KR20220113411A - Use of KV7 potassium channel openers for the treatment of pain - Google Patents

Abstract

In certain embodiments, the present disclosure provides a therapeutically effective amount of N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3 To a method of treating pain in a subject, such as a human, comprising orally administering ,3-dimethylbutanamide (Compound A) to a subject, such as a human, in need thereof. The present disclosure further relates to various improved methods of treatment and administration of Compound A.

Description

Use of KV7 potassium channel openers for the treatment of pain

1. Background

Pain is a major medical problem affecting nearly 120 million people in the United States. Pharmacotherapy is central to the management of acute and chronic pain of all ages, including newborns, infants, and children. Pain medications are classified into three main categories by the American Pain Society: 1) non-opioid analgesic (eg, acetaminophen) and non-steroidal anti-inflammatory drugs (NSAID) (eg, aspirin), 2) opioid analgesic, and 3) co-analgesic.

Sodium channel blockers have been shown to be useful in the treatment of pain, including acute, chronic, inflammatory and neuropathic pain (see, e.g., Wood, JN, et al. , J. Neurobiol. (2004), 61(1), 55-71). Preclinical evidence demonstrates that sodium channel blockers can inhibit neuronal firing in peripheral and central sensory neurons, and through this mechanism they are considered useful in relieving pain.

Many pain patients, especially those suffering from chronic pain, cannot be effectively treated. Consequences of ineffective pain treatment include reduced mobility, limited function, poor sleep, and overall poor quality of life. There is still a need in the art for novel and effective treatments of pain, including neuropathic pain and nociceptive pain, such as inflammatory pain. The present disclosure addresses this need and provides other related advantages by providing compositions and methods and uses for treating pain.

Citation of any reference in the background section of this application is not to be construed as an admission that such reference is prior art to this application.

The present disclosure relates to the small molecule N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide ( Specific methods and uses for (referred to herein as “Compound A”) are described.

In one embodiment, the present disclosure relates to a method of treating pain in a subject (preferably a mammal, such as a human) in need thereof, comprising administering a therapeutically effective amount of Compound A to said subject. will be. In certain instances, the pain treated by administration of Compound A is nociceptive pain, neuropathic pain, or a combination thereof. In certain embodiments, the pain treated by administration of Compound A is nociceptive pain, such as radicular pain, somatic pain, visceral pain, soft tissue pain, inflammatory pain. , post-operative pain, or a combination thereof, particularly post-operative pain.

In a further embodiment, the method of treating pain comprising administering a therapeutically effective amount of Compound A further comprises enhancing the opening of Kv7 potassium channels in a subject (eg, a human).

In another embodiment, the present disclosure is a method of opening or enhancing Kv7 potassium channel opening in a subject, comprising administering to the subject (preferably a mammal, such as a human) a therapeutically effective amount of Compound A, , wherein the subject is suffering from various types of pain described herein, including pain such as nociceptive pain, neuropathic pain, or combinations thereof, particularly inflammatory pain.

In some aspects, the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5. In certain instances, the opening or enhancement of opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 potassium channels is selective over Kv7.1. In other instances, the method comprises opening or enhancing the opening of a Kv7.2/Kv7.3 (KCNQ2/3) potassium channel.

In one embodiment, the present disclosure is a method of treating pain in a subject (preferably a mammal such as a human) in need thereof, wherein Compound A is administered to the subject (preferably orally). provide a way In certain instances, administration to a subject comprises a dose of 2 to 200 mg of Compound A per administration. In other cases, administration to a subject includes a dose of 5-1000 mg per day. In further instances, administration to the subject comprises a dose of 0.05-20 mg/kg, such as 0.1-10 mg/kg.

In some embodiments of the methods and uses of the invention, Compound A is administered orally to a subject (preferably a mammal, such as a human) between about 30 minutes before a meal and about 2 hours after a meal, e.g., Compound A may be administered orally to the subject during or within 15 minutes after a meal.

In certain embodiments, the present disclosure provides a therapeutically effective amount of Compound A to a subject (preferably a mammal, such as a human) in need of treatment of pain with one or more additional analgesics, such as opioid analgesics. A method of treating pain in a subject comprising administering in combination (eg, orally) is provided.

In a further embodiment, the present disclosure relates to a subject (preferably a mammal, such as a human) in need of a decrease in the dose (eg, maintenance dose) of an opioid analgesic, eg, administered a therapeutically effective amount of Compound A. ) (e.g., orally) to reduce the dose of an opioid analgesic required for the effective amount of Compound A to achieve pain relief in the subject. Methods are provided for reducing the dose (eg, maintenance dose) of an opioid analgesic.

Compound A is a small molecule currently being developed for the treatment of seizure disorders, and its use as a potassium channel modulator is disclosed in U.S. Pat. Nos. 8,293,911 and 8,993,593, as well as U.S. Application Serials. and the disclosure of which is incorporated herein by reference in its entirety.

These and other aspects of the present disclosure will become apparent upon reference to the following detailed description. To that end, various references are set forth herein, each of which is incorporated herein by reference in its entirety, in greater detail, for specific background information and procedures.

1 shows PK/PD correlations between brain and plasma Compound A concentrations for study 1 (top left), study 2 (top right), combination of study 1 and study 2 (bottom left), and observed efficacy. of visceral pain showing nociceptive events (y-axis) and compound A (x-axis) at doses of vehicle, 1 mg/kg, 3 mg/kg and 10 mg/kg for PK/PD correlation (bottom right) The results of the acetic acid-induced mouse model are shown.
Figure 2 shows the force inducing paw-withdrawal (g) (y-axis) and future treatments to be administered: vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 The von Frey test of non-lesion paws and lesion paws in a group of rats on day 13 before treatment, showing mg/kg retigabine, and 128 mg/kg morphine po administration (x-axis) (x-axis). ) is shown. Paired student's t-test (compared to unlesioned paws): NS = not significant; * = p <0.05; ** = p <0.01; *** = p < 0.001.
3 shows the variation (delta from baseline) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg, in force (g) (y-axis) inducing paw-avoidance. Results from the electronic von Frey test (assessment of tactile allodynia on Days 14 and 18) of lesion paws in rats, representing kg retigabine, and 128 mg/kg morphine po administration (x-axis) are shown. . Inter-group comparison (relative to vehicle (po)): NS = not significant; * = p <0.05; ** = p <0.01; *** = p < 0.001.
4 shows latency (s) (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg for the first paw-avoidance. Results from a cold plate test (assessment of thermal allodynia at 2 h on Day 14) on lesioned paws in rats, representing /kg morphine po administration (x-axis) are shown. Comparison between groups (relative to vehicle (po)): NS = not significant; * = p <0.05; ** = p <0.01; *** = p < 0.001.
Figure 5 shows the number of avoidance responses (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine po administration (x -axis), the results from the cold plate test (evaluation of heat allodynia at 2 h on day 14) on lesioned paws in rats are shown. Comparison between groups (relative to vehicle (po)): NS = not significant; * = p <0.05; ** = p <0.01; *** = p < 0.001.
6 shows total duration (s) of avoidance response (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg. Results from a cold plate test (evaluation of heat allodynia at 2 h on Day 14) on lesioned paws in rats, showing morphine po administration (x-axis) are shown. Comparison between groups (relative to vehicle (po)): NS = not significant; * = p <0.05; ** = p <0.01; *** = p < 0.001.
7 shows latency (s) (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg for the first paw-avoidance. Results from a cold plate test (evaluation of thermal allodynia at 2 h on Day 18) on lesioned paws in rats, representing /kg morphine po administration (x-axis) are shown. Comparison between groups (relative to vehicle (po)): NS = not significant; * = p <0.05; ** = p <0.01; *** = p < 0.001.
8 shows the number of avoidance responses (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg morphine po administration (x -axis), results from a cold plate test (evaluation of heat allodynia at 2 h on day 18) on lesioned paws in rats are shown. Comparison between groups (relative to vehicle (po)): NS = not significant; * = p <0.05; ** = p <0.01; *** = p < 0.001.
9 shows total duration (s) of avoidance response (y-axis) and vehicle, 8 mg/kg, 16 mg/kg, and 24 mg/kg Compound A, 20 mg/kg retigabine, and 128 mg/kg. Results from a cold plate test (evaluation of heat allodynia at 2 h on Day 18) on lesioned paws in rats, showing morphine po administration (x-axis) are shown. Comparison between groups (relative to vehicle (po)): NS = not significant; * = p <0.05; ** = p <0.01; *** = p < 0.001.

The present disclosure discloses novel and improved methods for compound A, particularly for the treatment of pain by administering compound A to a subject (preferably a mammal, such as a human) in need thereof by oral administration or other routes. to methods and uses.

In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, one of ordinary skill in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout the specification and claims that follow, the term "comprises" and variations thereof, such as "comprises" and "comprising", are in an open and inclusive sense, i.e., " should be construed as "including, but not limited to". Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Moreover, the particular features, structures, or properties may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its meaning including "and/or" unless the content dictates otherwise.

4.1. Justice

As used herein and in the appended claims, unless otherwise specified, the following terms and abbreviations have the indicated meanings:

"Compound A" has the formula: N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide refers to:

.

.

The preparation of Compound A and its use as Kv7.2/Kv7.3 (KCNQ2/3) openers are disclosed in U.S. Patent Nos. 8,293,911 and 8,993,593, as well as U.S. Application Serials Nos. 16/409,684 and 16/410,851. Compound A potentiates and enhances the opening of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2/Kv7.3), important for controlling neuronal excitability. Compound A is used in the methods and uses described herein.

"Acute pain" as used herein means pain that has recently started. Acute pain usually decreases over a short period of time (eg, days, hours, or minutes) and appears after a bodily injury, and usually disappears once the bodily injury has healed.

As used herein, “breakthrough pain” refers to a transient increase in pain above baseline or background pain experienced by a patient. In this context, "baseline pain" means pain experienced or reported as the average pain intensity experienced by a patient over a period of at least 12 hours.

"Chronic pain" as used herein means pain that lasts for at least one week. Typically, chronic pain lasts 3 to 6 months or longer.

The phrase “in combination” as used herein in the context of administering Compound A refers to the simultaneous or sequential administration of Compound A with one or more additional therapeutic agents, such as one or more other pain treatments, therapies, or analgesics. For example, administration of Compound A in combination with another therapeutic agent means that Compound A is administered concurrently or sequentially with the other therapeutic agent in separate unit dosage forms (eg, as part of a multi-dose regimen) or in a single unit dosage form. It means that it can be administered together with If the additional therapeutic agent and Compound A are administered sequentially, this may be up to 24 hours from the other, such as 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 from the other. , 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours or less.

“Pain” as used herein refers to all categories of pain and includes neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgia, orofacial pain, burning pain, burning mouth. Burning mouth syndrome, somatic pain neuralgia, visceral pain, myofacial pain, toothache, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, Childbirth pain, labor pain, reflex sympathetic dystrophy, brachial plexus avulsion, neurogenic bladder, acute pain (e.g., musculoskeletal musculoskeletal and post-operative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache ), familial hemiplegic migraine, conditions associated with cephalic pain, sinus headache, tension headache, phantom limb pain, peripheral nerve damage Peripheral nerve injury, pain following stroke, thalamic lesion, radiculopathy, HIV pain, post-herpetic pain, non-cardiac chest pain pain), hypersensitivity pain associated with irritable bowel syndrome and bowel disorders and dyspepsia, and combinations thereof.

As used herein, a “therapeutically effective amount” is sufficient to treat a disease, disorder, or condition referred to in a subject or for one or more mechanisms underlying the disease, disorder, or condition, or the disease, disorder, or condition. refers to the amount of compound A having the desired stated effect. In certain embodiments, when Compound A is administered for the treatment of pain, a therapeutically effective amount is an amount of Compound A that produces a detectable therapeutic effect in a subject that treats or ameliorates pain in a subject or results in a reduction in pain in a subject immediately after administration to the subject. refers to A pain rating scale can measure the change in pain experienced by a patient, and this scale is used to measure pain intensity in everyday clinical practice. Commonly used pain measurement scales are the Visual Analog Scale (VAS), the Graphic Rating Scale (GRS), the Simple Descriptor Scale (SDS), and the Numerical Rating Scale (Numerical). Rating Scale (NRS), and Faces Rating Scale (FRS). All of these measures were documented as valid measures of pain intensity.

“Treatment” as used herein refers to an indicated disease, disorder, or condition (eg, pain), or refers to a therapeutic application associated with the administration of Compound A that ameliorates one or more mechanisms underlying the disease, disorder, or condition. In certain embodiments, when Compound A is administered for the treatment of pain, the treatment is treatment to slow or stop the increase in pain (ie, to stabilize the level of pain) and/or to reduce or eliminate pain. refers to the negative application. In some embodiments, the treatment of pain comprising administration of Compound A is one or more Kv7 potassium channels (eg, Kv7.2, Kv7.3, Kv7.4, and / or alteration of the cellular activity of Kv7.5, in particular Kv7.2 and/or Kv7.3, optionally greater than Kv7.1).

"Under feeding conditions" refers to the ingestion of food for a period of time between about 4 hours prior to oral administration of an effective amount (e.g., within a therapeutically effective dose range) of Compound A and about 4 hours after administration of Compound A. . The food product may be a solid, liquid, or mixture of solid and liquid food of sufficient volume and fat content that does not dissolve and absorb rapidly in the stomach. In some cases, the food is breakfast, lunch, dinner or, alternatively, a meal such as baby food (eg, formula or breast milk). A therapeutically effective amount of Compound A may be administered orally to a subject, for example, between about 30 minutes before a meal and about 2 hours after a meal, most advantageously Compound A is administered orally during or within 15 minutes after a meal .

"Under fasting conditions" refers to the absence of food for a period of between at least 4 hours prior to oral administration of a therapeutically effective amount of Compound A and about 4 hours after administration of Compound A.

4.2. embodiment

In some embodiments, the present disclosure relates to a method of treating pain in a subject (preferably a mammal, such as a human) in need thereof, comprising administering a therapeutically effective amount of Compound A to said subject. will be. In certain instances, the pain treated by administering Compound A is nociceptive pain, neuropathic pain, or a combination thereof.

In some cases, the pain is nociceptive pain, such as myalgia, somatic pain, visceral pain, soft tissue pain, inflammatory pain, or combinations thereof, particularly inflammatory pain, including inflammatory pain associated with an inflammatory disease or condition, such as organ transplant rejection; Reoxygenation injury resulting from organ transplantation, including but not limited to transplantation of heart, lung, liver, or kidney (Grupp et al., J. Mol, Cell Cardiol. 31:297-303 (Grupp et al., J. Mol, Cell Cardiol . 31:297-303 ( 1999)); chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma and adult respiratory distress syndrome; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gums, including gingivitis and periodontitis; Tuberculosis; leprosy; inflammatory diseases of the kidneys, including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and eczema; Chronic demyelinating disease of the nervous system, multiple sclerosis, AIDS-related neurodegeneration, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease disease), inflammatory diseases of the central nervous system, including amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including type I and type II diabetes mellitus; Glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), foot gangrene, atherosclerotic coronary arterial disease, Peripheral arterial disease, foot ulcers, joint problems, and skin or mucosal complexes (such as infections, shin spots, candidal infections or necrobiosis lipoidica) diabeticorum), immune-complex vasculitis, and systemic lupus erythematosus (SLE); inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and pericarditis; as well as a variety of other diseases that can have a significant inflammatory component, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The methods and uses of the present invention of Compound A may also be used in cancer chemistry, for example, in gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or in response to pro-inflammatory cytokines. It may be used to treat pain associated with an inflammatory disease, which may be a systemic inflammation of the body exemplified by therapy induced shock, eg, shock associated with proinflammatory cytokines.

In certain embodiments, the pain is associated with spinal cord injury, spinal cord or brain stroke, multiple sclerosis, cancer, shingles, post-herpetic neuralgia, skin redness. erythromelalgia (including inherited erythromelalgia), chemotherapy-induced neuropathy, oxaliplatin-induced neuropathy, trigeminal neuralgia, phantom pain, Phantom limb pain, neuromyopathy, complex regional pain syndrome, causalgia, reflex sympathetic dystrophy, lower back pain, peripheral nerve trauma, herpes virus herpes virus infection, diabetes mellitus, diabetic neuropathy, plexus injury, neuroma, limb amputation, vasculitis, chronic alcoholism, human immunodeficiency virus) (HIV) infection, uremia, vitamin deficiency, pelvic pain, or a combination thereof. In some embodiments, the neuropathic pain is chronic neuropathic pain, such as pain resulting from damage to peripheral or central nervous tissue. In some embodiments, the neuropathic pain is a neuropathy, such as one of those described herein.

In certain embodiments, the neuropathic pain is spinal cord injury, spinal cord or stroke, postherpetic neuralgia, erythematosus (including hereditary cutaneous erythematosus), trigeminal neuralgia, neuromyopathy, complex regional pain syndrome, burning pain, reflex sympathetic nerve pain. pain associated with dystrophy, peripheral nerve trauma, diabetic neuropathy, plexus injury, neuroma, vasculitis, or a combination thereof.

In certain embodiments, the neuropathic pain is herpes zoster, multiple sclerosis, cancer, chemotherapy-induced neuropathy, oxaliplatin-induced neuropathy, herpes virus infection, diabetes mellitus, human immunodeficiency virus (HIV) infection, hypothyroidism pain associated with hypothyroidism, uremia, or a combination thereof, in particular pain associated with multiple sclerosis or cancer. In certain embodiments, the neuropathic pain is selected from pain associated with herpes zoster or herpes virus infection. In some embodiments, the neuropathic pain is selected from pain associated with cancer, chemotherapy-induced neuropathy, or oxaliplatin-induced neuropathy.

In some embodiments, the neuropathic pain is pain associated with phantom pain, phantom limb pain, back pain, amputation, chronic alcoholism, vitamin deficiency, pelvic pain, or a combination thereof, particularly pain associated with phantom pain, phantom limb pain, or amputation. is selected from

In certain instances, the pain treated by administering to a subject (preferably a mammal, such as a human) a therapeutically effective amount of Compound A is acute pain. In some embodiments, the pain is chronic pain. Such administration may be, for example, by oral, sublingual, buccal, occur, otic, vaginal, rectal, dermal, topical or transdermal administration; by intravenous, intramuscular, intrathecal, or subcutaneous injection; or by transplantation.

In some cases, the pain treated by administering to a subject (preferably a mammal, such as a human) a therapeutically effective amount of Compound A is mild, moderate or severe pain. In certain embodiments, the pain is moderate or severe pain, or moderate to severe pain. Such administration may be, for example, by oral, sublingual, buccal, occur, otic, vaginal, rectal, dermal, topical or transdermal administration; by intravenous, intramuscular, intrathecal, or subcutaneous injection; or by transplantation.

In certain instances, the pain treated by administering (eg, orally) to a subject (eg, a human) of a therapeutically effective amount of Compound A is a disease state or other condition, such as cancer pain, rheumatic pain, arthritis pain, bone pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, postoperative pain, headache pain, myalgia, pain associated with periodontal disease (including gingivitis and periodontitis), or combinations thereof. In some embodiments, the pain is of tumor origin. In other embodiments, the pain is of non-tumor origin. In certain embodiments, the pain is migraine without aura ("common migraine"), migraine with aura ("classic migraine"), migraine without headache, basilar migraine ), familial hemiplegic migraine, migraine infarction, migraine with prolonged aura, or a combination thereof.

In some embodiments, the pain treated by administering (eg, orally) to a subject (eg, a human) of a therapeutically effective amount of Compound A is breakthrough pain.

In some embodiments, the method of treating pain by administering a therapeutically effective amount of Compound A comprises enhancing the opening of Kv7 potassium channels in a subject (preferably a mammal, such as a human).

In certain embodiments, the present disclosure provides a Kv7 potassium channel, such as a Kv7.2, Kv7.3, Kv7.4, and/or Kv7.5 potassium channel, particularly Kv7.2/Kv7.3, by administering an effective amount of Compound A. (KCNQ2/3) There is provided a method or use comprising opening or enhancing the opening of a potassium channel in a subject in need thereof. In some of these embodiments, the subject suffers from a type of pain described herein, including pain, such as neuropathic pain or nociceptive pain, such as inflammatory pain.

In certain instances, the methods or uses described herein selectively open or enhance the opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 over Kv7 potassium channels, such as Kv7.1. include that In some embodiments, the method or use is selective for Kv7.2 over Kv7.1. In other embodiments, the method or use is selective for Kv7.3 over Kv7.1. In another embodiment, the method or use is selective for Kv7.4 over Kv7.1. In yet yet another embodiment, the method or use is selective for Kv7.5 over Kv7.1. In certain embodiments, the method or use is selective for Kv7.2 and Kv7.3 over Kv7.1. In certain embodiments, the method or use is selective for Kv7.2 and Kv7.3 over other Kv7 potassium channels. In certain embodiments, the method or use is selective for Kv7.2 and Kv7.3 over Kv7.4 and Kv7.5.

As an alternative to oral administration, in certain instances other routes of administration of Compound A may be employed in the methods and uses described herein, such as parenteral administration. Parenteral routes of administration include subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques or by implantation. For example, Compound A can be administered by injection, such as intravenous, intramuscular, intrathecal, or subcutaneous injection. In certain embodiments, the above-discussed dose of Compound A is for oral administration and can be converted to a dose suitable for parenteral administration, including administration by injection, by reducing the oral dose, for example, by about half.

Other routes of administration suitable for administration of Compound A according to the methods and uses described herein include sublingual and buccal (e.g., using a film or other composition that dissolves in the mouth under the tongue or on the inside of the cheek), ophthalmic (e.g., , eye drops), ear (e.g., by ear drops), oral or nasal inhalation (e.g., by infusion or spray), dermal or topical (e.g., by cream or lotion), or transdermally ( For example, by skin patches). In addition to oral administration, other enteral routes of administration may be used for Compound A, including vaginal and rectal (eg, by ointments, suppositories, enemas).

The methods and uses described herein comprising administering Compound A to treat pain can also include administering Compound A in combination with one or more other pain treatments, therapies, or one or more additional therapeutic agents, such as analgesics. . For example, in some embodiments, the present disclosure provides a therapeutically effective amount of Compound A in combination (eg, orally) to a subject (eg, a human) in need thereof with one or more additional analgesics. A method of treating pain in a subject comprising administering is provided.

In some embodiments, the one or more additional analgesics are narcotic analgesics, such as opioid agonists, mixed agonist-antagonists, or alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, Vegitramide, buprenorphine, butorphanol, clonitagen, codeine, desomorphine, dextromoramide, dezosine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, Dimepeptanol, dimethyl-thiambutene, dioxapetyl butyrate, dipifanone, eptazosine, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazen, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, peptazinol, methazocin, methadone, methopone, morphine, myrophine, Narcein, nicomorphine, norlevorphanol, normethadone, nalofine, nalbufen, normorphine, norpiphanone, opium, oxycodone, oxymorphone, papaveretum, pentazosine, phenadoxone, phenomorphan, phenadoxone any one of the foregoing, including partial agonists including nozocine, phenoperidine, piminodine, pyritramide, propeptazine, promedol, properidine, propoxyfen, sufentanil, tilidine and tramadol and mixtures of pharmaceutically acceptable salts of any one of the foregoing. In certain embodiments, the additional analgesic is a narcotic agonist, such as buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol, any of the foregoing. including, including mixtures of any one and a pharmaceutically acceptable salt of any one of the foregoing. In some embodiments, the additional analgesic is oxycodone or a pharmaceutically acceptable salt thereof, such as oxycodone HCl.

In other embodiments the one or more additional analgesics is a non-narcotic therapeutic agent such as aspirin; acetaminophen; nonsteroidal anti-inflammatory drugs (“NSAIDS”) such as ibuprofen, ketoprofen, naproxen, and the like; N-methyl-D-aspartate (NMDA) receptor antagonists such as morphinans such as dextromethorphan or dextrophan, or ketamine; cyclooxygenase-2 inhibitors (“COX-II inhibitors”) such as celecoxib, rofecoxib, and etoricoxib; and/or a glycine receptor antagonist.

In some embodiments, administering Compound A in combination with one or more additional analgesics may reduce the dosage of the additional analgesic without reducing the level of pain relief or analgesic efficacy provided. For example, in some embodiments, the present disclosure provides a method comprising administering a therapeutically effective amount of Compound A to a subject (eg, a human) in need thereof in combination with an amount of one or more additional analgesic agents, said subject wherein the amount of the additional analgesic is less than the amount of the additional analgesic required to achieve the same or similar level of pain relief or analgesic efficacy in the absence of administration of Compound A. In certain such embodiments, the one or more additional analgesics are narcotic analgesics, such as buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol, mixtures of any of the foregoing with a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the additional analgesic is oxycodone or a pharmaceutically acceptable salt thereof, such as oxycodone HCl.

In a related embodiment, the present disclosure provides, for example, a therapeutically effective amount of Compound A to a subject (preferably a mammal, such as a human) in need of a reduction in the dose (eg, maintenance dose) of an opioid analgesic administered. ) (e.g., orally) such that the effective amount of Compound A counteracts a decrease in the dose of the opioid analgesic such that the pain relief or analgesic efficacy experienced by the subject is maintained. Methods for reducing the dose (eg, maintenance dose) of an opioid analgesic administered are provided. In certain such embodiments, the opioid analgesic is selected from any of the foregoing and any of the foregoing, from buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol. selected, including mixtures of pharmaceutically acceptable salts of any one of the above. In some embodiments, the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof, such as oxycodone HCl.

In a further embodiment, the present disclosure relates to a subject (preferably a mammal, such as a human) in need of a decrease in the dose (eg, maintenance dose) of an opioid analgesic, eg, administered a therapeutically effective amount of Compound A. ) (e.g., orally) to reduce the dose of the opioid analgesic administered to the subject, wherein the effective amount of Compound A is required to achieve pain relief in the subject. A method of reducing a dose (eg, a maintenance dose) is provided. In certain such embodiments, the opioid analgesic is selected from any of the foregoing and any of the foregoing, from buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol. selected, including mixtures of pharmaceutically acceptable salts of any one of the above. In some embodiments, the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof, such as oxycodone HCl.

In one embodiment, the methods and uses described herein, such as methods of treating pain in a subject (preferably a mammal, such as a human) in need thereof, or uses in said method comprise a therapeutically effective amount of Compound A , such as about 0.05 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 20 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.05 mg/kg to about 5 mg/kg, about 0.05 mg/kg to about 20 mg/kg, including about 0.1 mg/kg to about 5 mg/kg, about 0.05 mg/kg to about 2 mg/kg, or about 0.1 mg/kg to about 2 mg/kg (eg, orally). More specific representative amounts are 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2 mg/kg, 5 mg/kg, 8 mg/kg, 10 mg/kg, 12 mg/kg, 15 mg/kg, 18 mg/kg, or 20 mg/kg or any of the preceding amounts Any range of amounts generated by using the two as endpoints is included. In some aspects, the method or use comprises administering (eg, orally) 0.1-1 mg/kg of Compound A. In certain aspects, the method comprises administering (eg, orally) 0.2-0.5 mg/kg of Compound A. In some aspects, the method or use comprises administering (eg, orally) 0.05-20 mg/kg of Compound A. In certain aspects, the method comprises administering (eg, orally) 1-10 mg/kg of Compound A.

In certain instances, the present disclosure provides a method comprising administering (eg, orally) a therapeutically effective amount of Compound A to a subject (preferably a mammal, such as a human) in need thereof. Provided is a method of treating pain in a method, wherein the pain is those described herein, including nociceptive pain, such as inflammatory pain, wherein Compound A is administered to a subject at 0.05-5 mg/kg, such as about 0.05 mg/kg, 0.1 mg /kg, 0.15 mg/kg, 0.2 mg/kg, 0.24 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.35 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg /kg, 0.75 mg/kg, 0.8 mg/kg, 0.81 mg/kg, 0.85 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.2 mg/kg, 1.5 mg/kg, 1.8 mg/kg, 2 mg at a dose of 0.1-5 mg/kg, 0.05-2 mg/kg, or 0.1-2 mg/kg, including /kg, 3 mg/kg, 4 mg/kg, or 5 mg/kg, or as previously mentioned Any range of amounts resulting from the use of two of the amounts as endpoints is administered.

In some cases, the present disclosure provides for treating pain in a subject (eg, orally) comprising administering (eg, orally) a therapeutically effective amount of Compound A to a subject (eg, a human) in need thereof. wherein the pain is neuropathic pain, such as those described herein, wherein Compound A is administered to the subject at 0.5-10 mg/kg, such as about 0.5 mg/kg, 0.8 mg/kg, 1 mg/kg , 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg 0.5-8 mg/kg, including 5.2 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, or 10 mg/kg , 1-10 mg/kg, or 1-8 mg/kg, or any range of amounts resulting from using two of the aforementioned amounts as endpoints.

In some embodiments, the methods and uses described herein, such as methods or uses of treating pain in a subject (eg, a human) in need thereof, comprise a therapeutically effective amount of Compound A, such as in single or multiple dosage units, such as This is achieved by administering (eg, orally) from 2 to 200 mg of Compound A. For example, the method may include, in single or multiple dosage units, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg , about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg , about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg , about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg , about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 m g, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, including administering (e.g., orally) about 199 mg, or about 200 mg (e.g., orally) or any range of amounts resulting from using two of the aforementioned amounts as endpoints (e.g., orally) can do. In some aspects, the method or use comprises orally administering 5 to 50 mg of Compound A to a subject (eg, a human) in single or multiple dosage units. In some aspects, the method or use comprises orally administering to a subject (eg, a human) 10, 20, or 25 mg of Compound A in single or multiple dosage units. In some aspects, the method or use comprises orally administering to a subject (eg, a human) 20 mg of Compound A in single or multiple dosage units.

In some aspects, the methods and uses described herein, such as methods or uses of treating pain in a subject (eg, a human) in need thereof, include at least 20 mg of Compound A, such as at least 25, 30, 35 , 50, 75, or 100 mg of Compound A (eg, orally). In some embodiments, the methods and uses described herein, such as methods or uses of treating pain in a subject (eg, a human) in need thereof, include at least 50 mg of Compound A per day, such as at least per day 60, 75, 85, 100, 125, 150, 175, or 200 mg of Compound A is administered (eg, orally) to a subject (eg, a human).

In some embodiments, the methods and uses described herein, such as methods or uses of treating pain in a subject (eg, a human) in need thereof, comprise a therapeutically effective amount of Compound A per day, such as from 5 to 5 per day. This is accomplished by administering (eg, orally) 1000 mg of Compound A, such as 5-500 mg or 5-250 mg of Compound A per day. For example, the method or use may comprise about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, per day, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, or administering (eg, orally) about 1000 mg of Compound A, or administering (eg, orally) a range of amounts resulting from using two of the aforementioned amounts as endpoints. can In some aspects, the method or use comprises 10-200 mg of Compound A per day, such as 10, 15, 20, 25, 30, 35, or 40 mg to 75, 100, 125, 150, 175, or 200 mg per day. orally administering to a subject (eg, a human), including 20 to 150 mg per day, of Compound A. In some aspects, oral administration comprises 50, 75, 100, or 125 mg of Compound A per day, such as 100 mg per day, for a subject (eg, a human).

In certain instances, the daily dose of Compound A is administered (eg, orally) as multiple daily doses, such as 2, 3, 4, or 5 doses per day. For example, a daily dose of 100 mg may be administered as 5 20 mg, 4 25 mg, 3 33.3 mg, or 2 50 mg doses throughout the day.

In some embodiments, said daily dose of Compound A is administered as a single dose (eg, orally). For example, from about 5, 10, 15, 20, 25, or 30 mg to about 50, 65, 75, 100, 125, or 150 mg of Compound A per day, 10-25 mg per day as a single dose, 10-30 mg, and 10-40 mg, such as 10-25 mg per day as a single dose, may be administered orally. In this regard, any of the doses of Compound A discussed in the preceding paragraphs may be comprised in a single unit dosage form or in multiple unit dosage forms, eg, two, three or four unit dosage forms.

In certain embodiments, the methods and uses described herein achieve steady state for Compound A within 6 to 9 days, such as within about 1 week, when using the daily dosages disclosed herein.

In some embodiments, the methods and uses described herein for treating pain by administering (eg, orally) Compound A are 12-hour (ie, twice daily), 24-hour (ie, 1 day). once), 48-hour (ie, once every 2 days), 72-hour, 96-hour, 5-day, 6-day, 1-week, or 2-week dosing regimen, especially 12-hour, 24 -hour, or 48-hour dosing regimen. Such therapy may include administering either the above-described doses or daily doses. For example, the present disclosure provides a method for administering to a subject (eg, a human) in need thereof a therapeutically effective amount of Compound A for 12-hour, 24-hour, 48-hour, 72-hour, 96-hour, the subject comprising administering (eg, orally) according to 5-day, 6-day, 1-week, or 2-week intervals, in particular 12-hour, 24-hour, or 48-hour intervals Provided is a method of treating pain in , wherein the amount of Compound A corresponds to any of the above-described doses or daily doses. In certain such embodiments, Compound A is administered orally to the human subject under feeding conditions, for example, between about 30 minutes before a meal and about 2 hours after a meal, including during or within 15 minutes after a meal.

In a further embodiment, the above-discussed method or use of treating pain by administering a therapeutically effective amount of Compound A comprises from about 30 minutes before a meal to about 30 minutes before a meal, including, for example, during or within 15 minutes after a meal, under an eating condition. Oral administration of Compound A to a human subject between about 2 hours after a meal. In some embodiments, oral administration of Compound A to a human subject under feeding conditions significantly enhances the bioavailability and exposure of Compound A compared to oral administration of Compound A to a subject under fasting conditions. In some embodiments, oral administration of Compound A to a human subject under feeding conditions results in one or more pharmacokinetic parameters for Compound A (e.g., C _max , AUC _inf , T _max , t½ _λz , etc.) are increased.

In certain embodiments, the methods and uses described herein administer Compound A in the form of a pharmaceutically acceptable oral composition comprising Compound A and one or more pharmaceutically acceptable carriers or excipients. The amount of Compound A included in these compositions may correspond to one or more of the amounts described herein. In some embodiments, the composition is a unit dose.

Examples of pharmaceutically acceptable oral compositions comprising Compound A include solid formulations (such as tablets, capsules, lozenges, dragees, granules, powders, wafers, multi-particulates and films), liquid formulations (such as aqueous solutions, elixirs, tinctures, slurries, suspensions, and dispersions), and aerosolized formulations (such as mists and sprays). In one embodiment, the pharmaceutically acceptable oral composition of Compound A comprises a pediatric suspension or granule. All of the above-mentioned amounts of Compound A may be included in such formulations, for example, in capsules containing 5, 10, 15, 10, 25, 30, or 35 mg of Compound A.

Examples of compositions suitable for parenteral administration of Compound A include sterile injectable solutions, suspensions, or dispersions, including aqueous or oleaginous preparations, particularly aqueous preparations. In some embodiments, Compound A is a parenterally acceptable diluent or solvent, such as water, Ringer's solution, isotonic sodium chloride solution, aqueous buffered solution, and an aqueous solution containing a miscible alcohol such as 1,3-butanediol. Use Administered according to a method or use described herein in a sterile aqueous formulation. Additional suitable excipients for parenteral preparations of Compound A include mono- or di-glycerides; fatty acids such as oleic acid and its glyceride derivatives; pharmaceutically acceptable natural oils such as olive oil or castor oil, including polyoxyethylated versions thereof; long chain alcohol diluents or dispersants such as alkyl celluloses, including carboxymethyl cellulose; and surfactants such as Tween, Span and other emulsifiers or bioavailability enhancers.

In another embodiment, a kit for oral administration of Compound A for the treatment of pain is provided. Such kits include a plurality of oral unit dosage forms of Compound A together with instructions for oral administration of Compound A.

Additional embodiments and examples of the present disclosure are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the claimed invention.

5. Examples

Studies were conducted to determine the effect of Compound A in rodent models of pain (eg, an acetic acid-induced mouse model of visceral pain and a rat spinal nerve ligation/Chung model of neuropathic pain). Further studies are conducted to determine the effect of Compound A, if any, in an acceptable model of pain.

5.1. Example 1. Acetic acid-induced mouse model of visceral pain

Purpose: An acetic acid test was performed to evaluate the potential efficacy of Compound A in the acetic acid writhing (AAW) model of inflammatory pain. The AAW test was performed as previously described (Yeping Bi et al., "Visceral hyperalgesia induced by forebrain-specific suppression of native Kv7/KCNQ/M-current in mice." Mol. Pain 2011, 7:84; Gabriela F. Pavao-de-Souza et al., "Acetic acid- and phenyl-p-benzoquinone-induced overt pain-like behavior depends on spinal activation of MAP kinases, PI3K and microglia in mice." Pharmacol. Biochem. Behav . 101 (2012) 320-328;Kazufumi Hirano et al., "Kv7.2-7.5 voltage-gated potassium channel (KCNQ2-5) opener, retigabine, reduces capsaicin-induced visceral pain in mice." Neurosci. Lett . 413 (2007) ) 159-162; " Molecules 23 (2018) 3238]; and Yaroslav A. Andreev et al., "Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIC3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds. " Mar. Drugs 16 (2018), 500]).

Study design: Briefly, acetic acid was injected intraperitoneally at a concentration of 0.4% in 6-7 week old CD1 mice. After injection of acetic acid, the animal was placed in the room and its subsequent torsional behavior was recorded on video. Torsion is defined as contraction of the abdominal muscles with body elongation and hind limb extension or trunk rotation. Torsion was counted between 5-15 minutes after acetic acid injection.

Acetic acid dose selection: Based on the concentration response (0.2-0.8%) of acetic acid in CD1 mice, an EC75 concentration (0.4%) was chosen to generate an optimal torsional response. Diclofenac was used as a positive control in the acetic acid model.

Results: The first study ( FIG. 1 , Study 1 ) showed that a dose-responsive decrease in the number of nociceptive events was observed across dose groups (Vehicle, 1 mg/kg, 3 mg/kg, and 10 mg/kg Compound A). indicates. The second study ( FIG. 1 , Study 2 ) shows a reduction in the number of nociceptive events at 10 mg/kg Compound A. A PK/PD correlation was shown between Compound A concentrations in brain and plasma for the observed efficacy ( FIG. 1 , PK/PD correlation). EC ₅₀ (effective concentrations providing a 50% reduction in nociceptive events) were 0.25 μM and 0.4 μM in plasma and brain, respectively.

5.2. Example 2. Spinal nerve ligation-induced model of neuropathic pain in rats

Purpose: To evaluate the efficacy of Compound A using the rat spinal nerve ligation (SNL)/Chung model of neuropathic pain. A rat SNL model was developed as previously described ( Chung JM , Kim HK , Chung K. "Segmental spinal nerve ligation model of neuropathic pain." Methods Mol. Med . 99 (2004) 35-45).

<Table 1>

Material of SNL model

^a Preprocessing time.

Study design: Briefly, the von Frey and cold plate tests on day 0 were used for baseline measurements of tactile and cold allodynia, respectively. Post-baseline measurements, rats (171-209 g male Sprague Dawley) were anesthetized and an L4-S2 level incision was made to expose the left L5 nerve. A suture was tightly tied around the L5 nerve (Chung et al.; R. Dost et al., "The anti-hyperalgesic activity of Retigabine is mediated by KCNQ potassium channel activation."Naunyn-Schmiedeberg's Arch. Pharmacol . 369 (2004) ) 382-390; Gordon Blackburn-Munro et al., "The anticonvulsant retigabine attenuates nociceptive behaviors in rat models of persistent and neuropathic pain." Eur. J. Pharmacol . 460 (2003) 109-116]; and [ Wu YJ et al. al., "Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7. 2) opener for the treatment of neuropathic pain." Bioorg Med. Chem. Lett . 23 (2013) 6188-91]). The next wound was then closed and the rats were allowed to recover. On day 13, the postoperative baseline for tactile and cold allodynia was measured to confirm neuropathic pain. Animals were assigned to treatment groups based on baseline scores after surgery. Table 2 and Figure 2 show the results of the tactile allodynia von Frey test in rats on day 13 prior to treatment with vehicle, compound A, retigabine or morphine.

<Table 2>

Day 13 Pretreatment Test: Electronic von Frey Test

Paired-Sample Student's t-test: NS = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001

Administration: For the efficacy test, Compound A was orally administered once a day for 5 consecutive days from days 14-18. Animals were re-evaluated for tactile and thermal allodynia at 2 hours on Days 14 and 18 after administration of Compound A. Morphine was used as a positive control. Table 3 shows the rat body weights over the duration of the experiment.

<Table 3>

weight

^a One treatment on days 14 and 18 in the morphine-treated group.

5.2.1 Evaluation of tactile allodynia using the electronic von Frey test

Rats were placed under an inverted acrylic plastic box on the grid floor. The tip of the electronic von Frey probe was then applied with increasing force to the surgical hind paw and the force required to induce paw-avoidance was automatically recorded. The procedure was performed in triplicate and the average paw bill avoidance force was calculated. The experimenter was double blinded to treatment.

Results: Tables 4-5 and FIG. 3 show the results of the evaluation of tactile allodynia von Frey on days 14 and 18. Compared to morphine, neither Compound A nor retigabine had a significant effect on the tactile allodynia endpoint. This is not surprising for the Kv7.2 mechanism (see Blackburn-Munro and Jensen, Eur J Pharmacol , 460(2-3): 109-116 (2003)).

<Table 4>

Assessing tactile allodynia at day 14: the electronic von Frey test of the lesioned foot.

Between groups: NS = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001.

^a One treatment on days 14 and 18 for groups treated with morphine.

^b Test 1 h after dosing.

^c For test substance-treated group: One-way ANOVA with group as factor.

^d Dunnett's test when one-way ANOVA is significant.

<Table 5>

Assessing tactile allodynia at Day 18: Electronic von Frey test of lesioned paws

Between groups: NS = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001.

^a One treatment on days 14 and 18 for groups treated with morphine.

^b Test 1 h after dosing.

^c For test substance-treated groups: one-way ANOVA with group as factor.

^d Dunnett's test when one-way ANOVA is significant.

5.2.2 Evaluation of thermal allodynia using the cold plate test

The cold plate apparatus was maintained at 4 ± 1 °C and surrounded by an acrylic glass enclosure. Rats were placed on the plate for a period of 5 minutes. The latency to the first paw-avoidance, the total number of paw withdrawals, and the total duration of the avoidance response were recorded for the surgical hindpaw.

Results: Tables 6-7 and Figures 4-9 show the results of von Frey evaluation of heat allodynia on days 14 and 18. 7-9 show that at both 16 and 24 mg/kg, Compound A outperformed morphine (128 mg/kg) at the thermal allodynia endpoint.

<Table 6>

Assessing heat allodynia at day 14: cold plate test on lesioned paws

Between groups: NS = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001.

^a One treatment on days 14 and 18 for groups treated with morphine.

^b Test 1 h after dosing.

^c For test substance-treated groups: one-way ANOVA with group as factor. Comparison-treated group: paired Student's test.

^d Dunnett's test when one-way ANOVA is significant.

<Table 7>

Assessing heat allodynia at day 18: cold plate test on lesioned paws

Between groups: NS = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001.

^a One treatment on days 14 and 18 for groups treated with morphine.

^b Test 1 h after dosing.

^c For test substance-treated groups: one-way ANOVA with group as factor. Comparison-treated group: paired Student's test.

^d Dunnett's test when one-way ANOVA is significant.

5.3. Example 3. Crossover Study with Pharmacokinetic Analysis

The pharmacokinetics (PK), safety, and tolerability of a single dose of Compound A in healthy right-handed male human subjects were investigated in a randomized, double-blind, placebo-controlled, transcranial magnetic stimulation (TMS) crossover study. .

The purpose of the study was to evaluate the safety, tolerability and pharmacokinetics of a single dose of Compound A in healthy male subjects.

Twenty healthy right-handed male subjects were enrolled and randomized in a blinded fashion to receive a single oral dose of 20 mg Compound A or placebo on Day 1 (1:1 randomization ratio), followed by a single dose of another treatment on Day 7 Crossed to receive dose.

Subjects were screened within 27 days prior to entering the Day 1 study. For Period 1, subjects were admitted to the study unit, received dosing on Day 1, and discharged on Day 2. For period 2, after a washout of day 6, the same subjects were admitted back to the study unit to receive dosing on day 7 and were discharged on day 8. All subjects returned to the clinical room for an outpatient visit on Day 14 and received follow-up calls on Day 37.

Subjects were administered in the fed state, however, the timing of dosing for meals was changed during the study, with a high-fat or standard meal consumed 2 h or 30 minutes prior to dosing, and a high-fat or standard meal consumed 1 h or 2.5 h post-dose. did it differently.

PK variables were maximum plasma concentration (C _max ), time to peak plasma concentration (T _max ), final elimination half-life (t1/2), clearance rate constant (λz), 0 to 24 h (AUC _0-24 h ), time 0 Area under the curve from to the last quantifiable concentration (AUC _0-tlast ), area under the curve from time 0 to infinity (AUC _0-inf ), percentage of AUC due to extrapolation from tlast to infinity (%AUC _extrap ), oral Apparent total body clearance after dosing (CL/F), CL/F normalized by body weight, mean residence time from time 0 to the last quantifiable concentration (MRTlast), mean residence time extrapolated to infinity (MRT _inf ), terminal Apparent volume (Vz/F) of the distribution during the period, and Vz/F normalized by body weight were included.

5.3.1. Pharmacokinetic analysis

The PK parameters for this study were summarized in two ways. First, PK parameters were calculated where possible using PK samples collected during each 24-hour sampling period separately for Period 1 and Period 2, respectively. Second, PK parameters were determined using samples after a 24 h sampling period (ie, 7/8 and/or 14 days). For subjects receiving Compound A in Period 1, PK samples taken prior to placebo treatment provided additional PK time points at >24 h. For subjects receiving Compound A in the second period, there was no >24 h PK time point until the Day 14 PK sample was added. Therefore, subjects randomized to receive Compound A in the second period enrolled prior to the administration of additional PK samples on Day 14 did not have PK data greater than 24 h. The full PK profile data set consists of 16 subjects with PK samples taken >24 h post-dose. For the discussion of PK parameters below, the full PK profile data set was generally used because it allows for more accurate estimation of PK parameters.

Initially, subjects were dosed 2 hours after a high fat meal and a relatively high fat lunch was served 1 hour post dose. After a blind review of the PK profile in the initial 8 subjects, the fat content of the lunch was reduced in an attempt to reduce the time to T _max . In addition, the choice of meal time versus dose was changed from 2 hours before dosing to 30 minutes before dosing and thereafter the fat content of breakfast was reduced. The timing and type of meal for each subject are specified in Table 8. Overall, there was no clear difference in C _max and T _max , despite changes in diet composition and timing relative to dose. As such, the PK data are presented without classification according to the content of the meal or the relative timing of the meal.

<Table 8>

Selection of type and timing for administration

^a ate a standard breakfast prior to dosing with the exception of subject 910

5.3.1.1. plasma concentration

Plasma concentrations over time for the overall PK profile were recorded. At 2 h, 4 h and 6 h time points, mean ± SD plasma concentrations were 15.9 ± 21.4 ng/mL, 30.2 ± 21.1 ng/mL and 42.1 ± 19.1 ng/mL, respectively.

There were no differences in mean C _max or T _max between periods ( Table 9 ). Total time to peak plasma concentration ranged from 1.9 to 12 h, with a median time of 7.8 h.

Subjects receiving placebo in Period 2 had low but measurable Compound A levels at the start of the placebo treatment period, with a mean C _max of 5.84 ng/mL (range of 3.34-9.61 ng/mL).

<Table 9>

Pharmacokinetic parameters according to duration, overall, and overall PK profile

5.3.1.2. Other pharmacokinetic parameters for the overall PK profile

A summary of other PK parameters is provided in Table 10 . The mean AUC _last was 2370 ng*h/mL, which included PK samples from follow-up visits when available. The AUC _inf from the same data set was 3155 ng*h/mL and the median (range) extrapolated area was 19.9% (range 10.6-40.5%). This relatively high level of extrapolated region in some subjects suggests that parameters calculated from λz (eg half-life, MRT _inf , clearance, volume distribution) should be carefully analyzed and their calculations may have higher intrinsic variances.

The mean normalized volume distribution (Vz/F) of 16.3 L/kg was significantly higher than the total blood volume for an average body weight of 72.3 kg, indicating distribution of the drug from plasma to surrounding tissues.

The body weight normalized clearance (CL/F) was 97.5 mL/h/kg (corresponding to approximately 1.6 mL/min/kg). This value is plasma clearance, not blood clearance; Even with hematocrit adjusted, the total hepatic blood flow is much lower than 17 mL/min/kg (Carlisle et al., Gut 1992, 33:92-97), suggesting a low drug extraction.

<Table 10>

Pharmacokinetic parameters (full PK data set)

5.3.2. Pharmacokinetic Conclusions

Compound A was absorbed slowly after the 20 mg oral dose and had a median peak plasma concentration that occurred approximately 8 hours after administration. Immediately after absorption, it distributes from the plasma to the surrounding tissues and is slowly cleared from the systemic circulation at a rate much lower than the hepatic blood flow, indicating minimal hepatic extraction (metabolism). It exhibited a mean half-life of 127 hours (range 48.2-306 h) and a mean residence time of 102 h (range 33-304 h), with many subjects having %AUC _extrap values greater than 20% and as high as 40% Because it can be underestimated.

Washouts between periods were not long enough to cause Compound A levels to fall below the limit of quantitation in subjects who received placebo in Period 2 (mean 3.1 ng/mL, ranged from 1.3-6.8 ng/mL).

* * * * *

All U.S. Patents, U.S. Patent Application Publications, U.S. Patents cited herein, including U.S. Provisional Application No. 62/945,093, filed December 6, 2019 and U.S. Provisional Application No. 62/948,010, filed December 13, 2019 Patent applications, foreign patents, foreign patent applications, and non-patent publications are incorporated herein by reference in their entirety.

Although the foregoing compositions, methods, and uses have been described in some detail in order to facilitate understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be regarded as illustrative and not restrictive, and the claimed invention is not limited to the details provided herein, but may be modified within the scope and equivalents of the appended claims.

Claims (96)

A method of treating pain in a human, comprising administering to the human in need thereof a therapeutically effective amount of Compound A;
wherein compound A is N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; A method of treating pain in said human. A method of treating pain in a human comprising administering to the human in need thereof a therapeutically effective amount of Compound A in combination with an opioid analgesic;
wherein compound A is N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; A method of treating pain in said human. A therapeutically effective amount of Compound A is administered to a human in need thereof, such that the effective amount of Compound A is the dose of opioid needed to achieve pain relief in the human. A method of reducing the dose of an opioid analgesic administered to a human, comprising reducing
wherein compound A is N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; A method of reducing the dose of an opioid analgesic administered to said human. 4. The method of claim 2 or 3, wherein the narcotic analgesic is from buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol, as described above. A method of selection, comprising a mixture of any one of and a pharmaceutically acceptable salt of any one of the preceding. 5. The method of any one of claims 1 to 4, comprising enhancing the opening of Kv7 potassium channels in humans. A method of enhancing the opening of Kv7 potassium channels in a human comprising administering to the human an effective amount of Compound A;
wherein compound A is N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide;
A method of enhancing the opening of Kv7 potassium channels in a human, wherein the human is suffering from pain. 7. The method of claim 5 or 6, wherein the Kv7 potassium channel is at least one of Kv7.2, Kv7.3, Kv7.4, or Kv7.5. 8. The method of claim 7, wherein the method is selective for enhancing the opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 relative to Kv7.1. 7. The method of claim 5 or 6, comprising opening of a Kv7.2/Kv7.3 (KCNQ2/3) potassium channel. 10. The method of any one of claims 1 to 9, wherein the pain is nociceptive pain, neuropathic pain, or a combination thereof. The method of claim 10 , wherein the pain is nociceptive pain. The method of claim 11 , wherein the nociceptive pain is radicular pain, somatic pain, visceral pain, soft tissue pain, inflammatory pain, or a combination thereof. The method of claim 12 , wherein the nociceptive pain is inflammatory pain. 14. The method of claim 13, wherein the inflammatory pain is associated with an inflammatory disease, such as an inflammatory disease of the intestine, lung, eye, gum, kidney, skin, central nervous system or heart. The method of claim 12 , wherein the nociceptive pain is visceral pain. The method of claim 10 , wherein the pain is neuropathic pain. 17. The method of claim 16, wherein the neuropathic pain is spinal cord injury, spinal cord or brain stroke, multiple sclerosis, cancer, post-herpetic neuralgia. herpetic neuralgia, trigeminal neuralgia, phantom pain, causalgia, reflex sympathetic dystrophy, lower back pain, peripheral nerve trauma, herpes Herpes virus infection, diabetes mellitus, diabetic neuropathy, plexus avulsion, neuroma, limb amputation, vasculitis, chronic alcohol Chronic alcoholism, human immunodeficiency virus (HIV) infection, hypothyroidism, uremia, vitamin deficiency, pelvic pain, complex regional pain syndrome ( complex regional pain syndrome), or a combination thereof. 18. The method of any one of claims 1-17, wherein the pain is acute pain. 18. The method of any one of claims 1-17, wherein the pain is chronic pain. 18. The method of any one of claims 1-17, wherein the pain is mild, moderate, or severe pain. The method of claim 20 , wherein the pain is moderate or severe pain. 22. The method of claim 21, wherein the pain is cancer pain, rheumatoid pain, arthritis pain, bone pain, labor pain, myocardial infarction pain, pancreatic pain, colic, post-surgical pain, headache pain, myalgia, pain associated with periodontal disease (gingivitis and periodontitis). included), or a combination thereof. 10. The method according to any one of claims 1 to 9, wherein the pain is of tumor origin. 10. The method according to any one of claims 1 to 9, wherein the pain is of non-tumor origin. 10. The method according to any one of claims 1 to 9, wherein the pain is breakthrough pain. 10. The migraine according to any one of claims 1 to 9, wherein the pain is migraine without aura ("general migraine"), migraine with aura ("classic migraine"), migraine without headache, basal migraine, familial hemiplegic migraine. , a migraine infarction, a migraine with prolonged aura, or a combination thereof. 27. The method of any one of claims 1-26, wherein Compound A is administered orally to the human. 28. The method of any one of claims 1-27, wherein Compound A is administered to the human at a dose of 2 to 200 mg. 29. The method of claim 28, wherein Compound A is administered to the human at a dose of 2 to 100 mg. 29. The method of claim 28, wherein Compound A is administered to the human at a dose of 5 to 50 mg. 29. The method of claim 28, wherein Compound A is administered to the human at a dose of 10, 20, or 25 mg. 29. The method of claim 28, wherein Compound A is administered to the human at a dose of 20 mg. 28. The method of any one of claims 1-27, wherein Compound A is administered to the human at a dose of at least 20 mg. 34. The method of claim 33, wherein Compound A is administered to the human at a dose of at least 50 mg. 34. The method of claim 33, wherein Compound A is administered to the human at a dose of at least 100 mg. 28. The method of any one of claims 1-27, wherein Compound A is administered to the human at a dose of 5-1000 mg per day. 37. The method of claim 36, wherein Compound A is administered to the human at a dose of 5-500 mg per day. 37. The method of claim 36, wherein Compound A is administered to the human at a dose of 5-250 mg per day. 37. The method of claim 36, wherein Compound A is administered to the human at a dose of 20-150 mg per day. 37. The method of claim 36, wherein Compound A is administered to the human at a dose of 100 mg per day. 41. The method of any one of claims 1-40, wherein Compound A is administered to the human at a dose of 0.05-20 mg/kg. 42. The method of claim 41, wherein Compound A is administered to the human at a dose of 0.1-10 mg/kg. 16. The method according to any one of claims 11 to 15, wherein compound A is administered orally to the human at a dose of 0.05-5 mg/kg. 16. The method according to any one of claims 11 to 15, wherein compound A is administered orally to the human at a dose of 0.1-2 mg/kg. 18. The method of claim 16 or 17, wherein Compound A is administered to the human at a dose of 0.5-10 mg/kg. 18. The method of claim 16 or 17, wherein Compound A is administered orally to the human at a dose of 1-8 mg/kg. 47. The method of any one of claims 1-46, wherein Compound A is administered orally to the human between about 30 minutes before a meal and about 2 hours after a meal. 48. The method of claim 47, wherein Compound A is administered orally to the human during a meal or within 15 minutes after a meal. as the use of compound A in the manufacture of a medicament for the treatment of pain in a human in need thereof;
wherein compound A is N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide . as the use of compound A in combination with an opioid analgesic in the manufacture of a medicament for the treatment of pain in a human in need thereof;
wherein compound A is N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide . as the use of compound A in the manufacture of a medicament for reducing the dose of an opioid administered to a human in need thereof;
wherein compound A is N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide . 52. The method of claim 50 or 51, wherein the narcotic analgesic is any of the foregoing, from buprenorphine, codeine, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tilidine, and tramadol. Uses of choice, including mixtures of one and a pharmaceutically acceptable salt of any one of the preceding. 53. Use according to any one of claims 49 to 52, comprising enhancing the opening of Kv7 potassium channels in humans. as the use of compound A in the manufacture of a medicament for enhancing the opening of Kv7 potassium channels in a human;
wherein compound A is N- [4-(6-fluoro-3,4-dihydro-1 H -isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide;
The use of human suffering here. 55. Use according to claim 53 or 54, wherein the Kv7 potassium channel is at least one of Kv7.2, Kv7.3, Kv7.4, or Kv7.5. 56. The use of claim 55, wherein enhancing the opening of Kv7 potassium channels is selective for enhancing the opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 relative to Kv7.1. 55. Use according to claim 53 or 54, wherein enhancing the opening of Kv7 potassium channels comprises opening of Kv7.2/Kv7.3 (KCNQ2/3) potassium channels. 58. The use according to any one of claims 49 to 57, wherein the pain is nociceptive pain, neuropathic pain, or a combination thereof. 59. The use according to claim 58, wherein the pain is nociceptive pain. 60. The use of claim 59, wherein the nociceptive pain is myalgia, somatic pain, visceral pain, soft tissue pain, inflammatory pain, or a combination thereof. 61. Use according to claim 60, wherein the nociceptive pain is inflammatory pain. 62. Use according to claim 61, wherein the inflammatory pain is associated with an inflammatory disease, such as an inflammatory disease of the intestine, lung, eye, gum, kidney, skin, central nervous system or heart. 61. The use according to claim 60, wherein the nociceptive pain is visceral pain. 59. The use according to claim 58, wherein the pain is neuropathic pain. 65. The method of claim 64, wherein the neuropathic pain is spinal cord injury, spinal cord or stroke, multiple sclerosis, cancer, postherpetic neuralgia, trigeminal neuralgia, phantom pain, burning pain, reflex sympathetic dystrophy, back pain, peripheral nerve trauma, herpes virus infection. , diabetes mellitus, diabetic neuropathy, plexus injury, neuroma, amputation, vasculitis, chronic alcoholism, human immunodeficiency virus (HIV) infection, hypothyroidism, uremia, vitamin deficiency, pelvic pain, complex regional pain syndrome, or pain associated with a combination thereof. 66. The use according to any one of claims 49 to 65, wherein the pain is acute pain. 66. The use according to any one of claims 49 to 65, wherein the pain is chronic pain. 66. The use according to any one of claims 49 to 65, wherein the pain is mild, moderate, or severe pain. 69. Use according to claim 68, wherein the pain is moderate or severe pain. 70. The method of claim 69, wherein the pain is cancer pain, rheumatoid pain, arthritis pain, bone pain, labor pain, myocardial infarction pain, pancreatic pain, colic, post-surgical pain, headache pain, myalgia, pain associated with periodontal disease (gingivitis and periodontitis). included), or a combination thereof. 58. The use according to any one of claims 49 to 57, wherein the pain is of tumor origin. 58. The use according to any one of claims 49 to 57, wherein the pain is of non-tumor origin. 58. The use according to any one of claims 49 to 57, wherein the pain is breakthrough pain. 58. The method according to any one of claims 49 to 57, wherein the pain is migraine without aura ("general migraine"), migraine with aura ("classic migraine"), migraine without headache, basal migraine, familial hemiplegic migraine. , a migraine infarction, a migraine with prolonged aura, or a combination thereof. 75. The use according to any one of claims 49 to 74, wherein compound A is administered orally to a human. 76. The use according to any one of claims 49 to 75, wherein compound A is administered to a human in a dose of 2 to 200 mg. 77. The use according to claim 76, wherein compound A is administered to a human in a dose of 2 to 100 mg. 77. Use according to claim 76, wherein Compound A is administered to a human in a dose of 5 to 50 mg. 77. The use of claim 76, wherein Compound A is administered to a human at a dose of 10, 20, or 25 mg. 77. The use of claim 76, wherein Compound A is administered to a human at a dose of 20 mg. 76. The use according to any one of claims 49 to 75, wherein compound A is administered to a human in a dose of at least 20 mg. 82. The use of claim 81, wherein Compound A is administered to a human in a dose of at least 50 mg. 82. The use of claim 81, wherein Compound A is administered to a human in a dose of at least 100 mg. 76. The use according to any one of claims 49 to 75, wherein compound A is administered to a human at a dose of 5-1000 mg per day. 85. The use according to claim 84, wherein compound A is administered to a human at a dose of 5-500 mg per day. 85. The use according to claim 84, wherein compound A is administered to a human at a dose of 5-250 mg per day. 85. The use according to claim 84, wherein compound A is administered to a human at a dose of 20-150 mg per day. 85. The use of claim 84, wherein Compound A is administered to a human at a dose of 100 mg per day. 89. The use according to any one of claims 49 to 88, wherein compound A is administered to a human at a dose of 0.05-20 mg/kg. 90. The use according to claim 89, wherein Compound A is administered to a human at a dose of 0.1-10 mg/kg. 64. The use according to any one of claims 59 to 63, wherein compound A is administered orally to a human at a dose of 0.05-5 mg/kg. 64. The use according to any one of claims 59 to 63, wherein compound A is administered orally to a human at a dose of 0.1-2 mg/kg. 66. Use according to claim 64 or 65, wherein compound A is administered to a human at a dose of 0.5-10 mg/kg. 66. Use according to claim 64 or 65, wherein compound A is administered orally to a human at a dose of 1-8 mg/kg. 95. The use according to any one of claims 49 to 94, wherein Compound A is administered orally to a human between about 30 minutes before a meal and about 2 hours after a meal. 96. Use according to claim 95, wherein Compound A is administered orally to a human during a meal or within 15 minutes after a meal.

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