Prodrugs of kv7 channel openers

Abstract

Prodrugs of pharmacologically active 1,2,4-triaminobenzene derivatives of general formula (I); or pharmaceutically acceptable salts thereof, wherein the symbols R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , and R 6c are defined, and wherein the symbol Z is defined. Synthesis, purification, testing, and methods of use as prodrugs of pharmacologically active agents at Kv7 ion channels are provided.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 163,470, filed March 19, 2021, the contents of which are hereby incorporated by reference. Technical Field

[0003] This disclosure relates to the field of prodrugs of pharmacologically active pharmaceutical ingredients, and more particularly to the field of prodrugs of pharmaceutical ingredients that are active at Kv7 potassium ion channels. The prodrugs of this disclosure comprise one or more hydrolyzable bonds among: a pharmacologically active pharmaceutical ingredient or compound, such as ezogabine, flupirtine, or other chemical substances active at Kv7 potassium ion channels; and a carbonyl-containing prodrug side group, such as those derived from amino acids, or a carbonyl-containing side group, such as those found in various acetal or ketal derivatives, as exemplified in gabapentinyl ester, which itself is not active at Kv7 potassium ion channels. The hydrolyzable bonds of the prodrugs of this disclosure are cleaved in mammals to produce a pharmacologically active pharmaceutical ingredient. Background Technology

[0004] Prodrug:

[0005] Prodrugs are biologically reversible derivatives of drug molecules that must undergo enzymatic and / or chemical transformations in vivo to release the active parent drug before they can exert their desired pharmacological effects.

[0006] Typically, prodrugs are biologically inactive compounds that are activated upon administration to their pharmacologically active form. Prodrugs are usually formulated to overcome pharmacokinetic barriers such as poor solubility and absorption, extensive first-pass metabolism, lack of cerebral osmosis, or rapid excretion; as well as physiological and chemical barriers such as poor stability, undesirable degradation products or impurities; and pharmacodynamic barriers such as toxicity, tolerability, side effects, and poor efficacy. Activation of prodrugs usually occurs through enzymatic processes, such as those by cytochrome enzymes, esterases, and amidases, or through chemical processes (intermolecular or intramolecular), such as hydrolysis and oxidation.

[0007] The development of prodrugs is now widely recognized as a strategy for improving the physicochemical, biopharmaceutical, or pharmacokinetic properties of pharmacologically effective compounds and thereby overcoming barriers to drug development and usefulness.

[0008] Compounds active at the Kv7 potassium ion channel:

[0009] Voltage-gated Kv7 (or KCNQ) channels play a crucial role in controlling membrane excitability. The Kv7 subfamily of voltage-gated potassium channels comprises five members (Kv7.1–5), each exhibiting characteristic tissue distribution and physiological functions. Given their functional heterogeneity, Kv7 channels are important pharmacological targets for developing novel drugs for neuronal, neuromuscular, cardiovascular, and metabolic diseases. Like typical voltage-gated ion channels, Kv7 channels undergo a transition from closed to open by sensing changes in transmembrane potential, thereby mediating an inhibitory K(+) current to reduce membrane excitability. Reduced Kv7 channel activity due to gene mutations leads to various human diseases caused by excessive membrane excitability, including epilepsy, arrhythmias, and deafness. Therefore, discovering small compounds that activate voltage-gated ion channels is an important strategy for clinical intervention in such conditions. Since ligand binding can induce conformational changes leading to subthreshold channel opening, understanding the molecular basis of these “gain-of-function” molecules is of great interest. Although small molecule activators for cation channels are scarce, several novel compounds that activate Kv7 voltage-gated channels have been identified.

[0010] Ezogabine (USAN, or retigabine [INN]) and flupirtine are in Kv7 K + Two examples of compounds with active sites at the channel have been developed into drugs but are no longer marketed as therapeutic agents.

[0011] Ezogabine, used in combination with other medications, is used to control partial-onset seizures (seizures involving only a part of the brain) and focal seizures in adults, and works by reducing neuronal overexcitability in the peripheral and central nervous systems. Overall, it is subject to the trademark registration of Valeant Pharmaceuticals North America, with the trademark name... The most frequently reported adverse reactions (≥4%, and approximately twice the placebo rate) among patients who received ezogabine were dizziness (23%), somnolence (22%), fatigue (15%), confusion (9%), vertigo (8%), tremor (8%), incoordination (7%), diplopia (7%), inattention (6%), memory impairment (6%), weakness (5%), blurred vision (5%), gait disturbance (4%), aphasia (4%), dysarthria (4%), and balance disturbance (4%). In most cases, the reactions were mild or moderate (Potiga label, revised May 2016).

[0012] Ezogabin has demonstrated efficacy in a range of cellular, tissue, animal models, and clinical trials related to these target sites. In addition to blocking seizures, the pharmacological properties exhibited by ezogab are consistent with its potential uses as an analgesic, neuroprotective agent, treatment of hearing impairment, treatment of status epilepticus associated with organophosphate poisoning (Barker 2021, *Neuroscience*), and treatment of demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis (ALS). Ezogabin is providing important information and clues for novel mechanistic approaches to treating a range of clinical conditions involving neuronal hyperexcitability.

[0013] Flupirtine has been used as a centrally acting analgesic for patients with a range of acute and persistent pain symptoms but without the adverse effects characteristic of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), and it is well tolerated by most patient populations. The pharmacological properties exhibited by flupirtine involve action on several cellular targets, including Kv7 channels, G protein-regulated inward rectifying K channels, and GABA type A receptors, but there is also evidence that flupirtine's action involves other, yet unidentified, mechanisms of action.

[0014] Flupirtine exhibits activity in a range of cells and tissues associated with these target sites. In addition to analgesia, flupirtine demonstrates pharmacological properties consistent with its use as an anticonvulsant, neuroprotective agent, skeletal and smooth muscle relaxant, treatment of hearing and visual impairments, and memory and cognitive impairments. Flupirtine is providing important information and clues for novel mechanistic approaches to treating a range of clinical conditions involving excessive cellular excitability. However, flupirtine does have some undesirable side effects, including nausea, vomiting, dizziness, itching, rash formation, abdominal pain, bloating, tremor, dry mouth, idiopathic liver toxicity, and fatigue.

[0015] More specifically, pharmacologically active compounds that interact with the Kv7.2 channel subtype were also investigated (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC2932606 / ) and these pharmacologically active compounds are potential candidates for future drug development. However, to date, only two drugs, ezogabine and flupirtine, have been approved for human use as medical treatments.

[0016] Kv7 channels offer promising targets for novel therapies for diseases caused by neuronal overexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism by which Kv7 is activated by retigabine has been elucidated as stabilizing the open conformation by binding to the pore region of the Kv7 channel (J Physiol, Maljevic. 2008).

[0017] Literature studies have shown that the pharmacological effects of Kv7 channel openers, such as retigabine, or those that enhance the opening state of the Kv72-5 subtype have demonstrated or have the potential to be effective in treating, improving, or preventing the progression of diseases or conditions selected from groups of diseases associated with neurological indications and pain. In one instance, channel opening has been shown to be affected by basal M-currents that set the resting membrane threshold. Enhancing the membrane threshold of seizure neurons composed of Kv7.2 (S559A) knock-in mice showed normal basal M-currents. Knock-in mice showed reduced M-current inhibition upon challenge with oxidative tremor-M, a muscarinic agonist. Kv7.2 (S559A) mice were resistant to chemosergic seizures without mortality. Administration of XE991, a Kv7.2 blocker, transiently exacerbated seizures in knock-in mice to a degree comparable to that in wild-type mice. In Kv7.2 (S559A) knock-in mice, no seizure-induced cell death or spontaneous seizure recurrence was observed after experiencing a state of epilepsy. (L Greene, Epilepsia, 2018) This example demonstrates how channel opening can block seizures and provide neuroprotection. ICA-105665, a Kv7.2 channel opener, reduced the SPR in patients at single doses of 100 (1 / 4), 400 (2 / 4), and 500 mg (4 / 6). This is the first evaluation of the role of Kv7 potassium channel activation in a photosensitivity proof-of-concept model. The reduction in SPR in this patient population provides evidence that ICA-105665 penetrates the central nervous system (CNS) and provides preliminary evidence of an anti-epileptic effect through binding to neuronal Kv7 potassium channels. (Epilepsia, Trenite, 2013).

[0018] In models of pain, more specifically neuropathic pain and chronic headache, paclitaxel-induced peripheral neuropathy and associated neuropathic pain were severe and resistant to intervention. Results from rodent models showed that retigabin / ezogabine could be used to alleviate the development of paclitaxel-induced peripheral neuropathy. (J Pain, Li. 2019).

[0019] Several drugs, including flupirtine and retigabine, enhance the activity of neural Kv7 / M channels primarily through their voltage-gated hyperpolarization shift. This reduces neural excitability and can inhibit noxious stimuli and their transmission. Flupirtine is one of the best-selling non-opioid analgesics in Europe and served as a central analgesic before being withdrawn from the market; retigabine is an analogue of flupirtine and is approved as adjunctive therapy for partial-onset seizures. It is also a broad-spectrum anticonvulsant in animals and an effective analgesic in animal models of chronic inflammation and neuropathic pain, central pain, pain associated with diabetic neuropathy, postherpetic neuralgia, and peripheral nerve injury (Brown, *British Journal of Pharmacology*, 2009).

[0020] Czuzcwar also summarized preclinical data suggesting that retigabine / ezogabine may be useful in patients with neuropathic pain and mood disorders, such as drug addiction and affective disorders. Preliminary clinical data also indicate that retigabine may be effective for Alzheimer's disease or stroke. (Czuzcwar, Pharmacological Reports 2010).

[0021] Numerous studies have demonstrated that Kv7 channel opening can be effective against a wide range of neurotherapeutic targets, including but not limited to anxiety, CNS damage caused by neurodegenerative disorders or diseases or injuries, cognitive deficits, obsessive-compulsive behaviors, dementia, depression, Huntington's disease, dystonia, and mania. Given the good tolerability of retigabin / ezogabine and flupirtine in humans, the significant anti-dystonia efficacy observed in dTSZ mutant mice suggests that neuronal Kv7 channel activators are promising candidates for treating dystonia-related movement disorders and potentially other types of dystonia. The established analgesic effects of Kv7 channel openers may help improve these conditions, which are often accompanied by painful muscle spasms (Richter, *British Journal of Pharmacology*, 2006).

[0022] In a recent article, retigabin was shown to delay the onset of diffuse depolarization following submaximal OGD stimulation (Aiba, *Brain*, 2021). Intriguingly, Kv7.2 activators have demonstrated neuroprotective effects in experimental ischemia and brain injury studies, and the anti-diffusion depolarization properties of these activators may contribute to these neuroprotective effects. Further reviews of recent research support the novel role of Kv7 channels in intrinsic and synaptic plasticity, as well as their contributions to cognition and behavior. Voltage-gated potassium channels of the KV7 family (KV7.2–5) play a crucial role in controlling neuronal excitability and are therefore attractive targets for the treatment of CNS disorders associated with overexcitation, such as cognitive impairment, memory loss, memory disorders, and memory dysfunction. (See, for example, Boehm, *Pain* 2019; Maghera, *Epilepsy* 2020; De Jong, *Physiological Reports* 2018; Jakubowski, *Epilepsy Behav* 2013; Zizhen Wu, *J Pharmacol Exp Ther* 2020; JE Larsson, *In Physiology* 2020; Yadav, *Saudi J Anaesth* 2017; Garakani, *Front Psychiatry* 2020; Maljevic, *Journal of Physiology* 2008; R. Brant, *Gastroenterology* 2017; HuiSun, *JCI Insight* 2019; R...) Brant, Gastroenterology 2017; Ravi Misra, Gastroenterology 2017; Parreno, Frontiers in Physiology 2020; Blom, PLoS One 2014; Feng, Neuroscience 2019; E, Redford, Physiology and Biochemistry 2021; J, Gunthrope, Epilepsy 2012; Epilepsy, Villalba 2018; Frontiers in Physiology, Baculis 2020; Frontiers in Physiology, Vigil 2020.

[0023] Given the critical role of Kv7 channels in neonatal brain development and inhibition (Peters et al., 2005; Soh et al., 2014), memory impairment in these genetic models can be attributed to aberrant hippocampal morphology and / or hyperexcitability (Peters et al., 2005; Milh et al., 2020). Kv7 channels also regulate a variety of behaviors. Behavioral phenotypes in globally or conditionally homozygous KCNQ2 knockout mice are not readily apparent, as they are associated with early postnatal lethality or premature death, respectively (Watanabe et al., 2000; Soh et al., 2014). However, heterozygous KCNQ2 knockout mice are viable and exhibit increased motor activity and exploratory behavior (Kim et al., 2020), consistent with transgenic inhibition of Kv7 currents (Peters et al., 2005) and amphetamine and XE991 (Sotty et al., 2009)-induced hyperactivity. These mice also showed decreased social skills and increased repetitive and compulsive behaviors (Kim et al., 2020), reminiscent of autism found in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al., 2012, 2013; Milh et al., 2013).

[0024] Recent animal studies have shown that enhancing M-currents (Kv7 opening) is a therapeutic target for a variety of brain disorders, including those for which there are currently no treatments, such as TBI and psychostimulant addiction and activity disorders (Lee, *Journal of Neurophysiology*, 2017), movement disorders, neurodegenerative diseases, Parkinson's disease, Parkinsonian movement disorders (*JAMA Neurol*, Wainger, 2021; *Neurosci Bulletin*, chen, 2017; *Neural Plast*, Ramirez, 2015), phobias, Pick's disease, psychosis, and bipolar disorder (*Frontiers in Physiology*, Vigil, 2020).

[0025] Spinal cord injury can be treated by opening the KCNQ / Kv7 channels to reduce neuronal activity, thereby protecting spinal cord neurons and axons from degeneration following spinal cord injury and promoting the recovery of motor and sensory functions. A study by We et al. showed that repeated application of retigabine in the acute phase of injury to open these channels promoted neurobehavioral recovery after spinal cord injury (Wu, Journal of Pharmacology, 2020).

[0026] Due to its important role in physiology, dysfunctional Kv7 channels are often associated with conditions characterized by abnormal potassium ion conduction, including arrhythmias, hearing impairment, epilepsy, pain, and hypertension (Frontiers in Physiology, larsson. 2020; Journal of Physiology, Maljevic. 2008).

[0027] A study by Lee et al. provides evidence that mouse Kv7 channels can contribute differently to the regulation of functional properties of cerebral and coronary arteries. This heterogeneity is of great significance for the development of novel therapies for cardiovascular dysfunction. (Lee, Microcirculation, 2015).

[0028] Ultimately, the Kv7 channel provides a promising target for novel therapies for diseases caused by neuronal overexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism by which Kv7 is activated via retigabine has recently been elucidated as stabilizing the open conformation by binding to pore regions, which may be crucial for the treatment of migraines and tension headaches (Journal of Physiology, Maljevic. 2008).

[0029] Further experiments have shown that inhibition of M-currents requires both a simultaneous increase in cytosol Ca2+ concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). PLC and Ca2 / PIP2-mediated inhibition of M-currents in sensory neurons may represent one of the general mechanisms underlying pain generated by inflammatory mediators, and therefore may open new therapeutic windows for treating this major clinical problem in intestinal disorders and inflammatory diseases such as ulcerative colitis, Crohn's disease, and Creutzfeid-Jacobs disease (Journal of Neuroscience, Linley, 2008).

[0030] Other Kv7 channel openers, such as QO58, can specifically activate Kv7.2 / 7.3 / M channels. Oral or intraperitoneal administration of QO58 can reverse inflammatory pain in rodent models (Acta Pharmacol Sin, Teng. 2016) and may be effective in peripheral hypertension.

[0031] Published data suggest that chemical channel openers can prevent the degeneration and progression of hearing loss in a DFNA2 mouse model by stabilizing KCNQ4-mediated conductance (Kv7.4) in hearing-related cells, which may be useful for progressive hearing loss or tinnitus (Journal of Physiology, Maljevic. 2008).

[0032] Behavioral studies have shown that SF0034 is a more effective and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. It is proposed that SF0034 not only provides a powerful tool for studying ion channel properties, but more importantly, offers a clinical candidate for the treatment of epilepsy and the prevention of tinnitus (British Journal of Pharmacology, Leithner, 2014; Journal of Neuroscience, Kalappa, 2015).

[0033] The functional roles of Kv7 channels may vary depending on cell type. Several studies have shown that damage to Kv7 channels has a strong impact on lung physiology, leading to the pathophysiology of various respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic cough, lung cancer, and pulmonary hypertension. Kv7 channels are now believed to play relevant physiological roles in many tissues, which encourages the search for Kv7 channel modulators with potential therapeutic uses in many diseases, including those affecting the lungs. Modulation of Kv7 channels has been proposed to provide beneficial effects in many lung conditions. Therefore, drugs that open / enhance Kv7 channels or act partially through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutic agents, and pulmonary vasodilators (Frontiers in Physiology, Mondejar-Parreno. 2020), as well as for obesity and disease-related hypertension (Frontiers in Cardiovascular Medicine, Fosmo. 2017).

[0034] Further research on autism and autism spectrum disorder may suggest that the administration of compounds that potentially positively regulate Kv7 channels may be effective for these neurological disorders. Data indicate that dysfunction of heterologous KV7.3 / 5 channels is associated with the pathogenesis of some forms of autism spectrum disorder, epilepsy, and possibly other mental disorders, and therefore, KCNQ3 and KCNQ5 are considered candidate genes for these disorders (Gilling, Frontiers in Genetics, 2013; Guglielmi, Frontiers in Cell Neurosci, 2015).

[0035] Several background references regarding this teaching content are cited and incorporated into this paper.

[0036] There is a need to deliver these compounds, which are capable of interacting with the Kv7.2 channel subtype, more efficiently, especially as prodrugs with improved properties in one or more aspects of the pharmacokinetic characteristics of physicochemically, biopharmaceutically, or pharmacologically effective compounds. Summary of the Invention

[0037] This disclosure provides compounds, particularly for the treatment of diseases by regulating potassium ion flux through voltage-dependent potassium channels. More specifically, this disclosure provides prodrugs, compositions, and methods of using these compounds for the treatment of central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, spasms, mood disorders, brain tumors, psychotic disorders, myofascitis, seizures, epilepsy, hearing and vision loss, dysmenorrhea, vulvar pain, dyspareunia, pain associated with endometriosis, multiple sclerosis, amyotrophic lateral sclerosis, spasms, muscle spasms, autism, Alzheimer's disease, age-related memory loss, learning disabilities, anxiety and motor neuron disease, organophosphate exposure, central and peripheral neuropathic pain symptoms), and as neuroprotective agents (e.g., prevention of stroke, spinal cord and brain injury, retinal degeneration, etc.). The compounds disclosed herein can be used as prodrugs for treating seizure states, such as grand mal seizures, absence seizures, psychomotor epilepsy, or postictal seizures. The prodrug compounds disclosed herein, when metabolized or converted into the active compounds, can also be used to treat disease states such as restless legs syndrome and postherpetic neuralgia.

[0038] Furthermore, the compounds disclosed herein can be used as prodrugs for treating pain, such as neuropathic pain, diabetic pain, inflammatory pain, cancer pain, migraine, vulvar pain, abdominal pain, and musculoskeletal pain. These compounds are also prodrugs that are metabolized in vivo to produce an active compound that can be used to treat conditions that may themselves be the source of pain, such as inflammatory conditions including arthritis conditions (e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, and gouty arthritis) and non-arthritis conditions (e.g., herniated discs, rupture and prolapse syndromes, bursitis, tendinitis, tenosynovitis, fibromyalgia syndrome, and other conditions associated with ligament sprains and regional musculoskeletal strain) as well as pain associated with neuronal demyelinating diseases. Particularly preferred compounds of this disclosure can exhibit lower central nervous system side effects, such as dizziness and drowsiness, due to more controlled release of the active drug. Furthermore, the compounds of this disclosure are prodrugs that are metabolized in vivo to compounds that can be used to treat conditions and pain associated with abnormally elevated skeletal muscle tone.

[0039] The disclosed compounds are also prodrugs for the treatment of anxiety (e.g., anxiety disorders) and depression. These disorders include separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, and anxiety disorder caused by other medical conditions.

[0040] Anxiety also occurs as a symptom associated with other mental disorders, such as obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, mood disorders, and major depressive disorder, as well as organic clinical symptoms, including but not limited to Parkinson's disease, multiple sclerosis, and another physical disability.

[0041] In view of the above findings, this disclosure provides prodrugs of compounds, compositions comprising these prodrugs, and methods for increasing ion flux in voltage-dependent potassium channels, specifically those channels responsible for M currents. As used herein, the terms “M current”, “channel responsible for M current”, etc., refer to slowly activated, non-inactivated, slowly inactivated voltage-gated potassium channels. + M-channels. M-currents are active at voltages close to the action potential generation threshold in various neuronal cells, and therefore, they are important regulators of neuronal excitability.

[0042] Members of the voltage-dependent potassium channel family have been shown to be directly involved in diseases of the central or peripheral nervous system. The prodrugs of the compounds presented herein are now shown to be metabolized and released compounds that act as potassium channel modulators, specifically openers, of KCNQ2 and KCNQ3, KCNQ4 and KCNQ5, as well as heteropolymer channels or M-currents such as KCNQ2 / 3 and KCNQ3 / 5.

[0043] One embodiment of this disclosure includes a compound of formula I:

[0044]

[0045] in

[0046] R 1 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 3-6 cycloalkyl;

[0047] R 2 It is H, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups;

[0048] Z is either N or CH;

[0049] R 3 It is "Pro", where "Pro" is selected from C(O)R. 10 The group formed;

[0050] R 10 Choose from the following groups:

[0051] Gabapentin residues; and

[0052] Pregabalin residues;

[0053] Each of R4 and R5 is H independently, or

[0054] R 4 and R 5 Together with the atoms they bond to, they form 5- to 6-membered rings, which optionally contain one or more degrees of unsaturation; and

[0055] R 6a R 6b and R 6c Each of them is independently H or a halogen, where R 6a R 6b and R 6c At least one of them is H.

[0056] Or its pharmaceutically acceptable salt.

[0057] One embodiment of this disclosure comprises a compound of formula II:

[0058]

[0059] in

[0060] R 1 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 3-6 cycloalkyl;

[0061] R 2 It is H, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups;

[0062] R 3 It is "Pro", where "Pro" is selected from C(O)R. 10 The group formed;

[0063] R 10 Choose from the following groups:

[0064] Gabapentin residues; and

[0065] Pregabalin residues;

[0066] Each of R4 and R5 is H independently, or

[0067] R 4 and R 5 Together with the atoms they bond to, they form 5- to 6-membered rings, which optionally contain one or more degrees of unsaturation; and

[0068] R 6a R 6b and R 6c Each of them is independently H or a halogen, where R 6a R 6b and R 6c At least one of them is H.

[0069] Or its pharmaceutically acceptable salt.

[0070] One embodiment of this disclosure includes a compound, wherein R 10 It is CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin or CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin.

[0071] One embodiment of this disclosure comprises a compound of formula IV:

[0072]

[0073] in

[0074] R 1 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 3-6 cycloalkyl;

[0075] R 2 It is H, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups;

[0076] Z is either N or CH;

[0077] R 10 It is a gabapentin residue or a pregabalin residue; and

[0078] Each of R4 and R5 is H independently, or

[0079] R 4 and R 5 Together with the atoms they bond to, they form 5- to 6-membered rings, which optionally contain one or more degrees of unsaturation; and

[0080] R 6a R 6b and R 6c Each of them is independently H or a halogen, where R 6a R 6b and R 6c At least one of them is H.

[0081] Or its pharmaceutically acceptable salt.

[0082] One embodiment of this disclosure includes a compound, wherein R 10 It is CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin.

[0083] One embodiment of this disclosure includes a compound, wherein R 10 CH is from Prebalin 2 CH(CH2CH(CH3)2)CH2NH2.

[0084] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof:

[0085]

[0086] One embodiment of this disclosure includes a pharmaceutical composition comprising the compounds of this disclosure and one or more pharmaceutically acceptable excipients.

[0087] One embodiment of this disclosure includes a method for inducing one or more of the following effects in a patient in need: antiepileptic, muscle relaxant, antipyretic, peripheral analgesic, or anticonvulsant, said method comprising administering an effective amount of the compound of this disclosure.

[0088] One embodiment of this disclosure includes a method for treating one or more of the following depressions: depression in cancer patients; depression in Parkinson's disease patients; post-myocardial infarction depression; depression in patients with human immunodeficiency virus (HIV); subsyndromic symptomatic depression; depression in infertile women; childhood depression; major depressive disorder; single-episode depression; recurrent depression; child abuse-induced depression; postpartum depression; DSM-IV major depressive disorder; treatment-resistant major depressive disorder; severe depression; psychotic depression; post-stroke depression; neuropathic pain; bipolar disorder, including bipolar disorder with mixed episodes and bipolar disorder with depressive episodes; seasonal affective disorder; bipolar disorder BP1; bipolar disorder BP II. Major depressive disorder or severe depression with dysphoric mood; dysphoric mood; phobias, including agoraphobia, social phobia, or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; chemical dependence, including addiction to alcohol, cocaine, amphetamines and other psychoactive substances, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including dementia, neurodepressant-induced Parkinson's disease, or tardive dyskinesia; headache, including headaches associated with vascular disease; withdrawal syndrome; age-related learning disorders. Habitual and mental disorders; emotional blunting; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorders; somatic symptom disorders, such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatic symptom NOS; incontinence; aspiration disorders; poisoning disorders; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase affective disorder; specific developmental disorders; SSRI "fecal incontinence" syndrome, or failure of a patient to maintain a satisfactory response after the initial period of satisfactory response to SSRI therapy; and tic disorders, including Tourette's disease, wherein the method comprises administering the compounds disclosed herein.

[0089] One embodiment of this disclosure includes a method for treating, improving, or preventing the progression of a disease or condition selected from the group consisting of: seizures, pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, postherpetic neuralgia, and peripheral nerve injury, drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative disorders or diseases or injuries, cognitive deficits, obsessive-compulsive behaviors, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory loss, memory impairment, memory dysfunction, activity disorders, motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinsonian kinesia, phobias, Picker's disease, psychosis, bipolar disorder, etc. Schizophrenia, schizophrenia subtypes as catatonic, paranoid, anisocytic, or residual, spinal cord injury, cardiomyopathy, arrhythmia, long QT syndrome, activity or movement disorders, myasthenia gravis, migraine, tension headache, intestinal disorders, inflammatory diseases, ulcerative colitis, Crohn's disease, Croutzfeld-Jacob disease, ophthalmic symptoms, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes or metastatic tumor growth, pneumoconiosis such as aluminosis, coal mine pneumoconiosis, asbestosis, stone pneumoconiosis, ostrich pneumoconiosis, iron pneumoconiosis, silicosis, smoke pneumoconiosis and cotton pneumoconiosis, as well as chronic obstructive pulmonary disease (COPD), obesity, and disease-related hypertension, the method comprising administering the compounds disclosed herein.

[0090] One embodiment of this disclosure includes a method for treating one or more movement disorders selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / movement disorder, tardive dystonia, neurodepressant-induced dystonia, treatment-induced dystonia / movement disorder in patients with Parkinson's disease, hereditary degenerative dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette syndrome, dystonia in patients with restless legs syndrome, dystonia-like symptoms in patients with tics, dystonia-related movement disorders, paroxysmal movement disorders, paroxysmal nonmotor movement disorders, paroxysmal dystonia-choreoathetosis, paroxysmal kinesiology, paroxysmal kinesiology-choreoathetosis, movement-induced movement disorders, sleep-related paroxysmal movement disorders, drug-induced movement disorders, myofascitis, neurogenic myotonia, autism, and autism spectrum disorders, the method comprising administering a compound of this disclosure.

[0091] One embodiment of this disclosure includes a method of delivering a broad-spectrum Kv7.2-7.5 active molecule into systemic circulation and releasing an effective concentration of the active Kv channel opener at a therapeutic concentration to treat one or more susceptible diseases or conditions, the method comprising administering a compound of this disclosure. In one aspect, the release of the active molecule is provided under one or more of the following conditions:

[0092] Enhanced by increasing absorption;

[0093] Delaying the onset time to improve adverse events occurring during treatment; and

[0094] Increase half-life or dwell time by delaying the cycle and releasing.

[0095] Therefore, the necessity of developing improved, sustained, delayed, or slow-release formulations is denied.

[0096] One embodiment of this disclosure includes a method for enhancing chemical stability and reducing impurities and degradation products during the preparation of pharmaceutical substances and pharmaceutical products, thereby improving the use and tolerability of the drugs.

[0097] One embodiment of this disclosure includes the use of a compound of this disclosure for the preparation of a medicament to induce one or more of the following effects in a patient in need: antiepileptic, muscle relaxant, antipyretic, peripheral analgesic, or anticonvulsant.

[0098] One embodiment of this disclosure includes the use of a compound of this disclosure for the preparation of a medicament to treat one or more of the following depressions: depression in cancer patients; depression in Parkinson's disease patients; post-myocardial infarction depression; depression in patients with human immunodeficiency virus (HIV); subsyndromic symptomatic depression; depression in infertile women; childhood depression; major depressive disorder; single episode depression; recurrent depression; child abuse-induced depression; postpartum depression; DSM-IV major depressive disorder; treatment-resistant major depressive disorder; severe depression; psychotic depression; post-stroke depression; neuropathic pain; bipolar disorder, including bipolar disorder with mixed episodes and bipolar disorder with depressive episodes; seasonal affective disorder; bipolar disorder BP I; bipolar disorder BP II. Major depressive disorder or severe depression with dysphoric mood; dysphoric mood; phobias, including agoraphobia, social phobia, or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; chemical dependence, including addiction to alcohol, cocaine, amphetamines and other psychoactive substances, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including dementia, neurodepressant-induced Parkinson's disease, or tardive dyskinesia; headache, including headaches associated with vascular disease; withdrawal syndrome; and other conditions related to age. Age-related learning and mental disorders; emotional blunting; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorders; somatic symptom disorders, such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatic symptom NOS; incontinence; aspiration disorders; poisoning disorders; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase affective disorder; specific developmental disorders; SSRI "fecal incontinence" syndrome, or failure to maintain a satisfactory response after the initial period of satisfactory response to SSRI therapy; and tic disorders, including Tourette's disease.

[0099] One embodiment of this disclosure includes the use of a compound of this disclosure for the preparation of a medicament to treat, improve, or prevent the progression of a disease or condition selected from the group consisting of: seizures, pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, postherpetic neuralgia, and peripheral nerve injury, drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative disorders or diseases or injuries, cognitive deficits, obsessive-compulsive behaviors, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory loss, memory impairment, memory dysfunction, activity disorders, motor disorders, neurodegenerative diseases, Parkinson's disease, and Parkinsonian kinesia. Disorders, phobias, Pick's disease, psychosis, bipolar disorder, schizophrenia, schizophrenia subtypes as catatonic, paranoid, disorganized, or residual, spinal cord injury, cardiomyopathy, arrhythmia, long QT syndrome, activity or movement disorders, myasthenia gravis, migraine, tension headache, intestinal disorders, inflammatory diseases, ulcerative colitis, Crohn's disease, Croutzfeld-Jacob disease, ophthalmic symptoms, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes or metastatic tumor growth, pneumoconiosis such as aluminosis, coal mine pneumoconiosis, asbestosis, stone pneumoconiosis, ostrich feather pneumoconiosis, iron pneumoconiosis, silicosis, smoke pneumoconiosis and cotton pneumoconiosis, as well as chronic obstructive pulmonary disease (COPD), obesity, and disease-related hypertension.

[0100] One embodiment of this disclosure includes the use of a compound of this disclosure for preparing a medicament to treat one or more movement disorders selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / movement disorder, tardive dystonia, neurodepressant-induced dystonia, treatment-induced dystonia / movement disorder in patients with Parkinson's disease, hereditary degenerative dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette syndrome, dystonia in patients with restless legs syndrome, dystonia-like symptoms in patients with tics, dystonia-related movement disorders, paroxysmal movement disorders, paroxysmal nonmotor movement disorders, paroxysmal dystonia-choreoathetosis, paroxysmal kinesiology, paroxysmal kinesiology-choreoathetosis, movement-induced movement disorders, sleep-related paroxysmal movement disorders, drug-induced movement disorders, myofascitis, neurogenic myotonia, autism, and autism spectrum disorders.

[0101] One embodiment of this disclosure includes the use of a compound of this disclosure for preparing a medicament to deliver a broad-spectrum Kv7.2-7.5 active molecule into systemic circulation and to release an effective concentration of the active Kv channel opener at a therapeutic concentration to treat one or more susceptible diseases or conditions. In one aspect, the release of the active molecule is provided under one or more of the following conditions:

[0102] Enhanced absorption through clinical administration;

[0103] Delaying the onset time to improve adverse events occurring during treatment; and

[0104] Increase half-life or dwell time by delaying the cycle and releasing.

[0105] Therefore, the necessity of developing improved, sustained, delayed, or slow-release formulations is denied.

[0106] One embodiment of this disclosure includes compounds of this disclosure, said compounds being used to induce one or more of the following effects in a patient in need: antiepileptic, muscle relaxant, antipyretic, peripheral analgesic, or anticonvulsant.

[0107] One embodiment of this disclosure includes compounds of this disclosure for treating one or more of the following depressions: depression in cancer patients; depression in Parkinson's disease patients; post-myocardial infarction depression; depression in patients with human immunodeficiency virus (HIV); subsyndromic symptomatic depression; depression in infertile women; childhood depression; major depressive disorder; single episode depression; recurrent depression; child abuse-induced depression; postpartum depression; DSM-IV major depressive disorder; treatment-resistant major depressive disorder; severe depression; psychotic depression; post-stroke depression; neuropathic pain; bipolar disorder, including bipolar disorder with mixed episodes and bipolar disorder with depressive episodes; seasonal affective disorder; bipolar disorder BP1; bipolar disorder BP II. Major depressive disorder or severe depression with dysphoric mood; dysphoric mood; phobias, including agoraphobia, social phobia, or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; chemical dependence, including addiction to alcohol, cocaine, amphetamines and other psychoactive substances, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including dementia, neurodepressant-induced Parkinson's disease, or tardive dyskinesia; headache, including headaches associated with vascular disease; withdrawal syndrome; and other conditions related to age. Age-related learning and mental disorders; emotional blunting; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorders; somatic symptom disorders, such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatic symptom NOS; incontinence; aspiration disorders; poisoning disorders; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase affective disorder; specific developmental disorders; SSRI "fecal incontinence" syndrome, or failure to maintain a satisfactory response after the initial period of satisfactory response to SSRI therapy; and tic disorders, including Tourette's disease.

[0108] One embodiment of this disclosure includes compounds of this disclosure for treating, improving, or preventing the progression of a disease or condition selected from the group consisting of: seizures, pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, postherpetic neuralgia, and peripheral nerve injury, drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative disorders or diseases or injuries, cognitive deficits, obsessive-compulsive behaviors, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory loss, memory impairment, memory dysfunction, activity disorders, motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinsonian dyskinesia, etc. Phobias, Picker's disease, psychosis, bipolar disorder, schizophrenia, schizophrenia subtypes as catatonic, paranoid, disorganized, or residual, spinal cord injury, cardiomyopathy, arrhythmia, long QT syndrome, activity or movement disorders, myasthenia gravis, migraine, tension headache, intestinal disorders, inflammatory diseases, ulcerative colitis, Crohn's disease, Croutzfeld-Jacob disease, ophthalmic symptoms, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes or metastatic tumor growth, pneumoconiosis such as aluminosis, coal mine pneumoconiosis, asbestosis, stone pneumoconiosis, ostrich feather pneumoconiosis, iron pneumoconiosis, silicosis, smoke pneumoconiosis and cotton pneumoconiosis, as well as chronic obstructive pulmonary disease (COPD), obesity, and disease-related hypertension.

[0109] One embodiment of this disclosure includes compounds of this disclosure for treating one or more movement disorders selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / movement disorder, tardive dystonia, neurodepressant-induced dystonia, treatment-induced dystonia / movement disorder in patients with Parkinson's disease, hereditary degenerative dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette syndrome, dystonia in patients with restless legs syndrome, dystonia-like symptoms in patients with tics, dystonia-related movement disorders, paroxysmal movement disorders, paroxysmal nonmotor movement disorders, paroxysmal dystonia-choreoathetosis, paroxysmal kinesiology, paroxysmal kinesiology-choreoathetosis, movement-induced movement disorders, sleep-related paroxysmal movement disorders, drug-induced movement disorders, myofascitis, neurogenic myotonia, autism, and autism spectrum disorders.

[0110] One embodiment of this disclosure includes compounds for delivering a broad-spectrum Kv7.2-7.5 active molecule into systemic circulation and releasing an effective concentration of the active Kv channel opener at a therapeutic concentration to treat one or more susceptible diseases or conditions. In one aspect, the release of the active molecule is provided under one or more of the following conditions:

[0111] Enhanced by increasing absorption;

[0112] Delaying the onset time to improve adverse events occurring during treatment; and

[0113] Increase half-life or dwell time by delaying the cycle and releasing.

[0114] Therefore, the necessity of developing improved, sustained, delayed, or slow-release formulations is denied.

[0115] One or more aspects and embodiments may be incorporated into different embodiments, although not specifically described. That is, all aspects and embodiments may be combined in any manner or combination. Attached Figure Description

[0116] Figure 1 This is a graphical representation of the stability and solubility test results of compound 3 over 3 to 7 days.

[0117] Figure 2 This is a graphical representation of the stability test of compound 4 over 4 days.

[0118] Figure 3 This is a graphical representation of the in vitro plasma stability test of compound 3 in mice and rats at 37°C.

[0119] Figure 4 This is a graphical representation of the in vitro plasma stability test of compound 4 in mice and rats at 37°C.

[0120] Figure 5A and Figure 5B Each of these figures is a graphical representation of the linear and semi-logarithmic plots of compounds 1 and 4 after administration of compound 4 at 100 mg / kg SC in male mice.

[0121] Figure 6 This is a graphical representation of the semi-logarithmic graph of compound 1 after oral administration of compound 1 at 20 mg / kg, compound 3 at 30 mg / kg, or compound 4 at 30 mg / kg in male mice.

[0122] Figure 7This is a graphical representation of the semi-logarithmic graphs of N-acetyl metabolites after oral administration of compound 1 at 20 mg / kg, compound 3 at 30 mg / kg, or compound 4 at 30 mg / kg in male mice.

[0123] Figure 8 This is a graphical representation of the semi-logarithmic plots of compounds 1 and 4 after administration of compound 4 at 75 mg / kg IM in male rats.

[0124] Figure 9 This is a semi-logarithmic graph of compound 1 administered orally in male Sprague-Dowley rats after administration of compound 1 at 20 mg / kg, compound 3 at 30 mg / kg, or compound 4 at 30 mg / kg.

[0125] Figure 10 This is a graphical representation of the semi-logarithmic graphs of N-acetyl metabolites after oral administration of compound 1 at 20 mg / kg, compound 3 at 30 mg / kg, or compound 4 at 30 mg / kg in male mice.

[0126] Figure 11 This is a graphical representation of the in vitro screening of Kv7.2 / 7.3 voltage-gated potassium channels.

[0127] Figure 12 This is a graphical representation of the test within the CF-1 mouse maximum electric shock (MES) test.

[0128] Figure 13 This is a graphical representation of the CF-1 concentration of compound 1 in mice.

[0129] Figure 14 This is a graphical illustration of the protective effect of compound 4 against MES-induced seizures in SD rats after IM administration.

[0130] Figure 15 This is a table showing the dose-related response of XYZ-203 / compound 3 from a CCI model of neuropathic pain.

[0131] Figure 16 This is a graphical representation of the results from the CCI model of neuropathic pain using XYZ-203 (compound 3).

[0132] Figure 17 This is a graphical representation of the results from the CCI model of neuropathic pain using XYZ-203 (compound 3).

[0133] Figure 18 This is a graphic illustration of a mouse twitching or licking its hind paw after an intrapedis injection of 5% formalin.

[0134] Figure 19 This is a graphical representation of compounds 4, 6, and 2 administered in male cannulated rats with the same formulation (0.5% methylcellulose in water) at equimolar doses as ezogabine (20 mg / kg).

[0135] Figure 20 The graph depicts the concentrations (ng / mL) of compound 28 and ezogabine at various dosage groups and their MES protection.

[0136] Figure 21 This is a graphical depiction of the concentrations (ng / mL) of compound 28, ezogabine, and pregabalin at 0.5 hours after a dose of 24 mg / kg.

[0137] Figure 22 This is a graphical depiction of the concentrations (ng / mL) of compound 28 and ezogabine over 24 hours.

[0138] Figure 23 This is a graphical representation of the concentrations of ezogabine in the brain and plasma of mice after administration of compound 29, as determined by MES. Detailed Implementation

[0139] As used herein, "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms. The hydrocarbon chain can be straight-chain or branched. Illustrative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "alkenyl" refers to an alkyl group having one or more double bonds present in the chain, and "alkynyl" refers to an alkyl group having one or more triple bonds present in the chain.

[0140] As used herein, "halogen" or "halogenated" refers to a halogen. In some embodiments, the halogen is preferably Br, Cl, or F.

[0141] As used herein, “haloalkyl” refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms, wherein at least one hydrogen atom is substituted by a halogen, including but not limited to fully halogenated groups in which all hydrogen atoms are substituted by halogen atoms. The haloalkyl chain can be straight-chain or branched. Illustrative alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, “haloalkenyl” refers to a haloalkyl group having one or more double bonds present in the chain, and “haloalkynyl” refers to a haloalkyl group having one or more triple bonds present in the chain. Furthermore, the “alkylene” linker group refers to a divalent alkyl group, i.e., (CH2). x , where x is 1 to 20, preferably 1 to 8, preferably 1 to 6, and more preferably 1 to 3.

[0142] The term "haloalkoxy" refers to O-haloalkyl.

[0143] As used herein, “alkoxy” refers to an O-alkyl group having a specified number of carbon atoms.

[0144] "alkylene" is an alkyl group as defined above, positioned between and used to connect two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0145] The term “heteroalkyl” refers to an alkyl group as defined above, wherein one or more carbon atoms in the chain are replaced by heteroatoms selected from the group consisting of O, S and N, such as NH or NR', where R' is a general indicator of a non-hydrogen group.

[0146] As used herein, “hydroxyalkyl” means an alkyl group substituted with one or more -OH groups as defined herein. Similarly, “hydroxyenyl” means a hydroxyalkyl group having one or more double bonds present in the chain, and “hydroxyynyl” means a hydroxyalkyl group having one or more triple bonds present in the chain. Likewise, “dihydroxyalkyl” also provides two -OH substituents.

[0147] The term "alkylamine" refers to NR x -alkyl, wherein R x It is hydrogen.

[0148] The term "dialkylamino" refers to N(R) y )2, where each R y It is independently a C1-C3 alkyl group.

[0149] The term "alkylaminoalkyl" refers to alkyl-NR x -alkyl, wherein R x It is hydrogen.

[0150] The term "dialkylaminoalkyl" refers to alkyl-N(R) y )2, where each R y Independently, they are C1-C4 alkyl groups, wherein the alkyl-N(R) y The alkyl group of 2 is an alkyl group as defined above and may optionally be substituted with a hydroxyl group or a hydroxyalkyl group.

[0151] As used herein, "aryl" refers to a substituted or unsubstituted carbocyclic aromatic ring system, whether side-chain or fused, such as phenyl, naphthyl, anthracene, phenanthryl, tetrahydronaphthyl, indene, or biphenyl. Phenyl is preferred.

[0152] "Arylalkyl" or "arylalkyl" includes an aryl group covalently linked to an alkyl group as defined above, any of which may be independently and optionally substituted or unsubstituted. Examples of arylalkyl groups are (C1-C6)alkyl (C6-C6)alkyl groups. 10 Aryl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl. Examples of substituted aralkyl groups are those in which the alkyl group is replaced by a hydroxyalkyl group.

[0153] As used herein, “cycloalkyl” refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms. Illustrative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and their partially saturated forms, such as cyclohexenyl and cyclohexadienyl. Furthermore, bridged rings, such as adamantane, are also included within the definition of “cycloalkyl”.

[0154] As used herein, the term "heterocyclic group" refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms, wherein one or more carbon atoms are replaced by heteroatoms selected from O, N, or S, wherein each N, S, or Si may be oxidized, and wherein each N may be quaternized. Heterocyclic groups can be attached to the rest of the molecule via heteroatoms. Heterocyclic groups do not contain heteroaryl groups.

[0155] The term “heterocyclic alkyl” refers to a heterocyclic group covalently linked to an alkyl group as defined herein, wherein the radical is on the alkyl group, and wherein the alkyl group of the heterocyclic alkyl group may optionally be substituted with a hydroxyl or hydroxyalkyl group.

[0156] As used herein, the term "heteroaryl" or "heteroaromatic" refers to an aromatic cyclic group having 5 to 14 ring atoms selected from carbon and at least one (usually 1 to 4, more usually 1 or 2) heteroatoms (e.g., oxygen, nitrogen, sulfur, or silicon). It includes monocyclic and polycyclic forms, wherein a monocyclic heteroaromatic ring is fused with one or more other carbocyclic aromatic rings or heteroaromatic rings. Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazoleyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), and pyrroleyl (…). Examples of monocyclic six-membered nitrogen-containing heteroaryl groups include pyrimidinyl, pyridinyl, and pyridinyl groups. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothiophene, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinel, or benzoisooxazolyl.

[0157] The terms “aralkyl,” “heteroaryl,” and “heterocyclic alkyl” refer to those groups in which an aryl, heteroaryl, or heterocyclic group is linked by an alkyl group. Examples include benzyl, phenethyl, pyridylmethyl, etc. The terms also include alkyl-linking groups in which a carbon atom, for example, a methylene group, has been replaced, for example, by an oxygen atom. Examples include phenoxymethyl, pyridin-2-yloxymethyl, and 3-(naphth-1-yloxy)propyl, etc. Similarly, as used herein, the term “benzyl” is a group in which a phenyl group is linked to a CH2 group, and therefore to a CH2Ph ​​group. Benzyl can be substituted or unsubstituted. The term substituted benzyl refers to a radical in which the phenyl or CH2 group contains one or more substituents. In one embodiment, the phenyl group may have 1 to 5 substituents, or in another embodiment, 2 to 3 substituents.

[0158] "Heteroarylalkyl" includes a heteroaryl group covalently linked to an alkyl group, wherein the radical is located on the alkyl group, and either group is independently and optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroarylalkyl groups include pyridylmethyl, pyridylethyl, pyrrolithylmethyl, pyrrolithylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indololinylethyl, isoquinolinylmethyl, isoindolylmethyl, cenylmethyl, and benzothiophenylethyl. The scope of this term specifically excludes compounds having adjacent cyclic O and / or S atoms.

[0159] As used herein, “optionally substituted” refers to the substitution of hydrogen atoms, which would otherwise be present in relation to the substituents. When discussing cyclic systems, optional substitution typically involves replacing the normally present hydrogen with one, two, or three substituents. However, when dealing with straight-chain and branched portions, the number of substitutions can be greater, occurring wherever hydrogen is present. The substitutions can be the same or different.

[0160] The illustrative substituents, which may be the same or different, include halogens, haloalkyl groups, R', OR', OH, SH, SR', NO2, CN, C(O)R', C(O) (where the alkyl group is substituted by one or more of halogens, haloalkyl groups, NH2, OH, SH, CN, and NO2), C(O)OR', OC(O)R', CON(R')2, OC(O)N(R')2, NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', and NRCOH. NHCO2H, NHCO2R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2, S(O)2H, S(O)2R', SO2NH2, S(O)H, S(O)R', SO2NHR', SO2N(R')2, NHS(O)2H, NR'S(O)2H, NHS(O)2R', NR'S(O)2R', Si(R')3, wherein each of the preceding terms can be connected via a divalent alkylene linker (CH2). xThe connection is specified, where x is 1, 2, or 3. In embodiments where the saturated carbon atom is optionally substituted with one or more substituents, the substituents may be the same or different, and may also include =O, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO2R', =NNHCO2H, =NNHSO2R', =NNHSO2H, =N-CN, =NH, or =NR'. For each of the preceding, each may be connected via an alkylene linker (CH2). x The connection is where x is 1, 2, or 3... Each occurrence of R' is the same or different, and represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl, or when two R's are each connected to a nitrogen atom, they can form a saturated or unsaturated heterocycle containing 4 to 6 ring atoms.

[0161] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of a target. This amount may be administered as a single dose or according to a prescribed regimen, thereby being effective.

[0162] As used herein, a "therapeuticly effective amount" of a compound is an amount sufficient to improve or alleviate symptoms in some way, or to stop or reverse disease progression, or to negatively regulate or inhibit the activity of a target. This amount may be administered as a single dose or according to a prescribed regimen, thereby being effective.

[0163] As used herein, treatment means any manner in which symptoms, signs, or pathology of a disease are improved or otherwise beneficially altered. Treatment also covers any pharmaceutical use of the compositions described herein.

[0164] As used herein, improvement of symptoms of a particular condition by application of a particular pharmaceutical composition means any relief that can be attributed to or associated with the application of the composition, whether permanent or temporary, persistent or transient.

[0165] As used herein, the term “about” when used to modify numerically defined parameters (e.g., the dose of an inhibitor detailed herein or a pharmaceutically acceptable salt thereof, or the duration of treatment described herein) means that the parameter may vary by as much as 25%, 20%, 15%, 10%, or 5% below or above the stated value of the parameter. For example, a dose of about 5 mg / kg may vary between 3.75 mg / kg and 6.25 mg / kg. When “about” is used at the beginning of a list of parameters, it means that each parameter is modified. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more mean about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.

[0166] As used herein, salt means any salt of the compounds disclosed herein that retains its biological properties and is not toxic or otherwise intended for pharmaceutical use.

[0167] Such salts can be derived from a variety of organic and inorganic counterions known in the art. These salts comprise acid addition salts formed using organic or inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfonamide acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauryl acid. Acids, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylaminosulfonic acid, quinic acid, mucoconic acid and similar acids.

[0168] For example, salts further include salts of non-toxic organic or inorganic acids, such as halides (e.g., chlorides and bromides), sulfates, phosphates, aminosulfonates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbic acid salts, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, and methanesulfonates. (nate / mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphor sulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, gluconate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthalate, salicylate, stearate, cyclohexylaminosulfonate, quinic acid salt, mucoconate, etc.

[0169] Examples of inorganic bases that can be used to form base addition salts include, but are not limited to, metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal amides such as lithium amide and sodium amide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; and ammonium bases such as ammonium hydroxide and ammonium carbonate.

[0170] Examples of organic bases that can be used to form base addition salts include, but are not limited to, metal alkoxides, such as lithium alkoxides, sodium alkoxides, and potassium alkoxides, including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; quaternary ammonium bases, such as choline hydroxide; and amines, including, but not limited to, aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines.

[0171] The base may be a quaternary ammonium hydroxide, wherein one or more of the alkyl groups of the quaternary ammonium ion are optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is substituted with one or more hydroxyl groups. Non-limiting examples of quaternary ammonium hydroxides that may be used according to this disclosure include choline hydroxide, trimethylethylammonium hydroxide, tetramethylammonium hydroxide, and preferably choline hydroxide. Alkylamine bases may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases that may be used according to this disclosure include methylamine, ethylamine, diethylamine, and triethylamine. Substituted alkylamine bases may be substituted with one or more hydroxyl groups, and preferably with one to three hydroxyl groups. Non-limiting examples of substituted alkylamine bases that may be used according to this disclosure include 2-(diethylamino)ethanol, N,N-dimethylethanolamine (de-alcoholized), tromethamine, ethanolamine, and diethanolamine.

[0172] In some cases, the described substituents can contribute to optical isomers and / or stereoisomers. Compounds with the same molecular formula but differing atomic bonding properties or sequences, or spatial arrangements of their atoms, are called "isomers." Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and those that are mirror images of each other without overlapping are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Molecules having at least one stereocenter can be characterized by the absolute configuration of their asymmetric center and are named (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angewandte Chemie 78:413-447, Angewandte Chemie International Edition 5:385-414 (Errata: Angewandte Chemie International Edition 5:511) (Prelog and Helmchen, 1982, Angewandte Chemie 94:614-631, Angewandte Chemie International Edition 21:567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4:657-668), or can be characterized by rotating the molecular plane of polarized light and designated as dextrorotatory or levorotatory (i.e., (+)- or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are called "racemic mixtures".

[0173] In some embodiments, the compounds disclosed herein may have one or more asymmetric centers, and such compounds may therefore be produced as racemic mixtures, mixtures enriched with enantiomers, or as individual enantiomers. Unless otherwise specified, e.g., by designating stereochemistry at any point in the formula, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers or racemic mixtures or other mixtures thereof. Methods for determining stereochemistry and the separation of stereoisomers are known in the art.

[0174] In some embodiments, the compounds disclosed herein are “stereochemically pure.” A stereochemically pure compound has a level of stereochemical purity that would be considered “pure” by someone skilled in the art. Of course, this level of purity can be less than 100%. In some embodiments, “stereochemically pure” specifies a compound that is substantially free of (i.e., at least about 85% or more) alternative isomers. In specific embodiments, the compound is free of at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9% of other isomers.

[0175] As used herein, the terms “subject” and “patient” may be used interchangeably. In one embodiment, the subject is a human. In one embodiment, the subject is a companion animal, such as a dog or cat. In another embodiment, the subject is an animal, such as a sheep, cow, horse, goat, fish, pig, or poultry (e.g., chicken, turkey, duck, or goose). In yet another embodiment, the subject is a primate, such as a monkey, such as a macaque or chimpanzee.

[0176] I. Regulators of voltage-dependent potassium channels

[0177] Compound 1 is a potassium ion channel modulator.

[0178]

[0179]

[0180] This disclosure provides novel prodrugs that are metabolized in vivo to release potassium ion channel modulators, such as the prodrug proposed as compound 1; specifically, novel prodrugs of compounds that effectively regulate the release of KCNQ according to the formula of this disclosure.

[0181] The embodiments of this disclosure include:

[0182]

[0183] R 1 It is C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkyl-C 3-6 cycloalkyl;

[0184] R 2 It is H, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups;

[0185] R 3 It is “Pro”, as described in this article, referring to the prodrug portion;

[0186] Each of R4 and R5 is H independently, or

[0187] R 4 and R 5 Together with the atoms they bond to, they form 5- to 6-membered rings, which optionally contain one or more degrees of unsaturation; and

[0188] R 6a R 6b and R 6c Each of them is independently H or a halogen, where R 6a R 6b and R 6c At least one of them is H.

[0189] Or its pharmaceutically acceptable salt.

[0190] Where C 1-3 The haloalkoxy group is -OCF3, -OCF2H, -OCFH2, -OC2F5, -OC2F4H, -OC2F3H2, -OC2F2H3, -OC2FH4, -OC3F7, -OC3F6H, -OC3F5H2, -OC3F4H3, -OC3F3H4, -OC3F2H5, or -OC3FH6.

[0191] In one embodiment, the variable "Pro" is selected from C(O)R. 10 The group consisting of R 10 yes

[0192] Alkylamine-containing residues, such as the alkylamine moiety derived from naturally occurring L-amino acids or D-amino acids; or

[0193] glycine; or

[0194] Theanine, gabapentin, or the alkylamine portion of pregabalin; or

[0195] Where R 10 Selected from hydrolyzable prodrug moieties, such as those found in groups having the following structure: -C(O)OL1 OC(O)R 11 ;and

[0196] Where R 11 It is C1-C 10 Alkyl, Bn, t-Bu, other substituted or unsubstituted C3-C 10 Secondary or tertiary alkyl groups; or Ar; and

[0197] L 1 It is C1-C 10 Branched or chain-like alkylene groups, wherein L 1 The two oxygen atoms on L 1 On the same carbon atom (i.e., the divalent alkyl group that forms a ketal or acetal-like moiety).

[0198] One embodiment of this disclosure includes a compound of formula I:

[0199]

[0200] in

[0201] R 1 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 3-6 cycloalkyl;

[0202] R 2 It is H, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups;

[0203] Z is either N or CH;

[0204] R 3 It is "Pro", where "Pro" is selected from C(O)R. 10 The group formed;

[0205] R 10 Choose from the following groups:

[0206] a) Alkylamine-containing residues, such as the alkylamine moiety of naturally occurring L-amino acids or D-amino acids; or

[0207] b) Glycine residues;

[0208] c) Theanine residues;

[0209] d) Gabapentin residues;

[0210] e) pregabalin residues; and

[0211] f) Selected from structure C(O)OL 1 OC(O)R 11 The hydrolyzable prodrug fraction, of which

[0212] R 11 It is unsubstituted or substituted C1-C 10 Alkyl, aryl, C1-C 10 Aryl alkyl groups;

[0213] L 1 It is C1-C 10 Alkylene, wherein is described as being attached to L 1 The two oxygen atoms in L 1 On the same carbon atom (i.e., the divalent alkyl group that forms a ketal or acetal-like moiety).

[0214] R is an alkylamine derived from naturally occurring amino acids. 10 Examples are as follows:

[0215] (CH2)-NH2 from glycine

[0216] CH(CH3)-NH2 from alanine

[0217] CH(CH(CH3)2)-NH2 from valine

[0218] CH(CH2CH(CH3)2)-NH2 from leucine

[0219] CH(CH(CH3)CH2CH3)-NH2 from isoleucine

[0220] CH(CH2Ph)-NH2 from phenylalanine

[0221] The ring-CHCH2CH2CH2NH- from proline,

[0222] CH(CH2OH)-NH2 from serine

[0223] CH(CH(OH)CH3)-NH2 from threonine

[0224] CH(CH2(PhOH))-NH2 from tyrosine

[0225] CH(CH2SH)-NH2 from cysteine

[0226] CH(CH2CH2SCH3)-NH2 from methionine

[0227] CH(CH2CH2CH2CH2NH2)-NH2 from lysine

[0228] CH(CH2CH2CH2NHC(NH)NH2)-NH2, derived from arginine

[0229] CH(CH2(C3N2H3))NH2 from histidine

[0230] CH(CH2-indole-3-yl)NH2 derived from tryptophan

[0231] CH(CH2CO2H)-NH2 from aspartic acid

[0232] CH(CH2CH2CO2H)-NH2 from glutamic acid

[0233] CH(CH2CONH2)-NH2 from asparagine and

[0234] CH(CH2CH2CONH2)-NH2 derived from glutamine or

[0235] CH(CH2CH2CONHCH2CH3)-NH2 derived from theanine or

[0236] CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin or

[0237] CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin;

[0238] Alkylamine moieties derived from the D or S isomers of the aforementioned amino acids are also examples of alkylamine moieties derived from amino acids considered in this disclosure;

[0239] Each of R4 and R5 is H independently, or

[0240] R 4 and R 5 Together with the atoms they bond to, they form 5- to 6-membered rings, which optionally contain one or more degrees of unsaturation; and

[0241] R 6a R 6b and R 6c Each of them is independently H or a halogen, where R 6a R 6b and R 6c At least one of them is H.

[0242] Or its pharmaceutically acceptable salt.

[0243] In other exemplary embodiments, this disclosure provides a prodrug according to Formula III, and more specifically according to Formula III-A, and specifically according to compound 3:

[0244]

[0245] R 1 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 3-6 cycloalkyl;

[0246] R 2 It is H, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups;

[0247] Z is either N or CH;

[0248] R 3 It is "Pro", as defined in this article as the prodrug portion;

[0249] Each of R4 and R5 is H independently, or

[0250] R 4 and R 5 Together with the atoms they bond to, they form 5- to 6-membered rings, which optionally contain one or more degrees of unsaturation; and

[0251] R 6a R 6b and R 6c Each of them is independently H or a halogen, where R 6a R 6b and R 6c At least one of them is H.

[0252] R 7 It is C 1-6 Alkyl (as described herein, including branched or straight chains), phenyl, or C 1-2 Alkyl-phenyl

[0253] Or its pharmaceutically acceptable salt.

[0254] One embodiment of this disclosure includes

[0255]

[0256] L 1 It is C1-C 10 Branched or chain-like alkylene groups, wherein L 1 The two oxygen atoms on L 1 On the same carbon atom (i.e., the divalent alkyl group that forms a ketal or acetal-like moiety).

[0257] One embodiment of this disclosure includes

[0258]

[0259] In another exemplary embodiment, this disclosure provides a prodrug compound having formula IV, and more specifically formula IV-A, and specifically compound 4:

[0260]

[0261] R 1 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 3-6 cycloalkyl;

[0262] R 2 It is H, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups;

[0263] Z is either N or CH;

[0264] R 3 It is “Pro”, as described in this article, referring to the prodrug portion;

[0265] Each of R4 and R5 is H independently, or

[0266] R 4 and R 5 Together with the atoms they bond to, they form 5- to 6-membered rings, which optionally contain one or more degrees of unsaturation; and

[0267] R 6a R 6b and R 6c Each of them is independently H or a halogen, where R 6a R 6b and R 6c At least one of them is H.

[0268] R 10Alkylamines derived from naturally occurring amino acids include: -(CH2)-NH2 from glycine, -CH(CH3)-NH2 from alanine, -CH(CH(CH3)2)-NH2 from valine, -CH(CH2CH(CH3)2)-NH2 from leucine, -CH(CH(CH3)CH2CH3)-NH2 from isoleucine, -CH(CH2Ph)-NH2 from phenylalanine, cyclic -CHCH2CH2CH2NH- from proline, -CH(CH2OH)-NH2 from serine, -CH(CH(OH)CH3)-NH2 from threonine, -CH(CH2(PhOH))-NH2 from tyrosine, -CH(CH2SH)-NH2 from cysteine, -CH(CH2CH2SCH3)-NH2 from methionine, and -CH(CH2CH2CH2CH2NH2)-NH2 from lysine. -CH(CH2CH2CH2NHC(NH)NH2)-NH2 from arginine, -CH(CH2(C3N2H3))NH2 from histidine, CH(CH2-indol-3-yl)NH2 from tryptophan, -CH(CH2CO2H)-NH2 from aspartic acid, -CH(CH2CH2CO2H)-NH2 from glutamic acid, -CH(CH2CONH2)-NH2 from asparagine, and -CH(CH2CH2CONH2)-NH2 from glutamine; or -CH(CH2CH2CONHCH2CH3)-NH2 from theanine, or –CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin, or –CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin; alkylamine moieties from the D isomers of the above amino acids are also examples of alkylamine moieties derived from amino acids considered in this disclosure;

[0269] Or its pharmaceutically acceptable salt.

[0270] One embodiment of this disclosure includes:

[0271]

[0272] The dashed bonds depicted are any enantiomers.

[0273] One embodiment of this disclosure comprises a compound having a pharmaceutically acceptable salt thereof:

[0274]

[0275] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof:

[0276]

[0277] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof:

[0278]

[0279] One embodiment of this disclosure includes a compound, wherein R 10 It is CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin or CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin.

[0280] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof:

[0281]

[0282] II. Determination of Kv7 channel modulators

[0283] The Kv7 channel was previously identified as the KCNQ channel and is the same channel. Determinations used to identify active molecules, i.e., orthoallosteric modulators, that maintain the Kv7 channel in an open-position state with a high probability are generally well known in the art. Those skilled in the art can determine appropriate determinations for studying the activity of selected compounds of this disclosure for specific ion channels. For simplicity, the following discussion focuses in part on Kv7.2 (KCNQ2) as a representative example; however, the discussion is equally applicable to other Kv7 subtype potassium ion channels.

[0284] The KCNQ (Kv7) monomer, along with KCNQ alleles and polymorphic variants, are subunits of potassium channels. The activity of potassium channels including the KCNQ subunit can be assessed using a variety of in vitro and in vivo assays, such as measuring current, membrane potential, ion flux (e.g., potassium or rubidium), potassium concentration, second messenger and transcriptional levels, potassium-dependent yeast growth assays, and using, for example, voltage-sensitive dyes, radiotracers, and patch-clamp electrophysiology.

[0285] Furthermore, such assays can be used to test inhibitors and activators of channels including KCNQ. These potassium channel modulators can be used to treat a variety of conditions involving potassium channels, including, but not limited to, central and peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, spasms, mood disorders, brain tumors, psychotic disorders, myofascitis, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning disabilities, anxiety, and motor neuron disease), and can also be used as neuroprotective agents (e.g., to prevent stroke). These modulators can also be used to study the diversity of channels provided by KCNQ and to regulate / modulate the potassium channel activity provided by KCNQ. Prodrugs metabolized in mammals or cells via amidases, esterases, and other metabolic or hydrolytic mechanisms can produce modulators of KCNQ channel activity. Some prodrugs themselves may have weak activity as KCNQ channel modulators. However, any activity may be due to degradation into the active drug in the test system, and in most cases, the KCNQ modulator produced by the metabolized prodrug is more active than the prodrug itself.

[0286] Potassium channel modulators are tested using recombinant or naturally occurring bioactive KCNQ, or using natural cells, such as cells expressing M-currents in the nervous system. KCNQ can be isolated, co-expressed, or expressed in cells, or expressed in cell-derived membranes. In such assays, KCNQ2 is expressed alone to form a homologous potassium channel, or co-expressed with a second subunit (e.g., another member of the KCNQ family, preferably KCNQ3) to form a heterologous potassium channel. Modulation is tested using one of the aforementioned in vitro or in vivo assays. The degree of modulation is examined by comparing a sample or assay treated with a potential potassium channel inhibitor or activator to a control sample without the test compound. The control sample (not treated with an activator or inhibitor) is assigned a relative potassium channel activity value of 100. Activation of a channel including KCNQ2 is achieved when the potassium channel activity value relative to the control is 130%, more preferably 150%, more preferably 170%. Compounds that increase ion flux will result in a detectable increase in ion current density by increasing the probability of opening channels including KCNQ2, decreasing their probability of closing, increasing conduction through the channels, and increasing the number or expression of channels. In these experiments, it is important that in each experiment there is material known to metabolize the prodrug of this disclosure into a compound active at the receptor site of interest. Alternatively, these experiments can be performed using the actual drug compound itself, assuming that the metabolized prodrug, once in vivo in a mammal, will have similar activity at the desired ion channel site.

[0287] The activity of the metabolites of these prodrug compounds disclosed herein can also be measured using EC. 50The preferred compounds of this disclosure release an active molecule upon hydrolysis or metabolism, which has an EC value of [missing information - likely related to potassium ion channel assays]. 50 The value is from about 0.1 nM to about 1 mM, preferably from about 1 nM to 10 μM, and more preferably from about 10 nM to 2 μM.

[0288] Changes in ion flux can be assessed by determining changes in the polarization (i.e., potential) or M current of cells or membranes expressing exemplary potassium channels, such as KCNQ2, KCNQ2 / 3. A preferred method for determining changes in cell polarization is to measure changes in current or voltage using voltage-clamp and patch-clamp techniques in “cell-connected” mode, “inside-out” mode, “outside-out” mode, “perforated cell” mode, “one or two electrode” mode, or “whole cell” mode (see, for example, Ackerman et al., New England Journal of Medicine 336:1575-1595 (1997)). Whole-cell currents can be readily determined using standard methods (see, for example, Hamil et al., Pflugers. Archiv. 391:85 (1981). Other known assays include: radiolabeled rubidium flux assays and fluorescence assays using voltage-sensitive dyes (see, for example, Vestergarrd-Bogind et al., Journal of Membrane Biology). Biol. 88:67-75 (1988); Daniel et al., Journal of Pharmacological Methods 25:185-193 (1991); Holevensky et al., Journal of Membrane Biology 137:59-70 (1994)). The determination of compounds capable of inhibiting or increasing potassium flux through channel proteins including KCNQ2 or heteropolymers of KCNQ subunits can be performed by applying the compound to a bath solution containing cells having the channels of this disclosure (see, for example, Blatz et al., Nature 323:718-720 (1986); Park, Journal of Physiology 481:555-570 (1994)). Typically, the compound to be tested is present in the range of about 1 pM to about 1 mM, preferably about 10 pM to 100 μM.

[0289] The effect of the test compound on channel function can be measured by changes in current or ion flux, or by the result of both. Changes in current or ion flux are measured by increases or decreases in ion flux, such as potassium or rubidium ions. Cations can be measured using various standard methods. They can be measured directly by changes in ion concentration or indirectly by membrane potential or radio tagging of ions. The effect of the test compound on ion flux can be varied. Therefore, any suitable physiological changes can be used to assess the effect of the test compound on the channels disclosed herein.

[0290] III. Pharmaceutical compositions of potassium channel modulators

[0291] On the other hand, this disclosure provides pharmaceutical compositions comprising pharmaceutically acceptable excipients and the compound of formula I provided above.

[0292] Compound formulations (compositions)

[0293] The compounds disclosed herein can be prepared and administered in a variety of oral, parenteral, and topical dosage forms. Therefore, the compounds of this disclosure can be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, duodenal, or intraperitoneal injection. Additionally, the compounds described herein can be administered by inhalation, such as intranasal inhalation. Furthermore, the compounds of this disclosure can be administered transdermally, ocularly, intracochlearly, or rectally. Therefore, this disclosure also provides pharmaceutical compositions comprising pharmaceutically acceptable carriers or excipients and compounds of Formula I or their pharmaceutically acceptable salts.

[0294] For pharmaceutical compositions prepared from the compounds of this disclosure, the pharmaceutically acceptable carrier can be solid or liquid. Solid formulations include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. The solid form can be immediate-release, sustained-release, modified-release, or delayed-release. The solid carrier can be one or more substances, which can also act as a diluent, flavoring agent, binder, preservative, tablet disintegrant, or encapsulation material.

[0295] In powder formulations, the carrier is a finely ground solid mixed with the finely ground active ingredient. In tablet formulations, the active ingredient is mixed with a carrier having the desired binding properties in a suitable proportion and compacted into the desired shape and size.

[0296] Powders and tablets preferably contain 5% or 10% to 85% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. The term "preparation" refers to the formulation of an active compound using an encapsulating material as a carrier to obtain a capsule in which the active component, with or without other carriers, is surrounded by and thus associated with the carrier. Similarly, this includes capsules and tablets. Tablets, powders, capsules, pills, capsules, and tablets can be used as solid dosage forms suitable for oral administration.

[0297] In a method for preparing suppositories, a mixture of low-melting-point waxes, such as fatty acid glycerides or cocoa butter, is first melted and the active ingredients are uniformly dispersed therein, for example, by stirring. The molten, homogeneous mixture is then poured into a mold of a convenient size, allowing it to cool and thus solidify.

[0298] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral administration, liquid formulations can be prepared in a solution of polyethylene glycol aqueous solution.

[0299] Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral administration can be prepared by dispersing finely dispersed active ingredients in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0300] It also includes formulations in solid form, which are intended to be converted into liquid formulations for oral administration shortly before use. These liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0301] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as tablets, capsules, and powders packaged in vials or ampoules. Similarly, the unit dosage form can be capsules, tablets, pills, sachets, sachets, or lozenges themselves, or it can be any appropriate quantity of these packaging forms.

[0302] Depending on the specific application and potency of the active ingredient, the amount of the active ingredient in a unit dose formulation can vary or be adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 5,000 mg, and most typically from 20 mg to 1,000 mg. If desired, the composition may also contain other compatible therapeutic agents.

[0303] IV. Effective dose

[0304] The pharmaceutical compositions disclosed herein comprise compositions containing a therapeutically effective amount, i.e., an amount of active ingredient that effectively achieves its intended purpose. The actual amount effective for a particular application will depend particularly on the condition being treated. For example, when administered in a manner for treating pain, epilepsy, depression, or anxiety, such compositions will contain an amount of active ingredient that effectively reduces the clinically relevant severity of the being treated condition. Similarly, when the pharmaceutical composition is used to treat or prevent central or peripheral nervous system disorders, such as Parkinson's disease, a therapeutically effective amount will reduce one or more symptomatic characteristics of the disease (e.g., tremor) below a predetermined stress threshold. The determination of the therapeutically effective amount of the compounds disclosed herein is entirely within the capabilities of those skilled in the art, particularly based on the disclosure detailed herein.

[0305] For any of the compounds described herein, the therapeutically effective amount can initially be determined by cell culture assays. The target plasma concentration will be the concentration of those active compounds that can modulate, for example, activate or open KCNQ channels. In preferred embodiments, KCNQ channel activity is altered by at least 5% at clinically effective free drug concentrations for certain diseases or treatments, and by at least 10% at clinically effective free drug concentrations for other diseases or treatments. The percentage change in KCNQ channels in patients using prodrugs of Kv7-positive allosteric modulators can be adjusted based on plasma drug activity concentrations, and the dose can be adjusted up or down to achieve the desired therapeutic effect.

[0306] As is well known in the art, the effective therapeutic dose for humans can also be determined using animal models. For example, human doses can be formulated to achieve effective circulating concentrations found in animals. A particularly useful animal model for predicting anticonvulsant doses is maximal shock assay (Fischer RS, Brain Res. Rev. 14:245-278 (1989)). As described above, the dose in humans can be adjusted by monitoring KCNQ channel activation and by adjusting the dose up or down.

[0307] The effective therapeutic dose can also be determined based on human data for compounds known to exhibit similar pharmacological activity, such as ezogabine (Rudnfeldt et al., Neuroscience Letters 282:73-76 (2000)).

[0308] Adjusting the dosage based on the methods described above and other methods well known in the art to achieve maximum efficacy in humans is entirely within the capabilities of a person of ordinary skill.

[0309] For example, when the compounds of this disclosure are used to prevent and / or treat exemplary diseases such as epilepsy and pain, the cyclic concentration of the applied compounds is considered effective at a concentration of about 0.001 μM to 1 mM, preferably about 0.01 μM to 100 μM.

[0310] The range of oral doses for patients taking the compounds described herein is typically from about 1 mg / day to about 10,000 mg / day, more typically from about 10 mg / day to about 3,000 mg / day, and most typically from about 1 mg / day to about 1,000 mg / day, which is the preferred mode of administration for the prevention and treatment of exemplary diseases such as epilepsy. In terms of patient weight, the typical dose range is from about 0.01 to about 150 mg / kg / day, more typically from about 0.1 to about 50 mg / kg / day, and most typically from about 0.5 to about 25 mg / kg / day.

[0311] For other administration regimens, the dosage and interval can be individually adjusted to provide plasma levels of the administered compound that are effective for the specific clinical indication being treated. For example, if acute seizures are the predominant clinical manifestation, in one embodiment, the compound according to this disclosure may be administered multiple times daily at relatively high concentrations. Alternatively, in one embodiment, if a patient presents only with infrequent, periodic, or irregular acute seizures, migraines, or other clinical signs or symptoms arising from a chronic or acute disease state, it may be preferable to administer the compound of this disclosure at the minimum effective concentration and use a less frequent administration regimen. This will provide a treatment regimen commensurate with the severity of the individual's disease.

[0312] Using the teachings provided in this article, effective preventative or therapeutic treatment plans can be devised that do not cause significant toxicity and remain effective overall in treating the clinical symptoms exhibited by a particular patient.

[0313] This plan should involve the careful selection of active compounds by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, preferred administration method, and the toxicological characteristics of the selected reagent. As an example, but not a limitation, intranasal administration can be used to treat migraines, and ocular administration can be used to treat one or more eye diseases. Therefore, a specific administration route can be selected based on the intended therapeutic indication of the compounds disclosed herein.

[0314] V. Compound toxicity

[0315] The ratio between the toxicity and therapeutic effect of a specific compound is called its therapeutic index, which can be expressed as LD50. 50 (The amount of a compound that causes 50% of the population to die) and ED 50 The ratio between (the amount of compound effective for 50% of the population). Compounds exhibiting a high therapeutic index are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used to formulate a range of doses for human use. The dosage of such compounds is preferably within the range containing ED. 50 The dosage is within a range of plasma concentrations with very low or no toxicity. Dosage can vary within this range depending on the dosage form and route of administration. See, for example, Fingl et al., *The Pharmacological Basis of Therapeutics*, Chapter 1, page 1, 1975. Precise formulation, route of administration, and dosage can be selected by an individual physician based on the patient's condition and the specific method of using the compound.

[0316] VII. Methods for treating symptoms mediated by voltage-dependent potassium channels

[0317] In another aspect, this disclosure provides a method for treating central or peripheral nervous system disorders or symptoms by modulating voltage-dependent potassium channels. In this method, an effective amount of a compound having the formula provided above is administered to a subject requiring such treatment.

[0318] The compounds presented herein are prodrugs of useful potassium channel modulators, and therapeutic efficacy is found through modulation by improving the pharmacokinetics, solubility, and stability of molecules active against voltage-dependent potassium channels in the treatment of diseases or symptoms. The potassium channel targets of the disclosed compounds are described herein as voltage-dependent potassium channels, such as KCNQ channels. As mentioned above, these channels may comprise homopolymers and heteropolymers of KCNQ2, KCNQ3, KCNQ4, and KCNQ5. Heteropolymers of two proteins, such as KCNQ2 and KCNQ3, are referred to as, for example, KCNQ2 / 3, KCNQ3 / 5, etc. Conditions treatable with the compounds and compositions of this disclosure may include, but are not limited to, central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, spasms, mood disorders, brain tumors, psychotic disorders, myofascitis, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning disabilities, anxiety, and motor neuron disease). The compounds and compositions of this disclosure may also act as neuroprotective agents (e.g., prevention of stroke, retinal degeneration, demyelinating diseases, etc.). In a preferred embodiment, the condition or symptom to be treated is epilepsy or seizures, central or peripheral neuropathic pain, chronic pain, or inflammatory pain. In another preferred embodiment, the condition or symptom is hearing loss or treatment of diseases associated with neuronal demyelination or neuronal overexcitability.

[0319] Subsequently, the dosage is increased in small increments until optimal results are achieved in various situations. For convenience, the total daily dose can be divided into several portions and administered in batches throughout the day as needed.

[0320] One embodiment of this disclosure includes a method for treating, improving, or preventing the progression of a disease or condition, including seizures, pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, postherpetic neuralgia, and peripheral nerve damage, drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative disorders or diseases or injuries, cognitive deficits, obsessive-compulsive behaviors, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory loss, memory impairment, memory dysfunction, activity disorders, motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinsonian kinesia, phobias, Pick's disease, etc. Psychosis, bipolar disorder, schizophrenia (as a catatonic, paranoid, disorganized, or residual subtype of schizophrenia), spinal cord injury, cardiomyopathy, arrhythmia, long QT syndrome, activity or movement disorders, myasthenia gravis, migraine, tension headache, intestinal disorders, inflammatory diseases, ulcerative colitis, Crohn's disease, Croutzfeld-Jacob disease, ophthalmic symptoms, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, metastatic tumor growth, pneumoconiosis (such as aluminosis, coal mine pneumoconiosis, asbestosis, stone pneumoconiosis, ostrich feather pneumoconiosis, iron pneumoconiosis, silicosis, smoke pneumoconiosis, and cotton pneumoconiosis), chronic obstructive pulmonary disease (COPD), obesity, and disease-related hypertension.

[0321] One embodiment of this disclosure includes a method for treating one or more movement disorders selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / movement disorder, tardive dystonia, neurodepressant-induced dystonia, treatment-induced dystonia / movement disorder in patients with Parkinson's disease, hereditary degenerative dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette syndrome, dystonia in patients with restless legs syndrome, dystonia-like symptoms in patients with tics, dystonia-related movement disorders, paroxysmal movement disorders, paroxysmal nonmotor movement disorders, paroxysmal dystonia-choreoathetosis, paroxysmal kinesthesia, paroxysmal kinesthesia-choreoathetosis, movement-induced movement disorders, sleep paroxysmal movement disorders, drug-induced movement disorders, myofascitis, neurogenic myotonia, autism, and autism spectrum disorders. Regarding this teaching on the relationship between this mechanism and applicable diseases or conditions, the following references may be incorporated by way of citation.

[0322] a. Seizures (L Greene, Epilepsy 2018; Journal of Neuroscience, Qiu. 2008).

[0323] Neurons from Kv7.2 (S559A) knock-in mice exhibited normal basal M-currents. Kv7.2 (S559A) knock-in mice showed reduced M-current inhibition upon challenge with oxidative tremor-M, a muscarinic agonist. Kv7.2 (S559A) mice were resistant to chemosergic-induced seizures without mortality. Administration of XE991 transiently exacerbated seizures in knock-in mice, with seizure severity comparable to that in wild-type mice. No seizure-induced cell death or spontaneous seizure recurrence was observed in Kv7.2 (S559A) knock-in mice after experiencing a state of epilepsy.

[0324] Using M-channel blockers, it was found that the coupling of SST4 to M-channels is crucial for its suppression of epileptiform activity. This is the first demonstration that endogenous enhancers of IM are important in controlling epileptic seizure activity. Therefore, the SST4 receptor may be an important novel target for the development of new antiepileptic and antiepileptic drugs.

[0325] b. Pain, neuropathic pain, chronic headache (Pain Journal, Li. 2019).

[0326] Paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. These findings suggest that retigabine (a clinically available drug) may be used to alleviate the progression of paclitaxel-induced peripheral neuropathy.

[0327] c. Central pain, pain associated with diabetic neuropathy, postherpetic neuralgia and peripheral nerve injury (Brown, British Journal of Pharmacology, 2009; Epilepsy, Trenite, 2013).

[0328] Several drugs, including flupirtine and retigabine, primarily enhance the activity of neural Kv7 / M channels through their voltage-gated hyperpolarization shift. Therefore, they reduce neural excitability and can inhibit noxious stimuli and their transmission. Flupirtine is used as a central analgesic; retigabine, as a broad-spectrum anticonvulsant, is undergoing clinical trials and has proven effective as an analgesic in animal models of chronic inflammation and neuropathic pain.

[0329] ICA-105665 reduced the seizure rate (SPR) in patients with single doses of 100 (1 / 4), 400 (2 / 4), and 500 mg (4 / 6). This is the first evaluation of the role of Kv7 potassium channel activation in a proof-of-concept model of photosensitivity. The reduction in SPR in this patient population provides evidence of ICA-105665 penetrating the central nervous system (CNS) and preliminary evidence of an anti-epileptic effect through binding to neuronal Kv7 potassium channels.

[0330] d. Alzheimer's disease (Czuzcwar, Pharmacology Reports 2010).

[0331] The most significant adverse reactions of retigabine in combination with existing antiepileptic therapies are dizziness, drowsiness, and fatigue. Preclinical data suggest that this antiepileptic drug may be useful in patients with neuropathic pain and mood disorders. Preliminary clinical data suggest that retigabine may also be effective for Alzheimer's disease or stroke.

[0332] e. Anxiety, CNS damage caused by neurodegenerative disorders or diseases or injuries, cognitive deficits, obsessive-compulsive behaviors, dementia, depression, Huntington's disease, dystonia, mania (Richter, *British Journal of Pharmacology*, 2006; Aiba, *Brain*, 2021; Boehm, *Pain*, 2019; Maghera, *Epilepsy*, 2020; De Jong, *Physiological Reports*, 2018; Jakubowski, *Epilepsy Behavior*, 2013; Zizhen Wu, *J Pharmacol Exp Ther*, 2020; JE Larsson, *In Physiology*, 2020; Yadav, *Saudi J Anaesth*, 2017; Garakani, *Frontiers in Psychiatry*, 2017. Psychiatry) 2020; Maljevic, Journal of Physiology 2008; R. Brant, Gastroenterology 2017; Hui Sun, JCI Insight 2019; R Brant, Gastroenterology 2017; Ravi Misra, Gastroenterology 2017; Parreno, Front Physiology 2020; Blom, PLoS One 2014; Feng Neuroscience 2019; E Redford, Physiology and Biochemistry 2021; J Gunthrope, Epilepsy 2012; Epilepsy, Villalba 2018.

[0333] Given the good tolerability of retigabin and flupirtine in humans, the significant anti-dystonic efficacy observed in the dtsz mutant suggests that neuronal Kv7 channel activators are promising candidates for treating dystonic movement disorders and potentially other types of dystonic disorders. The established analgesic effects of Kv7 channel openers may help improve these conditions, which are often accompanied by painful muscle spasms.

[0334] Retigabine showed that it can delay the onset of diffuse depolarization following submaximal OGD stimulation. Intriguingly, the Kv7.2 activator exhibits neuroprotective effects in experimental ischemia and brain injury studies, and the activator's anti-diffusion depolarization properties may contribute to these neuroprotective effects.

[0335] The study supports the novel role of the Kv7 channel in intrinsic and synaptic plasticity, as well as its contribution to cognition and behavior.

[0336] Voltage-gated potassium channels of the KV7 family (KV7.1-5) play an important role in controlling neuronal excitability and are therefore attractive targets for the treatment of CNS disorders associated with overexcitability.

[0337] f. Cognitive impairment, memory decline, memory disorders, memory dysfunction

[0338] (Frontiers in Physiology, Baculis. 2020; Frontiers in Physiology, Vigil. 2020).

[0339] Given the critical role of Kv7 channels in neonatal brain development and inhibition (Peters et al., 2005; Soh et al., 2014), memory impairment in these genetic models can be attributed to abnormal hippocampal morphology and / or hyperexcitability (Peters et al., 2005; Milh et al., 2020). Kv7 channels also regulate a variety of behaviors. Behavioral phenotypes in globally or conditionally homozygous KCNQ2 knockout mice are not yet possible because they are associated with early postnatal lethality or premature death, respectively (Watanabe et al., 2000; Soh et al., 2014).

[0340] However, heterozygous KCNQ2 knockout mice are viable and exhibit increased motor activity and exploratory behavior (Kim et al., 2020), consistent with transgenetic inhibition of Kv7 currents (Peters et al., 2005) and amphetamine and XE991 (Sotty et al., 2009)-induced hyperactivity. These mice also show decreased social skills and increased repetitive and compulsive behaviors (Kim et al., 2020), reminiscent of autism found in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al., 2012, 2013; Milh et al., 2013). The International Kv7 Symposium held in Naples, Italy in 2019 showed great translational potential. Animal studies have indicated that M-currents are therapeutic targets for a variety of brain disorders, including those currently without treatments, such as TBI and psychostimulant addiction.

[0341] g. Schizophrenia (Transl Psychiatry, Nielsen, 2017; British Journal of Pharmacology, Wang, 2020).

[0342] Genetic or pharmacological inhibition of neuronal Kv7 channels can alleviate NMDA antagonist-induced PPI and cognitive deficits, suggesting that such Kv7 channel inhibition has therapeutic potential in treating schizophrenia or cognitive impairment disorders.

[0343] h. Spinal cord injury (Journal of Pharmacology, Wu. 2020).

[0344] Reducing neuronal activity by opening KCNQ / Kv7 channels can protect spinal cord neurons and axons from degeneration after spinal cord injury (SCI), thereby promoting the recovery of motor and sensory functions. Repeated application of retigabine during the acute phase to open these channels promotes neurobehavioral recovery after SCI.

[0345] i. Cardiomyopathy, arrhythmia (Frontiers in Physiology, Larsson. 2020; Journal of Physiology, Maljevic. 2008; Lee, Microcirculation 2015).

[0346] Due to its important role in physiology, dysfunctional KV7 channels are often associated with conditions characterized by abnormal potassium ion conduction, including arrhythmias, hearing impairment, epilepsy, pain, and hypertension.

[0347] Kv7 channels in mice can contribute differently to the regulation of functional properties of cerebral and coronary arteries. This heterogeneity is of great significance for developing novel therapies for cardiovascular dysfunction.

[0348] h. Long QT syndrome (Journal of Physiology, Maljevic. 2008; Acta Physiologica Sinica, Skarsfeldt. 2020; Acta Physiologica Sinica, Bahannon. 2019).

[0349] Polyunsaturated fatty acids with double bonds closer to the head group exhibit a higher apparent affinity for IKs channels and increase IKs current; further offsetting the bond from the head group reduces the apparent binding affinity and effect on IKs current. Intriguingly, ω-6 and ω-9 PUFAs with the first double bond closer to the head group were found to result in the largest left-shifted voltage dependence of activation. These results allow for the informed design of novel therapies targeting IKs channels in long QT syndrome.

[0350] KV7 channels offer a promising target for novel therapies for diseases caused by neuronal overexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism by which retigabine, used in a phase III clinical trial for the treatment of drug-resistant focal epilepsy, activates KV7 has recently been elucidated as stabilizing the open conformation by binding to pore regions.

[0351] i. Intestinal disorders, inflammatory diseases, ulcerative colitis, Crohn's disease, ... (Journal of Neuroscience, Linley. 2008).

[0352] Further experiments have shown that inhibition of M-currents requires both a simultaneous increase in cytosol Ca2+ concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). This suggests that PLC and Ca2+ / PIP2-mediated inhibition of M-currents in sensory neurons may represent one of the general mechanisms underlying pain generated by inflammatory mediators, and thus may open a new therapeutic window for treating this major clinical problem.

[0353] j. Kreutzfeld-Jacob disease (Chinese Journal of Pharmacology, Teng. 2016).

[0354] The modified QO58 compound (QO58-lysine) can specifically activate Kv7.2 / 7.3 / M channels. Oral or intraperitoneal administration of QO58-lysine, which improves bioavailability and has a plasma half-life of approximately 3 hours, can reverse inflammatory pain in rodent models.

[0355] k. Progressive hearing loss or tinnitus (Journal of Physiology, Maljevic. 2008; British Journal of Pharmacology, Leithner. 2014; Journal of Neuroscience, Kalappa. 2015).

[0356] By stabilizing KCNQ4-mediated OHC conduction, chemical channel openers can prevent DFNA2 OHC degeneration and the progression of hearing loss.

[0357] Behavioral studies have shown that SF0034 is a more effective and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. This suggests that SF0034 not only provides a powerful tool for studying ion channel properties, but more importantly, it offers a clinical candidate for the treatment of epilepsy and the prevention of tinnitus.

[0358] l. Diabetes mellitus (Frontiers in Cardiovascular Medicine, Fosmo. 2017).

[0359] Kv7 channel activity may contribute to the development of cardiovascular risk factors such as hypertension, diabetes, and obesity. Questions and hypotheses have been raised regarding previous and future research. Alterations in Kv7 channels may contribute to the development of cardiovascular disease (CVD). Pharmacological modifications of Kv7 channels may represent potential future treatments for CVD.

[0360] m. Chronic obstructive pulmonary disease (COPD) (Frontiers in Physiology, Mondejar-Parreno. 2020).

[0361] The functional roles of Kv7 channels may vary depending on cell type. Several studies have shown that damage to Kv7 channels has a strong impact on lung physiology, leading to the pathophysiology of various respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic cough, lung cancer, and pulmonary hypertension. Kv7 channels are now believed to play relevant physiological roles in many tissues, encouraging the search for Kv7 channel modulators with potential therapeutic uses in many diseases, including those affecting the lungs. Modulation of Kv7 channels has been proposed to provide beneficial effects in many lung conditions. Therefore, Kv7 channel openers / enhancers or drugs that act partially through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutic agents, and pulmonary vasodilators.

[0362] n. A movement disorder selected from primary dystonia (A Richter, British Journal of Pharmacology, 2006).

[0363] These data suggest that dysfunction of neuronal Kv7 channels warrants attention in movement disorders. Given the good tolerability of retigabin and flupirtine in humans, the significant anti-dystonic efficacy observed in the dtsz mutant indicates that neuronal Kv7 channel activators are promising candidates for treating dystonia-related movement disorders and potentially other types of dystonia. The established analgesic effects of Kv7 channel openers may help improve these conditions, which are often accompanied by painful muscle spasms.

[0364] o. Autism, autism spectrum disorder, including administration of the compounds disclosed herein. (Gilling, Frontiers in Genetics 2013; Guglielmi, Frontiers in Cell Neurosci. 2015).

[0365] One embodiment of this disclosure includes a method of delivering a broad-spectrum Kv7.2-7.5 active molecule into systemic circulation and releasing an effective concentration of the active Kv channel opener at a therapeutic concentration to treat one or more susceptible diseases or conditions, the method comprising administering a compound of this disclosure. In one aspect, the release of the active molecule is provided by one or more of the following: enhanced by increased absorption.

[0366] Given the good tolerability of retegabine and flupirtine in humans, the significant anti-dystonic efficacy found in the dtsz mutant suggests that neuronal Kv7 channel activators are promising candidates for the treatment of dystonic movement disorders and potentially for the treatment of other types of dystonic disorders.

[0367] Mutations in neuronal Kv7 (KCNQ) potassium channels may lead to paroxysmal neurological disorders. Paroxysmal dyskinesia is a group of movement disorders considered ion channel diseases, but to date, the role of Kv7 channels in pathogenesis and as therapeutic targets has not been investigated.

[0368] The results indicate that dysfunction of heterologous KV7.3 / 5 channels is associated with the pathogenesis of some forms of autism spectrum disorders, epilepsy, and other possible mental illnesses. Therefore, KCNQ3 and KCNQ5 are considered candidate genes for these conditions.

[0369] Example

[0370] In the following examples, unless otherwise specified, temperatures are in degrees Celsius (°C). Operations are carried out at room temperature or ambient temperature (typically in the range of about 18-25°C); solvent evaporation is performed using a rotary evaporator under reduced pressure (typically 4.5-30 mmHg), with a bath temperature of no more than 60°C; the reaction process is typically followed by TLC, and reaction times are provided for illustrative purposes only; melting points are not corrected; products exhibit satisfactory performance. 1 H-NMR and / or trace analysis data; yield is for illustrative purposes only; and the following common abbreviations are also used: mp (melting point), L (liter), mL (milliliters), mmol (millimoles), g (grams), mg (milligrams), min (minutes), and h (hours).

[0371] Unless otherwise specified, all solvents (HPLC grade) and reagents were purchased from the supplier and used without further purification. Analytical thin-layer chromatography (TLC) was performed on Whatman Inc. 60 silica gel plates (0.25 mm thick). Compounds were visualized under a UV lamp (254 nM) or by development with KMnO4 / KOH, ninhydrin, or Hanesian solution. Rapid chromatography was performed using Selectro Scientific silica gel (particle size 32–63). Recordings were performed on a Varian 300 system at 300 MHz, 282 MHz, and 75.7 MHz. 1 H NMR, 19 F NMR and 13 C10 NMR spectra. Melting point was recorded on an electrothermal IA9100 device without correction.

[0372] The following examples are provided to illustrate, but not to limit, the claimed disclosure. Those skilled in the art can modify the general procedures of Examples 1 and 2 to synthesize compounds comprising Formula III by appropriately substituting ezogabine, flupyridine, and the acylating agent with appropriate amounts of other starting materials.

[0373] Those skilled in the art will further recognize that human clinical trials, including first-in-human trials, dose range and efficacy trials, can be conducted in healthy patients and / or patients with established conditions, using methods well-known in the clinical and medical fields.

[0374] This disclosure explicitly covers those compounds presented below, including their salt forms. This disclosure also covers those compounds presented below, including their stereoisomers. Compositions comprising any of these compounds in therapeutically acceptable amounts are within the scope of this disclosure. The composition may further comprise pharmaceutically acceptable excipients, diluents, carriers, or mixtures thereof. Such compositions can be administered to a subject in need to treat or control a disease or condition directly or indirectly, wholly or partially, mediated by one or more voltage-dependent potassium channels. As described herein, the composition may further comprise additional active agents.

[0375] The following examples provide a more detailed description of the process conditions for preparing the compounds of this disclosure. However, it should be understood that, as fully described herein and as set forth in the claims, this disclosure is not intended to be limited to the details of the following preparation methods or modes.

[0376] Certain abbreviations may be used to describe instances of this disclosure. These abbreviations are believed to be used consistently within the scope of common use accepted by those skilled in the art.

[0377] The compounds disclosed herein can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art.

[0378] In the following schemes, general substituents are represented by allocations that may differ from those in this disclosure. The following schemes provide the key to these substituents, which should be permitted for use in these schemes but not in the formulas of this disclosure.

[0379] plan

[0380] General Solution 1: Synthesis of prodrugs from Kv7 active drug molecules

[0381]

[0382] In general scheme 1, the Kv7 pharmacophore is the drug moiety active at the Kv7 potassium ion channel. Reagent LC(O)-R 1 Represents the activated carbonyl reagent or intermediate, and L is the leaving group. R G Represents H or various substituents, and R 1 As used in this article. The resulting product is a hydrolyzable prodrug that forms the Kv7 active drug upon hydrolysis.

[0383] Example 1

[0384] A general procedure for the preparation of ezogabine acetal / ketodiester prodrugs:

[0385] At room temperature, place 200 mL of dichloromethane in a 500 mL round-bottom flask equipped with a magnetic stirrer. Start stirring and add the following materials in sequence: ezogabine (10.0 g, 33.00 mmol; 1.0 equivalent; 303.33 g / mol; [CAS No. 150812-12-7]), triethylamine (6.68 g; 66.00 mmol; 2.0 equivalent; 101.19 g / mol), the desired 1-(((4-nitrophenoxy)carbonyl)oxy)alkyl ester of carboxylic acid (34.62 mmol; 1.05 equivalent), and HOBt (0.446 g; 3.30 mmol; 0.1 equivalent; 135.12 g / mol). Rinse the flask with nitrogen and seal it with a diaphragm. Maintain a nitrogen atmosphere at approximately 1 atm N2 using a needle connected to the nitrogen line, and monitor the reaction progress by TLC. When TLC showed no retention of ezogabine, the reaction was heated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separating funnel, and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles were removed under vacuum, and the residue was purified by column chromatography or recrystallization to obtain the desired ezogabine-derived prodrug.

[0386] Example 2

[0387] A general procedure for the preparation of flupyridine acetal / ketodiester prodrugs:

[0388] At room temperature, place 200 mL of dichloromethane in a 500 mL round-bottom flask equipped with a magnetic stirrer. Start stirring and add the following materials in sequence: flupyridine (10.0 g, 33.00 mmol; 1.0 equivalent; 303.33 g / mol; [CAS No. 56995-20-1]), triethylamine (6.68 g; 66.00 mmol; 2.0 equivalent; 101.19 g / mol), the desired 1-(((4-nitrophenoxy)carbonyl)oxy)alkyl ester of carboxylic acid (34.62 mmol; 1.05 equivalent), and HOBt (0.446 g; 3.30 mmol; 0.1 equivalent; 135.12 g / mol). Rinse the flask with nitrogen and seal it with a diaphragm. Maintain a nitrogen atmosphere at approximately 1 atm N2 using a needle connected to the nitrogen line, and monitor the reaction progress by TLC. When TLC showed no retention of flupirtine, the reaction was heated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separating funnel, and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles were removed under vacuum, and the residue was purified by column chromatography or recrystallization to obtain the desired flupirtine-derived prodrug.

[0389] Those skilled in the art can modify the general procedures of Examples 3 and 4 to synthesize compounds comprising Formula IV by replacing ezogabine, flupyridine, and the acylating agent with appropriate amounts of other starting materials.

[0390] Example 3

[0391] General procedure for the preparation of amino acid prodrugs of ezogabine:

[0392] Step 1: At room temperature, place 200 mL of dichloromethane in a 500 mL round-bottom flask equipped with a magnetic stirrer. Start stirring and add the following materials in sequence: ezogabine (10.0 g, 33.00 mmol; 1.0 equivalent; 303.33 g / mol; [CAS No. 150812-12-7]), triethylamine (6.68 g; 66.00 mmol, 2.0 equivalent; 101.19 g / mol), the desired Boc-protected amino acid O-succinimide ester (34.62 mmol; 1.05 equivalent), and HOBt (0.446 g; 3.30 mmol; 0.1 equivalent; 135.12 g / mol). Rinse the flask with nitrogen and seal it with a diaphragm. Maintain a nitrogen atmosphere at approximately 1 atm N2 using a needle connected to the nitrogen line and monitor the reaction progress by TLC. When TLC showed no retention of ezogabine, the reaction was heated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separating funnel, and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles were removed under vacuum, and the residue was purified by column chromatography or recrystallization to obtain the desired BOC-protected form of the prodrug.

[0393] Step 2: The product from Step 1 was added to a stirred solution of 25% trifluoroacetic acid in 100 mL of dichloromethane at room temperature. The flask was rinsed with nitrogen and sealed with a diaphragm. A nitrogen atmosphere was maintained at approximately 1 atm N2 using a needle attached to the nitrogen line, and the reaction progress was monitored by TLC. When TLC showed no retention of the starting material or intermediates, the reaction was continued by removing the volatile solvent under vacuum. The crude product was obtained as a mixture of trifluoroacetic acid salts of the desired prodrug free base. The material was purified by recrystallization or reversed-phase HPLC to obtain the desired prodrug material.

[0394] Example 4

[0395] General procedure for the preparation of flupyridine amino acid prodrugs:

[0396] Step 1: At room temperature, place 200 mL of dichloromethane in a 500 mL round-bottom flask equipped with a magnetic stirrer. Start stirring and add the following materials in sequence: flupyridine (10.0 g, 33.00 mmol; 1.0 equivalent; 303.33 g / mol; [CAS No. 56995-20-1]), triethylamine (6.68 g; 66.00 mmol, 2.0 equivalent; 101.19 g / mol), the desired Boc-protected amino acid O-succinimide ester (34.62 mmol; 1.05 equivalent), and HOBt (0.446 g; 3.30 mmol; 0.1 equivalent; 135.12 g / mol). Rinse the flask with nitrogen and seal it with a diaphragm. Maintain a nitrogen atmosphere at approximately 1 atm N2 using a needle connected to the nitrogen line and monitor the reaction progress by TLC. When TLC showed no retention of flupirtine, the reaction was heated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separating funnel, and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles were removed under vacuum, and the residue was purified by column chromatography or recrystallization to obtain the desired BOC-protected form of the prodrug.

[0397] Step 2: The product from Step 1 was added to a stirred solution of 25% trifluoroacetic acid in 100 mL of dichloromethane at room temperature. The flask was rinsed with nitrogen and sealed with a diaphragm. A nitrogen atmosphere was maintained at approximately 1 atm N2 using a needle attached to the nitrogen line, and the reaction progress was monitored by TLC. When TLC showed no retention of the starting material or intermediates, the reaction was continued by removing the volatile solvent under vacuum. The crude product was obtained as a mixture of trifluoroacetic acid salts of the desired prodrug free base. The material was purified by recrystallization or reversed-phase HPLC to obtain the desired prodrug material.

[0398] Example 5

[0399] Synthesis of ezogabine acetal prodrug.

[0400] Step 1:

[0401] Zinc oxide (44.73 g, 0.55 mol) was added to a solution of toluene (1800 mL) and 2-methylpropionic acid (450 mL), and the flask was heated at 120 °C. Water produced during this process was removed using a Dean Starktrap. After heating for 5 hours, the temperature was lowered to 70 °C, and then (1-chloroethyl)(4-nitrophenyl) carbonate (45 g, 0.18 mol) and NaI (43.97 g, 0.29 mol) were added together. The reaction mixture was stirred at 70 °C for 36 hours. After completion, the mixture was evaporated, and the residue was dissolved in EtOAc, washed with a saturated NaHCO3 solution, and then washed with brine. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:EtOAc = 50:1) to give the desired product (32.6 g, yield 55.68%) as a yellow solid.

[0402] Step 2:

[0403] Triethylamine (16.01 g, 0.16 mol), 1-[(4-fluorophenyl)methyl]amino}phenyl)carbamate (30.57 g, 0.10 mol), and 1-hydroxybenzotriazole (1.07 g, 0.007 mol) were added to a stirred solution of N-(2-amino-4-{[(4-fluorophenyl)methyl]amino}phenyl)carbamate (24 g, 0.079 mol) in dichloromethane (480 mL), and the mixture was stirred at 25 °C for 24 hours under a nitrogen atmosphere. After completion, the mixture was treated by adding 300 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separating funnel, and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles were removed under vacuum, and the residue was purified by column chromatography (petroleum ether: EtOAc = 6:1) to give compound 3 (3.4 g, yield 9.3%) as a yellow solid.

[0404] 1 ¹H-NMR (DMSO-d6): δ (ppm): (multiplicity; J (Hz); integral): 8.8-8.7 (bs, 1H), 8.3-8.2 (bs, 1H), 7.4 (m, 2H), 7.1 (m, 2H), 7.0-6.9 (bs, 1H), 6.8 (bs, 1H), 6.7 (q, 1H), 6.3 (m, 2H), 4.2 (m, 2H), 4.0 (m, 2H), 2.5 (m, 1H), 1.4 (m, 3H), 1.2 (m, 3H), 1.1 (m, 6H).

[0405] 13C-NMR:(DMSO-d6):δ(ppm):174.9,162.7,160.3,152.0,146.8,136.7,136.7,129.3,118 .9,115.5,115.3,109.0,107.2,89.5,60.6,46.3,39.6,33.6,20.0,19.0,18.9,15.0ppm.

[0406] LCMS R t = 1.38 minutes; [M+H] = 462

[0407] General Solution A

[0408]

[0409] Example 6

[0410] Step 1:

[0411] Triethylamine (6.68 g, 0.066 mol), N2,N6-bis(tert-butoxycarbonyl)-L-lysine 2,5-dioxopyrrolidine-1-yl ester (15.34 g, 0.035 mol), and 1-hydroxybenzotriazole (0.44 g, 0.003 mol) were added to a stirred solution of N-(2-amino-4-{[(4-fluorophenyl)methyl]amino}phenyl)carbamate (10 g, 0.033 mol) in dichloromethane (200 mL). The solution was stirred at 25 °C under nitrogen for 24 hours. After stirring, the mixture was treated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separating funnel, and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles were removed under vacuum, and the residue was purified by column chromatography (petroleum ether: EtOAc = 2:1) to give the desired product as a white solid (12.6 g, yield 60.5%).

[0412] Step 2:

[0413] A mixture of N-(5-{[(tert-butoxy)carbonyl]amino}-5-({2-[(ethoxycarbonyl)amino]-5-{[(4-fluorophenyl)methyl]amino}phenyl}carbamoyl)pentyl)carbamate (8.67 g, 0.014 mol) and HCl (in dioxane) (17.5 mL, 0.069 mol) was prepared in dichloromethane (86 mL). The mixture was stirred continuously at room temperature for 18 hours. After completion, the mixture was filtered, and the filter cake was washed with dichloromethane and dried under reduced pressure to give compound 4 (6.3 g, 98.1% yield) as a white solid.

[0414] 1 ¹H-NMR (DMSO-d6): δ (ppm); (multiplicity; J (Hz); integral): 10.0–10.2 (bs, 1H), 8.5–8.4 (bs, 3H), 8.1–7.9 (bs, 3H), 7.4 (m, 2H), 7.2 (m, 3H), 7.1 (bs, 1H), 6.7 (bs, 1H), 4.3–4.2 (bs, 2H), 4.1 (m, 3H), 2.7 (bm, 2H), 1.8 (bm, 2H), 1.6 (m, 2H), 1.4 (m, 2H), 1.2 (m, 3H).

[0415] 13 C-NMR: (DMSO-d6): δ (ppm): 168.3, 161.2, 154.6, 132.3, 125.4, 115.7, 115.5, 61.0, 52.8, 38.7, 30.7, 26.8, 21.6, 15.0ppm.

[0416] LCMS R t = 0.94 minutes; [M+H] = 432

[0417] General Solution B

[0418]

[0419]

[0420] Example 7

[0421] Aqueous and organic solubility and stability studies of ezogabine prodrug examples

[0422] Studies were conducted to evaluate the solubility of two ezogabine prodrugs (compound 1) in different aqueous and organic media, and their stability for up to 7 days was assessed by measuring UV absorbance at 230 nm using HPLC-UV / Vis, with mass spectrometry detection used for quality confirmation. The solubility of compound 1 is known and is presented in Table 1. The solubility of compound 1 in 0.1 N K₂HPO₄ solvent line 0.1 N Na₂HPO₄ was determined.

[0423] Compounds 3 and 4 were evaluated in various solvents to compare their solubility with that of compound 1. The compounds were weighed and placed in four-dose vials, and solvent was added to the target concentration. The compounds were subjected to eddy current and visual particle inspection, and were considered soluble if they appeared transparent during visual inspection under both magnification and non-magnification. Solubility was reported as greater than (>) or less than (<) the preparation concentration. The solubility of compound 4 was evaluated in water and 0.1N HCl at a maximum concentration of 20 mg / mL, and the compound was freely soluble. The compound was evaluated in 0.1N NaCl at 10 mg / mL, and the compound was freely soluble. The compound was evaluated in 0.1N NaOH and 0.1N Na₂HPO₄ at 1 mg / mL, and the compound was freely soluble. In ethanol and methanol, the compound was freely soluble at a concentration of 75 mg / mL.

[0424] Visual inspection revealed that compound 3 is insoluble in 0.1N HCl, 0.1N NaOH, 0.1N NaCl, water, and 0.1N Na₂HPO₄ at a concentration of 1 mg / mL. It is freely soluble in methanol and ethanol at a concentration of 75 mg / mL. The compound is soluble in 1N HCl at a concentration of 1 mg / mL.

[0425] Both prodrug compounds are more soluble in ethanol than compound 1. Compound 3 potentially has a similar absolute solubility in aqueous media as compound 1, while compound 4 exhibits excellent solubility in aqueous solvents. For in vivo studies, compound 4 has been prepared into a solution that is freely soluble in 0.9% w / v NaCl at a concentration of 150 mg / mL.

[0426] Table 1. Solvent solubility assessment of ezogabine prodrug

[0427] water >20 <1 0.05 0.1N HCl >20 <1 16 1N HCl ND >1 ND 0.1N NaOH >1 <1 0.04 0.1N NaCl >10 <1 0.04 0.1N Na2HPO4 >1 <1 0.18 methanol >75 >75 54 ethanol >75 >75 20

[0428] ND - Undetermined

[0429] The compound in the solvent was placed on a table and exposed to light for up to 7 days, since compound 1 is known to degrade with light within 3-7 days.

[0430] Stability was assessed by taking aliquots from the solubility vials on each test day. A single replica was injected for each test condition. The sample from compound 4 was diluted with water to a test concentration of 100 μg / mL. The sample from ethanol of compound 3 was diluted with methanol to 200 μg / mL, and then further diluted with water to 100 μg / mL. The sample from the aqueous solvent of compound 3 was diluted with methanol to 500 μg / mL.

[0431] The sample was injected into an HPLC system with an aqueous mobile phase and an acetonitrile organic phase, and the compound was separated on a C8 50 x 2 mm column. Absorption was monitored at 230 nm and peak area was integrated, while mass was confirmed using mass spectrometry. Samples were tested on day 1 and continued through day 7.

[0432] The increase in the stability and solubility of compound 3 is due to Figure 1 The solubility of compound 3 in 0.1N Na₂HPO₄, H₂O, and 0.1N NaCl increased over time from day 1 to day 3. Compound 3 appeared stable in 0.1N HCl for 4 days and unstable in 1N HCl for 7 days. Compound 3 was soluble and stable in ethanol and methanol for 3 days, but showed degradation on day 4.

[0433] The stability of compound 4 is in Figure 2 The results show that, except for 0.1N NaOH, compound 4 remained stable under all test conditions for 4 days. The peak area integral generally exhibited a variability of + / -20%, indicating a tendency for stability in all solvents except 0.1N NaOH, with the peak area of ​​compound 4 decreasing by >50%.

[0434] In summary, these results indicate that compounds 3 and 4 are more soluble in ethanol than compound 1, and compound 4 is more soluble in aqueous solvents than compound 1. Except in the selected solvents, both ezogabine prodrugs are stable for 3 days in the solvents.

[0435] Figure 1 The stability and solubility of compound 3 were demonstrated over a period of 3 to 7 days. Figure 2 The stability of compound 4 was demonstrated over 4 days.

[0436] Example 8

[0437] Plasma stability study of ezogabine prodrug examples

[0438] The study aimed to evaluate the stability of two prodrugs of ezogabine (compound 1) in vitro in mouse and rat plasma for up to 23 hours at 37°C.

[0439] The dried compounds 3 and 4 were dissolved in dimethyl sulfoxide (DMSO) to a concentration of 1 mg / mL and kept frozen at -20°C.

[0440] The plasma was collected by a biomaterials supplier and kept frozen at -20°C.

[0441] A 1 mg / mL DMSO solution of compounds 3 and 4 was diluted in rat and mouse plasma to a final concentration of 1000 ng / mL, vortexed, and immediately aliquots were collected. The plasma was precipitated with 4 volumes of acetonitrile, with tolbutamide used as an internal standard for mass spectrometry detection. The remaining fraction was incubated at 37°C for up to 23 hours. Samples were captured at time points 0 min, 5 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 23 h using ACN and tolbutamide solution (internal standard). The prodrug amount in the sample was analyzed by HPLC separation and mass spectrometry detection relative to the control sample at baseline time 0. Three samples were generated at each time point, and the average peak area response was calculated and converted to a baseline control percentage.

[0442] Compound 3 is unstable in mouse and rat plasma, thus exhibiting complete degradation after 1 hour in vitro, such as Figure 3 Compound 4 degraded in mouse plasma for 6 hours, but was stable in rat plasma for 6 hours, and then less than 50% remained at 23 hours, as... Figure 4 Ezogabin prodrug exhibits varying stability in plasma in vitro, suggesting that it may have different release kinetics in vivo.

[0443] Figure 3 The stability of compound 3 in mouse and rat plasma at 37 °C in vitro was demonstrated. Figure 4 The stability of compound 4 in mouse and rat plasma at 37 °C in vitro was demonstrated.

[0444] Example 9

[0445] Pharmacokinetics of ezogabine prodrug in mice.

[0446] Bioanalytical methods were developed on an API 4000MS / MS system coupled with an Agilent 1100HPLC and CTC PAL autosampler, set at 4°C, for the detection of compound 1, its major metabolite N-acetyl metabolite, and either compound 3 or 4. Separation was achieved by HPLC in reverse phase using a 50 x 2 mm C8 column. Blood was collected via myocardial puncture using a 25G 3 / 4 length needle attached to a 1 mL syringe. When studying compound 4, the blood was transferred to a K2EDTA tube containing 500 mM citric acid in aqueous solution, or when studying compound 3, the blood was transferred to 500 mM citric acid containing 50 mM dichlorvos. The blood was diluted 10% with these stabilizers. These solutions were evaluated from a set of experiments to stabilize compounds 3 and 4, determining the optimal method for preserving the ezogabine prodrug in plasma prior to extraction.

[0447] Molecular extraction was performed by taking 50 μL aliquots of plasma and adding 200 μL of acetonitrile containing 200 ng / mL tolbutamide as an internal standard. Samples were precipitated in 96-well plates, centrifuged, and the aliquots were transferred to new plates, dried under heating and nitrogen, and then reconstructed under the initial mobile phase conditions of the LC-MS / MS method. Standard curves for compound 1 were prepared, separated from the prodrug regardless of the presence of N-acetyl metabolites. Standard curves were prepared for each analyte ranging from 5000 ng / mL to 1 ng / mL. Concentration data from bioanalytical runs were analyzed using Phoenix Winnonlin version 8 for non-compartment sparse sampling PK analysis, plotting concentration-time curves, and listing PK parameters.

[0448] Compound 1, compound 3, or compound 4 were administered subcutaneously or orally to male mice weighing 20–25 g, with four mice administered at each time point. Animals were asphyxiated with carbon dioxide gas, blood was collected via myocardial puncture, and the animals were euthanized by cervical dislocation. Compound 4 was administered subcutaneously at a solution dose of 100 mg / kg in a 10 mL / kg saline solution. Concentration analysis of compounds 1 and 4 was performed at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h (N = 4 / time point). Figure 5 presents the mean (standard deviation) of compound 4 after subcutaneous (SC) administration. Compounds 1, 3, and 4 were administered orally to male mice at equimolar doses close to that of compound 1. Compound 1 was administered at a dose of 20 mg / kg, while compounds 3 and 4 were administered at 30 mg / kg in a 10 mL / kg solution. Compounds 1 and 3 were reconstituted in 5% ethanol, 20% Cremophor EL, and 75% saline. Compound 4 was reconstituted in saline. Plasma concentrations of compounds 1 and the N-acetyl metabolite were assessed at 0.5 h, 1 h, 1.5 h, 2 h, 4 h, and 6 h. Plasma concentrations of compound 1 after oral administration of compounds 1, 3, and 4 were shown in [data missing]. Figure 6 In, and the concentration of metabolites is shown in Figure 7 middle.

[0449] Table 2 summarizes the sparsely sampled non-compartmental pharmacokinetic (PK) parameters of these two studies. Based on similar molar doses and AUClast, compounds 3 and 4 delivered more compound 1 into systemic circulation 6 hours after oral administration than compound 1 administered directly. Compound 4 delivered a lower Cmax compared to compound 1, which, due to its lower Cmax and later Tmax, may reduce the incidence of adverse events in clinical trials. Metabolites formed at similar exposure levels regardless of whether it was a prodrug or ezogabine, but on a ratio basis, fewer metabolites were produced when compound 1 was administered as compound 3. When administered as a prodrug, compound 1 had a slightly longer MRTlast (mean residence time) than 6 hours, and when administered as compound 4 via subcutaneous injection, the compound had a longer half-life in mice. Based on AUClast / D values, the SC administration route delivered more compound 1 than the PO route when administered as compound 4.

[0450] Table 2. Non-compartmental PK parameters of compound 1 (ezogabine), metabolites and prodrugs after oral (PO) or SC administration.

[0451]

[0452] Cmpd-compound, NAM-N-acetyl metabolite, NC-not calculated, PO-oral, SC-subcutaneous, AUClast of 6 hours for PO route and 24 hours for SC route.

[0453] Figure 5A and Figure 5B Linear and semi-logarithmic plots of compounds 1 and 4 are shown after administration of compound 4 at 100 mg / kg SC in male mice. Figure 6 The semi-logarithmic plot of compound 1 is shown after administration of compound 1 at 20 mg / kg, compound 3 at 30 mg / kg, or compound 4 at 30 mg / kg in male mice via oral administration. Figure 7 The semi-logarithmic plots of N-acetyl metabolites after oral administration of compound 1 at 20 mg / kg, compound 3 at 30 mg / kg, or compound 4 at 30 mg / kg in male mice are shown.

[0454] Example 10

[0455] Pharmacokinetics of ezogabine prodrug in rats.

[0456] Bioanalytical methods were developed on an API 4000MS / MS system coupled with an Agilent 1100 HPLC and a CTC PAL autosampler, set at 4°C, for the detection of compound 1, its major metabolite N-acetyl metabolite, and either compound 3 or 4. Separation was achieved by HPLC operation in reverse phase using a 50 x 2 mm C8 column. Blood was collected via myocardial puncture using a 25G 3 / 4 length needle attached to a 1 mL syringe. When studying compound 4, the blood was transferred to a K2EDTA tube containing 500 mM citric acid in aqueous solution, or when studying compound 3, the blood was transferred to 500 mM citric acid containing 50 mM dichlorvos. The blood was diluted 10% with these stabilizers. These solutions were evaluated from a set of experiments to stabilize compounds 3 and 4, determining the optimal method for preserving the ezogabine prodrug in plasma prior to extraction.

[0457] Molecular extraction was performed by taking 50 μL aliquots of plasma and adding 200 μL of acetonitrile containing 200 ng / mL tolbutamide as an internal standard. Samples were precipitated in 96-well plates, centrifuged, and the aliquots were transferred to new wells, dried under heating and nitrogen, and then reconstructed under the initial mobile phase conditions of the LC-MS / MS method. Standard curves for compound 1 were prepared, separated from the prodrug regardless of the presence of N-acetyl metabolites. Standard curves were prepared for each analyte ranging from 5000 ng / mL to 1 ng / mL. Concentration data from the bioanalytical run were analyzed using Phoenix Winnonlin version 8 for non-compartmental PK analysis, plotting concentration-time curves, and listing PK parameters.

[0458] Male Sprague-Dürer rats weighing 225–250 g were cannulated via the jugular vein for intravenous administration and / or blood sample collection. Compound 1, Compound 3, or Compound 4 were administered to rats via intravenous, intramuscular, or oral routes, with two rats in each dose group. 150 μL of blood was collected at pre-specified time points. At the end of the study, animals were euthanized by asphyxiation with carbon dioxide gas and by exsanguination. Compounds 1 and 3 were prepared in 5% ethanol, 20% Cremophor EL, and 75% saline. Compound 4 was prepared in saline. Compounds 3 and 4 were administered via intravenous bolus at a dose of 5 mg / kg at a volume of 4 mL / kg. Compound 4 was administered via intramuscular injection at a dose of 75 mg / kg in the upper hind limbs of four rats at each time point at a volume of 0.5 mL / kg. Compounds 1, 3, and 4 were administered orally at equimolar doses of Compound 1. Compound 1 was administered at a dose of 20 mg / kg, while compounds 3 and 4 were administered at a dose of 30 mg / kg in a solution at a volume of 5 mL / kg.

[0459] Figure 8 The mean (standard deviation) of compound 4 after intramuscular (IM) administration is presented. Plasma concentrations of compound 1 after oral administration of compounds 1, 3, and 4 are presented as follows. Figure 9 In, and the concentration of metabolites is shown in Figure 10 middle.

[0460] Non-compartmental pharmacokinetic (PK) parameters were generated from individual rats and averaged for each study, summarized in Table 3. Based on a similar molar dose AUClast and a lower Cmax, compound 3 delivers more compound 1 into systemic circulation 24 hours after oral administration than compound 1 administered directly. Compared to compound 1 directly, compound 4 delivers a lower Cmax and an equivalent AUClast for the compound within 24 hours; however, it may be higher because there is no time point between 6 and 24 hours, and compound 1 has not yet begun to be cleared. The rate of formation of compound 1 in the prodrug is slower compared to the absorption rate when compound 1 is administered directly. This results in a later Tmax, which may reduce adverse events in early-onset treatment. The longer the half-life of the prodrug, the longer the half-life of compound 1. Based on AUClast / D, when administered as compound 4, the IM administration route delivers more compound 1 than the oral route. When administered as a prodrug, compound 1 has a slightly longer MRTlast (mean residence time) than 24 hours and a longer half-life in rats compared to autodrug administration. Compound 3 (unreported) was rarely exposed in systemic circulation after PO administration, while compound 4 (unreported) was slightly detectable in systemic circulation after PO administration.

[0461] Table 3. Non-compartmental mean PK parameters of compound 1 (ezogabine), metabolites and prodrugs after oral (PO), IV or IM administration.

[0462]

[0463]

[0464] Cmpd - compound, NA - not applicable, NAM - N-acetyl metabolite, NC - not calculated, PO - oral, IM - intramuscular, IV - intravenous, AUClast is 24 hours.

[0465] Figure 8 The semi-logarithmic plots of compounds 1 and 4 are shown after administration of compound 4 at 75 mg / kg IM to male rats. Figure 9 The semi-logarithmic plot of compound 1 after oral administration of compound 1 at 20 mg / kg, compound 3 at 30 mg / kg, or compound 4 at 30 mg / kg in male Sprague-Dürer rats is shown. Figure 10 The semi-logarithmic plots of N-acetyl metabolites after oral administration of compound 1 at 20 mg / kg, compound 3 at 30 mg / kg, or compound 4 at 30 mg / kg in male mice are shown.

[0466] Example 11

[0467] Ezogabin prodrug is inactive against the molecular targets Kv7.2 / 7.3.

[0468] Human Kv7.2 / 7.3 cells were collected, counted, and seeded at a density of 50,000 cells per well in 100 μl of black clear-bottomed 96-well plates and incubated overnight. The next day, the culture medium was removed, and 40 μl of loading buffer (4.895 mL HBSS:HEPES, 50 μl probenecid, 50 μl power loading, 5 μl FluxOR reagent) was added, and the plates were incubated at room temperature for 30 minutes. After incubation, the loading buffer was removed, and 40 μl of assay buffer (4.45 mL HBSS:HEPES, 500 μl FluxOR assay buffer, and 50 μl probenecid) was added, and the plates were incubated for 10 minutes. Then, FLIPR was added with 10 μl of stimulation buffer and the agonist, test compound, or reference agonist, and fluorescence was monitored for 5 minutes at ex / em: 488 nm / 510–570 nm. Compounds 3 and 4 were repeatedly tested at 7 concentration points from 0.03 to 30 μM, and ezogabine was repeatedly tested at 0.01 to 10 μM, and relative fluorescence units (RFU) were plotted against concentration. Compounds 3 and 4 showed no activity against the primary target of Kv7.2 / 7.3. The EC50 of compound 1 in this assay was... 50 The value is 1.6 μM.

[0469] Figure 11 In vitro screening of Kv7.2 / 7.3 voltage-gated potassium channels was demonstrated.

[0470] Example 11

[0471] Ezogab prodrug delivers an effective concentration of ezogabine in vivo to block maximum electric shock (MES) in mice.

[0472] CF-1 male mice (N=8) were treated with intraperitoneal injection (IP) with a mediator, compound 3, compound 4, compound 1, phenytoin, or diazepam (0 mg / kg, 150 mg / kg, 100 mg / kg, 100 mg / kg, 8 mg / kg, and 20 mg / kg, respectively), followed by 60 Hz corneal stimulation (50 mA). All treatments were administered 30 minutes before the start of MES, except for phenytoin, which was administered 1 hour before the start of MES.

[0473] All mice in the mediator group exhibited colonic seizures a few seconds after receiving MES. Mice treated with the remaining treatment typically reached a maximum duration of 6 seconds without showing signs of seizures.

[0474] Figure 12 The maximum electric shock (MES) test of CF-1 mice was demonstrated.

[0475] CF-1 mice (N=8) were treated with compounds 1, 3, and 4 (150 mg / kg, 100 mg / kg, and 100 mg / kg, respectively) via intraperitoneal injection (IP). Blood samples were collected after MES for compound 1 concentration analysis. After administration of compound 3 or compound 4, the plasma concentration of compound 1 was higher than that after administration of compound 1 alone. Figure 13 Compound 1 from compound 3 was 5.5 times higher, and compound 1 from compound 4 was 9 times higher.

[0476] Figure 13 The concentration of compound 1 in CF-1 mice is shown.

[0477] Example 12

[0478] Ezogab prodrug delivers an effective concentration of ezogabine in vivo to block maximal electric shock (MES) in rats.

[0479] SD rats (N=4) were treated with compound 4 (75 mg / kg) via intramyotherapy and given corneal stimulation at 60 Hz (100 mA). All treatments were performed at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, and 8 h before MES test administration, and those without seizures for 6 seconds were considered protected.

[0480] With increasing time, the protective effect against seizures in rats increased, with almost complete protection 1 hour after administration and complete protection 2 to 8 hours after administration. Figure 14 The mean time of seizures in the mean (SD) group was summarized.

[0481] Figure 14 The study demonstrated the protective effect of compound 4 against MES-induced seizures in SD rats after IM administration.

[0482] Example 13

[0483] In a CCI model of neuropathic pain, the reversal of compound 3's reflexivity to pinprick test of hind limb claw retraction and to von Frey hairs in response to Crizo's mechanical aberration pain was tested. Baseline sensitivity was assessed in male Sprague-Dürer rats (n=8 / group) on day 1 (ipsilateral and contralateral paws) after oral administration of XYG-203; 40 mg / kg on day 1, 20 mg / kg on day 3, 10 mg / kg on day 5, 5 mg / kg on day 7, 1 mg / kg on day 10, with baseline on day 12. Mechanosensitive responsiveness was assessed 1 hour after pretreatment. Data (mean ± SD) were analyzed using repeated measures ANOVA with Dunnet's adjustment for multiple comparisons. Compound 3, at 5 mg / kg, did not cross the baseline mean at the 95% confidence interval, and at 40 mg / kg, reduced the latency of neurogenic ipsilateral paw withdrawal by 9.2 seconds (p = 0.0003) and significantly increased the force of paw lifting. There were no significant differences in baseline values ​​between day 0 and day 12 for both ipsilateral and contralateral hind paws, indicating no learned behavior or cumulative drug effect in the ipsilateral paw. Furthermore, there were no significant changes in the contralateral paw response during the study. Results are shown in... Figure 15 , 16 and 17 in.

[0484] Compound 3 was administered in male cannulated rats at an equimolar dose of ezogabine (20 mg / kg) and in the same formulation (0.5% methylcellulose aqueous solution). Blood samples were collected at the same time points over 24 hours to generate concentration-time curves. Two male rats were administered to each group. Plasma samples were analyzed by LC / MS / MS, and the resulting concentration-time curves and p-K parameters are provided. At the given molar dose, the total ezogabine exposure provided by Cmpd 3 was >2 times that of ezogabine. Compound 3 was also substantially undetectable in systemic circulation.

[0485]

[0486] Compound 4 was evaluated in a rat formalin-induced inflammation model. The number of twitching / licking movements was recorded in a male CD1 mouse during the acute phase (0–10 min) and the inflammatory phase (15–40 min) following intrapedic administration of 50 μL of 5% formalin. Thirty minutes prior to formalin administration, physiological saline or compound 4 (100 mg / kg in water) was administered at 5 mL / kg SC (n = 8 groups). A 50% reduction in behavioral responses to compound 4 was observed in both phases compared to the mediator. Data were presented in a 2-minute incubator throughout the observation period. Compound 4 showed a reduction in inflammatory pain. Results are shown in… Figure 18 middle.

[0487]

[0488] Compounds 4, 6, and 29 were administered in male cannulated jugular rats at equimolar doses of ezogabine (20 mg / kg) and in the same formulation (0.5% methylcellulose aqueous solution). Blood samples were collected at the same time points over 24 hours to generate concentration-time curves. Two male rats were administered to each group. Plasma samples were analyzed by LC / MS / MS, and the resulting concentration-time curves and p-values ​​are provided. The dose-normalized AUC total exposure of ezogabine delivered by Cmpd 4, 6, and 29 was similar to that of ezogabine itself. However, cmpd 4 showed the lowest plasma exposure, followed by cmpd 29. The Cmax of ezogabine delivered by Cmpd 4 and 29 was approximately half that of ezogabine itself, while the Cmax of ezogabine delivered by Cmpd 6 was approximately twice that of ezogabine itself.

[0489]

[0490] The results are shown in Figure 19 middle.

[0491]

[0492] Compound 28 was tested in CF-1 mice at 30 minutes after administration via the IP route for maximal electric shock assays to determine its ability to release ezogabine and provide protection for the assays. Drug concentrations of compound 28, ezogabine, and pregabalin in plasma and brain were analyzed by LC / MS / MS. The dose-response of compound 28 at 1.5 mg / kg, 3 mg / kg, 6 mg / kg, 12 mg / kg, and 24 mg / kg mediators was evaluated in response to maximal electric shock. Drug levels of ezogabine and compound 28 were assessed. Exposure to compound 28, ezogabine, and pregabalin in plasma and brain was evaluated in another group at 24 mg / kg. No single dose completely prevented MES-induced seizures. One out of nine animals was protected from MES-induced seizures at 12 mg / kg, and three out of nine animals were protected at 24 mg / kg. However, the protective effect significantly increased with increasing ezogabine concentrations. Compound 28 was also present at a higher concentration than ezogabine, indicating that it had not completely released ezogabine. The results are shown in... Figure 20 and 21 middle.

[0493] Compound 28 was also administered in male cannulated rats at an equimolar dose of ezogabine (20 mg / kg) in the same formulation (0.5% methylcellulose in water). Blood samples were collected at the same time points over 24 hours to generate concentration-time curves. Two male rats were administered to each group. Plasma samples were analyzed by LC / MS / MS, and the resulting concentration-time curves and p-K parameters are provided. At the given molar dose, Cmpd 28 provided a lower total exposure to ezogabine than ezogabine. Both ezogabine and compound 28 were present in rats at similar concentrations.

[0494]

[0495] The results are shown in Figure 22 middle.

[0496]

[0497] The efficacy of compound 29 at an oral dose of 30 mg / kg was evaluated in a mouse maximum electric shock (MES) assay. After the assay, blood samples were collected for plasma analysis of compound 29 and ezogabine by LC / MS / MS. One data point was provided for each male CF-1 mouse in the MES assay and one data point in the concentration analysis. Eight mice were included at each time point. Ezogabin showed very high plasma exposure and was present in the brain, with decreasing concentrations at 0.25 h, 0.5 h, and 1 h. Pharmacological response decreased with decreasing brain concentration. Results are shown in… Figure 23 middle.

[0498] Example 14

[0499] Stability of ezogabine and prodrug in acid and organic solutions.

[0500] Ezogabin is insoluble at neutral pH but soluble at low pH. However, it degrades and forms chromophore dimers in low pH (1N HCl) and simulated gastric juices (hydrochloric acid, sodium chloride, and pepsin). An HPLC-UV-Vis method was developed using 0.1% formic acid / water as mobile phase A and 0.1% formic acid / acetonitrile as mobile phase B. A gradient method was developed on a 4.6 x 50 mm Zorbax C-18 column, with a gradient from 10% A to 90% B over 8 minutes and then back to 10% A over 8.5 minutes. 10 μL of the stability solution was injected for analyte detection.

[0501]

[0502] When ezogabine was prepared in simulated gastric juice (SGF) at a concentration of 8 mg / mL and stored at 38°C, the concentration of the dimer in the solution increased to 1980 ng / mL within 8 hours. The percentage and concentration of the dimer are shown in the table below. The structure of the dimer is presented.

[0503] SGF blank 0 0.00 ng / mL SGF time 0 0 0.00 ng / mL SGF time 1 hour 0.250％ 19.5 ng / mL SGF time 4 hours 7.95％ 623ng / mL SGF time 8 hours 25.2％ 1980 ng / mL

[0504] Ezogabin was prepared at a concentration of 5 mg / mL in a weak acid (0.1 N HCl), methanol, and acetonitrile, and its degradation at room temperature for up to 2 weeks was evaluated. Aliquots were collected at consecutive time points and then diluted to a nominal concentration of 100 μg / mL for injection into HPLC, monitored at 250 nm using a diode array detector. Data for approximately 10 days are presented. The acid solution turned pale purple on day 2 (indicating degradation), while the organic solvent solution did not begin to turn purple until day 7.

[0505]

[0506]

[0507] Compound 3 was prepared at a concentration of 5 mg / mL in acidic solutions (0.1 N and 1.0 N HCl), ethanol, methanol, and acetonitrile, and its degradation at room temperature for up to 3 weeks was evaluated. Aliquots were collected at consecutive time points and then diluted to a nominal concentration of 100 μg / mL for injection into HPLC, monitored at 250 nm using a diode array detector. Compound 3 turned light brown in 0.1 N HCl and golden yellow by day 9 in 1 N HCl. Organic solvents were clear and colorless by day 18. Compound 3 was converted to ezogabine under acidic conditions but not in organic solvents.

[0508]

[0509] Compound 4 was prepared at 5 mg / mL in acidic solutions (0.1N, 1N, 2N HCl), phosphate-buffered saline (PBS), and methanol, and its degradation at room temperature for up to 3 weeks was evaluated. Evaluation was also performed in 2N HCl at 37°C. Aliquots were collected at consecutive time points and then diluted to a nominal concentration of 100 μg / mL for injection into HPLC, monitored at 250 nm using a diode array detector. Compound 4 remained clear and colorless until day 18. Compound 4 showed very little degradation to ezogabine and therefore did not form dimers under acidic conditions.

[0510]

[0511] Compound 6 was prepared at a concentration of 5 mg / mL in acidic solutions (1N, 2N HCl) and methanol, and its degradation at room temperature for up to 3 weeks was evaluated. Evaluation was also performed in 2N HCl and at 37 °C. Aliquots were collected at consecutive time points and then diluted to a nominal concentration of 100 μg / mL for injection into HPLC, monitored at 250 nm using a diode array detector. Compound 6 remained clear and colorless until day 18. Compound 6 showed very little degradation to ezogabine and therefore a low likelihood of dimer formation under acidic conditions.

[0512]

[0513] Compound 28 was prepared at a concentration of 5 mg / mL in acidic solutions (0.1N, 1N, 2N HCl) and methanol, and its degradation at room temperature for up to 3 weeks was evaluated. Evaluation was also performed in 2N HCl and at 37 °C. Aliquots were collected at consecutive time points and then diluted to a nominal concentration of 100 μg / mL for injection into HPLC, monitored at 250 nm using a diode array detector. Compound 28 remained clear and colorless in acidic solutions and acetonitrile on day 11, and in methanol on day 7. Compound 28 exhibited degradation of ezogabine with increasing acid strength.

[0514]

[0515] Compound 29 was prepared at 5 mg / mL in acidic solutions (0.1N, 1N, 2N HCl), acetonitrile, and methanol, and its degradation at room temperature for up to 3 weeks was evaluated. Evaluation was also performed in 2N HCl and at 37 °C. Aliquots were collected at consecutive time points and then diluted to a nominal concentration of 100 μg / mL for injection into HPLC, monitored at 250 nm using a diode array detector. Compound 28 remained clear and colorless in acidic solution on day 18 and in methanol on day 3. Compound 29 exhibited degradation under acidic conditions and also converted to ezogabine, and thus could form a dimer under acidic conditions.

[0516]

[0517] All publications, patents and patent applications referenced in this specification are incorporated herein by reference for the purpose of teaching the use of such references.

[0518] The test compounds used in the experiments described herein were employed in free or salt form.

[0519] The observed specific response may vary depending on the specific active compound selected or the presence of a carrier, as well as the type of formulation and administration method employed, and such expected variations or differences in results are contemplated in accordance with the practice of this disclosure.

[0520] Although specific embodiments of this disclosure have been detailed and described herein, this disclosure is not limited thereto. The above detailed description is provided as an example of this disclosure and should not be construed as constituting any limitation thereof. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of this disclosure are to be included within the scope of the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof: Compound 28.

2. A pharmaceutical composition comprising the compound according to claim 1 and one or more pharmaceutically acceptable excipients.

3. Use of the compound according to claim 1 for preparing a medicament to induce one or more of the following effects in a patient in need: antiepileptic, muscle relaxant, antipyretic, peripheral analgesic, or anticonvulsant.

4. Use of the compound according to claim 1 for preparing a medicament to treat one or more of the following depressions: depression in cancer patients; depression in Parkinson's disease patients; post-myocardial infarction depression; depression in patients with human immunodeficiency virus (HIV); subsyndromic symptomatic depression; depression in infertile women; childhood depression; major depressive disorder; single episode depression; recurrent depression; child abuse-induced depression; postpartum depression; psychotic depression; post-stroke depression.

5. Use of the compound according to claim 1 for preparing a medicament to treat one or more of the following depressions: DSM-IV major depressive disorder; treatment-resistant major depressive disorder; severe depression; bipolar disorder with mixed episodes and bipolar disorder with depressive episodes; major depressive disorder with dysphoric mood.

6. Use of a compound according to claim 1 for preparing a medicament to treat, improve, or prevent the progression of a disease or condition, said disease or condition being selected from the group consisting of: seizures, pain, drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative disorders or diseases or injuries, cognitive deficits, obsessive-compulsive behaviors, dementia, depression, Huntington's disease, dystonia, mania, memory loss, memory impairment, Parkinson's disease, phobias, Pick's disease, bipolar disorder, schizophrenia, spinal cord injury, cardiomyopathy, arrhythmia, long QT syndrome, activity disorders or movement disorders, myasthenia gravis, migraine, tension headache, intestinal disorders, inflammatory diseases, Crohn's disease, Crout-Jacob disease, ophthalmic symptoms, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes or metastatic tumor growth, pneumoconiosis, and obesity and disease-related hypertension.

7. Use of the compound according to claim 1 for preparing a medicament to treat, improve or prevent the progression of a disease or condition, said disease or condition being selected from the group consisting of: neurodegenerative diseases, psychosis.

8. Use of a compound according to claim 1 for preparing a medicament to treat, improve, or prevent the progression of a disease or condition, said disease or condition being selected from the group consisting of: neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, postherpetic neuralgia, and peripheral nerve injury, cognitive impairment, memory impairment, movement disorder, aluminosis, coal mine pneumoconiosis, asbestosis, stone pneumoconiosis, ostrich feather pneumoconiosis, iron pneumoconiosis, silicosis, smoke pneumoconiosis, and cotton dust pneumoconiosis, and chronic obstructive pulmonary disease (COPD).

9. Use of the compound according to claim 1 for preparing a medicament to treat, improve, or prevent the progression of Parkinson's-like movement disorder.

10. Use of the compound according to claim 1 for preparing a medicament to treat one or more movement disorders, said one or more movement disorders being selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / movement disorder, tardive dystonia, neurodepressant-induced dystonia, treatment-induced dystonia / movement disorder in patients with Parkinson's disease, hereditary degenerative dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette syndrome, dystonia in patients with restless legs syndrome, dystonia-like symptoms in patients with tics, dystonia-related movement disorders, paroxysmal movement disorders, paroxysmal nonmotor movement disorders, paroxysmal dystonia-choreoathetosis, paroxysmal kinesthesia, paroxysmal kinesthesia-choreoathetosis, movement-induced movement disorders, sleep-related paroxysmal movement disorders, drug-induced movement disorders, myofascitis, neurogenic myotonia, autism, and autism spectrum disorders.

11. Use of the compound according to claim 1 for preparing a medicament to deliver a broad-spectrum Kv7.2-7.5 active molecule into systemic circulation and to release an effective concentration of the active Kv channel opener at a therapeutic concentration to treat one or more susceptible diseases or conditions.

12. The use according to claim 11, wherein the release of said active molecule is provided under one or more of the following conditions: Enhanced by increasing absorption; Delaying the onset time to improve adverse events occurring during treatment; and Increase half-life or dwell time by delaying the cycle and releasing. This avoids the need to develop improved, sustained, delayed, or slow-release formulations.

13. Use of a compound according to claim 1 for preparing a medicament to treat neuropathic pain; bipolar disorder; seasonal affective disorder; bipolar disorder BP I; bipolar disorder BP II; dysphoric disorder; phobias; eating disorders; chemical dependence; Parkinson's disease; headache; withdrawal syndrome; age-related learning and mental disorders; emotional blunting; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorder; somatic symptom disorder; incontinence; aspiration disorder; poisoning disorder; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase affective disorder; specific developmental disorder; SSRI "fecal incontinence" syndrome, or failure of a patient to maintain a satisfactory response after the initial period of satisfactory response to SSRI therapy; and one or more of the following:

14. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of agoraphobia, social phobia, or simple phobia; anorexia nervosa or bulimia nervosa; addiction to alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; dementia in Parkinson's disease, depressant-induced Parkinson's disease or tardive dyskinesia; headache associated with vascular disease; somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder and somatic form NOS; and one or more of Tourette's disease.

15. Use of the compound according to claim 1 for preparing a medicament to treat, improve or prevent the progression of a disease or condition, said disease or condition being selected from the group consisting of: subtypes of schizophrenia as tension subtype, paranoid subtype, anisocytic subtype or residual subtype, and ulcerative colitis.

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