100 In vivo efficacy of BHV-2100 was evaluated in male Wistar rats with acute pain induced by a single injection of PS in the right hindpaw.
  • BHV-2100 The dose-dependent effect of BHV-2100 on PS-induced nociceptive behavior was analyzed for the total time of licking/lifting of the injected paw and the number of licks and lifts as shown in FIG. 11. ED50 values were 1.3 mg/kg and 1.4 mg/kg for total time of licking/lifting and the number of licks and lifts, respectively. Analysis of BHV-2100 or CIM124750 concentration in plasma showed that all groups were exposed to drug and that concentration in plasma increased with BHV-2100 dose. BHV-2100 did not evoke any sign of lethargy during the period of 45 minutes post-dose.
  • EXAMPLE 8 Evidence of efficacy of BHV-2100 in spared nerve injury model of tactile allodynia in rats
  • the spared nerve injury (SNI) model in the rat involves a selective transection to two (tibial and peroneal) of the three terminal branches of the sciatic nerve, the sural nerve remaining intact. Over a period of days, the lateral portion of the affected paw, which is innervated by the sural branch, develops a hypersensitivity to a tactile or thermal stimulus. Quantification of the behavioral, i.e. flinch or withdrawal, response to an evoked sensory stimulus applied to the affected region represents the primary measure of this model. [00151] The primary purpose of these studies in male SD rats was to examine the effect of BHV-2100 (1, 5, 25 mg/kg p.o.) in the tactile allodynia in the rat SNI model. GRTR322 (pregabalin) was used a blinded control in this study. Pregabalin (30 mg/kg i.p.) was included as a reference control.
  • BHV-2100 (5 and 25 mg/kg oral) produced a significant attenuation of the tactile allodynia in SNI rats (FIG. 12).
  • EXAMPLE 9 Evidence of efficacy of BHV-2100 in partial sciatic nerve ligation-induced neuropathic pain in rats
  • BHV-2100 and GRTR322 were screened for efficacy in partial sciatic nerve ligation (PSNL) model of neuropathic pain.
  • PSNL partial sciatic nerve ligation
  • BHV-2100 at 25 mg/kg p.o. showed significant reversal of mechanical allodynia at 1 and 2 hr post treatment.
  • GRTR322 (pregabalin) at 30mg/kg p.o. also exhibited antinociceptive effect over a period of 2hr.
  • Significant elevation of contralateral PWT with GRTR322 pregabalin; 30 mg/kg showed good correlation with signs of mild sedation noticed during cage-side observation.
  • MPE maximum possible effect of BHV-2100 at 5 mg/kg and 25 mg/kg was observed at 1 hr and 2 hr post administration.
  • BHV-2100 at 25 mg/kg produced maximum possible nociceptive effect of about 60% whereas GRTR322 (pregabalin) at 30mg/kg achieved a peak effect of 107% and pregabalin at 20 mg/kg showed 92% MPE at 2 hr post dose.
  • the goal is to determine the effect of multiple-dose administration of BHV-2100 on the single dose PK of drospirenone/ethinyl estradiol (DSRP/EE).
  • the study population is 24 healthy females of non-childbearing potential, 18-65 years of age.
  • Day 1 A single oral dose of DSRPZEE 3 mg/0.3 mg administered in the morning after an overnight fast of at least 10 hours.
  • Days 5-17 150 mg BHV-2100 BID, approximately every 12 hours.
  • Day 15 a single oral dose of DSRPZEE 3 mg/0.3 mg administered at 1 hour ⁇ 5 minutes after administering BHV-2100 in the morning. All morning doses administered after an overnight fast of at least 10 hours. Evening doses administered at least 2 hours after completion of the evening meal. It is expected that there will be no effect on BHV-2100 PK with the coadministration of DSRPZEE.
  • EXAMPLE 11 Randomized double-blind, placebo and active reference controlled, 6-way intra-individual crossover trial
  • the goal of this study is to evaluate the anti -nociceptive and anti- hyperalgesic properties of BHV-2100 vs. placebo and BHV-7000 (selective Kv7.2/7.3 activator) vs. placebo in 2 laser-evoked potential (LEP) skin models.
  • the study population is 24 healthy adult males. Treatments are as follows:
  • EXAMPLE 12 Phase 2 study of BHV-2100 in the acute treatment of migraine
  • the Phase 2 clinical study will be a randomized, double-blind, placebo-controlled trial.
  • the population will be 450 participants with at least a one year history of migraine with and without aura.
  • Patients will be randomized 1 : 1 : 1 : 1 across 3 doses and placebo.
  • the BHV-2100 doses are projected to be 25 mg/75 mg/150 mg.
  • the treatment phase will be a single dose once daily for up to 45 days to treat eligible migraine.
  • Clinical endpoints can include pain relief/freedom (2 hours post dose), and freedom from the most bothersome symptoms of migraine (2 hours post dose).
  • FIG. 5 is a schematic of the Phase 2 clinical trial.

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Abstract

L'invention concerne des méthodes de traitement de la migraine, de la céphalée, de la douleur neuropathique et/ou de la douleur nociceptive chez un patient humain en ayant besoin, comprenant l'administration par voie orale au patient d'une composition pharmaceutique pour administration orale comprenant un véhicule pharmaceutiquement acceptable et une quantité thérapeutiquement efficace d'un antagoniste de TRPM3, ou d'un sel physiologiquement acceptable de celui-ci, tel que décrit dans le présent document.
PCT/IB2025/054157 2024-04-21 2025-04-21 Antagonistes de trpm3 pour le traitement de la migraine et de la douleur Pending WO2025224601A1 (fr)

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