WO2015095549A1 - Régime posologique pour médicament sélectif du sous-type du récepteur gabaa - Google Patents

Régime posologique pour médicament sélectif du sous-type du récepteur gabaa Download PDF

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Publication number
WO2015095549A1
WO2015095549A1 PCT/US2014/071207 US2014071207W WO2015095549A1 WO 2015095549 A1 WO2015095549 A1 WO 2015095549A1 US 2014071207 W US2014071207 W US 2014071207W WO 2015095549 A1 WO2015095549 A1 WO 2015095549A1
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day
compound
pharmaceutically acceptable
subject
acceptable salt
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PCT/US2014/071207
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English (en)
Inventor
Roger D. Tung
Virginia BRAMAN
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Concert Pharmaceuticals, Inc.
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Publication of WO2015095549A1 publication Critical patent/WO2015095549A1/fr

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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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • GABA A receptors can possess one of a number of a subunits, including al, a2, a3 and a5.
  • the pharmacological effects of activating a GABA A receptor in the nervous system are believed to depend mainly on which type of a subunit the receptor contains.
  • Several classes of widely used drugs target GABA A receptors, including benzodiazepines such as diazepam (Valium). Benzodiazepines are used for the treatment of anxiety, spasticity, muscle tension, insomnia, acute alcohol withdrawal and seizures.
  • al GABA A receptors Activation of al GABA A receptors is believed to be mainly responsible for sedation and ataxia, which is a lack of muscle control during voluntary movements, associated with benzodiazepine use, and may also contribute to their amnesiac and habituating effects.
  • Activation of a2, a3 and a5 GABA A receptors is believed to cause other therapeutic effects of benzodiazepines, including anti-spasticity, muscle relaxation, anti-anxiety, anti-seizure and potentially anti-pain activities.
  • Certain sleep agents such as Zolpidem (Ambien®) and zaleplon (Sonata®) also target GABA A receptors.
  • TPA023 was found to be a non-sedating anxiolytic in rodents and primates with essentially no abuse potential in a primate. It was effective in rodent anxiolytic models without overt sedation at plasma levels that produced between 70 and 88% GABA A receptor occupancy, as determined by Positron Emission Tomography (PET) imaging studies (Atack, J. R. et al., Journal of Pharmacology and Experimental Therapeutics, 2010, 332(1) 17-25).
  • PET Positron Emission Tomography
  • the structurally related L-838417 exhibited similar receptor subtype selectivity as TPA023 and had more potent agonist activity for the a2 and a3 subunits.
  • TPA023 was selected for further development due to its more favorable pharmacokinetic properties.
  • TPA023 was well-tolerated in single ascending doses (SAD) administered orally up to 2.0 mg. However, at 3.0 mg, dose-limiting adverse events observed were dizziness, altered perception and motor incoordination. (Atack, Advances in Pharmacology, 2009, Volume 57, 137-185).
  • the fact that TPA023 was not well-tolerated above 2 mg suggested that receptor occupancies above about 50% in humans could not be achieved for this class of drugs without significant undesirable side effects.
  • the short half- life of TPA023 in young, healthy males of 3.3 to 5.2 hours suggested that the drug might require repeated dosing during the day.
  • L-838417 Deuterium substituted analogs of L-838417 were described in US patents 8,003,646 and 8,399,467. These analogs were previously reported to have improved bioavailability and metabolic stability in animal models compared to L-838417. See
  • Spasticity is a chronic condition characterized by involuntary tightness, stiffness or contraction of muscles that occurs in patients who have damage to the brain or spinal cord. Spasticity can result from a wide range of disorders, including multiple sclerosis, spinal cord injury, cerebral palsy, amyotrophic lateral sclerosis, stroke and hereditary spastic paraplegia. Symptoms can range from mild muscle tightness to more severe symptoms, including crippling and painful inability to move limbs that can result in disability and diminished quality of life. The American Association of Neurological Surgeons estimated in 2006 that there were 12 million patients suffering from spasticity worldwide.
  • GABA A receptor modulators though limited by severe side effects, can be broadly effective for the treatment of spasticity.
  • diazepam has demonstrated clinical efficacy as an anti- spasticity agent in patients with spinal cord injury, multiple sclerosis, cerebral palsy and stroke.
  • the leading oral drugs for spasticity, baclofen and tizanidine, are also highly sedating.
  • (I) (also referred to herein as CTP-354), a deuterated analog of L-838417, can be achieved in humans using certain dosage regimens that do not cause dose-limiting adverse events in humans (Example 2).
  • High brain GABA A receptor occupancy levels were achieved with Compound (I) at doses that were well-tolerated in a Phase 1 clinical trials.
  • Compound (I) produced much higher levels of GABA A receptor occupancy than benzodiazepines without causing substantial sedation (Example 3) and, therefore, may provide similar clinical efficacy against spasticity without the dose-limiting effects of benzodiazepines .
  • Compound (I) for treating a disorder of the central nervous system or pain in a subject are disclosed herein.
  • a first embodiment of the invention is a method of treating a disorder of the central nervous system, such as anxiety or spasticity, or pain.
  • the method comprises administering to a subject an amount of Compound (I) or a pharmaceutically acceptable salt thereof in the ranges of 2 mg/day to 40 mg/day; 2 mg/day to 20 mg/day; 2 mg/day to 18 mg/day; 2 mg/day to 16 mg/day; 2 mg/day to 12 mg/day; 2 mg/day to 8 mg/day; 2 mg/day to 4 mg/day; 4 mg/day to 40 mg/day; 4 mg/day to 20 mg/day; 4 mg/day to 18 mg/day; 4 mg/day to 16 mg/day; 4 mg/day to 12 mg/day; 4 mg/day to 8 mg/day; 8 mg/day to 40 mg/day; 8 mg/day to 20 mg/day; 8 mg/day to 18 mg/day; 8 mg/day to 16 mg/day; or 8 mg/day to 12 mg/day.
  • 2 mg/day; 4 mg/day; 8 mg/day; 16 mg/day; 18 mg/day; 20 mg/day or 40 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject.
  • 2 mg/day; 4 mg/day; 6 mg/day; 8 mg/day; 12 mg/day; 16 mg/day; 18 mg/day; 20 mg/day or 40 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject.
  • 2 mg/day; 6 mg/day; or 12 mg/day of Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject.
  • Compound (I) or a pharmaceutically acceptable salt thereof is administered one time per day at any of the foregoing dosages.
  • Compound (I) or a pharmaceutically acceptable salt thereof is administered orally at any of the foregoing dosages. More preferably, Compound (I) or a pharmaceutically acceptable salt thereof is administered one time per day and orally at any of the foregoing dosages.
  • a second embodiment is Compound (I) or a pharmaceutically acceptable salt thereof for treating in a subject a disorder of the central nervous system, such as anxiety or spasticity, or pain.
  • the compound may be administered at the dosing regimens disclosed herein.
  • a third embodiment of the invention is the use of Compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a subject with a disorder of the central nervous system, such as anxiety or spasticity, or pain.
  • the compound may be administered at the dosing regimens disclosed herein.
  • Another embodiment of the invention relates to a method of modulating/activating in the brain of a subject a2 and a3 subtypes of the GABA A receptor, the method comprising administering to the subject a daily dose of Compound (I) or a pharmaceutically acceptable salt thereof according to one of the dosage regimens described herein, e.g., in the range of 2 mg to 60 mg.
  • Yet another embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and between 2 mg to 40 mg; 2 mg to 20 mg; 2 mg to 18 mg; 2 mg to 16 mg; 2 mg to 12 mg; 2 mg to 8 mg; 2 mg to 4 mg; 4 mg to 40 mg; 4 mg to 20 mg; 4 mg to 18 mg; 4 mg to 16 mg; 4 mg to 12 mg; 4 mg to 8 mg; 8 mg to 40 mg; 8 mg to 20 mg; 8 mg to 18 mg; 8 mg to 16 mg; or 8 mg to 12 mg of Compound (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises 2 mg; 4 mg; 8 mg; 16 mg; 18 mg; 20 mg or 40 mg of Compound (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises 2 mg; 4 mg; 6 mg; 8 mg; 12 mg; 16 mg; 18 mg; 20 mg or 40 mg of Compound (I) or a pharmaceutically acceptable salt thereof.
  • Figure 1 is a graph showing a comparison of the plasma levels in ng/mL of
  • Figure 2 is a graph showing the plasma concentrations in ng/mL over time in hours from a single ascending dose study in humans with Compound (I).
  • Figure 3 comprises brain images obtained from PET scans of two subjects in a Phase 1 imaging study with Compound (I).
  • the first row of images were baseline scans obtained after injection with positron emitting flumazenil; the second row of images were obtained immediately after injection with positron emitting flumazenil, which was given five hours after a single oral dose of 20 mg of Compound (I); and the third row of images were obtained immediately after injection with positron emitting flumazenil, which was given twenty-four hours after the single oral dose of 20 mg of Compound (I).
  • Figure 4 is a graph showing the relationship between plasma concentration and brain
  • Figure 5 shows the steady- state Day 10 plasma concentration vs. time profile and the Day 1-10 Chough (C 2 4hr) plasma concentration vs. time profile.
  • This invention in one embodiment relates to Compound (I) or a pharmaceutically acceptable salt thereof; and certain pharmaceutical compositions comprising Compound (I) or a pharmaceutically acceptable salt thereof and methods of use thereof involving certain dosing regimens.
  • the pharmaceutical compositions and dosing regimens are useful for treating diseases or disorders that can be treated by GABA A receptor agonists.
  • Compound (I) and pharmaceutically acceptable salts thereof and the pharmaceutical compositions and methods are useful for treating diseases and disorders that can be treated by compounds that more selectively activate the a2 and/or a3 subunits of the GABA A receptor rather than the l subunit.
  • compositions comprise a pharmaceutically acceptable carrier and Compound (I) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.
  • Compound (I) is
  • Each position that is specifically designated as “D” has deuterium at an abundance that is at least 5500 times the natural abundance of deuterium, which is about 0.015%, or at least 82.5% incorporation of deuterium.
  • each position that is specifically designated as “D” has deuterium incorporation of at least 90%, more preferably of at least 95%, and even more preferably of at least 99%.
  • Each position that is specifically designated as "H” in Compound (I) refers to hydrogen at its natural isotopic abundance. Except for the deuterium atoms, all atoms of Compound (I) are present at their natural isotopic abundance.
  • Compound (I) has been disclosed in US patent 8,003,646 and US patent 8,399,467.
  • the dosing regimens of Compound (I) or a pharmaceutically acceptable salt thereof are useful for treating various central nervous system disorders.
  • the dosing regimens of Compound (I) are useful for treating spasticity, pain and anxiety.
  • the dosing regimens of Compound (I) are also useful for treating fibromyalgia; epilepsy; obsessive- compulsive disorder; stress disorders (e.g., post-traumatic and acute stress disorder);
  • neuroses convulsions; depressive disorders or bipolar disorders (e.g., single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders); organophosphate (OP) nerve agent-induced seizures and neuronal damage;
  • depressive disorders or bipolar disorders e.g., single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders
  • organophosphate (OP) nerve agent-induced seizures and neuronal damage organophosphate (OP) nerve agent-induced seizures and neuronal damage
  • Compound (I) or pharmaceutically acceptable salts thereof may also be used as a protectant against nerve-gas (agent) exposure and disorders associated with exposure to nerve gas as well as a treatment for such disorders.
  • the disorders disclosed herein are treatable by the dosage regimen disclosed herein.
  • Examples of types of pain that are treatable by the disclosed dosing regimen with Compound (I) or a pharmaceutically acceptable salt thereof include neuropathic pain, inflammatory pain, migraine pain, and pain related to spasticity.
  • Neuropathic pain encompasses a range of painful conditions of diverse origins including diabetic neuropathy, post-herpetic neuralgia, nerve injuries after surgery, pain following paraplegia, hypersensitivity to non-painful stimuli (allodynia), e.g. after surgery or during migraine attacks, spontaneous pain, hyperalgesia, diffuse muscle tenderness of myofacial syndromes, sensory abnormalities of the gastrointestinal tract, e.g. in irritable bowel disease, or chest pain and a large proportion of back pain. Cancer pain and AIDS- associated pain also qualify as neuropathic pain.
  • Inflammatory pain is triggered by nerve endings that become irritated when surrounded by inflamed tissue. Inflammatory pain is most commonly associated with conditions such as trauma, osteoarthritis, rheumatoid arthritis, post surgery recovery and some forms of cancer pain.
  • Migraine-associated pain attacks affect about 10 to 20% of the middle European population. Pain attacks are believed to originate from the sensitization of meningeal nociceptors by neuropeptides and/or their excitation by dilated meningeal blood vessels.
  • spasticity examples include spasticity associated with multiple sclerosis and spinal cord injury. Other examples of spasticity include spasticity associated with stroke, cerebral palsy, traumatic brain injury, amyotrophic lateral sclerosis (ALS), or other neurodegenerative conditions or diseases.
  • ALS amyotrophic lateral sclerosis
  • anxiety disorders examples include general anxiety disorder, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, substance-induced anxiety disorder and phobias such as animal phobias or social phobias).
  • This invention also relates to a method of treating a disorder of the central nervous system, such as anxiety or spasticity, or pain, comprising administering to the subject an amount of Compound I or a pharmaceutically acceptable salt thereof in the range of 2 mg/day to 40 mg/day; 2 mg/day to 20 mg/day; 2 mg/day to 18 mg/day; 2 mg/day to 16 mg/day; 2 mg/day to 12 mg/day; 2 mg/day to 8 mg/day; 2 mg/day to 4 mg/day; 4 mg/day to 40 mg/day; 4 mg/day to 20 mg/day; 4 mg/day to 18 mg/day; 4 mg/day to 16 mg/day; 4 mg/day to 12 mg/day; 4 mg/day to 8 mg/day; 8 mg/day to 40 mg/day; 8 mg/day to 20 mg/day; 8 mg/day to 18 mg/day; 8 mg/day to 16 mg/day; or 8 mg/day to 12 mg/day.
  • Compound (I) or a pharmaceutically acceptable salt thereof is administered one time per day at any of the foregoing dosages.
  • Compound (I) or a pharmaceutically acceptable salt thereof is administered orally at any of the foregoing dosages. More preferably,
  • Compound (I) or a pharmaceutically acceptable salt thereof is administered one time per day and orally at any of the foregoing dosages.
  • emesis including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing loss.
  • the disclosed dosage regimen with Compound (I) or a pharmaceutically acceptable salt thereof may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.
  • Compound (I) can be prepared according to procedures disclosed in U.S. Patent No. 8,003,646 and 8,399,467.
  • compositions can also be used with the disclosed dosage regimens.
  • a salt of the compound represented by Structural Formula (I) is formed between an acid and a basic group of the compound, such as an amino functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite
  • Compound (I) or pharmaceutically acceptable salts therein is preferably administered orally according to the disclosed dosage regimen. Suitable formulations for this route of administration are described in U.S. Patent No. 8,003,646.
  • a "subject” as used herein is a primate, preferably a human.
  • Treating a subject with a disease or disorder refers to ameliorating or improving a clinical symptom or indicator associated with the disease or disorder.
  • the invention is illustrated by the following examples, which are not intended to be limiting in any way.
  • Compound (I) and L-838417 were orally dosed at 1 mg/kg in eight male Sprague- Dawley rats.
  • the plasma levels of Compound (I) were significantly greater than those of L- 838417.
  • the maximum observed peak plasma concentration for Compound (I) was 4.8 times higher than that of L-838417 and the total exposure to Compound (I) was three times higher as compared to L-838417.
  • the results are shown in Figure 1.
  • the corresponding study in humans showed that Compound (I) has a longer half-life in humans than it does in rats (see Figure 3 and Example 3).
  • Pharmacokinetic data from our single ascending dose trial indicated that Compound (I) was well-absorbed with low inter-subject variability and a long plasma half-life, potentially supporting once-daily dosing of the compound.
  • the graph in Figure 2 shows the mean plasma concentration over time following administration of single ascending doses of Compound (I) in the six subjects in each cohort of the trial who received Compound (I).
  • doses of Compound (II) of 20 mg and higher resulted in plasma concentrations in excess of 100 ng/mL, maintained for 24 hours following dosing.
  • the Phase 1 imaging study described in Example 3 indicated that these plasma concentrations corresponded to brain GABA A receptor occupancy of greater than 50%.
  • the high GABA A receptor occupancy of Compound (1) at well-tolerated doses supports its potential as a non-sedating oral treatment for spasticity.
  • Compound (I) was generally well tolerated in our Phase 1 single ascending dose trial. No serious adverse events were reported in the trial.
  • single doses of Compound (I) of 4 mg, 20 mg, 40 mg and 60 mg were evaluated in a total of nine healthy volunteers. These doses were selected because they did not produce dose-limiting side effects in the single ascending dose clinical trial and with the goal of providing a wide range of GABA A receptor occupancy.
  • the objectives in this study were to assess whether Compound (I) could provide similar or higher brain GABA A receptor occupancy levels than those typically provided by benzodiazepines at doses that do not cause dose-limiting sedation; and to compare the relationship between Compound (I) plasma levels and GABA A brain receptor occupancy.
  • Subjects lay supine on the PET imaging camera for administration of [ 18 F]-flumazenil and preparation for PET imaging. Subjects were injected at a target dose of 5 mCi (+ 0.5) by intravenous injection over approximately 3 minutes using an infusion pump. PET imaging commenced at the time injection begins.
  • OEM 4 iterations iterations, 16 subsets
  • GABA A receptor occupancies of between 34% to 82% were observed in subjects receiving Compound (I) at single doses of 4 mg, 20 mg, 40 mg and 60 mg.
  • a baseline scan was conducted in which a small amount of flumazenil, a radiolabeled, positron emitting benzodiazepine, was injected and the brain was imaged to show flumazenil binding to the GABA A receptors.
  • the subject was given a single oral dose of Compound (I) within two weeks of the baseline scan. Five hours after
  • the graph in Figure 4 shows the relationship between plasma concentration and brain
  • GABA A receptor occupancy for Compound (I) in the first part of the imaging study The 17 data points on the graph below each represent a single reading in a single subject. These include two readings for each subject, one at five hours and one at 24 hours following dosing, with the exception of one subject for whom we could not calculate receptor occupancy at five hours due to a computer error.
  • the graph in Figure 4 shows how receptor occupancy increases with increasing plasma concentration. As illustrated in the graph, we observed that plasma concentrations in excess of 100 ng/mL resulted in GABAA receptor occupancy in excess of 50%.
  • Compound (I) appears to have therapeutic potential for the treatment of spasticity when administered once daily.
  • the ECso was estimated to be 94.4 + 7.0 ng/mL.
  • Methodology This was a randomized, 2-part study in healthy subjects. At least 3 subjects of each gender were enrolled into each dosing group.
  • Subjects in Cohort 1 were randomized, 8 subjects to a 2 mg oral suspension dose of Compound (I) and 2 to matching placebo. Subjects were then dosed once daily (QD) for 10 days with double-blind suspension. • Following completion of Cohort 1 (and an acceptable safety/tolerability outcome), subjects in Cohort 2 were randomized, 8 subjects to a 6 mg oral suspension dose of Compound (I) and 2 to matching placebo. Subjects were then dosed QD for 10 days with double-blind suspension.
  • Cohort 3 Following completion of Cohort 2 (and an acceptable safety/tolerability outcome), subjects in Cohort 3 were randomized, 8 subjects to a 12 mg solid dose of Compound (I) and 2 to matching placebo. Subjects were then dosed QD for 10 days with double- blind capsules.
  • Monitor to determine whether to escalate to the next dose. Upon determination of whether (or not) to dose the next subsequent cohort, data from the prior cohort could have been unblinded.
  • Part B randomized 12 new subjects, 4 subjects per sequence, into 1 of 3 treatment sequences. Subjects were then treated (in an open-label fashion) with a single 6 mg dose of suspension in a fasted state or 6 mg solid dose Compound (I) in a fasted or fed state. Note that Periods 1 and 2 were each followed by a washout period of at least 7 days. The effects of food (as compared to fasting) were assessed and a comparison between the suspension and the solid dose was assessed.
  • BMI body mass index
  • test products were Compound (I) Capsules, 6 mg (Lot no. Compound (I)-2014-
  • Compound (I) either as a suspension or solid dose, with or without a high-fat meal.
  • Part A subjects were treated with QD doses of Compound (I) or placebo for 10 days.
  • the total duration (excluding the screening period) of participation in the study for each subject in Cohorts 1, 2, and 3 was approximately 2 weeks.
  • Part B subjects were treated in 3 successive periods with a 7-day washout between periods.
  • the total duration (excluding the screening period) of participation in the study for each subject in (Part B) was approximately
  • Ora-Blend ® Flavored Suspending Vehicle In Part A, subjects randomized to receive placebo treatment were administered oral doses of Ora-Blend ® or placebo capsules QD for 10 days.
  • Compound (I) demonstrated a favorable PK profile supporting once-daily dosing.
  • Compound (I) provided high and sustained brain GABA(A) receptor occupancy levels following both single and repeat doses. Treatment was generally well tolerated.
  • Compound (I) may be dosed without regard to food.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne une méthode de traitement d'un patient atteint d'un trouble du système nerveux central ou présentant une douleur. Le procédé consiste à administrer au patient une quantité située dans la plage comprise entre 2 mg/jour et 60 mg/jour d'un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2014/071207 2013-12-18 2014-12-18 Régime posologique pour médicament sélectif du sous-type du récepteur gabaa WO2015095549A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030158203A1 (en) * 1999-01-27 2003-08-21 Merck & Co., Inc. Triazolo-pyridazine derivatives as ligands for GABA receptors
US20100056529A1 (en) * 2008-08-29 2010-03-04 Concert Pharmaceuticals Inc. Substituted triazolo-pyridazine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030158203A1 (en) * 1999-01-27 2003-08-21 Merck & Co., Inc. Triazolo-pyridazine derivatives as ligands for GABA receptors
US20100056529A1 (en) * 2008-08-29 2010-03-04 Concert Pharmaceuticals Inc. Substituted triazolo-pyridazine derivatives

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