JP2013536178A - Arylsulfonamide derivatives, compositions, and methods of use - Google Patents

Abstract

The present invention provides acylsulfonamides, including bumetanide derivatives, and compositions comprising such analogs. All of these analogs include addictive disorders, Alzheimer's disease, anxiety disorders, ascites, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar disorder, cancer, cognitive function Improvement, cognitive dysfunction, cognitive dysfunction, depression, corneal endothelial dystrophy, edema, epilepsy, glaucoma, Huntington's disease, inflammatory pain, insomnia, ischemia, migraine, migraine with aura, migraine without aura Neuropathic pain, nociceptive neuralgia, nociceptive pain, eye disease, pain, Parkinson's disease, periodic limb movement disorder (PLMD), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), For the treatment and / or prevention of conditions involving Na + K + Cl− cotransporter or GABAA receptors, including schizophrenia, seizure disorders, spasticity, tinnitus, and withdrawal syndrome It is particularly useful to.

Description

This International Patent Application claims priority to US Provisional Patent Application No. 61 / 367,709, filed July 26, 2010, the disclosure of which is hereby incorporated by reference. Incorporated.

The present invention relates to arylsulfonamide derivatives, their positional isomers, and prodrugs, compositions containing them, and methods of making and using them. The invention also relates to pharmaceutical compositions comprising these compounds and methods of using these compounds. The compounds described herein include, but are not limited to, addictive disorder, anxiety disorder, ascites, attention deficit hyperactivity disorder (ADHD), bipolar disorder, cancer, depression, edema, corneal endothelial dystrophy Na ⁺ K ⁺ Cl ⁻ cotransport, including epilepsy, glaucoma, inflammatory pain, ischemia, migraine, neuropathic pain, nociceptive pain, eye disease, pain, postherpetic neuralgia, and schizophrenia It is particularly useful for the treatment and / or prevention of diseases, disorders, and conditions that involve the body (NKCC1 or NKCC2 or combinations thereof). The compounds described herein also include, but are not limited to, Alzheimer's disease, addictive disorders, anxiety disorders, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar Disability, cognitive function (eg cognitive dysfunction, cognitive dysfunction), depression, epilepsy, Huntington's disease, inflammatory pain, insomnia, migraine, migraine with aura, migraine without aura, neuropathic pain , Nociceptive pain, pain, Parkinson's disease, periodic limb movement disorder (PLMD) (nocturnal myoclonus), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, seizure disorder, spasticity It is particularly useful for the treatment and / or prevention of diseases, disorders, and conditions involving GABA _A receptors, including tinnitus, and withdrawal syndrome.

BACKGROUND OF THE INVENTION Na ⁺ K ⁺ Cl ⁻ Cotransporter In the absorptive and secretory epithelia, transcellular ion transport is a specific plasma membrane protein for mediating the entry and exit of ions from cells. Depends on. In the basolateral membrane of almost all epithelia (except for the choroid plexus), sodium withdrawal and potassium entry occur via Na ⁺ K ⁺ -ATPase, providing driving force for Na ⁺ influx and K ⁺ efflux. Create a constituent electrochemical gradient. The transport of these ions according to their ion gradient can be achieved by specific ion channels, allowing the ions to pass through the membrane alone or by the transporter. In transporters, Na ⁺ or K ⁺ transport is accompanied by other ions or solutes by several different solute transporters. These membrane proteins are known as secondary transporters because ion transfer does not depend on ATP hydrolysis but rather on the gradient produced by the primary transporter. The secondary transport mechanism for transcellular ion transport in epithelial cells involves coupling of cations (Na ⁺ or K ⁺ ) with chloride (Cl ⁻ ) with 1: 1 stoichiometry, and thus The ion transfer does not cause a change in the membrane potential difference. For this reason, these transporters are known as electronically neutral cation-chloride coupling cotransporters. In addition to being highly implicated in ion absorption and secretion mechanisms, electronically neutral cation-chloride coupling cotransporters maintain and regulate cell volume in both epithelial and non-epithelial cells. Plays an important role. Since Na ⁺ influx and K ⁺ efflux by electronically neutral cotransporters are rapidly corrected by Na ⁺ K ⁺ -ATPase, the net effect of its activity is Cl ⁻ to the inside or outside of the cell. Is a move. It is known that changes in intracellular chloride concentration are accompanied by changes in cell volume. Finally, various novel physiological roles for electronically neutral symporters are emerging (eg, regulation of intraneuronal Cl ⁻ concentration, and thus modulation of neurotransmission). Gamba (2005), Physiol. Rev. 85: 423-493.

Four groups of electronically neutral co-transport systems (also known as “symporters”) are sensitive to cations coupled with chloride (s), stoichiometry of the transport process, and sensitivity to inhibitors. Have been functionally identified on the basis. These systems consist of (1) benzothiadiazine (or thiazide) sensitive Na ⁺ Cl ⁻ cotransporter; (2) sulfamoylbenzoic acid (or bumetanide) sensitive Na ⁺ K ⁺ 2Cl ⁻ cotransporter; (3) sulfamoyl. A benzoic acid (or bumetanide) sensitive Na ⁺ Cl ⁻ cotransporter; and (4) a dihydroindenyloxy-alkanoic acid (DIOA) sensitive K ⁺ Cl ⁻ cotransporter. There is some overlap in sensitivity to inhibitors in the last two groups. This is because the Na ⁺ K ⁺ 2Cl ⁻ and K ⁺ Cl ⁻ cotransporters can be suppressed by high concentrations of DIOA or loop diuretics, respectively. However, the affinity for the inhibitor and the cations coupled to the chloride are clearly different between both groups of transporters. Gamba (2005), Physiol. Rev. 85: 423-493. Loop diuretics (eg, bumetanide, furosemide, piretanide, azosemide, and torsemide) are antagonists of the Na ⁺ K ⁺ Cl ⁻ cotransporter (eg, NKCC2) in the thick ascending limb of Henleloop, due to the Cl ⁻ binding site It acts to inhibit the reabsorption of sodium and chloride by competing with each other. See also Russell (2000), Physiological Reviews, 80 (1): 211-275.

  Major progress has been made in the past decade in identifying and characterizing molecules in solute carriers. As of 2005, the Human Genome Organization (HUGO) Nomenclature Committee database includes single transporters (passive transporters), cotransporters (coupling transporters), counter transporters (exchangers), vesicular transporters, and It recognizes 43 solute carrier (SLC) families, including a total of 298 transporter genes encoding mitochondrial transporters. This amount of solute carrier gene represents approximately 1% of the total pool of genes that have been calculated to constitute the human genome. Gamba (2005), Physiol. Rev. 85: 423-493.

One isoform (NKCC1) of the Na ⁺ K ⁺ Cl ⁻ cotransporter (NKCC) is widely distributed throughout the body. NKCC1 transports sodium, potassium, and chloride into cells. NKCC1 is also found throughout the nervous system and is expressed on astrocytes, oligodendrocytes, and Schwann cells. Lenart et al. (2004), The Journal of Neuroscience, 24 (43): 9585-9597. Another isoform, NKCC2, is found primarily in the kidney and plays a role in extracting sodium, potassium, and chloride from urine. Haas (1994), Am J Physiol Cell Physiol, 267: C869-C885.

Mediators of transcellular Cl ^- cotransport (Na-Cl cotransporters, NKCC1, NKCC2, KCC1, and KCC2) are all related members of the SLC12A family of cation / Cl ^- cotransporters. Each utilizes an inward Na ⁺ gradient or an outward K ⁺ gradient to move Cl ⁻ into or out of the cell, respectively. The importance of this family of transporters is their use as pharmacological targets (thiazide diuretics act on NKCC, loop diuretics act on NKCC2), and these mutations can be used in various diseases. Emphasized by bringing. For example, perturbation of NKCC1 in mice results in hearing loss, changes in pain perception, neuronal excitability, and changes in blood pressure. Kahle et al. (2004), Proc. Natl. Acad. Sci. USA, 102 (46): 16783-16788.

Regulation of Cl ^- transport to and from cells also plays a crucial role in maintaining intracellular volume and excitability of GABA-responsive neurons regulated by at least two ion cotransporters. Cl ⁻ influx is mediated by NKCC1 that mediates Cl ⁻ influx, and KCC1 or KCC2 that mediates Cl ⁻ efflux. Kahle et al. (2004), Proc. Natl. Acad. Sci. USA, 102 (46): 16783-16788. Maintenance of intracellular and extracellular electrolyte homeostasis can be attributed to a wide range of essential physiological processes (general functions (eg, maintaining proper cell volume), specialized cellular functions (eg, controlling neuronal excitability) ), And overall function (eg, regulation of blood pressure). This homeostasis is achieved by the regulated movement of Na ⁺ , K ⁺ , and Cl ⁻ across the cell membrane by ion channels, cotransporters, exchangers, and pumps that cause electrolyte flow through the membrane. Kahle et al. (2004), Proc. Natl. Acad. Sci. USA, 102 (46): 16783-16788.

The dominant mechanism by which intracellular volume is maintained in cells in response to changes in cell externality increases or decreases intracellular Cl ⁻ concentration ([Cl ⁻ ] _i ), thereby causing water flow through the membrane. Is to minimize. [Cl ⁻ ] _i is modulated by changing the balance of Cl ⁻ entry and exit. The main mediator of Cl ^- entry is NKCC1, and Cl ^- exit is largely mediated by KCC1. Both of these symporters are regulated by the degree of cell exocytosis. Hypertonicity activates NKCC1 and suppresses KCC1, while hypotonicity has the opposite effect. Kahle et al. (2004), Proc. Natl. Acad. Sci. USA, 102 (46): 16783-16788.

Similar systems play an important role in the control of neuronal excitability, and variations in [Cl ⁻ ] _i in neurons are determined by a mechanism very similar to the mechanism governing cell volume. Cl ⁻ influx occurs mostly by NKCC1, while Cl ⁻ efflux is mediated by KCC2, a neuron-specific K-Cl cotransporter. Kahle et al. (2004), Proc. Natl. Acad. Sci. USA, 102 (46): 16783-16788.

GABA Receptor Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system (CNS). In the central nervous system, approximately 30% of all synapses use GABA as a transmitter. Thus, GABA receptors are critical for balancing proper cognitive function and excitatory and inhibitory signals in the brain. There are three classes of GABA receptors: GABA _A (ligand-gated ion channel), GABA _B (G protein-coupled receptor), and GABA _C (ligand-gated ion channel). Chloride flow into the cell results from activation of the GABA _A receptor through binding of GABA molecules, hyperpolarizing the resting membrane potential and reducing the chance that post-synaptic neurons propagate the action potential.

The GABA _A receptor is a pentamer and approximately 19 GABA receptor subunits have been cloned from mammals (6 α subunits, 3 β subunits, 3 γ subunits). 1 δ subunit, 1 ε subunit, 1 θ subunit, 1 π subunit, and 3 ρ subunits). GABA subunit heterogeneity is further increased by alternative splicing (eg, short γ2 and long γ2 are the two major splice variants of γ2). In general, a functional GABA _A receptor requires two α subunits, two β subunits and a third “regulatory” subunit (usually γ or δ). Patent Document 1. The particular subunit combination determines the pharmacological and ligand binding properties of the GABA _A receptor. The most abundant subunit combination found in the CNS is α ₁ β ₂ γ ₂ . This subtype represents approximately 40% of GABA _A receptors in the brain, is expressed across the CNS, and is located on postsynaptic cells. Patent Document 2.

The importance of [Cl ⁻ ] _i regulation has been recognized by the discovery that GABA neurotransmission is not uniformly inhibitory (eg, GABA neurotransmission is predominantly excitatory in neonatal period). When [Cl ⁻ ] _i is below its equilibrium potential, Cl ⁻ enters the cell, resulting in hyperpolarization and inhibition. When [Cl ⁻ ] _i exceeds its equilibrium potential, GABA induces Cl ⁻ efflux, depolarization, and neuronal excitation. Similarly, neurons in the suprachiasmatic nucleus show circadian variation in their response to GABA and the ability to dynamically regulate [Cl ⁻ ] _i . Finally, GABA neurotransmission in the peripheral nervous system is predominantly excitable.

GABA _A receptors are a wide range of therapeutically and clinically relevant compounds, including benzodiazepines, barbiturates, neurosteroids, ethanol, certain intravenous anesthetics, and subtype-specific modulators (eg, zolpidem) Is the target of. These compounds serve as anxiolytics, sedatives / hypnotics, antiepileptics (AEDs), and memory enhancers. Many of these therapies are effective but cause side effects by unwanted effects in the α ₁ GABA _A and / or α ₂ GABA _A variants, or by a low therapeutic index. For example, benzodiazepines, such as diazepam (VALIUM), are excellent anxiolytic agents but provide unwanted sedation. Patent Document 2.

At the cellular level, GABA _A receptors are located at both pre-synaptic sites, post-synaptic sites, and extrasynaptic positions (pre-synaptic and extra-synaptic are defined herein as near-synaptic to distinguish them from post-synaptic). Expressed and at these sites GABA _A receptors respond to large changes in GABA concentration caused by the release of neurotransmitters into the synaptic space, and outside the synapse, these receptors are synaptic junctions Responds to lower concentrations of GABA that "leak" from Postsynaptic receptors respond to acute changes in neuronal firing, and presynaptic receptors are involved in suppressing GABA release in the setting of high GABA levels, whereas extrasynaptic receptors are global in the neuronal network Is involved in maintaining the right direction. Patent Document 1. Strain suppression occurs by sustained activation of extrasynaptic (peri-synaptic) GABA _A receptors and regulates the excitability of individual neurons and neural networks. Jia et al. (2008) The Journal of Pharmacology and Experimental Therapeutics, 326 (2): 475-482.

Presynaptic GABA _A receptors located at the external synaptic location can include α ₄ βδ and α ₆ βδ isoforms. Extrasynaptic α ₄ βδ GABA _A receptor isoforms and α ₆ βδ GABA _A receptor isoforms show significant sensitivity to GABA, alcohol, and anesthetics, which are physiological and pathological This suggests that in both situations, it may present a critical site for regulating synaptic function in the developing brain. Xiao et al. (2007), J Physiol. 580 (Pt. 3): 731-43. For example, temporal lobe epilepsy (TLE), Parkinson's disease (PD), and Huntington's disease (HD) are neurodegenerative disorders that involve disturbances in GABA signaling. TLE attacks reflect excessive excitement that may be due to local inhibitory circuit dysfunction. PD destroys input to striatum GABAergic neurons, and HD destroys striatum GABAergic neurons. Directing the synthesis, degradation, release, transport or receptor of GABA may be useful in controlling GABA signaling in specific brain regions as it is useful for each of these diseases. Thus, novel drugs that target GABA synthesis, release, and binding may be useful for epilepsy and improved therapeutic treatment for both Parkinson's disease and Huntington's disease. Kleppner and Tobin (2001), Expert Opin The Targets. 5 (2): 219-39. Shumate et al. (1998), Epilepsy Research (32): 114-128; Fritschy (2008), Frontiers in Molecular.
Neuroscience, 1 (5): 1-5; Roberts et al. (2006), The Journal of Biological Chemistry, 281 (40): 29431-29435; and Roberts et al., PNAS, 102 (33). No.): 11894-11899.

Addictive disorders Addictive and / or obsessive-compulsive disorders, such as eating disorders (including obesity), stimulants, narcotics (eg, cocaine, heroin), sedatives / hypnotics, and addiction / physical dependence (alcohol) Addiction and smoking are major public health issues that affect society at multiple levels. Substance abuse alone has been estimated to cost over $ 484 billion annually in the United States.

The alcohol sensitive α ₄ βδ GABA _A receptor has also been postulated to be involved in alcohol addiction (alcohol dependence). For example, decreased expression of GABA _A receptors containing the alpha ₄ subunit in the nucleus accumbens (NAc) reduced the free consumption and preferences of alcohol in rats. Furthermore, the nucleus accumbens contributes to the rewarding and strengthening effects of drugs including alcohol, indicating that GABA _A receptors in NAc, especially the α ₄ βδ isoform, are important mediators of alcohol self-administration. Suggests. Rewal et al. (2009), The Journal of Neuroscience, 29 (2): 543-549. Most GABA _A receptor subunit combinations can be activated by high (anesthetic) alcohol concentrations, but to date very specific GABA _A receptor subunit combinations (δ subunits) And (containing the β ₃ subunit) only show a dose dependence that reflects blood alcohol levels associated with mild to moderate poisoning in humans. These δ subunit-containing GABA _A receptors containing the δ subunit are located outside or around the synapse but not in the subsynaptic membrane. Patent Document 2.

Current strategies for the treatment of additive disorders include psychological counseling and support, use of therapeutic agents, or a combination of both. Various drugs known to affect the central nervous system have been used in various situations to treat some indications that are directly or indirectly related to addictive behavior, but improved addictive disorders There is still a great need for a cure. GABA _A specific agents may be an effective treatment for addictive behavior.

Alzheimer's disease Alzheimer's disease (AD) is an age-related irreversible brain disorder that occurs over a period of several years and is the most common cause of dementia among people over the age of 65. Initially, a person experiences memory loss and confusion, which can be mistaken for the type of memory change associated with normal aging. However, AD symptoms gradually lead to problems with behavior and personality changes, cognitive decline (such as decision making and language skills), and recognition of family and friends. AD ultimately leads to severe loss of mental function. NINDS Alzheimer's Disease Information Page (2009).

  AD results in neuronal death in the brain. When neurons die across the brain, the affected area begins to atrophy. By the final stage of AD, the damage has spread and brain tissue has shrunk significantly. Two major salient features associated with AD disease processes in the brain are amyloid plaques and neurofibrillary tangles. Amyloid plaques include fragments of β-amyloid peptide mixed with a collection of additional proteins, and neuronal remnants. Neurofibrillary tangles (NFT) are found in neurons and contain tau protein. NINDS Alzheimer's Disease Information Page (2009).

Currently there are no drugs that can slow the progression of AD. However, four medications approved by the FDA are used to treat AD symptoms. Donepezil (Alicept), rivastigmine (Exelon), galantamine (Reminyl), and memantine (Namenda) are prescribed to treat symptoms of AD. NINDS Alzheimer's Disease Information Page (2009). Moreover, treatment of the AD transgenic mouse model with picrotoxin, a GABA _A antagonist, showed improved cognitive function in mice. Yoshiike et al. (August 21, 2008), PLoS One. 3 (8): e3029. Furthermore, NKCC1 expression was found to be elevated in AD patients. Johanson et al. (2004), Cerebrospinal Fluid Research, 1: 3. Unfortunately, these medications do not seem to stop or reverse AD and only help individuals for months to years. Thus, novel treatments based on the regulation of GABA _A receptor activity may alleviate the symptoms of AD.

Anxiety disorders Anxiety disorders fall into several subtypes. Anxiety, acute anxiety, panic disorder, social anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, panic symptoms, post-traumatic stress disorder (PTSD), generalized anxiety disorder, and specific phobia. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th edition (1994).

  As one group, anxiety disorders have the highest prevalence of all mental disorders in the United States, afflict 15.7 million people each year in the United States, and 30 million at some point in their lives in the United States. Tormenting people. Lepine (2002), J.M. Clin. Psychiatry. 63: Supplement 14: 4-8; Kessler et al. (1994), Arch Gen Psychiatry 51: 8-19.

  Several animal models are recognized in the art as predicting anxiolytic activity. These are described in Davis, Psychopharmacology, 62: 1: 1979, Behav. Neurosci. , 100: 814; 1986 and TiPS, January 1992, Vol. 13, pages 35-41, the fear-enhanced startle model, Lister, Psychopharmacol, 92: 180-185; 1987 The elevated plus model described by the year, and “Psychopharmacology of Anxiolytics and Antipressants”, S. E. Includes the well-known punishment (conflict) model described in File, pp. 131-153, Raven Press, New York, 1991.

Anxiety disorders are generally treated with drugs and psychotherapy. The most commonly prescribed drugs for all types of anxiety are benzodiazepines and selective serotonin reuptake inhibitors (SSRIs). However, while these drugs are effective, both benzodiazepines and SSRIs have adverse effects during treatment. Denys and de Geus (August 2005), Curr Psychiatry Rep. 7 (4): 252-7. In addition, a number of side effects such as sexual dysfunction and weight gain are associated with long-term use of SSRIs. Hirschfeld (2003), J.M. Clin. Psychiatry. 64: Supplement 18: 20-4. In addition, existing drugs that target the postsynaptic type of GABA _A receptors produce undesired results because they target indiscriminately the majority of GABA _A receptors in the brain. Patent Document 3. There is a great need for improved anxiety treatments in view of those that do not respond and adverse side effects.

Ascites Ascites is an excess of fluid in the space between the tissues lining the abdomen and the abdominal organs (peritoneal cavity), typically caused by liver disease. Disorders that can be associated with ascites include cirrhosis, hepatitis, portal thrombosis, constrictive pericarditis, congestive heart failure, liver cancer, ovarian cancer, protein-losing enteropathy, nephrotic syndrome, and pancreatitis . Although some drugs are available for the treatment of ascites (eg, furosemide), there remains a great need for improved ascites treatment. Shiozaki et al. (2006), J. MoI. Physiol. Sci, 56 (6): 401-406.

Attention deficit hyperactivity disorder (ADHD)
ADHD is a problem with inattention, overactivity, impulsivity, or a combination. ADHD is the most commonly diagnosed behavioral disorder in childhood. ADHD affects about 3-5% of school-aged children. ADHD is diagnosed more in boys than in girls. Although ADHD can be transmitted in families, it is not clear what exactly causes ADHD. Whatever the cause, ADHD appears to occur in younger years as the brain develops. Depression, sleep deprivation, learning deficits, tic disorders, and behavioral problems can be confused with ADHD or appear with ADHD. All children suspected of having ADHD should be carefully examined by a physician to rule out other possible conditions or reasons for behavior. Most children with ADHD also have at least one other developmental or behavioral problem. Most children with ADHD can also have psychiatric problems (such as depression or bipolar disorder). ADHD symptoms are divided into three groups: lack of attention (carelessness), hyperactivity, and impulse behavior (impulsivity). Some children struggle primarily with carelessness, while others have a combination of these symptoms. ADHD is difficult to diagnose but can be identified by a series of developmental, mental, nutritional, physical, and psychosocial tests. Attention definition hyperactivity disorder (ADHD), (2011), PubMed Health.

  Current treatments for ADHD are pharmaceutical combinations (eg, amphetamine-dextroamphetamine (ADDERRAL), dexmethylphenidate (FOCALIN), dextraamphetamine (DEXEDRINE, DEXTROSTATT), risdexamphetamine (lisdexminamine et al.). ) (Vyvance), and methylphenidate (RITALIN) and behavioral therapy Attention defect hyperactivity disorder (ADHD), (2011), PubMed Health Sustained release valproate (EVA), GABA potentiator in the study of ADHD Recent studies have suggested improved hyperactivity and impulsivity.M Yazaki et al., (2006), Brain and Development, 28 (7): 470-472. Reduction of feedback suppression by striatal GABA neurons and interneurons has also been implicated in animal models of ADHD. Viggiano et al., (2002), Behavioural Brain Research, 130 (1-2): 181-189, however, current treatments for ADHD still have greatly improved therapies for ADHD. It has been demanded.

Autism spectrum disorder (Autism)
Autism Spectrum Disorder (ASD) is a series of complex features characterized by social dysfunction, difficulty in communication, and restricted, repetitive, and crested behavior patterns It is a neurodevelopmental disorder. Autistic disorders, sometimes referred to as autism or classic ASD, are the most severe form of ASD, while other conditions along the spectrum are mild, known as Asperger's syndrome Morphology, a rare condition called Rett syndrome, and childhood disintegrative disorder and unspecified pervasive developmental disorder (usually referred to as PDD-NOS). Although ASD differs significantly in nature and severity, it occurs in all ethnic and socioeconomic groups and affects all age groups. Experts estimate that 3 to 6 people per 1,000 people can develop ASD. Men are four times more likely to have ASD than women. NINDS Autorism Fact Sheet (2009).

Numerous evidence (including genetic and imaging studies) suggests that the anterior cingulate cortex and gamma-aminobutyric acid (GABA) system can be affected in autism. Compared to controls, patients with autism had a significant decrease in the average density of GABA _A receptors in the upper granular layer (46.8%) and lower granular layer (20.2%) of the anterior cingulate cortex (ACC), and Shows a significant decrease in the density of benzodiazepine binding sites in the intragranular lamina (28.9%) and subgranular lamina (16.4%). In addition, a trend of decreasing density of benzodiazepine sites was found in the subgranular layer in the autistic group (17.1%). In the autistic group, this down-regulation of both the benzodiazepine site and GABA _A receptor in ACC disrupts the delicate excitement / suppression balance of major neurons and output to key limbic cortical targets These findings suggest that it may be the result of increased GABA innervation and / or release. These disruptions can underlie core changes in social affect behavior in autism spectrum disorders. Oblak et al. (August 2009), Autoism Res. 2009 Aug; Volume 2 (4): 205-19. Furthermore, various GABA _A subunit type (such as alpha ₃ variant sequences and alpha ₄ isoforms) have been associated with autism spectrum disorders. Patent Document 1. Since there is no cure for ASD, there is a great need for a cure to treat autism spectrum disorders. Accordingly, therapies that target the GABA _A receptor may be useful in the treatment of autism spectrum disorders.

Bipolar disorder Bipolar disorder (manic depression) is a brain disorder that results in an abnormal shift in a person's mood, energy, and ability to function. Bipolar disorder (manic depression) can cause impaired relationships, poor work or school performance, and even suicide. Approximately 2.6 percent of the approximately 5.7 million American adults or the population over 18 years of age have bipolar disorder in any given year. Bipolar disorder typically occurs in late adolescence or early adulthood. However, some people have the first symptoms during childhood and some people develop later. Bipolar disorder (manic depression) is often not recognized as a disease, and one can suffer for years until bipolar disorder (manic depression) is properly diagnosed and treated. National Institute of Mental Health, “Bipolar Disorder” (2008), Complete Publication.

  Bipolar disorder leads to dramatic mood swings that become overly “high” and / or irritable to sad and undesired and then back again (often with a period of normal mood between them) . Severe changes in energy and behavior are in sync with these changes in mood. The high and low periods are called episodes of mania and depression. National Institute of Mental Health, “Bipolar Disorder” (2008), Complete Publication.

  Signs and symptoms of gonorrhea (or manic episode) include increased energy, activity, and restlessness; being “high” excessively, overly good euphoria; extreme irritability; Speaking fast, jumping from one idea to another; conversion, difficulty concentrating; not requiring much sleep; unrealistic beliefs about one's abilities and powers; Misjudgment; prosperous miscellaneous goods; unusual behaviors of sustained duration; increased sexual impulses; drug abuse, especially cocaine, alcohol, and sleep medications; provocative, impulsive or aggressive behavior; and / or Or it includes denying that something is wrong. A manic episode is diagnosed when mood upset, along with three or more of the other symptoms, occurs most of the day, almost daily for more than a week. National Institute of Mental Health, “Bipolar Disorder” (2008), Complete Publication.

  Signs and symptoms of depression (or a depressive episode) include persistent sadness, anxiety, or vain mood; despair or pessimism; feelings of guilt, worthlessness, or helplessness; Loss of interest or pleasure in; including a loss of energy, fatigue or “stagnation” sensation; concentration, memory, difficulty in determining; restlessness or irritability; Or inability to sleep; changes in appetite and / or unintentional weight loss or increase; chronic pain or other persistent body symptoms not caused by physical illness or injury; and / or thought of death or suicide, or Includes attempted suicide. A depression episode is diagnosed when five or more of these symptoms persist for a period of more than two weeks, most of the day, almost daily. National Institute of Mental Health, “Bipolar Disorder” (2008), Complete Publication.

  Mild to moderate levels of mania are referred to as mild mania. Hypomania feels good for those who experience it and may even be associated with good work and increased productivity. Thus, even when family and friends become aware of mood swings as a possible bipolar disorder, the person can deny that something is wrong. However, if not treated properly, hypomania can become severe mania in some people, or it can switch to depression.

  However, in some people the symptoms of mania and depression can occur together in so-called mixed bipolar conditions. Symptoms of mixed state often include agitation, difficulty sleeping, significant changes in appetite, psychosis, and thoughts of suicide. A person may feel very sad and unwilling while at the same time being extremely energetic.

  The classic form of the disease involving recurrent episodes of mania and depression is called bipolar disorder type I. However, some people never experience severe mania but instead experience a milder episode of hypomania that alternates with depression. This form of illness is referred to as bipolar disorder type II. A person is said to have rapidly alternating bipolar disorder when more than 4 episodes of the disease occur within a 12 month period. Some people experience multiple episodes within a single week or even within a single day. Rapid alternation tends to occur later in the disease process and is more common among women than men.

  Pharmaceuticals known as “mood stabilizers” are usually formulated to help control bipolar disorder (eg, lithium or valproic acid-DEPAKOTE / VALPROATE). In addition to pharmaceuticals, psychosocial treatments, including certain forms of psychotherapy, are often used to treat bipolar disorder. Side effects include weight gain, nausea, tremor, reduced sexual drive or ability, anxiety, hair loss, exercise problems, or dry mouth, depending on the medication. Lithium treatment can result in low thyroid levels and require thyroid replacement. In addition, Valproate® can cause harmful hormonal changes in teenage girls and can lead to polycystic ovary syndrome in women who have begun taking medications before the age of 20. In addition, women who want to become pregnant or who are pregnant and suffering from bipolar disorder are exposed to special burdens by the potential effects of existing tranquilizers on developing fetuses and infants. encounter. National Institute of Mental Health, “Bipolar Disorder” (2008), Complete Publication. Improved bipolar disorder therapies may be developed that act to increase GABA activity.

Postmortem and genetic studies have associated neuropsychiatric disorders (including schizophrenia and bipolar disorder) with GABAergic neurotransmission and various specific GABA _A receptor subunits. Furthermore, GABA _A receptor-related proteins are involved in GABA _A receptor transport, targeting, clustering, and anchoring, which often cause these functions in a subtype-specific manner. Charych et al. (2009) Neuropharmacology 57 (5-6): 481-95. Thus, GABA _A receptor-specific treatments that improve suppression may be beneficial because bipolar disease is an abnormal suppression / excitement change state without appropriate suppression.

Depression Depression is a common but serious illness, the most common being major depressive disorder and dysthymic disorder. Major depressive disorder, also called major depression, is characterized by a combination of symptoms that interfere with a person's ability to work, sleep, learn, eat, and enjoy activities that were once enjoyable. Major depression interferes with daily life and prevents a person from functioning properly. A major depressive episode can occur only once in a person's lifetime, but usually recurs over the lifetime of a person. National Institute of Mental Health, “Depression” (2008), Complete Publication.

  Depressive forms include the following.

  Dysthymia disorder, also called dysthymia, can not interfere with a person's daily life, but can prevent a person from functioning normally or feeling good for a long period (two years). Above) but less serious symptoms. People with dysthymia may also experience one or more episodes of major depression during their lifetime.

  Psychotic depression (occurs when a severe depressive illness is associated with some form of psychosis (such as separation from reality, hallucinations, and delusions)). Postpartum depression (diagnosed when a newly born mother develops a major depressive episode within one month after delivery). It is estimated that 10-15 percent of women experience postpartum depression after giving birth.

  Seasonal affective disorder (SAD) (characterized by the development of a depressive illness during the winter months with less sunlight). Depression is generally temporarily reduced during spring and summer. Although SAD can be treated effectively with light therapy, almost half of those with SAD do not respond to light therapy alone. Antidepressants and psychotherapy can reduce the symptoms of SAD alone or in combination with light therapy. National Institute of Mental Health, “Depression” (2008), Complete Publication.

  Depression can be treated by several methods. The most common treatment is pharmaceuticals and psychotherapy. Antidepressants act to normalize neurotransmitters, particularly serotonin, norepinephrine, and dopamine. The newest and most popular type of antidepressant drug is referred to as a selective serotonin reuptake inhibitor (SSRI). SSRIs include fluoxetine (Prozac®), citalopram (Celexa®), sertraline (Zoloft®), and several others. Serotonin and norepinephrine reuptake inhibitors (SNRI) are similar to SSRIs and include venlafaxine (Effexor®) and duloxetine (Cymbalta®). SSRIs and SNRIs are more popular than older classes of antidepressants (such as tricyclics (named from their chemical structure) and monoamine oxidase inhibitors (MAOI)) because they tend to have fewer side effects . However, there is no approach to a drug that fits all in one size, because drugs have a different impact on everyone. National Institute of Mental Health, “Depression” (2008), Complete Publication.

  For all classes of antidepressants, patients can experience side effects. Antidepressants can cause mild and often temporary side effects in some people, but these side effects are usually not prolonged. The most common side effects associated with SSRIs and SNRIs include headache, nausea, insomnia, irritability, agitation, and sexual problems. National Institute of Mental Health, “Depression” (2008), Complete Publication. Tricyclic antidepressants can also have side effects including dry mouth, constipation, bladder problems, sexual problems, blurred vision, and daytime somnolence. Furthermore, patients taking MAOI must adhere to significant food and pharmaceutical restrictions to avoid potentially serious interactions. These patients must avoid certain medications, including certain foods that contain the high levels of the chemical tyramine found in many cheeses, wines and pickles, and decongestants. MAOI interacts with tyramine in a manner that can lead to a sharp rise in blood pressure that can lead to stroke. National Institute of Mental Health, “Depression” (2008), Complete Publication.

  GABA is involved in both clinical depression and animal models of depression. Kram et al. (2000), Neuroscience Research, 38 (2): 193-198. Thus, improved treatments for depression based on GABAergic systems can achieve better pharmaceuticals.

Epilepsy Epilepsy is characterized by abnormal firing of cerebral neurons and is typically manifested as various types of seizures. Epileptiform activity is identified by the spontaneous and synchronized firing of a population of neurons that can be measured using electrophysiological techniques. Epilepsy is one of the most common neurological disorders affecting about 1% of the population. There are various forms of epilepsy, including idiopathic epilepsy, symptomatic epilepsy, and unexplained epilepsy. Genetic predisposition is thought to be the dominant etiological factor in idiopathic epilepsy. Symptomatic epilepsy usually occurs as a result of structural abnormalities in the brain.

  Status epilepticus is a particularly severe form of seizure that manifests as multiple seizures that persist for a significant period of time or as continuous seizures with no recovery of consciousness between seizures. The overall mortality rate in adults with status epilepticus is approximately 20 percent. Patients with the first episode are at substantial risk for further episodes and the development of chronic epilepsy. The frequency of status epilepticus in the United States is approximately 150,000 cases per year, with approximately 55,000 deaths associated with status epilepticus each year. Sirven and Waterhouse (2003), American Family Physician, 68: 469-476. Acute processes associated with status epilepticus include refractory epilepsy, metabolic disorders (eg, electrolyte abnormalities, renal failure, and sepsis), central nervous system infection (meningitis or encephalitis), stroke, degenerative disease, head trauma , Drug toxicity, and hypoxia. The underlying pathophysiology of status epilepticus usually involves failure of the mechanism that interrupts isolated seizures. This failure can result from an abnormal persistence of abnormally persistent, excessive excitement or suppression. Studies have shown that excessive activation of excitatory amino acid receptors can lead to long-term seizures, suggesting that excitatory amino acids may play a causative role. Status epilepticus can also be caused by penicillin and related compounds that antagonize the action of γ-aminobutyric acid (GABA).

  Epilepsy is a chronic neurological condition characterized by recurrent seizures caused by abnormal cranial nerve cell activity. Epilepsy is classified as idiopathic or symptomatic. Neurons release chemicals called (1) by changing the concentration of intracellular salts (sodium, potassium, calcium) and (2) neurotransmitters (eg gamma aminobutyric acid, GABA) Signal to and from the brain in two ways. Changes in salt concentration conduct impulses from one end of the neuron to the other. At this end, the neurotransmitter is released, which carries the impulse to the next neuron. Neurotransmitters delay or stop intercellular communication (referred to as inhibitory neurotransmitters) or stimulate this process (referred to as excitatory neurotransmitters). Normally, neurotransmission in the brain occurs in an ordered manner, allowing a smooth flow of electrical activity. Inappropriate intracellular concentrations of salt and excessive activity of either type of neurotransmitter can disrupt ordered neuronal transmission and cause seizure activity. Certain areas of the brain are more likely to be involved in seizure activity than other areas. The motor cortex that allows the body to move, and the temporal lobes involved in memory (including the hippocampus) are responsible for biochemical changes that cause abnormal brain cell activity (eg, decreased oxygen levels, metabolic anomalies). Particularly sensitive to balance and infection).

  Two molecules regulate cellular chloride levels. KCC2 transports chloride from the cell, and NKCC1 carries chloride to the cell. Previous studies in rats have shown that the majority of adult neurons have KCC2 and the chloride concentration is lower on the inside than on the outside. Therefore, when the GABA receptor is activated, chloride tends to enter with an inhibitory action. In newborn rats, the situation is reversed. Newborn rat neurons mostly have NKCC1, and chloride is actively transported inward, resulting in very high initial chloride concentrations. As a result, GABA activation leads to the exit of chloride from cells with excitatory effects. For example, Cohen (1981), J.M. Clin. Pharmacol. 21: 537-542; Dzhala et al. (2005), Nat Med. 11: 1205-1213; Martinez et al. (1998), Am. J. et al. Clin. Nutr. 68: 1354S-1357S (the disclosures of each of which are incorporated herein by reference in their entirety). Thus, the compounds described herein can inhibit seizure activity in a rat model of seizures induced by kainic acid.

  Studies have shown that NKCC antagonists can help treat seizures in neonates that are difficult to control with existing anticonvulsants. The conventional anticonvulsants phenobarbital and benzodiazepine are ineffective in neonates because the neonatal brain is biochemically different from the adult brain. Conventional anticonvulsants work by mimicking the action of GABA, a natural inhibitory chemical in the brain, by activating GABA receptors on the surface of brain cells. In adult neurons, activation of GABA opens a channel that allows chloride to move into the cell. This causes the cell to gain a negative charge, become less excitable and suppress seizure activity. However, in neonates, chloride is already high, so activation of the GABA receptor results in a paradoxical excitatory response that can lead to the migration of the chloride out of the neuron and indeed exacerbate the seizure.

  Traditional antiepileptic drugs exert their main effects by one of three mechanisms. (A) suppression of repetitive and frequent neuronal firing by blocking voltage-gated sodium channels; (b) enhanced post-synaptic suppression mediated by γ-aminobutyric acid (gamma-aminobutyric acid, GABA); and ( c) Blockade of T-type calcium channels. Many current antiepileptic drugs exert pharmacological effects on all brain cells, regardless of their involvement in seizure activity. Common side effects are hypersedation, dizziness, memory loss and liver damage. Furthermore, 20-30% of patients with epilepsy are resistant to current treatment. Accordingly, there is a great need for improved treatments for epilepsy that reduce both morbidity and mortality.

Glaucoma Glaucoma is a group of diseases that occur when the normal fluid pressure inside the eye slowly rises and damages the optic nerve of the eye, resulting in blindness and blindness. Open-angle glaucoma is the most common form, and other types include (1) low-tension glaucoma or normal-tension glaucoma; (2) closed-angle glaucoma; (3) congenital glaucoma; Secondary glaucoma; and (5) pigmentary glaucoma (including neovascular glaucoma). Glaucoma is usually detected by a comprehensive eye test including (a) visual acuity test; (b) visual field test; (c) magnifying eye test; (d) intraocular pressure measurement; and (e) corneal thickness measurement. Current glaucoma treatment includes drugs, laser trabeculoplasty, conventional surgery, or any combination thereof. However, there is a great need for improved treatments for glaucoma. National Eye Institute Glaucoma Fact Sheet (2008).

Huntington's Disease Huntington's disease (HD) results from neuronal degeneration that results in uncontrolled behavior, loss of intellectual ability, and emotional impairment. HD is an autosomal dominant disease resulting from CAG stretch in the Htt gene resulting in poly-glutamine expansion of the disease protein huntingtin. GABAergic interneurons are particularly sensitive to the accumulation of mutant huntingtin and die early in the development of HD. Some early symptoms of HD are mood swings, depression, driving, learning new things, learning facts, or being hypersensitive or difficult to make decisions. As the disease progresses, it is increasingly difficult to concentrate on intellectual tasks and patients can have difficulty eating and swallowing themselves. The rate of disease progression and the age of onset vary from person to person. NINDS Publication, “Huntington's Disease: Hope Through Research” (2009).

Huntington's disease (HD) is a neurodegenerative disorder involving disturbances in GABA signaling. GABA _A is a major inhibitory neurotransmitter in the central nervous system (CNS). HD destroys GABAergic neurons in the striatum. Because targeting GABA _A synthesis, degradation, transport, or receptors can control GABA signaling, drugs that target these aspects of GABA metabolism have improved treatment for Huntington's disease Can be used for treatment. Kleppner and Tobin (2001), Expert Opin The Targets. 5 (2): 219-39. Physicians prescribe several medications that help control emotional and behavioral problems associated with HD, including tetrabenazine to treat Huntington's disease (involuntary involuntary movements). However, drugs used to treat HD symptoms have side effects such as fatigue, restlessness, or hyperexcitability. NINDS Publication, “Huntington's Disease: Hope Through Research” (2009).

Insomnia Insomnia is a symptom of sleep disorders characterized by persistent difficulty in falling asleep or staying asleep, despite the opportunity. NHLBI Diseases and Conditions Index [Insomnia] (2009). There are several different degrees of insomnia, but three types of insomnia (transient, acute, and chronic) have been clearly identified. Transient insomnia lasts days to weeks. Insomnia may be caused by another disorder, changes in the sleep environment, timing of sleep, severe depression, or stress. The consequences (drowsiness and impaired psychomotor performance) are similar to the consequences of sleep deprivation. Acute insomnia is the inability to sleep well for a period of 3 weeks to 6 months. Chronic insomnia lasts several years at a time. This can be caused by another obstacle or it can be a major obstacle. Its action can vary depending on its cause. Although its effects can include sleepiness, muscle fatigue, hallucinations, and / or mental fatigue, people with chronic insomnia often show increased arousal. NHLBI Diseases and Conditions Index [Insomnia] (2009). Hypnotics (eg, benzodiazepines) that are current insomnia pharmacotherapy targeting GABA _A receptors may have undesirable side effects and therefore there is a great need for improved insomnia treatments with reduced side effects. It has been.

Ischemia Ischemia is a restriction of blood supply, generally due to factors in the blood vessels, resulting in tissue damage or dysfunction due to inadequate oxygen supply and lack of tissue nutrients. Insufficient blood supply makes the tissue hypoxic, or oxygen free if no oxygen is supplied. In contrast to hypoxia, which is a more general term for oxygen deficiency (usually the result of a deficiency of inhaled oxygen), ischemia is an absolute or relative lack of blood supply to an organ. This can lead to necrosis (eg, cell death). In aerobic tissues (such as the heart and brain), ischemic necrosis usually takes about 3-4 hours at body temperature before it becomes irreversible. Later, further damage occurs due to the accumulation of metabolic waste products due to a lack of adequate blood supply to the tissue. A complete pause of more than 20 minutes of oxygen supply in such organs typically results in irreversible damage.

  Inhibition of NKCC1 activity by bumetanide and furosemide significantly reduces infarct volume and cerebral edema after focal cerebral ischemia, suggesting that NKCC1 antagonists may be useful in the treatment of ischemia . Chen and Sun (2005), Neurol. Res. 27 (3): 280-286. A typical treatment for ischemia involves “clot-disrupting” drugs that are usually given for stroke and heart attack within this period (eg, Alteplace®). However, recovery of blood flow after the period of ischemia can actually cause more damage than ischemia. This is because reintroduction of oxygen results in more production of damaging free radicals, resulting in reperfusion injury and, ultimately, necrosis. Therefore, there is a great need for improved ischemic treatments.

Migraine Migraines afflict 10-20% of the US population, and it is estimated that 64 million work days are lost annually. Migraine is characterized by irritation, unilateral or bilateral throbbing head pain that lasts between 4 and 72 hours, often associated with nausea, vomiting, and hypersensitivity to light and / or sound. When accompanied by prodromal symptoms (such as vision, sensation, speech or motor symptoms), the headache is referred to as “migraine with aura”, formerly known as classic migraine. In the absence of such symptoms, headache is referred to as “migraine without aura”, formerly known as general migraine. Both types provide evidence of a strong genetic component, and both are three times more common in women than in men. The exact etiology of migraine has not yet been determined. It has been theorized that those who are prone to migraine have a reduced threshold for neuronal excitability, probably due to reduced GABA activity. GABA normally suppresses the activity of the neurotransmitters serotonin (5-HT) and glutamate, both of which appear to be involved in migraine attacks. Glutamate, an excitatory neurotransmitter, is implicated in an electrical phenomenon called cortical spreading inhibition that can initiate a migraine attack, while serotonin changes blood vessels that occur as migraine progresses Related.

  Cortical spreading depression (CSD) has been suggested to underlie migraine (including migraine with visual aura). CSD is also thought to underlie migraine as part of the trigeminal pain circuit. CSD is characterized by a short burst of strong depolarization in the occipital cortex, followed by a wave of neurons quietness and reduced evoked potentials (advancing across the surface of the cerebral cortex). Enhanced excitability of occipital cortical neurons has been proposed to be the basis for CSD. The visual cortex may have a lower threshold for excitability and is therefore most prone to CSD. It has been suggested that mitochondrial damage, magnesium deficiency, and abnormal presynaptic calcium channels may be involved in neuronal excitability. Welch (1997), Seminars in Neurobiol. 17: 4. During the spreading suppression event, significant ion perturbation occurs, including interstitial acidification, extracellular potassium accumulation, and redistribution of sodium and chloride ions into the intracellular compartment. Furthermore, prolonged glial swelling occurs as a homeostatic response to altered extracellular fluid composition and accumulation of interstitial neurotransmitters and fatty acids. Studies have shown that furosemide suppresses regenerative cortical spreading inhibition in cats under anesthesia. Read et al., (1997), Cephalagia, 17: 826.

Drug therapy is given according to the severity and frequency of migraine. For occasional seizures, acute treatment may be applied, but for seizures that occur more than once per month, or when seizures greatly affect the patient's daily life, prophylactic treatment may be applied. Good. The side effects of acute and prophylactic treatments, including serotonin agonists, beta blockers, tricyclic antidepressants, anticonvulsants, and botulinum toxin type A injections may limit their use. GABA modulates nociceptive input to the trigeminal cervical spinal cord complex primarily through GABA _A receptors. Storer et al. (2001), Br J Pharmacol. 134 (4): 896-904. Thus, GABA _A receptors may provide a target for the development of new therapeutic agents for both acute and prophylactic treatment of headache, including migraine.

Nociceptive pain Nociceptive pain occurs in response to activation of nociceptors, a specific subset of peripheral sensory neurons. A nociceptor is a nerve that senses and responds to a part of the body suffering from injury. Nociceptors send signals of tissue hypersensitivity, imminent injury, or actual injury. This is generally acute (with the exception of joint pain), self-regulating, and serves a protective biological function by acting as a warning of ongoing tissue damage. When activated, nociceptors transmit pain signals (via peripheral nerves and spinal cord) to the brain. Pain is typically well localized, constant, and often has a tingling or pulsatile quality. Examples include postoperative pain, sprains, fractures, burns, gallbladders, contusions, inflammation (from infection or joint damage), obstruction, and myofascial pain. Visceral pain is a subtype of nociceptive pain that involves internal organs. Visceral pain is idiopathic and tends to be poorly localized.

Nociceptive pain is usually treated with opioids and / or nonsteroidal anti-inflammatory drugs (NSAIDs), but due to their low efficacy, unacceptably severe side effects, and addiction potential, May be limited. GABA _A receptor is a target for therapeutics to treat nociceptive pain. For example, Hara et al. (2004), Anesth Anal, 98: 1380-1384 report that a combination of GABA agonists and L-type calcium channel blockers can be used to reduce visceral pain. . However, most GABA _A agonists are known to have side effects (including sedation, dizziness, euphoria, nausea, and blurred vision). Therefore, there is a great need for a treatment for nociceptive pain.

Neuropathic pain Neuropathic pain and nociceptive pain differ in their etiology, pathophysiology, diagnosis, and treatment. Neuropathic pain is a common type of chronic non-malignant pain, is the result of injury or dysfunction in the peripheral or central nervous system, and does not perform protective biological functions. It is estimated to affect over 1.6 million people in the US population. Neuropathic pain has many different etiologies such as trauma, diabetes, herpes zoster infection, HIV / AIDS (peripheral neuropathy), terminal cancer, amputation (including mastectomy) ), Carpal tunnel syndrome, chronic alcohol use, exposure to radiation, and unintended side effects of neurotoxic treatments such as certain anti-HIV and chemotherapeutic agents.

  In contrast to nociceptive pain, neuropathic pain is often described as “cautery”, “electrical”, “spirit” or “electric shock” in nature. Neuropathic pain is often characterized by chronic allodynia (pain resulting from stimuli that do not normally trigger a pain response, such as a light touch) and hyperalgesia (usually increased sensitivity to pain stimuli), and any damaged tissue Apparent healing can last for months or years.

Neuropathic pain is difficult to treat. Analgesics that are effective against nociceptive pain (eg, opioid narcotics and non-steroidal anti-inflammatory drugs) are rarely effective against neuropathic pain. Similarly, drugs that have activity in neuropathic pain are usually not effective against nociceptive pain. Standard drugs that have been used to treat neuropathic pain often appear to selectively act to alleviate certain symptoms in a given patient, but alleviate other symptoms No (eg, alleviates allodynia but does not relieve hyperalgesia). Bennett (1998), Hosp. Pract. (Off Ed), 33: 95-98. Treatments typically used in the management of neuropathic pain include tricyclic antidepressants (eg, amitriptyline, imipramine, desimipramine, and clomipramine), generalized local anesthetics, and antiepileptic drugs ( AED) (eg, phenytoin, carbamazepine, valproic acid, clonazepam, gabapentin, and pregabalin (LYRICA®)). See Lowther (2005), “Pharmacotherapy Update the Department of Pharmacy”, Volume VIII, No. 5. Common side effects include oversedation, dizziness, memory loss and liver damage. In addition, drugs that have not previously been considered useful for the treatment of neuropathic pain, but that target only a subset of benzodiazepine (GABA _A ) receptors, have been proposed for inflammatory and neuropathic pain. Recent studies from genetically engineered mice have shown that it is possible to achieve an unambiguous antihyperalgesic activity. Zeilhofer et al. (2009), J Mol Med, 87: 465-469. Furthermore, in the spinal cord injury (SCI) model of neuropathic pain, the NKCC1 antagonist bumetanide showed analgesia, which indicates that normal or elevated NKCC1 activity is induced by SCI-induced neuropathic pain. Suggests a role in development and maintenance. Cramer et al. (2008), Molecular Pain, 4:36. Accordingly, there is a great need for improved treatments for neuropathic pain.

Postherpetic neuralgia Postherpetic neuralgia is a complication of herpes zoster, the second outbreak of varicella-zoster virus that initially leads to chickenpox. Postherpetic neuralgia occurs when nerve fibers are damaged during the development of shingles. During the first infection of chickenpox, some of the virus remains in the body and becomes dormant in the nerve cells. Years later, the virus reactivates and can result in shingles. Once reactivated, the virus moves along the nerve fibers causing pain. When the virus reaches the skin, rashes and blisters occur. Cases of shingles (herpes zoster) usually heal within a month. However, these damaged nerves can lead to chronic, often very severe pain that can last for months (or even years) in the area where shingles first occurred. Some patients continue to feel pain long after the rash and blisters healed (a type of pain called postherpetic neuralgia). There are various treatments for postherpetic neuralgia, but one does not experience complete relief from pain.

  This complication of shingles occurs much more frequently in the elderly. About 50 percent of adults over the age of 60 experience postherpetic neuralgia after herpes zoster, while only 10 percent of all people with herpes zoster experience postherpetic neuralgia. Symptoms of postherpetic neuralgia generally include the development of herpes zoster, including sharp stinging pain, burning pain, or deep and tingling pain; extreme sensitivity to touch and temperature changes; itching and numbness; and headache Limited to the area of skin that occurred first. In rare cases, patients can also experience weakness or paralysis if the nerves involved also control muscle movement. There is a great need for improved post-herpetic neuralgia treatment.

Eye diseases (eg, visual impairment, ophthalmic diseases)
The total lifetime cost for all people born in 2000 with visual impairment is estimated to be $ 2.5 billion (2003, dollars). In general, Centers for Dissemination Control and Prevention, Economic Costs Associated With Mental Retardation, Cerebro Palsy, Healing Loss, &, United States, Year 53, United States. These costs include both direct and indirect costs. Direct medical costs (such as doctor visits, prescription drugs, and hospitalization of inpatients) make up 6% of these costs. Direct non-medical expenses (such as home renovation and special education) make up 16% of the cost. Indirect costs, including lost wage values when a person dies early, cannot work, or is restricted in the amount or type of work that can be done, constitutes 77% of the cost. These estimates do not include other expenditures such as outpatient visits to hospitals, emergency department visits, and family cash outlays. Thus, the actual economic cost of visual impairment is higher than what is generally reported. Patent Document 4.

Both NKCC and KCC2 are expressed in the outer and inner plexiform layers and coexist in many putative amacrine and ganglion cell layer cells. However, the putative horizontal cell body displayed only NKCC immunoreactivity, and many bipolar cells were immunopositive only for KCC2. In the outer retina, application of bumetanide, a specific inhibitor of NKCC activity, (1) ^{K +} extracellular concentration steady state increase ^([K _{+] o),} induced by light ^[K _{+] o} (2) ERG sPIII photoreceptor-dependent components were increased, and (3) the extracellular space volume was decreased. In contrast, in the outer retina, the application of furosemide, a specific inhibitor of KCC activity, reduced the decrease in sPIII and light-induced [K ⁺ ] _o but to steady-state [K ⁺ ] _o . There was almost no effect on it. In the retinal lining, bumetanide increased the sustained component of the light-induced increase in [K ⁺ ] _o . Thus, these findings indicate that NKCC and KCC2 regulate [K ⁺ ] _o and extracellular space volume in the retina, in addition to regulating GABA and glycine-mediated synaptic transmission. Furthermore, anatomical and electrophysiological results together suggest that all major neuron types in the retina are affected by chloride cotransporter activity. Dmitriev et al. (2007), Vis Neurosci, 24 (4): 635-45.

The bumetanide-sensitive Na ⁺ K ⁺ 2Cl ⁻ cotransporter (NKCC) also clearly contributes to Cl ⁻ uptake into the pigment epithelium (PE). This action reinforces the general consensus that active secretion of Cl ⁻ is a major driver of aqueous humor formation in the mammalian eye, and demonstrates the existence of species differences in the mechanism to achieve transepithelial Cl ⁻ transport. Demonstrate further. Kong et al. (2006), Invest Ophthalmol Vis Sci. 47 (12): 5428-36.

In addition, cation-chloride cotransporters are involved in retinal function by mediating neural computations in the retina. The directional response of DS ganglion cells is mediated in part by the directional release of gamma-aminobutyric acid from starburst dendrites, and the two cotransporters (K ⁺ ) along the starburst cell dendrites. Cl ^- cotransporter and ^Na + ^K + Cl ^- asymmetrical distribution of cotransporter) mediates direction selectivity. Gavrikov et al. (2003), Proc Natl Acad Sci USA, 100 (26): 16047-52.

Furthermore, retinal function is determined by the cation chloride transporter that regulates GABA. In particular, different cation chloride cotransporters in retinal neurons allow an inverse response to GABA. Thus, in the retina, the opposite effect of GABA on different cell types and different cell regions is probably determined primarily by the differential targeting of these two chloride transporters. See, for example, Barbour et al. (May 1991), J Physiol. 436: 169-193; Keller et al. (1988), Pflugers Arch. 411 (1): 47-52; and Vardi et al. (2000), Journal of Neuroscience, 20 (20): 7657-63. Also, Basu et al. (1998), Invest Ophthalmol Vis Sci. 39 (12): 2365-73; Cia et al. (2005), J Neurophysiol. 93 (3): 1468-75; Do et al. (2006), Invest Ophthalmol Vis Sci. 47 (6): 2576-82; Hunt et al. (2005), Anat Rec A Discover Mov Cell Evol Biol. 287 (1): 1051-66; MacLeish and Nurse (2007), J Neurophysiol. 98 (1): 86-95; Mito et al. (1993), Am J Physiol. 264 (3Pt1): C519-26; Moody (1984), Annu Rev Neurosci, 7: 257-78; Mroz and Lechene (1993), Hair Res. 70 (2); 146-50; Schnetkamp (1980), Biochem Biophys.
Acta. 598 (1): 66-90; and Uhl and Desel (1989), J Photochem Photobioi B. et al. 3 (4): 549-64.

  Thus, some disorders that threaten eye vision currently do not have effective treatments. One major problem in the treatment of such diseases is the inability to deliver the therapeutic agent into the eye where it can be maintained at a therapeutically effective concentration. Therefore, there is a great need for therapeutic methods for treating eye diseases.

Parkinson's disease Parkinson's disease (PD) belongs to a group of conditions called motor system disorders caused by the loss of brain cells that produce dopamine. The four main symptoms of PD are tremor or trembling of hands, arms, legs, chin, and face; stiffness or stiffness of limbs and torso; slow movement or slow movement; and posture instability Or impaired balance and coordination. As these symptoms become more apparent, patients may have difficulty walking, talking, or completing other simple tasks. PD usually affects people over 50 years of age. Early symptoms of PD are slight and occur gradually. Other symptoms may include depression and other emotional changes; difficulty swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disturbances. NINDS Parkinson's Disease Information Page (September 23, 2009).

  Currently, there is no cure for PD, but various medications provide dramatic relief from symptoms. Patients are usually given levodopa combined with carbidopa. Carbidopa delays the conversion of levodopa to dopamine until levodopa reaches the brain. Neurons can use levodopa to make dopamine and replenish the brain's tapering supply. Levodopa helps at least three-quarters of Parkinson's disease cases, but all symptoms do not respond equally to drugs. Slow motion and firmness respond best, while tremor may only decrease slightly. Problems with balance and other symptoms cannot be alleviated. Anticholinergics can help control tremor and stiffness. Other drugs (such as bromocriptine, pramipexole, and ropinirole) mimic the role of dopamine in the brain and cause neurons to respond to dopamine. Amantadine, an antiviral drug, also appears to reduce symptoms. In May 2006, the FDA approved rasagiline (AZILECT®) for use with levodopa for patients with advanced PD or as a single drug treatment for early PD. NINDS Parkinson's Disease Information Page (2009).

  Parkinson's disease (PD) pathology also disrupts GABA signaling by disrupting input from the substantia nigra to striatal GABAergic neurons. Targeting GABA synthesis, degradation, transport, or receptors by novel therapies can control GABA signaling and thus can be used for improved therapeutic treatment for Parkinson's disease. Kleppner and Tobin (2001), Expert Opin. Ther. Targets. 5 (2): 219-39.

Periodic Foot Movement Disorders Periodic Limb Movement Disorder (PLMD) (formerly known as nocturnal myoclonus) is a sleep disorder in which the patient's limbs move involuntarily during sleep and suffer from movement related problems. PLMD is that restless leg syndrome (RLS) occurs while the patient is awake and sleeping, and has a spontaneous response to an unpleasant sensation of the foot when awake. Different from RLS. In contrast, in PLMD, patients are often unaware of movement. Cleveland Clinic, “Periodic Limb Movement Disorder” (2011).

Currently, several drugs have been used to treat PLMD, including Sinemet (levodopa), anticonvulsant medications, benzodiazepines, and narcotics. Although medical treatment of PLMD often significantly reduces or eliminates the symptoms of these disorders, there is no cure for PLMD and medical treatment must continue to achieve relief. Cleveland
Clinic, “Periodic Limb Movement Disorder” (2011). Recent studies have found that valproate has a long-term beneficial effect on sleep enhancement in patients with PLMD. The main mechanism of action of valproate is thought to be inhibition of GABA transamination (eg, inhibition of GABA transaminase results in an increase in GABA). Ehrenberg et al. (2000), Journal of Clinical Psychopharmacology, 20 (5): 574-578.

Restless leg syndrome (restless leg disorder)
Restless leg syndrome (restless leg disorder) is a disorder that suffers from the urge or need to move the foot in order for the patient to stop the most frequent discomfort that occurs in middle-aged and elderly people. The cause is unknown in most patients, but can occur more often in patients with peripheral neuropathy, chronic kidney disease, Parkinson's disease, pregnancy, iron deficiency, or as a side effect of some medications. Restless leg syndrome can lead to poor sleep quality (insomnia). Many patients may also have a rhythmic foot movement called periodic limb movement disorder (PLMD) during sleep time. PubMed Health website, “Restress Leg Syndrom” (2011).

  With current treatments aimed at reducing stress and muscle relaxation, there is no known cure for restless leg syndrome. Pramipexole or ropinirole, Sinemet, or tranquilizers (eg, clonazepam) have been used to alleviate symptoms of restless leg syndrome. PubMed Health website, “Restress Leg Syndrom” (2011). For example, the GABA analog gabapentin (FANATREX) has been tested as a treatment for restless leg syndrome with some promising results. Imamura & Kusida (2010), Expert Opin Pharmacother. 11 (11): 1925-32; see also Misra et al. (2011) Neurology 76 (4): 408. Therefore, GABA-based therapies may be useful in the treatment of restless leg syndrome (restless leg disorder).

Schizophrenia Schizophrenia is a brain disorder that affects approximately 1.1% of the US population over the age of 18 in a given year, and interferes with chronic and severe daily life. People with schizophrenia hear that others cannot hear, believe that others are speaking their thoughts to the world, or that others are planning to harm themselves May be convinced. With these experiences, people with schizophrenia become scared and withdrawn, creating difficulties when trying to establish relationships with others. National Institute of Mental Health, “Schizophrenia” website (2008).

  Symptoms usually occur in late teens or early twenties for men and in the twenties and thirties for women, but rarely may appear in childhood. Symptoms can include hallucinations, delusions, confused thoughts, movement disorders, emotional flattening, social withdrawal, and cognitive deficits. The cause of schizophrenia has not been determined and there is no curative therapy. However, antipsychotic agents are used in the treatment of symptoms. National Institute of Mental Health, “Schizophrenia” website (2008).

  Furthermore, schizophrenia is associated with both a decrease in the number and distribution abnormalities of GABAergic neurons in the cortex, particularly the cortical layer. Kaplan & Sadock's Comprehensive Textbook of Psychiatry (7th edition) (2008). In postmortem studies of schizophrenic patients, antipsychotic-free schizophrenic patients and non-schizophrenic controls showed a significant decrease in the number of GABA-containing interneurons, and both of these interventions in the schizophrenia group 2 shows a decrease in the amount of GABA production within neurons. Nestler (1997), Nature, 385 (No. 6617): 578-9. Accordingly, therapeutic agents that target the GABA system may be useful in the treatment of schizophrenia.

Tinnitus Tinnitus is the perception of sound in a human ear in the absence of the corresponding external sound. Tinnitus is not a disease, but can include infections of the ear, foreign objects or wax in the ear, nasal allergies that prevent (or induce) the drainage of fluids and cause accumulation of ear wax, and loud sound injury It is a symptom caused by the basic cause of Tinnitus can also be caused by hearing impairment and as a side effect of some medications. Some cases of tinnitus are not medically explained.

  Tinnitus can be perceived with one or both ears or with the head. This is usually described as a sound that continues to ring, but in some patients, tinnitus is a high-pitched crawl, buzzing, screaming, screaming, humming, singing or whistling Or ticks, clicks, crawls, “crickets” or “tree frogs” or “grasses”, songs, songs, or beeps. Tinnitus has also been described as a “hue” sound like wind or waves. Tinnitus can be intermittent or continuous, in which case it can cause great distress. In some individuals, tinnitus intensity can vary with shoulder, head, tongue, jaw, or eye movements. To date, there is no satisfactory treatment for tinnitus.

  Partial afferent blockage results in a loss of tone suppression in the auditory system that can result in inappropriate neuroplastic changes that eventually appear as the pathophysiology of tinnitus. The pathological down-regulation of GABA provides a potential mechanism for this loss of suppression. For example, in animal models of tinnitus, the GABA agonist vigabatrin completely and reversibly removed the psychophysical evidence of tinnitus. Brozoski et al. (2007), J Assoc Res Otalyngol. 8 (1): 105-118. Furthermore, perturbation of the NKCC1 gene in mice results in hearing loss. Kahle et al. (2004), Proc. Nati. Acad. Sci. USA, 102 (46): 16783-16788. Therefore, therapies targeting the GABAergic system and / or NKCC1 may be useful in the treatment of tinnitus.

Withdrawal syndrome A withdrawal syndrome is a drug that can produce physical dependence (eg, alcohol withdrawal syndrome, nicotine withdrawal syndrome, opioid withdrawal syndrome, benzodiazepine withdrawal syndrome, methadone withdrawal syndrome, SSRI interruption syndrome, hydrocodone withdrawal syndrome) , Drugs, recreational drugs, and / or alcohol), generally associated with abnormal physical or psychological characteristics following abrupt discontinuation. Common withdrawal symptoms include sweating, tremor, vomiting, anxiety, insomnia, and muscle pain. There are different stages of withdrawal. In general, a person begins to feel progressively worse, reaches a plateau, and then symptoms begin to disappear. However, withdrawal from certain drugs (eg, benzodiazepines, alcohol) can be fatal and therefore abrupt discontinuation of any type of drug is not recommended. In addition, many additions involve compounds that affect the GABAergic system (eg, alcohols and benzodiazepines). Thus, when a person stops using a compound, the GABAergic system is involved in the symptoms of withdrawal syndrome. Nutt and Lingford-Hughes (2008), British Journal of Pharmacology, 154 (2): 397-405. Thus, agents that act on the GABAergic system may provide a therapeutic method for treating withdrawal syndrome.

International Publication No. 2009/100040 International Publication No. 2007/002359 International Publication No. 2007/136838 US Pat. No. 7,251,528

Thus, but not limited to, addiction disorder, anxiety disorder, ascites, attention deficit hyperactivity disorder (ADHD), bipolar disorder, cancer, corneal endothelial dystrophy, edema, depression, epilepsy, glaucoma, ischemia, fragment Diseases involving Na ⁺ K ⁺ Cl ⁻ cotransporters (eg, NKCC1 and NKCC2), including headache, neuropathic pain, nociceptive neuralgia, eye disease, pain, postherpetic neuralgia, and schizophrenia, There is an ongoing need for compositions and methods for the treatment and / or prevention of disorders and conditions. In addition, but not limited to, Alzheimer's disease, addictive disorder, anxiety disorder, autism spectrum disorder (autism), bipolar disorder, depression, epilepsy, Huntington's disease, inflammatory pain, insomnia, migraine, nerve Pain, nociceptive pain, pain, Parkinson's disease, periodic limb movement disorder (PLMD) (nocturnal myoclonus), personality disorder, psychosis, restless leg syndrome (RLS), schizophrenia, seizure disorder, spasticity, There is a continuing need for compositions and methods for the treatment and / or prevention of diseases, disorders, and conditions involving GABA _A receptors, including tinnitus and withdrawal syndrome.

SUMMARY OF THE INVENTION The present invention provides compounds according to Formulas I, II, III and IV that are arylsulfonamides including bumetanide derivatives as provided herein:
Formula I

または薬学的に許容されるその塩
（式中、
Ｚは、酸素または窒素であり、
Ｒ_１およびＲ_２は、各々独立に、水素、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキルであり、またはＲ_１およびＲ_２は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、ただし、Ｚが酸素である場合、Ｒ_２は存在せず、
Ｒ_３およびＲ_４は、各々独立に、水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、またはヘテロアリールアルキル（ｈｅｔｅｒｏａｒｙｌａｌｋｙ）であり、またはＲ_３およびＲ_４は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、
Ｒ_５は、アルコキシ、ハロ、アリール、アリールオキシ、アルカリルオキシ、アリールアミノ、ヘテロアリールアミノ、ヘテロシクロアルキル、ヘテロアリール、ヘテロアリールオキシ、ヘテロシクロアルコキシ、またはアルキルチオ（ａｌｋｙｔｈｉｏ）であり、
Ｒ_６およびＲ_７は、各々独立に、水素、アシル、アルキル、シクロアルキルアルキル、アリールまたはアリールアルキルであり、またはＲ_６およびＲ_７は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成する）。

Or a pharmaceutically acceptable salt thereof, wherein
Z is oxygen or nitrogen;
R ₁ and R ₂ are each independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or R ₁ and R ₂ together with the atoms to which they are attached To form a 4- to 7-membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents, provided that Z is oxygen If R ₂ is not present,
R ₃ and R ₄ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or R ₃ and R ₄ are Together with the atoms to which it is attached forms a 4-7 membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents;
R ₅ is alkoxy, halo, aryl, aryloxy, alkaryloxy, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio,
R ₆ and R ₇ are each independently hydrogen, acyl, alkyl, cycloalkylalkyl, aryl or arylalkyl, or R ₆ and R ₇ together with the atoms to which they are attached are 1 One or more additional heteroatoms and may have one or more substituents to form a 4-7 membered heterocycle).

  Formula II

または薬学的に許容されるその塩
（式中、
Ｚは、酸素または窒素であり、
Ｒ_１およびＲ_２は、各々独立に、水素、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキルであり、またはＲ_１およびＲ_２は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、ただし、Ｚが酸素である場合、Ｒ_２は存在せず、
Ｒ_３およびＲ_４は、各々独立に、水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、またはヘテロアリールアルキルであり、またはＲ_３およびＲ_４は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、
Ｒ_５は、ハロ、アリール、アリールオキシ、アリールアミノ、ヘテロアリールアミノ、ヘテロシクロアルキル、ヘテロアリール、ヘテロアリールオキシ、ヘテロシクロアルコキシ、またはアルキルチオであり、
Ｒ_６およびＲ_７は、各々独立に、水素、アシル、アルキル、シクロアルキルアルキル、アリールまたはアリールアルキルであり、またはＲ_６およびＲ_７は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成する）。

Or a pharmaceutically acceptable salt thereof, wherein
Z is oxygen or nitrogen;
R ₁ and R ₂ are each independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or R ₁ and R ₂ together with the atoms to which they are attached To form a 4- to 7-membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents, provided that Z is oxygen If R ₂ is not present,
R ₃ and R ₄ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or R ₃ and R ₄ are Together with the atoms present, form a 4-7 membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents;
R ₅ is halo, aryl, aryloxy, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio;
R ₆ and R ₇ are each independently hydrogen, acyl, alkyl, cycloalkylalkyl, aryl or arylalkyl, or R ₆ and R ₇ together with the atoms to which they are attached are 1 One or more additional heteroatoms and may have one or more substituents to form a 4-7 membered heterocycle).

  Formula III

または薬学的に許容されるその塩
（式中、
Ｚは、酸素または窒素であり、
Ｒ_１およびＲ_２は、各々独立に、水素、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキルであり、またはＲ_１およびＲ_２は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、ただし、Ｚが酸素である場合、Ｒ_２は存在せず、
Ｒ_３およびＲ_４は、各々独立に、水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、またはヘテロアリールアルキルであり、またはＲ_３およびＲ_４は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、
Ｒ_５は、アルコキシ、ハロ、アリール、アリールオキシ、アルカリルオキシ、アリールアミノ、ヘテロアリールアミノ、ヘテロシクロアルキル、ヘテロアリール、ヘテロアリールオキシ、ヘテロシクロアルコキシ、またはアルキルチオであり、
Ｒ_６およびＲ_７は、各々独立に、水素、アシル、アルキル、シクロアルキルアルキル、アリールまたはアリールアルキルであり、またはＲ_６およびＲ_７は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、
Ｒ_８およびＲ_９は、各々独立に、水素、アルキルであり、またはＲ_８およびＲ_９は、これらが結合している原子と一緒になって、３〜６員の置換もしくは非置換のシクロアルキルまたはヘテロシクロアルキル環を形成する）。

Or a pharmaceutically acceptable salt thereof, wherein
Z is oxygen or nitrogen;
R ₁ and R ₂ are each independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or R ₁ and R ₂ together with the atoms to which they are attached To form a 4- to 7-membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents, provided that Z is oxygen If R ₂ is not present,
R ₃ and R ₄ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or R ₃ and R ₄ are Together with the atoms present, form a 4-7 membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents;
R ₅ is alkoxy, halo, aryl, aryloxy, alkaryloxy, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio;
R ₆ and R ₇ are each independently hydrogen, acyl, alkyl, cycloalkylalkyl, aryl or arylalkyl, or R ₆ and R ₇ together with the atoms to which they are attached are 1 Form a 4-7 membered heterocycle, which may have one or more additional heteroatoms and may have one or more substituents;
R ₈ and R ₉ are each independently hydrogen, alkyl, or R ₈ and R ₉ together with the atoms to which they are attached are 3-6 membered substituted or unsubstituted cycloalkyl Or form a heterocycloalkyl ring).

  Formula IV

または薬学的に許容されるその塩
（式中、
Ｚは、酸素または窒素であり、
Ｒ_１およびＲ_２は、各々独立に、水素、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキルであり、またはＲ_１およびＲ_２は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、ただし、Ｚが酸素である場合、Ｒ_２は存在せず、
Ｒ_３およびＲ_４は、各々独立に、水素、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、またはヘテロアリールアルキルであり、またはＲ_３およびＲ_４は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、
Ｒ_５は、アルコキシ、ハロ、アリール、アリールオキシ、アルカリルオキシ、アリールアミノ、ヘテロアリールアミノ、ヘテロシクロアルキル、ヘテロアリール、ヘテロアリールオキシ、ヘテロシクロアルコキシ、またはアルキルチオであり、
Ｒ_６およびＲ_７は、各々独立に、水素、アシル、アルキル、シクロアルキルアルキル、アリールまたはアリールアルキルであり、またはＲ_６およびＲ_７は、これらが結合している原子と一緒になって、１個もしくは複数のさらなるヘテロ原子を有することができ、かつ１個もしくは複数の置換基を有することができる、４〜７員の複素環を形成し、
Ｒ_８およびＲ_９は、各々独立に、水素、アルキルであり、またはＲ_８およびＲ_９は、これらが結合している原子と一緒になって、３〜６員の置換もしくは非置換のシクロアルキルまたはヘテロシクロアルキル環を形成する）。

Or a pharmaceutically acceptable salt thereof, wherein
Z is oxygen or nitrogen;
R ₁ and R ₂ are each independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or R ₁ and R ₂ together with the atoms to which they are attached To form a 4- to 7-membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents, provided that Z is oxygen If R ₂ is not present,
R ₃ and R ₄ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or R ₃ and R ₄ are Together with the atoms present, form a 4-7 membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents;
R ₅ is alkoxy, halo, aryl, aryloxy, alkaryloxy, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio;
R ₆ and R ₇ are each independently hydrogen, acyl, alkyl, cycloalkylalkyl, aryl or arylalkyl, or R ₆ and R ₇ together with the atoms to which they are attached are 1 Form a 4-7 membered heterocycle, which may have one or more additional heteroatoms and may have one or more substituents;
R ₈ and R ₉ are each independently hydrogen, alkyl, or R ₈ and R ₉ together with the atoms to which they are attached are 3-6 membered substituted or unsubstituted cycloalkyl Or form a heterocycloalkyl ring).

  Embodiments of the present invention include compounds of Formulas I-IV, pharmaceutically acceptable salts, solvates, tautomers, hydrates, or combinations thereof, and pharmaceutically acceptable carriers, additions Pharmaceutical compositions comprising an agent or excipient are provided. Embodiments of the present invention provide methods for making compounds, including the compounds described herein, by the synthetic methods described herein for providing compounds of Formulas I-IV. Further provided is an intermediate compound formed.

In some embodiments, the arylsulfonamides described herein exclude furosemide, bumetanide, and piretanide. In other embodiments, the arylsulfonamides described herein exclude one or more compounds disclosed in Examples 1-43 of US Patent Application Publication No. 2007/0149526. In other embodiments, the arylsulfonamides described herein exclude one or more compounds disclosed in Examples 100-136 of WO2010 / 085352. In still other embodiments, the arylsulfonamides described herein are European Journal of Medicinal Chemistry (1976), 11 (5): 399-406; GB 2127129; Liebigs Analender der Chemie (1979). Year (4): 461-9; American Journal of Physiology (1993), 265 (5, Pt. 1): G942-G954; Journal of Medicinal Chemistry (1971), 14 (No. 5) ): 432-9; U.S. Pat. No. 4,247,550; U.S. Pat. No. 3,985,777; WO2008 / 052190; U.S. Pat. No. 7,282,519; ional journal of
Pharmaceuticals, 60: 163-169 (1990); U.S. Pat. No. 5,073,641; Revista Portugales de Pharmacia, 44: 164-169 (1994); Pharmalogy, 26: 172-80 (1983); U.S. Patent Application Publication No. 2007/0155729; European Journal of Pharmacology, 344: 269-277 (1998); or excludes one or more compounds disclosed in JP49 / 081334 . In yet other embodiments, the arylsulfonamides described herein exclude one or more compounds of the formula.

また他の実施形態において、式ＩおよびＩＩのスルホンアミドは、式の１種または複数の化合物を除外する。

In yet other embodiments, the sulfonamides of formulas I and II exclude one or more compounds of the formula.

本発明の化合物は、ＮＫＣＣ１および／またはＧＡＢＡ_Ａ受容体をアンタゴナイズする。本発明の化合物は、ＮＫＣＣ１および／またはＧＡＢＡ_Ａ受容体が関与する状態の処置において有用である。好ましい実施形態において、これらの化合物は、ＮＫＣＣ１および／またはＧＡＢＡ_Ａ受容体の選択的アンタゴニストである。好ましい実施形態において、これらの化合物は、ＧＡＢＡ_Ａ受容体の選択的アンタゴニストである。好ましい実施形態において、これらの化合物は、α_４サブユニット、α_５サブユニット、またはα_６サブユニットを含むＧＡＢＡ_Ａ受容体の選択的アンタゴニストである。

The compounds of the present invention antagonize NKCC1 and / or GABA _A receptors. The compounds of the present invention are useful in the treatment of conditions involving NKCC1 and / or GABA _A receptors. In preferred embodiments, these compounds are selective antagonists of NKCC1 and / or GABA _A receptors. In preferred embodiments, these compounds are selective antagonists of GABA _A receptors. In a preferred embodiment, these compounds, alpha ₄ subunit, which is a selective antagonist of GABA _A receptors containing the alpha ₅ subunit or alpha ₆ subunit.

Methods of Use In another embodiment, the invention provides an addictive disorder, Alzheimer's disease, anxiety disorder, ascites, attention deficit hyperactivity disorder, comprising administering an effective amount of a compound of formula I, II, III or IV. ADHD), autism spectrum disorder (autism), bipolar disorder, cancer, cognitive function (eg cognitive dysfunction, cognitive dysfunction), depression, edema, corneal endothelial dystrophy, epilepsy, glaucoma, Huntington's disease , Inflammatory pain, insomnia, ischemia, migraine with aura, migraine, migraine without aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, eye disease, pain, Parkinson's disease, cycle Limb movement disorder (PLMD) (nocturnal myoclonus), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, seizure disorder, spasticity, tinnitus, or It relates to a method of treating withdrawal syndrome.

In another aspect, the present invention relates to a method of inhibiting a Na ⁺ K ⁺ Cl ⁻ cotransporter comprising administering an effective amount of a compound of formula I, II, III or IV.

In yet another aspect, the present invention inhibits the NKCC1 (CCC1, BSC2) isoform of the Na ⁺ K ⁺ Cl ⁻ cotransporter comprising administering an effective amount of a compound of formula I, II, III or IV On how to do. In yet another aspect, the present invention inhibits the NKCC2 (CCC2, BSC1) isoform of the Na ⁺ K ⁺ Cl ⁻ cotransporter comprising administering an effective amount of a compound of formula I, II, III or IV On how to do. In another embodiment, the present invention provides administration of an effective amount of a compound of formula I, II, III or IV, the NKCC1 (CCC1, BSC2) isoform of the Na ⁺ K ⁺ Cl ⁻ cotransporter and NKCC2 ( CCC2, BSC1) relates to a method for suppressing both isoforms.

The present invention also includes, but is not limited to, addictive disorders (eg obsessive compulsive disorder, eating disorders (eg obesity), addiction / physical dependence, alcohol addiction, narcotic addiction, cocaine addiction, heroin addiction, Opiate addiction, alcoholism, and smoking); anxiety disorders (eg, anxiety, acute anxiety, panic disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder, panic symptoms, post traumatic stress disorder (PTSD), Generalized anxiety disorder and specific phobia); ascites (eg, peritoneal fluid, ascites fluid excess, hydroperitoneum, ascites, cancer associated with ascites, tumor associated with ascites); attention deficit hyperactivity disorder ( ADHD); bipolar disorder (eg manic depression, manic phase, depression phase, mixed bipolar state, bipolar disorder type I, bipolar disorder type II, rapid alternation bipolar disorder); cancer (eg tumor Cancer associated with ascites, tumor associated with ascites); depression (eg, psychotic depression, postpartum depression, seasonal affective disorder (SAD), cortical spreading depression, dysthymia (mild depression)) Edema (eg, central nervous system edema); corneal endothelial dystrophy (eg, post-chamber ocular diseases); epilepsy (eg, seizures, epileptic seizures, cluster seizures, acute seizures (eg, Status epilepticus), seizure disorders, and other neurological disorders involving seizures (eg, cerebral palsy, Otawara syndrome)); glaucoma (eg, increased intraocular pressure, closed angle glaucoma, neovascular glaucoma, open angle) Glaucoma); ischemia (eg, cardiac ischemia (myocardial ischemia), intestinal ischemia, mesenteric artery ischemia (acute mesenteric ischemia), liver ischemia, and brain ischemia (brain ischemia) ); Migraine (example) For example, headache, migraine variant, migraine, cervical migraine syndrome, acute confusion migraine, migraine with aura, migraine without aura, Neuropathic pain (eg, neuropathic pain associated with diabetic neuropathy, nerve injury, nerve tract injury, visceral pain and / or somatic pain, peripheral neuropathy, chemotherapy-induced neuropathy, chemotherapy Induced peripheral neuropathy, neuralgia, polyneuropathy, mononeuropathy, polyneuropathy, autonomic neuropathy, symmetric peripheral neuropathy, radiculopathy, large fiber peripheral neuropathy, Fibrous peripheral neuropathy, idiopathic neuropathic pain; nociceptive neuralgia; ocular diseases (eg, retinal disease-retinal detachment and injury response; various retinal elements (rod, retina) Diseases of electrical transmission between cones, amacrine cells and horizontal cells), retinal ganglion cell activity, Mueller (glia) dysfunction, abnormal function of retinal pigment epithelium; nerves following maturation and development Dysfunction of retina formation in the development and proper maintenance of communication; regulation of normal electrolyte homeostasis in various chorioretinal and vitreous retinal diseases; abnormal function of Mueller cells in diabetic retinopathy; Loss of normal electrical activity in inherited and unknown etiology); eye inflammation Diseases and conditions (choroidal retinitis, multiple sclerosis, etc.); infection processes in the eye with abnormal inflammatory and injury responses; uveitis; abnormal function of Muller cells of the retina and its disease; RPE-retinal pigment Epithelial dysfunction (eg, RPE disease); corneal endothelium (posterior) dystrophy resulting from primary endothelial dysfunction (eg, Fuchs corneal endothelial dystrophy (FECD), posterior polymorphic corneal dystrophy (PPCD) and congenital inheritance Retinitis pigmentosa (CHED)); retinitis pigmentosa; age-related macular degeneration (eg, dry age-related macular degeneration, exudative age-related macular degeneration, and myopic degeneration); retinopathy (eg, diabetic) Retinopathy, proliferative vitreoretinopathy, and toxic retinopathy) and diseases of aqueous humor formation (eg glaucoma)); pain (eg chronic Inflammatory pain, chronic musculoskeletal pain, pain associated with arthritis, pain associated with osteoarthritis, fibromyalgia, back pain, bone pain associated with cancer, pain associated with cancer, induced by chemotherapy Neuropathy induced, peripheral neuropathy induced by chemotherapy, neuropathy induced by HIV treatment, neuralgia induced by HIV treatment, pain associated with gastrointestinal diseases, pain associated with Crohn's disease, associated with autoimmune diseases Pain associated with endocrine disease, pain associated with diabetic neuropathy, pain associated with shingles or herpes, phantom limb pain, spontaneous pain, chronic postoperative pain, chronic temporomandibular joint pain, causalgia, postherpetic neuralgia , Pain associated with AIDS, complex regional pain syndrome type I and II, trigeminal neuralgia, chronic back pain, spinal cord injury and related To pain and / or recurrent acute pain); postherpetic neuralgia (eg, shingles, zoster); including and schizophrenia, Na ⁺ K ⁺ Cl ^- symporter is to treat disorders involving Methods of using compounds of Formulas I-IV are provided. In a preferred embodiment, these compounds are selective antagonists of NKCC1.

The invention also includes, but is not limited to, Alzheimer's disease (AD), addictive disorders (eg obsessive-compulsive disorder, eating disorders (eg obesity, anorexia nervosa, bulimia)), addiction / body to drugs Addiction, alcohol addiction, drug addiction, cocaine addiction, heroin addiction, opium addiction, alcohol dependence, and smoking); anxiety disorders (eg, anxiety, acute anxiety, panic disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic) Disorder, panic symptoms, post-traumatic stress disorder (PTSD), generalized anxiety disorder, and specific phobia); autism spectrum disorder (autism); bipolar disorder (eg manic depression, manic phase, Depression phase, mixed bipolar state, bipolar disorder type I, bipolar disorder type II, rapid alternation bipolar disorder, bipolar disorder type I, bipolar disorder type II); depression (eg, psychotic Depression, postpartum depression, seasonal affective disorder (SAD), cortical spreading depression, dysthymia (mild depression); epilepsy (eg, seizures, epileptic seizures, cluster seizures, acute seizures (eg, status epilepticus) ), Seizure disorders, and other neurological disorders involving seizures (eg, cerebral palsy, Otawara syndrome)); Huntington's disease (HD) (eg, Huntington's chorea); insomnia, migraine (eg, headache, migraine) Variant, migraine, cervical migraine syndrome, acute confounding migraine, migraine with aura, migraine without aura, chronic migraine, migraine including transforming migraine); neuropathic pain ( For example, diabetic neuropathy, cluster headache, nerve injury, nerve tract injury, neuropathic pain associated with visceral and / or somatic pain, peripheral neuropathy, neuronal induced by chemotherapy C, peripheral neuropathy induced by chemotherapy, neuropathy induced by HIV treatment, neuralgia induced by HIV treatment, neuralgia, polyneuropathy, mononeuropathy, polyneuropathy, autonomic neuropathy, symmetrical peripherality Neuropathy, radiculopathy, thick-fiber peripheral neuropathy, thin-fiber peripheral neuropathy, idiopathic neuropathic pain); nociceptive pain; pain (eg, acute pain, acute inflammatory pain, chronic inflammatory pain, chronic muscle bone Case pain, pain associated with arthritis, pain associated with osteoarthritis, fibromyalgia, back pain, bone pain associated with cancer, pain associated with cancer, neuropathy induced by chemotherapy, chemotherapy -Induced peripheral neuropathy, digestive disorders-related pain, Crohn's disease Pain, pain associated with autoimmune disease, pain associated with endocrine disease, pain associated with diabetic neuropathy, pain associated with shingles or herpes zoster, phantom limb pain, spontaneous pain, pain after chronic surgery, chronic temporomandibular joint Pain, causalgia, postherpetic neuralgia, pain associated with AIDS, complex regional pain syndrome type I and II, trigeminal neuralgia, chronic back pain, pain associated with spinal cord injury, post-incision, trauma related, burn, recurrent Acute pain, head pain, headache, non-migraine headache, specific non-migraine head pain, tic dolureaux, postherpetic neuralgia, ice pick headache); Parkinson's disease, periodic limb movement disorder ( PLMD) (nocturnal myoclonus), personality disorder, psychosis, restless leg syndrome (RLS), seizure disorder, personality disorder, schizophrenia, tinnitus, And GABA _A receptors, including withdrawal syndrome (eg, alcohol withdrawal syndrome, nicotine withdrawal syndrome, opioid withdrawal syndrome, benzodiazepine withdrawal syndrome, methadone withdrawal syndrome, SSRI interruption syndrome, hydrocodone withdrawal syndrome, cocaine withdrawal syndrome, heroin withdrawal syndrome) There is provided a method of using a compound of formulas I-IV for treating disorders involving

  The present invention relates to addictive disorder, Alzheimer's disease, anxiety disorder, ascites, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, comprising administering an effective amount of a compound of formula I, II, III or IV (Autism), bipolar disorder, cancer, cognitive function (eg cognitive dysfunction, cognitive dysfunction), depression, corneal endothelial dystrophy, edema, epilepsy, glaucoma, Huntington's disease, inflammatory pain, insomnia, void Blood, migraine, migraine with aura, migraine without aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, eye disease, pain, Parkinson's disease, periodic limb movement disorder (PLMD) ( Nocturnal myoclonus), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, seizure disorder, spasticity, tinnitus, and withdrawal syndrome Further provides a method of treating a patient diagnosed with risk factors for that state.

  Embodiments of the present invention provide kits comprising compounds, including the compounds described herein. These kits can be used in the treatment methods disclosed herein. In another embodiment, the kit may include instructions, usage instructions, labels, warnings, or information brochures.

  Embodiments of the present invention provide the use of a compound described herein for the preparation of a medicament for practicing the above utilities.

  In a preferred embodiment, the compounds described herein exhibit a more potent action on the central nervous system and differential activity with less diuretic action. For example, the compounds described herein can be used in long-term (maintenance) therapy without significant diuretic effects. The arylsulfonamides described herein can also be used in combination therapy with diuretics due to their lack of diuretic action. Furthermore, the compounds described herein do not interfere with diuretics or cause severe side effects when administered in conjunction with or concurrently with diuretics.

  In another embodiment, the compound described herein can be administered in combination with a second agent.

Enhanced Permeability Embodiments of the present invention cross the blood brain barrier comprising a compound of formula I-IV, or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof. Provided are compounds capable of In some embodiments, the compounds of the invention may have increased lipophilicity and / or decreased diuretic action compared to a diuretic or diuretic-like compound. Lipophilicity can be measured by determining the hydrophilic-lipophilic balance (HLB) or partition coefficient (eg, partitioning of the compound between water and octanol). In further embodiments, the compounds of the invention may result in fewer undesirable side effects when used in the modulation (ie, prevention, management) and / or treatment methods described herein. In preferred embodiments, the compounds described herein exhibit improved CNS pharmacological properties and increased passage across the blood brain barrier (BBB).

Weak diuretic action In some embodiments, the level of diuresis following administration of an effective amount of a compound provided herein as Formulas I-IV is a comparable amount of diuretic compound (eg, bumetanide, furosemide, piretanide). Less than about 99%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30% of the level of diuresis that occurs after administration of (piratanide) % Or less than 10%. For example, the compound may have a diuretic effect less than a diuretic compound (eg, bumetanide, furosemide, piretanide, torsemide, azosemide) when administered at the same mg / kg dose.

Selective Activity Na ⁺ K ⁺ Cl ⁻ Cotransporter The compounds of the present invention of Formulas I-IV described herein include, but are not limited to, the Na ⁺ K ⁺ Cl ⁻ cotransporter (eg, NKCC1 , KNCC2) or for a series of conditions (including prevention, management and treatment) including disorders involving at least one of the K ⁺ Cl ⁻ cotransporters (eg, KCC1, KCC2, KCC3, KCC4) Can be used.

In preferred embodiments, the present invention inhibits basolateral bumetanide-sensitive Na ⁺ K ⁺ Cl ⁻ cotransporters (eg, NKCC1) comprising administering a composition comprising a compound described herein. Inhibition of apical bumetanide sensitive Na ⁺ K ⁺ Cl ⁻ cotransporter (eg NKCC2) is less than 10% of the effect on basolateral bumetanide sensitive Na ⁺ K ⁺ Cl ⁻ cotransporter (eg NKCC1) , 15% or less, 25% or less, or 50% or less. In yet another embodiment, the invention provides an apical bumetanide sensitive Na ⁺ K ⁺ Cl ⁻ cotransporter (eg, NKCC2) comprising administering a composition comprising a compound described herein. includes a method of suppressing, basolateral bumetanide-sensitive ^Na + ^K + Cl ^- symporter (e.g., NKCC1) inhibition of the apical bumetanide-sensitive ^Na + ^K + Cl ^- symporter (e.g., NKCC2) 10 effects on % Or less, 15% or less, 25% or less, or 50% or less. Some preferred compounds described herein are only exhibit minimal activity against GABA _A Eze act on a receptor or GABA _A receptor.

GABA _A Receptors The compounds of the invention of formulas I-IV described herein include, but are not limited to, regulation of a range of conditions, including disorders involving at least one GABA _A receptor. , Including management and treatment).

In another embodiment, the compounds described herein have a selective effect on a subset of GABA _A receptors in the CNS and fewer side effects usually associated with agents that act on GABA _A receptors. Can be shown. For example, the compounds described herein exhibit lower sedation and lower suppression of respiratory, cognitive, or motor function. In another embodiment, the compounds described herein may exhibit selective action against GABA _A receptors, including alpha ₅ subunit or alpha ₆ subunit. In another embodiment, the compounds described herein exhibit selective action against GABA _A receptor comprising the alpha ₄ subunit.

In one embodiment, the invention includes administering a composition comprising an effective amount of a compound of Formulas I-IV or a pharmaceutically acceptable salt thereof, in the vicinity of synapses (herein, pre-synaptic or synaptic). _A method of antagonizing GABA _A receptors (defined as outside). In another embodiment, the invention comprises administering an effective amount of a composition comprising a compound of Formulas I-IV or a pharmaceutically acceptable salt thereof, an α ₄ subunit, an α ₅ subunit, or It includes a method of antagonizing the synaptic vicinity GABA _a receptors containing the alpha ₆ subunit.

The compounds described herein may have an antagonistic effect on GABA _A receptors located near the synapse. In one embodiment, the compounds described herein, alpha ₄ subunit located synaptic vicinity, antagonistic effect on GABA _A receptors, including alpha ₅ subunit or alpha ₆ subunit, Can have. In another embodiment, the present invention comprises administering a composition comprising a compound as described herein, alpha ₄ subunit, alpha ₅ subunit or alpha ₆ synaptic vicinity GABA containing subunits, includes a method of antagonizing _a receptor, alpha ₁ subunit, GABA _a receptor antagonism with alpha ₂ subunit or alpha ₃ subunits, (antagonism) is, alpha ₄ subunit, alpha ₅ subunit, Or 10% or less, 15% or less, 25% or less, or 50% or less of the action on GABA _A receptor having α ₆ subunit.

The compounds described herein can bind preferentially to the GABA _A receptor. In one embodiment, a compound described herein comprises a GABA _A comprising an α ₁ subunit, an α ₂ subunit, an α ₃ subunit, an α ₄ subunit, an α ₅ subunit, or an α ₆ subunit. It can bind preferentially to the receptor. The preferential binding of the compounds of the present invention can be reflected in an effective concentration (EC ₅₀ ), ie the concentration of the compound in vitro where the antagonistic action is half of the maximum antagonism exhibited by each compound for a particular receptor. . In particular, more preferred compounds of the present invention are those wherein the EC ₅₀ of the compound for GABA _A receptor having an α ₄ subunit, an α ₅ subunit, or an α ₆ subunit is an α ₁ subunit, an α ₂ subunit, or alpha ₃ 10% of the _{EC 50} for the same compounds for GABA _a receptors with subunit or less than 15%, but 25% or less, or 50% or less.

The compounds described herein are effective in humans and animals to reduce seizures, reduce pain response, and reduce migraine in humans and animal models. For example, the compounds described herein may preferentially bind to GABA _A receptor subtypes and have antagonistic effects on GABA _A receptors that differ from the classical benzodiazepine and barbiturate mechanisms. The compounds described herein cannot act on the Na ⁺ K ⁺ 2Cl ⁻ cotransporter (NKCC1 or NKCC2). Unlike diuretic compounds (eg, bumetanide, furosemide, piretanide, azosemide, and torsemide), the compounds described herein cannot induce diuresis. For example, the compounds described herein cannot increase urine output, sodium excretion, or potassium excretion.

  These and other objects and aspects of the present invention will be described in more detail with reference to the drawings and descriptions set forth herein.

FIG. 1 is a schematic representation of possible mechanisms for the action of the compounds described herein that selectively antagonize the near-synaptic GABA _A receptor isoform in GABAergic interneurons. In this suggested mechanism, (1) GABA is released from the presynaptic terminal by activated inhibitory neurons, and (2) GABA binds to these postsynaptic GABA _A receptors and binds these receptors. Activates and thereby increases repression (eg, hyperpolarization of post-synaptic neurons), (3) GABA also binds to GABA _A receptors in the vicinity of synapses (eg, pre-synaptic and extra-synaptic), (4) in the mechanism of action with one possibility, compounds described herein can selectively bind to synapses vicinity alpha ₄ mutant GABA _a receptor (suppressing negative feedback loop), such Increase GABA release. By increasing the inhibitory stimuli applied to the post-synaptic neurons, this results in a restoration of excitement and inhibition balance. FIG. 2 illustrates the activation effect of 1 μM clobazam, 0.1 μM zolpidem, and 1 μM diazepam on the current in α ₁ -containing GABA _A receptor isoforms with 10 μM GABA. 3, in the GABA of 10 [mu] M, alpha _1-containing GABA _A receptor isoforms, alpha ₄ containing GABA _A receptor isoforms, alpha ₅ containing GABA _A receptor isoforms, and alpha ₆ containing GABA _A receptor isoform 1 illustrates the inhibitory effect of 10 μM of selected compounds on the current at. FIG. 4 illustrates the inhibitory effect of selected compounds at a concentration of 10 μM on GABA _A receptor activity in the presence of 10 μM GABA. 100% represents complete activation of GABA _A receptor. Values between 50% and 20% represent a strong suppression of GABA _A receptor activity. Bumetanide (BTX) was used as a negative control. FIG. 5 illustrates the inhibitory effect of 10 μM of the selected compound on the α ₄ β ₃ γ _2L GABA _A receptor isoform activity in the presence of 10 μM GABA. 100% represents complete activation of GABA _A receptor. Values between 50% and 20% represent a strong suppression of GABA _A receptor activity. Bumetanide (BTN) was used as a negative control. 6A-D show (A) α ₄ β ₃ γ _2L GABA _A receptor isoform activity, (B) α ₆ β ₃ γ _2L GABA _A receptor isoform activity in the presence of 10 μM GABA, ( C illustrates the inhibitory effect of 10 μM of the selected compound on α ₁ β ₃ γ _2L GABA _A receptor isoform activity and (D) α ₅ β ₃ γ _2L GABA _A receptor isoform activity. 100% represents complete activation of GABA _A receptor. Values between 50% and 20% represent a strong suppression of GABA _A receptor activity. Bumetanide (BTN) was used as a negative control. FIGS. 7A-B show 10 μM against (A) α ₄ β ₃ γ _2L GABA _A receptor isoform activity and (B) α ₆ β ₃ γ _2L GABA _A receptor isoform activity in the presence of 10 μM GABA. Illustrates the inhibitory effect of selected compounds at various concentrations. 100% represents complete activation of GABA _A receptor. Values between 50% and 20% represent a strong suppression of GABA _A receptor activity. Bumetanide (BTN) was used as a negative control. 8A-D show (A) α ₄ β ₃ γ _2L GABA _A receptor isoform activity, (B) α ₆ β ₃ γ _2L GABA _A receptor isoform activity in the presence of 10 μM GABA, ( C illustrates the inhibitory effect of 10 μM of the selected compound on α ₁ β ₃ γ _2L GABA _A receptor isoform activity and (D) α ₅ β ₃ γ _2L GABA _A receptor isoform activity. 100% represents complete activation of GABA _A receptor. Values between 50% and 20% represent a strong suppression of GABA _A receptor activity. Bumetanide (BTN) was used as a negative control. Figures 9A-J show the results from the tail flick assay. Figures 9A-J show the results from the tail flick assay. Figures 9A-J show the results from the tail flick assay. FIGS. 10A-F show data for mIPSC frequency, mIPSC amplitude, average mIPSC decay time, average mIPSC rise time, and average mIPSC half-width for compound 3034. FIGS. 10A-F show data for mIPSC frequency, mIPSC amplitude, average mIPSC decay time, average mIPSC rise time, and average mIPSC half-width for compound 3034. FIGS. 11A-F show data for compound 6009 regarding mIPSC frequency, mIPSC amplitude, average mIPSC decay time, average mIPSC rise time, and average mIPSC half-width. FIGS. 11A-F show data for compound 6009 regarding mIPSC frequency, mIPSC amplitude, average mIPSC decay time, average mIPSC rise time, and average mIPSC half-width. FIGS. 12A-F show data for compound 7049 for mIPSC frequency, mIPSC amplitude, average mIPSC decay time, average mIPSC rise time, and average mIPSC half width. FIGS. 12A-F show data for compound 7049 for mIPSC frequency, mIPSC amplitude, average mIPSC decay time, average mIPSC rise time, and average mIPSC half width.

DETAILED DESCRIPTION These and other aspects of the invention will now be described in greater detail with respect to the embodiments described herein. It should be appreciated that the present invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

Definitions The terminology used herein in describing the present invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments of the present invention and the appended claims, the singular forms “a”, “an”, and “the”, unless the context clearly indicates otherwise. The plural is also intended to be included. Also, as used herein, “and / or” means and includes any and all possible combinations of one or more of the associated listed items. Furthermore, “about” as used herein means a measurable value (amount of compound, dose, time, temperature, etc.) 20%, 10%, 5% of the specified amount, It is meant to encompass variations of 1%, 0.5%, or even 0.1%. Unless defined otherwise, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

  “Administration” as used herein broadly means any means of providing a composition to a patient. The preferred route of administration is oral, and unless otherwise indicated, any reference to “administration” herein includes “oral administration”.

  “Alkenyl” as used herein broadly refers to a straight or branched hydrocarbon radical having one or more double bonds and containing 2 to 20 carbon atoms. . Examples of alkenyl groups include propenyl, butenyl, pentenyl and the like. “Cycloalkenyl” or “cyclic alkenyl” as used herein means carbocycles containing no heteroatoms, monocyclic, bicyclic and tricyclic saturated carbocycles, and fused rings. Includes systems. Examples of cycloalkenyl groups include cyclopropenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl and the like. Such alkenyl and cycloalkenyl groups may be optionally substituted as described herein.

  “Alkyl” as used herein refers broadly to straight or branched chain saturated hydrocarbon radicals. “Alkyl” also refers broadly to cyclic (ie, cycloalkyl) alkyl groups. Examples of alkyl groups include, but are not limited to, linear alkyl groups (including methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl), And branched alkyl groups (including isopropyl, tert-butyl, iso-amyl, neopentyl, iso-amyl) and the like. “Cycloalkyl” or “cyclic alkyl” as used herein means carbocycles containing no heteroatoms, monocyclic, bicyclic and tricyclic saturated carbocycles, and fused rings. Includes systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Cycloalkyl may be substituted or unsubstituted, and cyclic alkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Such alkyl groups may be optionally substituted as described herein. When substituted, the substituents include, but are not limited to, cycloalkyl; hydroxy; alkoxy; aryl; heteroaryl; amino optionally substituted with alkyl; carboxy; amido; optionally substituted with alkyl. Carbamoyl; alkylsulfonyl; acylsulfonyl; acyl; aroyl; heteroaroyl; acyloxy; aroyloxy; heteroaroyloxy; alkoxycarbonyl; nitro; cyano; halogen; Alkyl is included and multiple degrees of substitution are possible on the alkyl group.

  “Alkylcyano” broadly refers to a straight or branched, saturated or partially unsaturated hydrocarbon radical attached to a cyano (ie, C≡N) group.

  “Alkylhalo” broadly refers to a straight or branched, saturated or partially unsaturated hydrocarbon radical attached to a halogen (eg, fluoro, chloro, bromo, and iodo).

  “Alkaryl” or “arylalkyl” as used herein broadly refers to a straight or branched chain saturated hydrocarbon radical attached to an aryl group. Examples of alkaryl groups include, but are not limited to, benzyl, 4-chlorobenzyl, methylbenzyl, dimethylbenzyl, ethylphenyl, propyl- (4-nitrophenyl), and the like. Such alkaryl groups may be optionally substituted as described herein.

  “Alkylene”, as used herein, has two terminal monovalent radical centers derived from the removal of one hydrogen atom from each of the two terminal carbon atoms of a linear parent alkane. Broadly means straight or branched chain.

  “Aryl” or “Ar” as used herein includes, but is not limited to, alkyl; alkoxy; alkylsulfanyl; alkylsulfenyl; alkylsulfonyl; oxo; hydroxy; mercapto; Carboxamoyl optionally substituted with alkyl; aminosulfonyl optionally substituted with alkyl; acyl; aroyl; heteroaroyl; acyloxy; aroyloxy; heteroaroyloxy; alkoxycarbonyl; Optionally substituted with a suitable substituent (including multiple degrees of substitution), optionally substituted aromatic group, including nitro; cyano; halogen; or perfluoroalkyl, or 1 One or more Broadly it refers to an aromatic radical which is optionally substituted fused to an aromatic group substituted with meaning selected. Examples of aryl include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, and the like. In some embodiments, two adjacent hydroxy groups on an aromatic group can form a dioxolane.

  “Alkoxy” as used herein, alone or as part of another group, is an alkyl as defined herein appended to the parent molecular moiety through an oxy group. Broadly means group. In some embodiments, an alkyl group can be interrupted by one or more heteroatoms (eg, O, S, or N). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, ethyloxyethyl and the like.

  “Alkaryloxy” or “oxyalkaryl” as used herein broadly refers to the group —O-alkyl-aryl, where Ar is aryl. Examples include, but are not limited to, benzyloxy, oxybenzyl, 2-naphthyloxy, and oxy-2-naphthyl.

  “Alkaryloxyalkyl” or “alkyloxyalkaryl” as used herein broadly refers to the group -alkyl-O-alkyl-aryl, where Ar is aryl. Examples include, but are not limited to, benzyloxyethyl.

  “Analog” as used herein broadly refers to the modification or substitution of one or more chemical moieties on a parent compound and includes derivatives, regioisomers, and prodrugs of the parent compound. May be included.

  “Aryloxy” as used herein refers broadly to the group —ArO, where Ar is aryl or heteroaryl. Examples include, but are not limited to, phenoxy, benzyloxy, and 2-naphthyloxy.

“Amino” as used herein, one or both of the hydrogen atoms may be optionally replaced by alkyl, aryl or heteroaryl, and alkyl, aryl and heteroaryl groups may be any selection is substituted with, broadly refers to -NH _2.

  “Alkylthio” or “thioalkyl” as used herein, as defined herein, alone or as part of another group, is appended to the parent molecular moiety through a sulfur moiety. Such alkyl groups are broadly meant. Representative examples of alkylthio include, but are not limited to, methylthio, thiomethyl, ethylthio, thioethyl, n-propylthio, thio-n-propyl, isopropylthio, thio-isopropyl, n-butylthio, thio-n-butyl, and the like It is.

  “Arylthio” or “thioaryl” as used herein broadly refers to the group —ArS, where Ar is aryl. Examples include, but are not limited to, phenylthio, thiophenyl, 2-naphthylthio, and thio-2-naphthyl.

  “Alkarylthio” or “thioalkaryl” as used herein broadly refers to the group —S-alkyl-aryl, where Ar is aryl. Examples include, but are not limited to, benzylthio, thiobenzyl, 2-naphthylthio, and thio-2-naphthyl.

  “Alkylheterocycloalkyl” as used herein broadly refers to a straight or branched chain saturated hydrocarbon radical attached to a heterocycloalkyl group.

“Biocompatible polymer” as used herein broadly means a polymer moiety that is substantially non-toxic and does not tend to produce a substantial immune response, coagulation, or other undesirable effects. To do. According to some embodiments of the present invention, the polyalkylene glycol is a biocompatible polymer, and as used herein, a polyalkylene glycol is a linear or branched polyalkylene glycol polymer (polyethylene). Glycol, polypropylene glycol, and polybutylene glycol), and further includes monoalkyl ethers of polyalkylene glycols. In some embodiments of the invention, the polyalkylene glycol polymer is a lower alkyl polyalkylene glycol moiety, such as a polyethylene glycol moiety (PEG), a polypropylene glycol moiety, or a polybutylene glycol moiety. PEG has the formula —HO (CH ₂ CH ₂ O) _n H, where n can range from about 1 to about 4000 or more. In some embodiments, n is 1-100, and in other embodiments, n is 5-30. The PEG moiety may be linear or branched. In further embodiments, PEG can be attached to groups such as hydroxyl, alkyl, aryl, acyl, or ester. In some embodiments, the PEG can be an alkoxy PEG, eg, methoxy-PEG (or mPEG), one terminus is a relatively inert alkoxy group, while the other terminus is a hydroxyl group. It is.

  “Bioavailability”, as used herein, broadly refers to the availability of a drug to an animal after administration and can be used interchangeably with “systemic exposure” (eg, drug Bioavailability is expressed as systemic exposure of cells to the drug).

“Carboxy” as used herein refers broadly to the group —CO ₂ H.

  “Cycloalkyl” as used herein means a carbocycle containing no heteroatoms and includes monocyclic, bicyclic and tricyclic saturated carbocycles, and fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Cycloalkyls can be substituted or unsubstituted.

  “Effective amount” or “effective” as used herein refers to the alleviation of symptoms of a disease or disorder, as noted by clinical trials and assessments, patient observations, and / or the like. Broadly meaning the resulting dose. “Effective amount” or “effective” can further specify a dose that produces a detectable change in biological or chemical activity. Detectable changes can be detected and / or further quantified by one skilled in the art for the relevant mechanism or process. Further, an “effective amount” or “effective” designates an amount that maintains a desired physiological state, ie, reduces or prevents a significant decrease in the subject's state and / or promotes improvement. be able to. As is generally understood in the art, the dosage will vary depending on the route of administration, symptoms, and patient weight, but also depending on the compound being administered.

  “Halo” as used herein broadly means bromo, chloro, fluoro, or iodo. Instead, the term “halide” as used herein broadly means bromide, chloride, fluoride, or iodide.

  “Hydroxy” as used herein refers broadly to the group —OH.

  “Heteroaryl” as used herein means an aromatic 5- or 6-membered ring, wherein at least one atom consists of a heteroatom (eg, O, S, or N); The remaining atoms are carbon. The 5-membered ring has 2 double bonds and the 6-membered ring has 3 double bonds. A heteroaryl group may be monocyclic or bicyclic (fused or non-fused). Examples of monocyclic heteroaryl groups include furanyl, thiophen-yl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like . Examples of bicyclic heteroaryl groups are indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl Is included. A heteroaryl group may be substituted or unsubstituted.

  “Heterocycloalkyl” as used herein means a cycloalkyl group in which at least one of the carbon atoms in the ring has been replaced with a heteroatom (eg, O, S, or N). A heterocycloalkyl group may be monocyclic or bicyclic (fused or non-fused). Examples of monocyclic heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, tetrahydrooxazolyl, Tetrahydroisoxazolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrothiazolidinyl, tetrahydroisothiazolidinyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, 4-piperadonyl and the like are included. Examples of bicyclic non-fused heterocycloalkyl groups include quinuclidinyl, adamantyl, 2-azobicyclo [3.2.1] octyl and the like. Examples of fused heterocycloalkyl groups include any of the above monocyclic heterocycloalkyl groups fused to another cycloalkyl or heterocycloalkyl group. Examples of non-fused heterocycloalkyl groups include the spiro ring of any of the above monocyclic heterocycloalkyl groups with another cycloalkyl or heterocycloalkyl group. A heterocycloalkyl group may be substituted or unsubstituted. When substituted, the substituents include, but are not limited to, cycloalkyl; hydroxy; alkoxy; aryl; heteroaryl; amino optionally substituted with alkyl; carboxy; amido; optionally substituted with alkyl. Carbamoyl; alkylsulfonyl; acylsulfonyl; acyl; aroyl; heteroaroyl; acyloxy; aroyloxy; heteroaroyloxy; alkoxycarbonyl; nitro; cyano; halogen; Alkyl is included and multiple degrees of substitution are possible on the alkyl group.

  “Increased” or “increased” as used herein is preferably a quantified change in measurable quality that is greater than the error limits inherent in the measurement technique, ie, about the control measurement. Broadly means an increase of 2 times or more, more preferably an increase of about 5 times or more, most preferably an increase of about 10 times or more. In particular, the term “increase” as used herein broadly means to increase (as in number, size, strength, or quality); add; and / or increase. “Increasing” as used herein also includes expanding, stretching, extending, increasing, expanding, growing, generating, and / or swelling. “Increase” as used herein, a given parameter (eg, level, quantity, size, range, duration, weight) is once greater (as in number, size, strength, or quality). Further includes the case. Furthermore, an “increase” in any number, size, intensity, or quality of a given parameter is two or more time points, particularly before or after treatment, event, or administration of a drug or composition Can be determined. Furthermore, “increase” broadly means a significant or detectable functional, analytical, and / or clinical change in the number, size, intensity, or quality of a given parameter in question.

  “Mammal”, as used herein, is a mammal class, including humans, characterized by the fact that the skin is covered with hair and, in females, the mammary glands that produce milk to feed the child. Broadly refers to all kinds of warm-blooded vertebrates. Examples of mammals include, but are not limited to, alpaca, armadillo, capybara, cat, chimpanzee, chinchilla, cow, dog, goat, gorilla, hamster, horse, human, lemur, llama, mouse, non-human primate , Pigs, rats, sheep, shrews, and tapirs. Mammals include, but are not limited to, bovine, dog, horse, cat, mouse, sheep, pig, primate, and rodent species. Mammals are also listed in any of the DCs, including Mammal Specialties of the World, National Museum of Natural History, Smithsonian Institution, Washington DC, which is incorporated herein by reference in its entirety.

  “N-oxide” or “amine N-oxide” as used herein broadly refers to a chemical structure having an N—O bond, where nitrogen is positively charged and oxygen is negatively charged. Charged.

“N-substituted sulfonamide” as used herein broadly refers to a chemical structure having a —SO ₂ —NH (R) group. In this context, the R-group includes, but is not limited to, lower alkyl (eg, C ₁ -C ₅ alkyl), lower alkenyl (eg, C ₂ -C ₆ alkenyl), alkaryl, aryl, cycloalkenyl, cyclo Alkyl, dialkylaminoalkyl, heterocycloalkyl, and heteroaryl are included.

“N, N-disubstituted sulfonamide” as used herein broadly refers to a chemical structure having a —SO ₂ —NRR ′ group. In this situation, R and R ′ are the same or different and are independently lower alkyl, lower alkenyl, alkaryl, aryl, cycloalkenyl, cycloalkyl, dialkylaminoalkyl, heterocycloalkyl, heteroaryl, or they are attached 4-8 membered, which may be substituted or unsubstituted with one or more heteroatoms (eg, N, O, or S) together with the nitrogen atom Form a ring.

“Near synapse” as used herein broadly refers to receptors (eg, GABA _A receptors) located outside or around the synapse (eg, synaptic cleft). Also, “near synapse” broadly means any receptor located around, outside, and in front of the synapse.

  “Patient” as used herein broadly means any animal in need of treatment to alleviate the condition or prevent the condition from occurring or recurring. A “patient”, as used herein, has risk factors, history of disease, susceptibility, symptoms, signs, is previously diagnosed as being a disease, is at risk for the disease, or disease Broadly means any animal that is a member of any patient population. The patient may be a clinical patient, such as a human or animal patient (such as a companion animal, domestic animal, domestic animal, rare animal, or zoo animal). The animal may be a mammal, reptile, bird, amphibian, or invertebrate.

  “Pharmaceutical composition” means a chemical or biological composition suitable for administration to a subject (eg, a mammal). Such compositions include, but are not limited to, oral cavity, skin, epidermal, epidural, infusion, inhalation, intraarterial, intracardiac, intraventricular, intradermal, intramuscular, intranasal, intraocular, Several, including intraperitoneal, intrathecal, intrathecal, intravenous, oral, parenteral, pulmonary, enema or suppository, subcutaneous, subcutaneous, sublingual, transdermal, and transmucosal It may be specifically formulated for administration by one or more of the routes. Further, administration may be by capsule, drop, foam, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other means of administration.

  A “pharmaceutical additive” or “pharmaceutically acceptable additive” is a normally liquid carrier in which an active therapeutic agent is formulated. Additives generally do not impart pharmacological activity to the formulation, but may provide chemical and / or biological stability and release characteristics. Exemplary formulations can be found, for example, in Remington, The Science And Practice of Pharmacy (20th edition) (Editor Gennaro, A. R.), Philadelphia College of Pharmacy and Science (2000).

  As used herein, “pharmaceutically acceptable carrier” or “additive” includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and Absorption retardants are included. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier may be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions of the present invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

  “Pharmaceutically acceptable salt” as used herein allows its use or formulation as a medicament, retains the biological effectiveness of the free acids and bases of a particular compound, and Broadly refers to salt forms of compounds that are not biologically or otherwise undesirable.

  A “prophylactically effective amount” as used herein is sufficient to provide such prevention for disease or recurrence when administered to a patient to prevent disease or prevent recurrence of disease. Broadly means the amount of compound. A prophylactically effective amount may be an amount effective to prevent the occurrence of signs and / or symptoms. A “prophylactically effective amount” can vary depending on the disease and its severity, and the age, weight, medical history, predisposition to the condition, predisposition to the condition being treated.

  “Prophylaxis”, as used herein, broadly refers to a series of treatments in which signs and / or symptoms are not present in the patient, are in remission, or previously existed in the patient. Prevention includes preventing a disease from occurring after treatment of the disease in a patient. Furthermore, prevention treats patients who can potentially develop the disease, particularly those who are susceptible to the disease (eg, members of a patient population, having risk factors, or at risk of developing the disease). Including that.

  “Protective”, as used herein, broadly means reducing the number or severity of disease in a patient. Protective, as used herein, broadly means to suppress a disease, stop the development of the disease or its clinical symptoms, and / or cause regression of the disease or its clinical symptoms. Prevention also preferably includes preventing or reducing the incidence or severity of the disease in the patient.

  A “protective effective amount” as used herein reduces the severity of the occurrence of signs and / or symptoms when administered to a patient and the occurrence of the occurrence of signs and / or symptoms. Broadly refers to the amount of a compound that delays and prevents the occurrence of the occurrence of signs and / or symptoms. A “protective effective amount” can vary depending on the disease and its severity and the age, weight, medical history, predisposition to the condition, predisposition to the condition being treated.

“Quaternary ammonium” as used herein refers to a chemical structure having four bonds to a nitrogen having a positive charge on the nitrogen in the “onium” state, ie, “R ₄ N ⁺ ” or By “quaternary nitrogen” is meant broadly and R is an organic substituent (such as alkyl or aryl). The term “quaternary ammonium salt” as used herein broadly refers to the association of a quaternary ammonium cation with an anion.

  A “sign” of a disease, as used herein, is any indication that indicates a disease that can be found in a patient's examination, which is an objective indicator of disease as opposed to symptoms that are subjective indicators of disease. Abnormality means broadly.

  A “symptom” of a disease, as used herein, is a deviation from any pathological phenomenon or normal of structure, function, or sensation that a patient experiences and is an indicator of the disease. It means broadly.

  “Subject” as used herein includes, but is not limited to, avian and mammalian subjects, preferably mammals, suitable for being treated by the present invention. It means broadly. Mammals of the present invention include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents (eg, rats and mice), rabbits, primates, humans, and the like, and intrauterine Of mammals. Any mammalian subject in need of being treated by the present invention is suitable. A human subject is preferred. Human subjects of both genders and any developmental stage (ie, neonate, infancy, boyhood, adolescence, adult) can be treated according to the present invention.

  The present invention also provides animal subjects, particularly mammalian subjects (mouse, rat, dog, cat, cow, goat, sheep, for veterinary purposes and for drug screening and drug development purposes. And horses). The invention is also directed to birds, including chickens, ducks, turkeys, geese, quails, pheasants, migratory birds (eg, ostriches), and domesticated birds (eg, parrots and canaries), and birds in the embryo. It can be carried out. “Subject” is used interchangeably with “patient”.

  “Solvate” as used herein broadly means a molecular complex of a compound having one or more solvent molecules in a stoichiometric or non-stoichiometric amount. Such solvent molecules are those commonly used in pharmaceutical technology (eg, water, ethanol, etc.). A molecular complex of a compound or a portion of a compound and a solvent can be stabilized by non-covalent intramolecular forces (such as electrostatic forces, van der Waals forces, and hydrogen bonds). The term “hydrate” means a complex in which one or more solvent molecules is water, including monohydrate and hemihydrate. Examples of solvates include, but are not limited to, compounds of the invention in combination with water, 1-propanol, 2-propanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

  “Substituted”, as used herein, replaces one or more of the hydrogen atoms of a group with a substituent known to those skilled in the art, resulting in a stable compound as described below. , Broadly means replacement. Examples of suitable substituents include, but are not limited to, alkyl, acyl, alkenyl, alkynylcycloalkyl, aryl, alkaryl, hydroxy, thio, alkoxy, aryloxy, acyl, amino, amide, carboxy, carboxyalkyl, thio Carboxyalkyl, carboxyaryl, thiocarboxyaryl, halo, oxo, mercapto, sulfinyl, sulfonyl, sulfonamido, amidino, carbamoyl, cycloalkyl, heterocycloalkyl, dialkylaminoalkyl, carboxylic acid, carboxamide, haloalkyl, dihaloalkyl, trihaloalkyl , Trihaloalkoxy, alkylthio, aralkyl, alkylsulfonyl, arylthio, amino, alkylamino, dialkylamino, guanidino, urea De, include nitro and the like. Substitution is permissible when such a combination results in a stable compound for the intended purpose. For example, substitution is acceptable when the resulting compound is sufficiently strong to withstand isolation from the reaction mixture to a useful degree of purity and formulation into a therapeutic or diagnostic agent or reagent.

  “Treatment” or “therapeutic” as used herein treats a disease, stops or reduces the occurrence of the disease or its clinical symptoms, and / or alleviates the disease, or the disease or its clinical symptoms It means broadly to bring about regression. Treatment includes the prevention, prevention, treatment, cure, treatment, remedy, minimization, reduction, reduction, and / or realization of a disease, sign, and / or symptom of the disease. Treatment includes relief of signs and / or symptoms in patients with ongoing disease signs and / or symptoms (eg, pain, inflammation). Treatment also includes “prevention” and “prevention”. Prevention includes preventing the disease from occurring after treatment of the disease in the patient or reducing the incidence or severity of the disease in the patient. The term “reduced” broadly means a clinically significant reduction in signs and / or symptoms for therapeutic purposes. Treatment includes treating relapsed or recurrent signs and / or symptoms (eg, pain). Treatment includes, but is not limited to, eliminating the appearance of signs and / or symptoms at any point in time and reducing existing signs and / or symptoms and eliminating existing signs and / or symptoms. Is included. Treatment includes treating chronic diseases ("maintenance") and acute diseases.

  Treatment includes patients with risk factors, patients at risk in susceptible populations, patients with a history of disease, patients with symptoms, patients with symptoms, patients with symptoms but no symptoms, and symptoms May be for patients who have symptoms but no symptoms. Treatment is also for patients who do not have risk factors, patients who are not at risk, patients who are not in the susceptible population, patients who do not have a history of disease, patients who have no symptoms, patients who have no symptoms It's okay. Treatment reduces, relieves, ameliorates, satisfies, reduces, reduces, facilitates, reduces, lightens, makes better, healthier, relaxes, soothes the disease, symptoms of the disease, and / or symptoms Can be stored, relaxed, rehabilitated, rescued, repaired and / or calmed.

“Treatment” or “treatment” as used herein broadly refers to a series of therapies, and signs and / or symptoms are present in the patient. The term “decrease” broadly means a clinically significant reduction in signs and / or symptoms for therapeutic purposes. Treatment includes treating chronic diseases (“maintenance”) and acute diseases. Treatment may be for patients with risk factors, patients at risk in susceptible populations, patients with a history of disease, and / or patients with symptoms, patients with symptoms. Treatment reduces, relieves, remits, satisfies, reduces, reduces, facilitates, reduces, lightens, improves, makes healthy, relaxes, soothes the disease, signs of disease, and / or symptoms Can be stored, relaxed, rehabilitated, rescued, repaired and / or calmed. The term “treating” or “treatment” for disorders involving the Na ⁺ K ⁺ Cl ⁻ cotransporter refers to the severity of the disorder or the disorder as compared to what would occur in the absence of treatment. It is intended that symptoms are reduced or that the disorder is partially or totally eliminated. Treatment does not require complete healing of the disorder to be achieved. The term “preventing” or “preventing” a disorder involving the Na ⁺ K ⁺ Cl ⁻ cotransporter is compared to what the method of the invention would cause in the absence of treatment. It is intended to eliminate or reduce the number or occurrence of. In other words, the method delays, slows, controls, or reduces the likelihood or likelihood of a disorder in a subject as compared to what would occur in the absence of treatment. Furthermore, the terms “treating” or “treatment” for disorders involving GABA _A receptors reduce the severity of the disorder or the symptoms of the disorder compared to what would occur in the absence of treatment. Or the fault is intended to be partially or totally eliminated. Treatment does not require complete healing of the disorder to be achieved.

Compounds According to some embodiments, the present invention provides novel compounds. Thus, any of the R groups as defined herein can be excluded or modified to exclude known compounds and / or provide new compounds. Also, any of the R groups as defined herein can be excluded from the compounds of the present invention, particularly in connection with showing novel compounds of the present invention. The compounds of the present invention include compounds according to formula I, II, III or IV.

  Embodiments of the present invention further provide intermediate compounds formed by the synthetic methods described herein for providing compounds of Formulas I-IV. Intermediate compounds may have utility as therapeutic agents for the series of indications described herein, and / or reagents for further synthetic methods and reactions.

  In some embodiments, the invention includes the following compounds, including their esters, amides, N-substituted sulfonamides and N, N-disubstituted sulfonamides.

Synthetic Methods Embodiments of the present invention provide methods for modifying compounds of the present invention to increase the lipophilicity of the compounds of the present invention. Lipophilicity can be measured by determining the hydrophilic-lipophilic balance (HLB) or partition coefficient (eg, partitioning of the compound between water and octanol). In some embodiments, the compound is a diuretic or diuretic-like compound, and in certain embodiments, the compound is referred to as a “loop diuretic”. For a discussion of the pharmacological properties of diuretics, see generally Hardman, Limbird and Gilman (eds.) (2001), Goodman &Gilman's Theological Biological of Therapeutics, McGraw-Hild. Please refer. Also included are compounds that affect the cation-chloride cotransporter. Furosemide and bumetanide are classic examples of NKCC antagonists.

  Starting materials for the synthesis of the compounds of the present invention are described in US Pat. No. 3,634,583; US Pat. No. 3,806,534; US Pat. No. 3,058,882; US Pat. No. 4,010, 273; U.S. Pat. No. 3,665,002; and U.S. Pat. No. 3,665,002.

  The compounds of the present invention can include these isomers, tautomers, zwitterions, enantiomers, diastereomers, racemates, or stereochemical mixtures. The compounds of the present invention can also include isosteres.

  The term “isostar” as used herein broadly refers to elements, functional groups, substituents, molecules, or ions that have different molecular formulas but exhibit similar or identical physical properties. For example, tetrazole is a carboxylic acid isostere. This is because tetrazole mimics the properties of carboxylic acids, even though both of these have different molecular formulas. Typically, the two isosteric molecules have similar or identical volumes and shapes. Other physical properties that are commonly shared by isosteric compounds include boiling point, density, viscosity, and thermal conductivity. However, the specific properties (dipole moment, polarity, polarization, size, and shape) are usually different because the outer trajectories can hybridize differently.

  The term “isomer” as used herein broadly means compounds that have the same number and kind of atoms and thus have the same molecular weight, but differ with respect to the arrangement or configuration of the atoms in space. . Furthermore, the term “isomer” includes stereoisomers and geometric isomers. The term “stereoisomer” or “optical isomer” as used herein has at least one chiral atom, or a constrained rotation that produces a vertical asymmetric surface (eg, a particular biphenyl, Allene and spiro compounds), meaning stable isomers capable of rotating plane polarized light. Since asymmetric centers and other chemical structures can exist in some of the compounds of the present invention, which can give rise to stereoisomerism, the present invention contemplates stereoisomers and mixtures thereof. The compounds of the invention and their salts can contain asymmetric carbon atoms and can therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically such compounds are prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, ie as individual enantiomers or diastereomers, or as a mixture enriched in stereoisomers. Tautomers are structural isomers that can be readily interconverted, and there is a change in ligand binding, such as in the keto and enol forms of ethyl acetoacetate (the tautomers of any of the above compounds). Including). Zwitterions are internal salts or bipolar compounds that have acidic and basic groups in the same molecule. At neutral pH, most zwitterionic cations and anions are equally ionized.

Pharmaceutical Compositions The compounds of the invention (eg, analogs, derivatives, and prodrugs) or pharmaceutically acceptable salts thereof may be formulated into pharmaceutical compositions in a variety of dosage forms. For preparing the pharmaceutical compositions of the present invention, at least one compound as an active ingredient, or a pharmaceutically acceptable salt thereof, together with suitable carriers and additives by techniques well known to those skilled in pharmaceutical formulation. Mix closely. Remington, The Science And Practice of Pharmacy (20th edition) (Editor Gennaro, A. R.), Philadelphia College of Pharmacy and Science (2000).

  The pharmaceutically acceptable salts of the compounds described herein allow for pharmaceutical use or formulation, retain the biological effectiveness of the free acids and bases of the particular compound, Or salt forms of the compounds, which are not otherwise undesirable. Examples of such salts are Wermuth and Stahl (eds.) (2002), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-Verlag Helveta, which is incorporated herein by reference in its entirety. , Zurich. Examples of such salts include alkali metal salts and free acid and base addition salts. Examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate Salt, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, Propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-diacid, hexyne-1,6-diacid Salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, pheny Butyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, ethanesulfonate, propanesulfonate, toluenesulfonate, naphthalene-1-sulfonate , Naphthalene-2-sulfonate, and mandelate. In some embodiments, pharmaceutically acceptable salts include sodium, potassium, calcium, ammonium, trialkylarylammonium, and tetraalkylammonium salts.

  Similarly, compositions for liquid preparations include solutions, emulsions, dispersions, suspensions, syrups, and elixirs, suitable carriers and additives include, but are not limited to, Water, alcohol, oil, glycol, preservatives, flavoring agents, coloring agents, and suspending agents are included. Typical preparations for parenteral administration are carriers such as sterile water or parenterally acceptable oils including, but not limited to, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil Along with the active ingredient, other additives may also be included to aid solubility or storage. In the case of a solution, the solution can be lyophilized to a powder and then reconstituted just prior to use. For dispersing and suspending agents, suitable carriers and additives include aqueous gums, celluloses, silicates or oils.

  Pharmaceutical compositions according to embodiments of the invention include oral, rectal, topical, nasal, inhalation (eg, by aerosol), buccal (eg, sublingual), vaginal, topical (eg, skin and mucosal surfaces (airway surface) ), Transdermal administration and parenteral (eg, subcutaneous, intramuscular, intradermal, intraarticular, intrapleural, intraperitoneal, intrathecal, intracerebral, intracranial, intraarterial, The most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the particular active agent being used. The pharmaceutical compositions of the invention are particularly suitable for oral, sublingual, parenteral, implant, nasal, and inhalation administration. The carriers and additives used for such pharmaceutical compositions can take a variety of forms depending on the anticipated mode of administration.

  Compositions for oral administration may be solid preparations including but not limited to tablets, sugar-coated tablets, hard capsules, soft capsules, granules, lozenges, and powders, suitable carriers and Additives are starches, sugars, binders, excipients, granulating agents, lubricants, and disintegrants. Tablets and capsules represent advantageous oral dosage forms for many medical conditions because of their ease of use and higher patient compliance.

  Compositions for injection can be prepared in suitable carriers (organic solvents, propylene glycol-alcohol-water, isotonic water, sterile water for injection (USP), emulPhor®-alcohol-water, cremophor-EL®. Or any other suitable carrier known to those skilled in the art). These carriers can be used alone or in combination with other conventional solubilizers (such as ethanol, glycol, or other agents known to those skilled in the art).

  When the compound of the present invention is applied in the form of a solution or injection, the compound can be used by dissolving or suspending in any conventional excipient. Excipients include, but are not limited to, saline, Ringer's solution, glucose aqueous solution, dextrose aqueous solution, alcohol, fatty acid ester, glycerol, glycol, oils derived from plant or animal sources, and paraffin. These preparations may be prepared by any conventional method known to those skilled in the art.

  Compositions for nasal administration may be formulated as aerosols, drops, powders and gels. Aerosol formulations typically include a solution or fine suspension of the active ingredient in a physiologically acceptable aqueous or non-aqueous solvent. Such formulations are typically presented in single or multiple doses in sterile form in a sealed container. The sealed container may be a cartridge or refill container for use with the nebulizer. Instead, the sealed container is a single-use dispensing device (single-use nasal inhaler with a metering valve set to deliver an effective amount, intended to be disposed of when the contents are fully used, Pump atomizer or aerosol dispenser). When the dosage form includes an aerosol dispenser, the aerosol dispenser contains a propellant, such as a compressed gas (for example, air), or an organic propellant (including fluorochlorohydrocarbons or fluorohydrocarbons).

  Compositions suitable for buccal or sublingual administration include, but are not limited to, tablets, lozenges and pastilles, and the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth or gelatin and glycerin. The

  Compositions for rectal administration include, but are not limited to, suppositories containing conventional suppository bases such as cocoa butter.

  Compositions suitable for transdermal administration include, but are not limited to, ointments, gels, and patches.

  The preferred form of administration in the present invention is the oral form known in the art of pharmacology. The pharmaceutical compositions of the present invention can be capsules (hard or soft), tablets (film coated, enteric coated or uncoated), powders or granules (not coated or coated), or liquids (solutions or suspensions). As an agent). The formulation may be conveniently prepared by any of the methods well known in the art. The pharmaceutical composition of the present invention comprises one or more suitable production aids or additives (fillers, binders, disintegrants, lubricants, excipients, flow agents, buffers, wetting agents, preservatives). , Colorants, sweeteners, flavors, and pharmaceutically compatible carriers).

  For each of the described embodiments, the compound can be administered in a variety of dosage forms as are known in the art. Any biologically acceptable dosage form known to those skilled in the art, and combinations thereof are contemplated. Examples of such dosage forms include, but are not limited to, chewable tablets, instant dissolving tablets, effervescent tablets, reconstitutable powders, elixirs, solutions, solutions, suspensions, emulsions, tablets, multilayer tablets , Bilayer tablet, capsule, soft gelatin capsule, hard gelatin capsule, caplet, lozenge, chewable lozenge, beads, powder, gum, granule, particle, fine particle, dispersible granule, cachet, pressure injection Container, suppository, cream, topical, inhalation, aerosol inhalation, patch, particle inhalation, implant, accumulation implant, ingestible, injectable (under the skin, intramuscular, intravenous, and skin And so on), as well as combinations thereof.

  Other compositions known to those skilled in the art can also be applied for transdermal or subcutaneous administration (such as plaster).

  Furthermore, in the preparation of such pharmaceutical compositions comprising active ingredients or components mixed with the components necessary for formulation of the composition, such as, but not limited to, additives, stabilizers, preservatives, wetting agents Other conventional pharmacologically acceptable additives may be incorporated, including emulsifiers, lubricants, sweeteners, colorants, flavoring agents, isotonic agents, buffering agents, and antioxidants. Additives include, but are not limited to, starch, sucrose, fructose, dextrose, lactose, glucose, mannitol, sorbitol, precipitated calcium carbonate, crystalline cellulose, carboxymethylcellulose, dextrin, gelatin, acacia, EDTA, magnesium stearate, talc , Hydroxypropylmethylcellulose, and sodium metabisulfite.

  The compounds of the present invention may be used in conjunction with delivery systems that facilitate the delivery of drugs to the central nervous system. For example, various blood brain barrier permeability enhancers can be used to transiently and reversibly increase the blood brain barrier permeability of the treatment agent as needed. Such BBB permeability enhancers include, but are not limited to, leukotrienes, bradykinin agonists, histamines, tight junction breakers (eg, zonulin, zot), hyperosmotic fluids (eg, mannitol), cytoskeleton Constrictors, and single chain alkyl glycerol (eg, 1-O-pentyl glycerol) are included. Oral, sublingual, parenteral, implant, nasal and inhalation routes can achieve delivery of the active agent to the CNS. In some embodiments, the compounds of the invention may be administered to the CNS with minimal effect on the peripheral nervous system.

  A pharmaceutical composition typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. For example, the proper fluidity can be maintained by using a coating (such as lecithin), in the case of a dispersant, by maintaining the required particle size, and by using a surfactant. it can.

  In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. Further, the compounds described herein can be formulated into sustained release formulations, for example, compositions comprising sustained release polymers. Active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic acid, polyglycolic acid copolymer (PLG). Many methods for preparing such formulations are known to those skilled in the art.

  Other compounds that can be included by mixing include, for example, medically inert ingredients (eg, solid and liquid excipients) such as lactose, dextrose saccharose, cellulose, starch or calcium phosphate (tablets or capsules Olive oil or ethyl oleate (for soft capsules), and water or vegetable oil (for suspensions or emulsions); lubricants (silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol) Gelling agents (such as colloidal clay); thickeners (such as tragacanth gum or sodium alginate), binders (such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone); Agents (such as starch, alginic acid, alginates or sodium starch glycolate); saturants; pigments; sweeteners; wetting agents (such as lecithin, polysorbate or lauryl sulfate); and other therapeutically acceptable auxiliary ingredients (such as Known additives for formulations, such as wetting agents, preservatives, buffers and antioxidants).

  In a further embodiment, the present invention provides a kit comprising one or more containers comprising a pharmaceutical dosage unit comprising an effective amount of one or more compounds of the invention. The kit may include instructions, usage instructions, labels, marketing information, warnings, or information brochures.

Prodrugs The blood brain barrier (BBB) is the physical barrier and system of cellular transport mechanisms between blood vessels in the central nervous system (CNS) and most areas of the CNS itself. The BBB maintains homeostasis by limiting the entry of potentially harmful chemicals from the blood and by allowing the entry of essential nutrients. However, the BBB is a formidable barrier to the delivery of pharmacological agents to the CNS for the treatment of disorders or to maintain or enhance normal and desirable brain functions (such as cognition, learning, and memory). be able to. The prodrugs of the present invention can cross the blood brain barrier and can be hydrolyzed by CNS esterase to provide the active compound. In addition, the prodrugs provided herein also have improved bioavailability, improved water solubility, improved passive intestinal absorption, improved transporter-mediated intestinal absorption, enhanced metabolism Protection against tissue, tissue selective delivery, milder (or fewer) side effects, reduced or no adverse drug interactions with other pharmaceuticals, and / or passive enrichment in target tissues .

  The term “prodrug” is intended to mean a compound that is converted under physiological conditions by solvolysis or metabolically into a specific pharmaceutically / pharmacologically active compound. A “prodrug” is a compound of the invention that is chemically derivatized such that some or all of the biological activity of the parent drug compound is retained or not retained and is metabolized in the subject to yield the parent drug compound. It may be a compound. The prodrugs of the present invention may also be modified so that a compound is metabolized in a subject to yield a biologically active derivative of the compound, some or all of the biological activity of its parent drug compound is retained or not retained. It may be a “partial prodrug” that has been derivatized.

  In addition, as shown in the scheme shown previously, prodrugs are those previously described, including polyethylene glycol (PEG), to the compounds of the invention using linkages that are degradable under physiological conditions. It can be formed by bonding biocompatible polymers. See also Schacht et al. (1997), Poly (ethylene glycol) Chemistry and Biological Applications, American Chemical Society, San Francisco, CA, 297-315. Conjugation of PEG to proteins can be used to reduce immunogenicity and / or increase the half-life of the compounds provided herein. Any conventional pegylation method can be used provided that the PEGylating agent retains at least some pharmaceutical activity.

  The present invention further provides prodrugs comprising the compounds described herein. Prodrugs can be formed utilizing hydrolyzable couplings to the compounds described herein. Ettmayer et al. (2004), J. MoI. Med. Chem. 47 (No. 10): 2394-2404, Testa and Mayer (2003), Hydrology in Drug and Prodrug Metabolism: Chemistry, Biochemistry-Enzymology, Wiley-VH, V. 1-780 pages.

Dosage The amount of active compound in the therapeutic composition according to the present invention depends on factors such as pathology, age, sex, weight, patient history, risk factors, predisposition to the disease, route of administration, existing treatment regimes (eg other Possible interactions with other drugs) and the individual's weight. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be reduced or increased proportionally as indicated by the circumstances of the treatment situation Good.

  It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, means a physical discrete unit suitable as a single dosage for a mammalian subject to be treated, each unit comprising a required pharmaceutical carrier and Contains a predetermined amount of active compound calculated to produce the desired therapeutic effect together. The specification for the dosage unit forms of the present invention is based on the unique properties of the active compound and the specific therapeutic effect achieved and the limitations inherent in the art of formulating such active compounds for the treatment of sensitivity in individuals. Determined and directly depends on these. In therapeutic use for the treatment of conditions in mammals (eg, humans) where a compound of the present invention or a suitable pharmaceutical composition thereof is effective, the compound of the present invention may be administered in an effective amount. A suitable dosage for the present invention can be a composition, pharmaceutical composition or any other composition described herein.

  For each of the described embodiments, the dose for the patient is about 0.01 μg, 0.02 μg, 0.03 μg, 0.04 μg, 0.05 μg, 0.06 μg, 0.07 μg, 0.08 μg, 0.09 μg, or 0.10 μg, and about 0.1 μg, 0.2 μg, 0.3 μg, 0.4 μg, 0.5 μg, 0.6 μg, 0.7 μg, 0.8 μg, 0.9 μg, or 1. 0 μg and about 1 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, or 10 μg, and about 10 μg, 11 μg, 12 μg, 13 μg, 14 μg, 15 μg, 16 μg, 17 μg, 18 μg, 19 μg, or 20 μg, And about 10 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 g, 85μg, 90μg, 95μg, or 100 [mu] g, and about 100μg, 200μg, 300μg, 400μg, 500μg, 600μg, 700μg, 800μg, or a 900μg or 1,000μg and all increments therein. Preferably, the dose for the patient may be about 0.05-5 μg and all increments therein. Alternatively, the dose for the patient may be about 1-10 μg and all increments therein. The dose for the patient is also about 10-40 μg and all increments therein, about 6-24 μg and all increments therein, about 20-80 μg and all increments therein, about 40-80 μg and All increments in, about 100-250 μg and all increments therein, or about 100-500 μg and all increments therein. More preferably, the dosage may be about 0.5 μg, 1 μg, 2 μg, 5 μg, 6 μg, 10 μg, 12 μg, 18 μg, 20 μg, 24 μg, 30 μg, 40 μg, 50 μg, 80 μg, or 90 μg. Preferably, the dosage may be 0.5 μg, 2 μg, 6 μg, 8 μg, 10 μg, 12 μg, 18 μg, 20 μg, 30 μg, 40 μg, or 80 μg.

  Instead, for each of the described embodiments, the dose for the patient is about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0 0.08 mg, 0.09 mg, or 0.10 mg, and about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, Or 1.0 mg, and about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, and about 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, Or 20 mg and about 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg, and about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1,000 mg and all increments therein Good. Preferably, the dose for the patient may be about 0.05-5 mg and all increments therein. Alternatively, the dose for the patient may be about 1-10 mg and all increments therein. The dose for the patient is also about 10-40 mg and all increments therein, about 6-24 mg and all increments therein, about 20-80 mg and all increments therein, about 40-80 mg and All increments in, about 100-250 mg and all increments therein, or about 100-500 mg and all increments therein. More preferably, the dosage may be about 0.5 mg, 1 mg, 2 mg, 5 mg, 6 mg, 10 mg, 12 mg, 18 mg, 20 mg, 24 mg, 30 mg, 40 mg, 50 mg, 80 mg, or 90 mg. Preferably, the dosage may be 0.5 mg, 2 mg, 6 mg, 8 mg, 10 mg, 12 mg, 18 mg, 20 mg, 30 mg, 40 mg, or 80 mg.

  Instead, for each of the described embodiments, the dose for the patient is about 0.01 g, 0.02 g, 0.03 g, 0.04 g, 0.05 g, 0.06 g, 0.07 g, 0 0.08 g, 0.09 g, or 0.10 g, and about 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, Or 1.0 g, and about 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, or 10 g, and about 10 g, 11 g, 12 g, 13 g, 14 g, 15 g, 16 g, 17 g, 18 g, 19 g, Or 20 g, and about 10 g, 20 g, 25 g, 30 g, 35 g, 40 g, 45 g, 50 g, 55 g, 60 g, 65 g, 70 g, 75 g, 80 g, 85 g, 90 g, 95 g or 100 g, and about 100 g, 2 0g, 300g, 400g, 500g, 600g, 700g, 800g, may be 900g or 1,000g and all increments therein. Preferably, the dose for the patient may be about 0.05-5 g and all increments therein. Alternatively, the dose for the patient may be about 1-10 g and all increments therein. The dose for the patient is also about 10-40 g and all increments therein, about 6-24 g and all increments therein, about 20-80 g and all increments therein, about 40-80 g and All increments in, about 100-250 g and all increments therein, or about 100-500 g and all increments therein. More preferably, the dosage may be about 0.5 g, 1 g, 2 g, 5 g, 6 g, 10 g, 12 g, 18 g, 20 g, 24 g, 30 g, 40 g, 50 g, 80 g, or 90 g. Preferably, the dosage may be 0.5 g, 2 g, 6 g, 8 g, 10 g, 12 g, 18 g, 20 g, 30 g, 40 g, or 80 g.

  For each of the described embodiments, the dose for the patient is about 0.01 μg / kg, 0.02 μg / kg, 0.03 μg / kg, 0.04 μg / kg, 0.05 μg / kg,. 06 μg / kg, 0.07 μg / kg, 0.08 μg / kg, 0.09 μg / kg, or 0.10 μg / kg, and about 0.1 μg / kg, 0.2 μg / kg, 0.3 μg / kg, 0 .4 μg / kg, 0.5 μg / kg, 0.6 μg / kg, 0.7 μg / kg, 0.8 μg / kg, 0.9 μg / kg, or 1.0 μg / kg, and about 1 μg / kg, 2 μg / kg kg, 3 μg / kg, 4 μg / kg, 5 μg / kg, 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, or 10 μg / kg, and about 10 μg / kg, 11 μg / kg, 12 μg / kg, 13 μg / Kg, 4 μg / kg, 15 μg / kg, 16 μg / kg, 17 μg / kg, 18 μg / kg, 19 μg / kg, or 20 μg / kg, and about 10 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg or 100 μg / Kg, and about 100 μg / kg, 200 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, or 1,000 μg / kg and so on All increments of Preferably, the dose for the patient may be about 0.05-5 μg / kg and all increments therein. Alternatively, the dose for the patient may be about 1-10 μg / kg and all increments therein. The dose for the patient is also about 10-40 μg / kg and all increments therein, about 6-24 μg / kg and all increments therein, about 20-80 μg / kg and all increments therein, It may be about 40-80 μg / kg and all increments therein, about 100-250 μg / kg and all increments therein, or about 100-500 μg / kg and all increments therein. More preferably, the dosage is about 0.5 μg / kg, 1 μg / kg, 2 μg / kg, 5 μg / kg, 6 μg / kg, 10 μg / kg, 12 μg / kg, 18 μg / kg, 20 μg / kg, 24 μg / kg. 30 μg / kg, 40 μg / kg, 50 μg / kg, 80 μg / kg, or 90 μg / kg.

  Preferably, the dosage is 0.5 μg / kg, 2 μg / kg, 6 μg / kg, 8 μg / kg, 10 μg / kg, 12 μg / kg, 18 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, or 80 μg / kg may be sufficient. Instead, for each of the described embodiments, the dose for the patient is about 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg. , 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, or 0.10 mg / kg, and about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, or 1.0 mg / kg, and about 1 mg / kg 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg, and about 10 mg / kg, 11 mg / kg, 2 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg, and about 10 mg / kg, 20 mg / kg, 25 mg / kg 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / Kg, 95 mg / kg or 100 mg / kg, and about 100 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, or 1,000 mg / kg and all of them Increment may be. Preferably, the dose for the patient may be about 0.05-5 mg / kg and all increments therein. Alternatively, the dose for the patient may be about 1-10 mg / kg and all increments therein. The dose for the patient is also about 10-40 mg / kg and all increments therein, about 6-24 mg / kg and all increments therein, about 20-80 mg / kg and all increments therein, It may be about 40-80 mg / kg and all increments therein, about 100-250 mg / kg and all increments therein, or about 100-500 mg / kg and all increments therein. More preferably, the dosage is about 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, 12 mg / kg, 18 mg / kg, 20 mg / kg, 24 mg / kg. 30 mg / kg, 40 mg / kg, 50 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg. Preferably, the dosage is 0.5 mg / kg, 2 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 18 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 41 mg / Kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg Or 100 mg / kg.

  Instead, for each of the described embodiments, the dose for the patient is about 0.01 g / kg, 0.02 g / kg, 0.03 g / kg, 0.04 g / kg, 0.05 g / kg. 0.06 g / kg, 0.07 g / kg, 0.08 g / kg, 0.09 g / kg, or 0.10 g / kg, and about 0.1 g / kg, 0.2 g / kg, 0.3 g / kg kg, 0.4 g / kg, 0.5 g / kg, 0.6 g / kg, 0.7 g / kg, 0.8 g / kg, 0.9 g / kg, or 1.0 g / kg, and about 1 g / kg 2 g / kg, 3 g / kg, 4 g / kg, 5 g / kg, 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg, or 10 g / kg, and about 10 g / kg, 11 g / kg, 12 g / kg kg, 13 g / kg, 14 g / kg, 15 g / kg, 16 g / g, 17 g / kg, 18 g / kg, 19 g / kg, or 20 g / kg, and about 10 g / kg, 20 g / kg, 25 g / kg, 30 g / kg, 35 g / kg, 40 g / kg, 45 g / kg, 50 g / Kg, 55 g / kg, 60 g / kg, 65 g / kg, 70 g / kg, 75 g / kg, 80 g / kg, 85 g / kg, 90 g / kg, 95 g / kg or 100 g / kg, and about 100 g / kg, 200 g / Kg, 300 g / kg, 400 g / kg, 500 g / kg, 600 g / kg, 700 g / kg, 800 g / kg, 900 g / kg, or 1,000 g / kg and all increments therein. Preferably, the dose for the patient may be about 0.05-5 g / kg and all increments therein. Alternatively, the dose for the patient may be about 1-10 g / kg and all increments therein. The dose for the patient is also about 10-40 g / kg and all increments therein, about 6-24 g / kg and all increments therein, about 20-80 g / kg and all increments therein, It may be about 40-80 g / kg and all increments therein, about 100-250 g / kg and all increments therein, or about 100-500 g / kg and all increments therein. More preferably, the dosage is about 0.5 g / kg, 1 g / kg, 2 g / kg, 5 g / kg, 6 g / kg, 10 g / kg, 12 g / kg, 18 g / kg, 20 g / kg, 24 g / kg. 30 g / kg, 40 g / kg, 50 g / kg, 80 g / kg, or 90 g / kg. Preferably, the dosage is 0.5 g / kg, 2 g / kg, 6 g / kg, 8 g / kg, 10 g / kg, 12 g / kg, 18 g / kg, 20 g / kg, 30 g / kg, 40 g / kg, or 80 g / kg may be sufficient.

  For each of the described embodiments, the dosage is typically administered once a day, twice a day, or three times a day, although more frequent dosing intervals are possible. The dose may be administered daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, and / or every 7 days (once a week). In one embodiment, the dosage may be administered daily for up to 30 days (including 30 days), preferably up to 7-10 days. In another embodiment, the dosage may be administered twice a day for 10 days. If the patient needs treatment due to a chronic disease or condition, the dosage can be administered as long as the signs and / or symptoms persist. The patient may require “maintenance treatment”, in which case the patient is dosed daily, months, years or for the rest of his life. Furthermore, the composition of the present invention may provide prevention of recurrent symptoms. For example, the dosage may be administered once or twice daily to prevent the onset of symptoms in patients at risk, particularly asymptomatic patients.

  For each of the described embodiments, the patient can undergo “pretreatment” with the compounds described herein, in which case the compounds described herein are daily 2 Administered daily, every 3 days, every 4 days, every 5 days, every 6 days, and / or every 7 days (once a week). In one embodiment, the dosage can be administered daily for up to 30 days (including 30 days), preferably up to 7-10 days. In another embodiment, the dosage can be administered twice a day for 10 days. If the patient needs treatment for a chronic disease or condition that requires prolonged treatment, the alkaline dose can be administered as long as the symptoms persist.

  In one embodiment, the compounds described herein are administered in an initial dose of 20-80 mg on the first day of treatment, followed by two doses of at least about 40 mg on the second day. In another embodiment, the compound described herein is administered in an initial dose of 0.5-2 mg on the first day of treatment, followed by two doses of at least about 2 mg on the second day. The In another embodiment, the compound described herein is administered in an initial dose of 10-20 mg on the first day of treatment, followed by two doses of at least about 20 mg on the second day. In yet another embodiment, the compound described herein is administered in a first dose of 5-10 mg on the first day of treatment, followed by two doses of at least about 10 mg on the second day. .

  For administration by injection, in one embodiment, treatment begins as a series of four injections at 0, 12, 24, and 36 hours. The injection may then continue once, twice, or three times daily as long as signs and / or symptoms persist. Alternatively, injections can be maintained to prevent disease recurrence. Injection can also be administered as a prophylaxis for patients at risk, particularly asymptomatic patients.

  The dosage can be administered as a single dose, a two dose, a three dose, a four dose, and / or a five dose. Doses can be administered alone, simultaneously, and sequentially.

  For each of the described embodiments, the dosage of the compound described herein is effective for the effective amount, prevention, and acute treatment of the compound described herein. It can be an amount, or an effective amount for prevention. A dosage of a compound described herein is an amount of a compound described herein effective to reduce a sign or symptom of a disease and prevents the sign and / or symptom of the disease. Reduce the severity of the signs and / or symptoms of the disease, eliminate the signs and / or symptoms of the disease, delay the occurrence of signs or symptoms of the disease, prevent the occurrence of signs and / or symptoms of the disease, Alternatively, it may be an amount effective to produce prevention of disease signs or symptoms.

  The dosage form can be any release form known to those skilled in the art. The composition of the present invention may be formulated to achieve immediate release of the active ingredient or sustained or controlled release of the active ingredient. In sustained or controlled release preparations, the release of the active ingredient is such that the blood concentration remains within the therapeutic range but below the toxic level over an extended period of time (eg, 4-24 hours). Can happen. Preferred dosage forms include immediate release, extended release, pulsed release, variable release, controlled release, timed release, sustained release, delayed release, long acting, and combinations thereof. The ability to obtain immediate release, extended release, pulsed release, variable release, controlled release, timed release, sustained release, delayed release, long acting characteristics, and combinations thereof are known in the art.

  It should be understood that the pharmacological activity of the composition can be monitored using standard pharmacological models known in the art. Furthermore, the compositions of the present invention may be incorporated or encapsulated in a polymer matrix or membrane suitable for site-specific delivery, or functionalized with a specific targeting agent capable of producing site-specific delivery. It should be understood that it may be converted. For example, the dosage form can be made to release preferably in the central or peripheral nervous system. These techniques, and other drug delivery techniques, are well known in the art. The determination of the optimal dosage for a particular situation is within the ability of those skilled in the art. For example, see Gennaro (2000), Remington, The Science And Practice of Pharmacy (20th edition), Philadelphia College of Pharmacy and Science.

  In a further embodiment, the compound according to the invention may be administered 1.5-6 mg daily, for example 3 times a day, in one tablet or capsule. In some embodiments, a compound according to the invention may be administered at 60-240 mg / day, for example, 3 times a day, in one tablet or capsule. In another embodiment, the compound according to the invention may be administered 10-20 mg daily, for example once a day in one tablet or capsule. In some embodiments, the compound according to the invention may be administered 60 mg per day. In another embodiment, the compound according to the invention may be administered 10-20 mg daily, for example once a day in one tablet or capsule. It should be noted that lower doses may be administered, particularly for intravenous administration. Furthermore, administration of lower doses administered for the parent compound may prevent undesirable peripheral effects such as diuresis.

  In yet further embodiments, the compound is administered at about 0.5 mg, 1.0 mg, or 2.0 mg. The compound is administered at about 20-80 mg daily or in two 40 mg doses. The compound is administered at 0 mg / kg, 200 mg / kg, 500 mg / kg, or 1,250 mg / kg, preferably about 10-30 mg / kg or 200-500 mg / kg. The compound is administered at 5 mg, 10 mg, 20 mg, 40 mg, or 200 mg. More preferably, the compound is administered orally at about 1 mg, 10 mg, or 20 mg daily.

Routes of administration The compositions described herein can be administered via the following routes (oral, dermal, epidural, infusion, inhalation, intraarterial, intracardiac, intraventricular, intradermal, intramuscular, intranasal, (Intraocular, intraperitoneal, intrathecal, intrathecal, intravenous, oral, parenteral, lung, rectum (via enemas or suppositories), subdermal, subcutaneous, sublingual, transdermal, and transmucosal) Can be administered either. Preferred routes of administration are buccal and oral. Administration may be local, in which case the composition is administered directly, close, locally, nearby, where, near or close to the site (s) of the disease, eg inflammation Alternatively, administration may be systemic, in which case the composition is given to the patient and passes extensively through the body, thereby reaching the site (s) of the disease. Topical administration is a cell, tissue, organ, and / or organ that includes and / or is affected by a disease and / or where signs and / or symptoms of the disease are active or likely to occur Administration to the system may be sufficient. Administration can be local with local action, and the composition is applied directly to the place where its action is desired. Administration can be enteral, in which case the desired effect is systemic (non-local) and the composition is given via the gastrointestinal tract. Administration may be parenteral, in which case the desired effect is systemic and the composition is provided by other routes than the gastrointestinal tract.

Nutritional compositions Compositions of the compounds described herein include nutritional supplements; dietary supplements; special diets for the sick; nutritional supplements; food products such as pharmaceutically advantageous foods (eg, “functional Beverages including fortified beverages (eg orange juice with calcium); traditional (eg normal oatmeal, wholemeal bread) and “designer” products (eg protein bars, smart spreads) , Smart bar, energy bar) (or can be consumed in). The compounds described herein may be formulated into health bars, sugar confectionery, animal feed, cereals, dietary supplements, yogurt, cereal coatings, foods, nutritional foods, functional foods, and combinations thereof.

Second Agent A second agent for treatment in combination with the composition of the present invention includes, but is not limited to, phenytoin, carbamazepine, barbiturate, phenobarbital, mefobarbital, trimetadione, mephenytoin, parameterdione, Phethenylate, phenacemide, metalbital, benzchlorpropamide, fenceximide, primidone, methosuccimide, ethotoin, aminoglutethimide, diazepam, clonazepam, chlorazepic acid, phosphenitomer, ethosuximide , Gabapentin, lacosamide, lamotrigine, retigabine, rufinamide, topiramate, vigabatrin, Pregabalin, tiagabine, zonisamide, clobazam, thiopental, midazolam, propofol, levetiracetam, oxcarbazepine, CCPene, GYK152466, serotonin receptor agonist, ergotamine, dihydroergotamine, sumatriptan, propranolol, metoprolol, etoprolol ), Nimodipine, verapamil, aspirin, ketoprofen, tofenamic acid, mefenamic acid, naproxen, methysergide, paracetamol, clonidine, lisuride, iprazochrome, butalbital, benzodiazepine, divalprox sodium and other similar classes of compounds It is. See U.S. Patent No. 6,495,601 and U.S. Patent Application Publication No. 2002/0082252.

  For example, in addition to the compositions described herein, patients may also have antidepressants (eg, tricyclic antidepressants [eg, amitriptyline (Elavil®), desipramine® )), Imipramine (Tofranil®), nortriptyline (Aventyl®, Pamelor®)]; serotonin and norepinephrine reuptake inhibitor (SNRI) [eg, venlafaxine (Effexor®)] , Duloxetine (Cymbalta®)]; norepinephrine and dopamine reuptake inhibitors (NDRI) [eg, bupropion (Wellbutrin®)]; combined reuptake inhibitors and receptor blockers [eg For example, trazodone (Desyrel®), nefazodone (Serzone®), maprotiline, mirtazapine (Remeron®)]; monoamine oxidase inhibitor (MAOI) [eg, isocarbox] Sajid (Marplan®), phenelzine (Nardil®), tranylcypromine (Parnate®)] and selective serotonin reuptake inhibitors (SSRI) [eg, Celexaram (Celexa ( Registered trademark)), escitalopram (Lexapro (registered trademark)), fluoxetine (Prozac (registered trademark)), paroxetine (Paxil (registered trademark)) ), Pexeva®), sertraline (Zoloft®)], fluvoxamine (Luvox®), and amitriptyline); abnormal electrical activity in the nervous system caused by the injured nerve Stabilizing anticonvulsants (eg, gabapentin (NEURONTIN®), pregabalin (LYRICA®), carbamazepine (Tegretol®), lamotrigine (Lamictal®), topiramate (Topamax®) Trademark)), felbamate (Felbatol (registered trademark)), tiagabin (Gabitril (registered trademark)), rectal diazepam (Diastat (registered trademark)), phenobarbital, phenytoin (registered trademark) Standard)) Primidone (Mysoline®), Valproate (Depakote®), Vigabatrin, Oxcarbazepine (Trieptal®), Zonisamide (Zonegran®), and Levetiracetam (Keppra) Steroids (eg corticosteroids); analgesics (eg acetaminophen (Tylenol®), codeine (Tylenol # 2,3,4 (registered trademark)), propoyl (propoyl). ) APA (Darvocet®), propoxyphene (Darvon®), fentanyl patch (duragesic®), hydromorphone (Palladone®) , Morphine (MS Contin (R)), oxycodone (Percocet (R), OxyContin (R), Percodan (R)), pentazocine (Talwin NX (R)), tramadol APAP (Ultracet (R)) ), Tramadol (Ultram®), hydrocodone APAP (Vicodin®)); lithium, and non-steroidal anti-inflammatory drugs (NSAIDs) (eg, Tylanol®, Motrin®, salicylate) (For example, acetylsalicylic acid (aspirin), amoxipurine, benorylate / benolinate, choline magnesium salicylate, diflunisal Registered trademark), etenzaamide, faislamine, methyl salicylate, magnesium salicylate, salicylsalicylate and salicylamide), arylalkanoic acids (eg, Diclofenac®, Aceclofenac®, Acemethacin®) , Alclofenac (R), Bromfenac (R), Etodolac (R), Indomethacin (R), Nabumetone (R), Oxamecin (R), Programumecin (R), Sulindac (R), and Tolmetin®) 2-arylpropionic acid (profen) (eg, Ibuprofen®) Trademark), Alminoprofen (registered trademark), Carprofen (registered trademark), Dexibuprofen (registered trademark), Dextoprofen (registered trademark), Fenbufen (registered trademark), Fenoprofen (registered trademark), Flunoprofen (registered trademark), and Roflufen trademark (registered trademark). , Ibuproxam (R), Indoprofen (R), Ketorolac (R), Loxoprofen (R), Naproxen (R), Oxaprozin (R), Pirprofen (R), Suprofen (R), Chiaprofen Acid); N-arylanthranilic acid (phenamic acid) (for example, mefenamic acid, flufenamic acid, meclofene) Mumic acid, tolfenamic acid, pyrazolidine derivative, Phenylbutazone (registered trademark), Ampyrone (registered trademark), Azapropzone (registered trademark), Clofzone (registered trademark), Kebuzone (registered trademark), Metamazole (registered trademark), Mofezone registered trademark , Oxyphenbutone®, Phenazole®, and Sulfinpyrazone®); and oxicams (eg, Piroxicam®, Droxicam®, Loroxicam®, Meloxicam, registered trademark) As well as Tenoxicam®).

  Such second agent can be administered in the same formulation (eg, the same pill) as the compound of the invention, or in a separate formulation. Preferably, the second agent is co-administered with the compound of the present invention. The second agent described herein can be administered with the compound of the invention simultaneously, sequentially, before or after administration of the compound of the invention. When administration of the second agent described herein is simultaneous, the second agent and the compound of the invention are administered together or within a very short time interval (eg, 5 minutes). Where administration of the second agent is administered as a pretreatment, the second agent is administered prior to administration of the compound of the invention for any period contemplated herein.

Psychotherapy The compounds, pharmaceutical compositions, and treatment regimes described herein can be used in combination with psychotherapy. In one embodiment, the method of treating addictive disorder, anxiety disorder, bipolar disorder, and / or depression may further comprise psychotherapy.

  Several types of psychotherapy (or “discussion therapy”) can be helpful for people with depression. In some embodiments, depending on individual needs, measures are short term (eg, 10-20 weeks) and other measures are longer term (eg, 1-10 years). Two main types of psychotherapy (cognitive behavioral therapy (CBT) and interpersonal therapy (IPT)) are effective in the treatment of neuropsychiatric disorders (eg, addictive disorder, anxiety disorder, bipolar disorder, and depression) Has been shown.

GABA _A receptor GABA _A receptor in the disease with the fifth regulatory subunit has a pentameric structure comprising two α subunits and two β subunits generally. Certain GABA _A subunits are expressed across the brain in distinct spatial and developmental patterns and show different responses to known pharmacological modulators. The GABA _A α ₁ mutant receptor is a major post-synaptic receptor that mediates the action of GABA at most inhibitory synapses, and thus effective properties of drugs acting on the GABA _A α ₁ mutant receptor. Not only is it believed to be involved in the sedative effects of these drugs. GABA _A alpha ₂ variants receptors and alpha ₃ mutant receptors, hippocampus, have been expressed in the thalamus, and other CNS position, is believed to mediate the anxiolytic activity of benzodiazepine. Alpha ₄ containing GABA _A receptors that are located in the hippocampus are thought to play a role in epilepsy. alpha ₅ containing GABA _A receptor is expressed in the hippocampus, it has been thought to play a role in learning and memory. alpha ₄ containing GABA _A receptors and alpha ₆ containing GABA _A receptor, are insensitive to benzodiazepines. Certain GABA _A subunits (such as α ₁ and α ₄ ) show increased expression in patients with epilepsy. GABA _A receptor alpha ₄ variant is important in the action of the negative feedback loop in presynaptic GABA release, stimulation wherein alpha ₄ mutant GABA _A receptors, acts to suppress GABA release .

Trace amounts of “regulatory” subunits ε and θ are expressed in specific CNS locations (such as cortex, substantia nigra, amygdala and hypothalamus). Another minor regulatory subunit, π, is expressed outside the CNS in uterus and breast tissue (overexpression of π has been observed in breast cancer). Another regulatory subunit, γ, is a component of the benzodiazepine sensitive GABA _A receptor. GABA _A subunits γ ₂ and δ are believed to be involved in the pathology of certain single gene forms of epilepsy. GABA _A α ₂ and δ subunits have also been implicated in alcohol consumption and addiction. WO2009 / 100040.

The focus of pharmacological intervention in many disorders of the central and peripheral nervous system has been to reduce neuronal excitability. Most drugs currently used to treat such disorders are, for example, ion channels that modulate excitatory neurotransmitter release or activity, enhance inhibitory pathways, and participate in impulse generation Target synaptic activity in the excitatory pathway by blocking and / or acting as a membrane stabilizer. Thus, conventional drugs and therapeutic approaches for the treatment of central and peripheral nervous system disorders reduce neuronal excitability and suppress synaptic firing. One significant drawback of these treatments is that they are non-selective and exert their effects on both normal and abnormal neuronal populations. This leads to negative unintended side effects that can affect normal CNS function (cognition, learning and memory, etc.) in the treated patient and cause adverse physiological and psychological effects. . Common side effects include oversedation, dizziness, memory loss and liver damage. For example, classic anticonvulsants and antinociceptives reduce non-excitatory or non-selective GABAergic drugs that act indiscriminately on multiple GABA _A receptor isoforms (eg, benzodiazepines and Increase the suppression by barbiturates). While this produces good efficacy, non-selective GABAergic drugs result in undesirable CNS side effects.

GABA _A receptors are localized at synaptic and extrasynaptic levels. Synaptic GABA _A receptors are involved in phase suppression, while extrasynaptic GABA _A receptors are involved in tone suppression. Strain suppression results from sustained inhibitory conduction that contributes to “signal integration” in the brain. This is because tension suppression sets a threshold for action potential generation and shorts excitatory synaptic inputs. Thus, tone suppression plays a crucial role in the regulation of neuronal excitability. This is because tension suppression sets a threshold for action potential generation and integrates excitatory signals. This conduction is maintained by “ambient” GABA (the amount of neurotransmitter present in the extracellular space). Ambient GABA arises from overflow of neurotransmitters released at neighboring synapses, from astrocytes, or from non-vesicular release. Furthermore, GABA _A receptors cluster in synapses and extrasynaptic regions (eg, presynaptic cells). Clustering of GABA _A receptors acts as an additional regulator for tone suppression. This is because clustered extrasynaptic GABA _A receptors can mediate greater tonic currents. Petrini et al. (2004), The Journal of Biological Chemistry, 279 (44): 45883-45843.

α ₄ GABA _A receptor variants are primarily located pre-synaptically or extra-synaptically (eg, on presynaptic cells). Please refer to FIG. Activation of α ₄ GABA _A receptor mutants results in hyperpolarization of presynaptic cells, reducing GABA release and thus reducing suppression (eg, specific for α ₄ GABA _A receptor mutants). Agonists result in a decrease in GABA release and a subsequent decrease in inhibitory signaling). In contrast, inhibition of antagonism of α ₄ GABA _A receptor mutants reduces presynaptic cell hyperpolarization and thus allows GABA release to continue, producing inhibitory signals to post-synaptic cells. Prolongs and potentiates (eg, antagonists specific for α ₄ GABA _A receptor variants result in increased GABA release and subsequent increases in inhibitory signaling). In effect, antagonists specific for α ₄ GABA _A receptor variants achieve physiological effects similar to those observed in current GABA agonists.

Activation of presynaptic GABA _A receptors depolarizes presynaptic nerve endings. Neuronal presynaptic action can suppress or enhance neurotransmitter release, a process called presynaptic inhibition and presynaptic facilitation, respectively. Some of the best analyzed examples of presynaptic inhibition and presynaptic facilitation have been studied in invertebrate neurons, and in vertebrate mechanoreceptor afferent neurons (dorsal root nerves) Node node). These studies, and studies in the intact mammalian spinal cord, indicate that there are at least two mechanisms for presynaptic inhibition. One is due to synaptic mediated inhibition of Ca ²⁺ channels, resulting in a decrease in Ca ²⁺ influx to the end. Other Cl ^- due to conduction increases for, which results in reduction in the height of the action potential in the presynaptic terminals (or short circuit). As a result, lower depolarization occurs and fewer Ca ²⁺ channels are activated by the action potential, and therefore less Ca ²⁺ flows into the terminal. GABA _A presynaptic receptor activation is of this latter type. Receptor antagonism then leads to presynaptic facilitation. Conversely, presynaptic facilitation is due to an enhanced influx of Ca ²⁺ . The neurotransmitter acts to inhibit the K ⁺ channel, thereby broadening the action potential and allowing Ca ²⁺ influx to last for a longer period of time.

Proper neural activity depends on maintaining an appropriate balance between excitement and suppression. Too much balance to suppress leads to sedation, conversely, too much balance to excitement can cause seizures. For example, extrasynaptic δ subunit-containing GABA _A receptors contribute to temporal lobe epilepsy by reducing inhibitory input to dentate gyrus granule cells and increasing inhibition of inhibitory interneurons. Peng et al. (2004), J. MoI. Neurosci. 24: 8629-8039. This increase in the suppression of inhibitory interneurons results in seizures by over-biasing balance excitement by reducing inhibitory signaling.

Presynaptic effects also tend to occur at the time of sensory influx. For example, presynaptic inhibition is found in the retina, spinal cord, and posterior nuclei. Presynaptic effects are important because they allow selective control of the actions of individual branches of neurons. Interaxonal synapses can suppress or promote transmitter release by changing Ca ²⁺ influx. Presynaptic inhibition can occur as a result of the activity of postsynaptic cells (presynaptic inhibitory neurons, or presynaptic facilitating neurons). In presynaptic inhibition, the result of the activity of presynaptic inhibitory neurons is to cause suppression of Ca ²⁺ currents with action potentials of presynaptic neurons. A decrease in Ca ²⁺ influx results in a decrease in the amount of neurotransmitter released, so that the synaptic potential in the postsynaptic cell is suppressed. In presynaptic facilitation, the activity of presynaptic facilitating neurons results in suppression of K ⁺ currents in presynaptic neurons, resulting in an increase in action potentials and thus an increase in Ca ²⁺ currents. As a result, neurotransmitter release increases and, as a result, the amplitude of the synaptic potential in the postsynaptic cell also increases. Kandel and Schwartz, Principles of Neural Science, 2nd edition (1985), pages 128-131.

The α ₄ GABA _A mutant is expressed at a high level in the hippocampus, striatum and thalamus, and the α ₄ GABA _A mutant is responsible for the suppression of tension mediated by the near-synaptic GABA _A receptor. Become. Furthermore, alpha ₄ expression, electric shock, alcohol exposure / withdrawal, steroid withdrawal, social isolation, and is significantly changed by epilepsy. The α ₄ βδ subtype is modulated by non-benzodiazepine GABAergic drugs such as steroids, anesthetics, and ethanol. Chandra et al. (October 10, 2006), Proc. Natl. Acad. Sci. 103 (41): 15230-15235.

Several clinical trials, including but not limited to Huntington's disease, Parkinson's disease, periodic limb movement disorder (PLMD) (nocturnal myoclonus), spasticity, epilepsy, schizophrenia, bipolar disorder, and late-onset dyskinesia The condition is thought to arise in part from an imbalance between GABA neurotransmission. For example, GABA receptors have been implicated in sleep regulation and periodicity, and the anxiolytic, amnestic, sedative, and anesthetic effects of alcohol. Jia et al. (2008), The Journal.
of Pharmacology and Experimental Therapeutics, 326 (2): 475-482. A decrease in GABA activity appears to contribute to the pathogenesis of these diseases. In addition, analgesia and satiety appear to be regulated by GABA activity. Without being limited thereto, addiction disorder, Alzheimer's disease, anxiety disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar disorder, cognitive improvement, cognitive impairment, cognition Dysfunction, depression, epilepsy, Huntington's disease, inflammatory pain, insomnia, migraine, migraine with aura, migraine without aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, pain, Several, including Parkinson's disease, periodic limb movement disorder (PLMD), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, seizure disorder, spasticity, tinnitus, and withdrawal syndrome Diseases and conditions are due at least in part to an imbalance between excitement and suppression in the central nervous system. Thus, antagonists specific for α ₄ GABA _A receptor variants that result in increased GABA release and subsequent increased inhibitory signaling may be used to treat these diseases and conditions. This is because these antagonists act to restore the balance between excitement and inhibition in the central nervous system by increasing inhibition. For example, an antagonist specific for alpha ₄ GABA _A receptor variants, binds to alpha ₄ GABA _A receptor variants that are extra-synaptic antagonist, it is prevented from being activated by ambient GABA. This prevents hyperpolarization of presynaptic cells and allows GABA release into the extended synaptic cleft, which results in a longer and stronger inhibitory signal. This in turn provides a means by which the proper balance between excitement and suppression in the central nervous system can be restored by increasing suppression that counteracts excessive excitement or lack of suppression.

The compounds described herein selectively antagonize GABA _A receptors. In a preferred embodiment, GABA _A receptor is a GABA _A receptor isoforms comprising at least one alpha ₄ subunit. In another embodiment, GABA _A receptor is a GABA _A receptor isoforms comprising at least one alpha ₅ subunit. In one embodiment, the invention includes a composition comprising a compound described herein with GABA _A receptor antagonist activity. In a further embodiment, the invention relates to a pharmaceutical composition comprising at least one compound with GABA _A receptor antagonist activity and a pharmaceutically acceptable additive. In one embodiment, the compounds described herein have GABA _A receptor antagonist activity. In another embodiment, the compounds described herein have no effect on GABA _B receptors.

GABA _A receptors may be located near synapses (eg, presynaptic and extrasynaptic) and are responsible for controlling the frequency of IPSCs. While not being bound by a specific mechanism, selected compounds described herein are believed to act at sites near synapses by suppressing negative feedback by GABA on the terminals of synaptic buttons. The inventors consider. When there is sufficient GABA in the synaptic cleft to bind to and activate these near-synaptic GABA _A receptors, the near-synaptic GABA _A receptors act to reduce GABA release (eg, Negative feedback loop). By inhibiting this negative feedback loop, the compounds described herein can increase GABA levels in the synaptic cleft and decrease neuronal firing. This increase in GABA restores the proper excitatory / inhibitory balance for normal neuronal activity.

Many of the compounds described herein can exhibit high selectivity at the end of GABA interneurons. In vitro electrophysiology studies with selected compounds described herein may show selective activity at presynaptic and / or extrasynaptic (near synaptic) terminals, which increases GABA release (inhibition). Indicates. For example, see FIGS. Without being bound to a particular theory of action, the selected compounds described herein increase the number of inhibitory events as measured by inhibitory postsynaptic current (IPSC). We believe that it can be a GABA _A receptor antagonist. For example, selected compounds described herein increase the frequency of spontaneous IPSCs (a combination of both action potentials and microevents that release GABA) and the frequency of microIPSCs (microevents are Can be increased) (by tonic release of synaptic vesicles containing GABA into the presynaptic space).

The present inventors have surprisingly discovered that selected compounds described herein can increase GABA _A inhibitory drive because increased frequency indicates a presynaptic mechanism. The interval between microinhibitory post-synaptic current and spontaneous inhibitory post-synaptic current (mIPSC and sIPSC, respectively) events can be substantially reduced in the presence of selected compounds described herein. . The pre-synaptic mechanism that increases the release of GABA from neurons is that selected compounds described herein antagonize GABA _A receptors on pre-synaptic cells, leading to prepolar cell hyperpolarization. We believe that this may be to prevent. Please refer to FIG. This can then allow additional GABA to be released into the synaptic cleft, resulting in longer and more powerful GABA-mediated suppression.

Compound selected are described herein may be selectively antagonize specific GABA _A receptor isoforms (e.g., alpha ₄ variants). α ₄ GABA _A receptor variants have been found at sites near the synapse and account for less than 1% of GABA _A receptors in the mammalian brain. Activation of α ₄ GABA _A receptor isoforms can suppress the release of GABA from GABAergic neurons (eg, activation of α ₄ GABA _A receptor results in hyperpolarization of synaptic terminals, This delays the release of GABA from the synaptic vesicle and allows the GABA clearance mechanism to reduce the amount of GABA in the synaptic cleft, resulting in a decrease in GABA in the synaptic cleft). Furthermore, the inventors surprisingly discovered that inhibition of the near-synaptic α ₄ GABA _A receptor isoform resulted in an increase in GABA release, which resulted in an increase in inhibitory stimulation on post-synaptic neurons. . This particular near-synaptic effect is a CNS-inhibiting effect exhibited by the compounds described herein, even at very high systemic exposure (eg, after> 100 mg / kg / day dose). For example, support a possible mechanism for lack of sedation. This mechanism of action is the exact opposite of GABA _A receptor activation by benzodiazepines working at low GABA concentrations. For example, selected compounds described herein may exhibit selective effects on specific GABA _A receptor isoforms (eg, α ₄ GABA _A mutants) and may exhibit typical CNS side effects ( It produces potent efficacy in hyperexcitatory states (eg, epilepsy, migraine, pain) without causing sedation and cognitive decline.

In particular, the compounds of Formulas I-IV described herein can prevent a range of conditions involving the GABA _A receptor, including but not limited to disorders described herein, It can be used for regulation including prevention, diagnosis, prognosis, management, and treatment.

In another embodiment, the compounds described herein exhibit a selective effect on GABA _A receptors in the CNS and less side effects that are usually associated with drugs that act on GABA _A receptors. For example, the compounds described herein exhibit reduced sedation, reduced breathing, reduced cognition, or reduced motor function.

For example, the compounds described herein are effective in reducing seizures, reducing pain response, and reducing migraine in humans and animals. Some of the compounds described herein bind preferentially to the GABA _A receptor subtype and have an antagonistic action on the GABA _A receptor that differs from the classical benzodiazepine and barbiturate mechanisms. Unlike some compounds described herein, some compounds described herein do not act on the Na ⁺ K ⁺ 2Cl ⁻ cotransporter (NKCC1 or NKCC2). Several compounds described herein that are equally ineffective at NKCC1 or NKCC2 are contemplated. The compounds described herein cannot cause diuresis. For example, many compounds described herein are unable to increase urine output, sodium excretion, or potassium excretion.

  Overall, the compounds described herein can be toxicologically well tolerated and do not show CNS side effects after oral administration. The inventors were surprised that selected compounds described herein may act to specifically increase neuronal inhibition by a novel mechanism of action (not NKCC-dependent). I found it. The inventors are surprised that selected compounds described herein act on interneuron endings that regulate neuronal firing, and thus these compounds can suppress abnormal firing. I discovered that. More specifically, selected compounds described herein can increase presynaptic inhibition without inhibiting all GABA receptors. This highly selective mechanism of action is novel and contrasts with the broad nonspecific activity of benzodiazepines and barbiturates.

Although benzodiazepines and barbiturates are known to be effective, these compounds are poorly tolerated to activate most GABA _A subtype receptors (eg, “fire hose action”). . In contrast, compounds selected are described herein, certain GABA _A receptor subtypes, may enhance the preferentially inhibited through the action of the alpha ₄ variants of GABA _A. This selectivity of the selected compounds described herein avoids typical CNS side effects (eg, sedation) normally associated with known GABAergic compounds.

  Further embodiments of the invention will now be described with reference to the following examples. The examples contained herein are provided by way of illustration and not by way of limitation. Exemplary syntheses for compounds according to the invention are provided, for example, in US Patent Application Publication No. 2007 / 0149526A1 and WO 2010/085352.

Example 1
3- (Butyl (ethyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

一般方法Ａ

General method A

ステップ１：３−ブチルアミノ−５−（ジメチルアミノメチレン−スルファモイル）−４−フェノキシ−安息香酸メチルエステル。丸底フラスコに、３−ブチルアミノ−４−フェノキシ−５−スルファモイル安息香酸（５００ｍｇ、１．３７ｍｍｏｌ）およびメタノール（５０ｍＬ）を充填した。塩化チオニル（４９０ｍｇ、４．１２ｍｍｏｌ）を室温でゆっくりと加え、反応混合物を５０℃に一晩加熱した。溶媒を減圧下で除去し、残渣を酢酸エチルに再溶解し、飽和炭酸水素ナトリウム溶液、水およびブラインで洗浄した。有機溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、生成物を淡黄色の固体（５１２ｍｇ）として得た。ＭＳ ｍ／ｚ：３７９［Ｍ＋１］^＋。

Step 1: 3-Butylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. A round bottom flask was charged with 3-butylamino-4-phenoxy-5-sulfamoylbenzoic acid (500 mg, 1.37 mmol) and methanol (50 mL). Thionyl chloride (490 mg, 4.12 mmol) was added slowly at room temperature and the reaction mixture was heated to 50 ° C. overnight. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a pale yellow solid (512 mg). MS m / z: 379 [M + 1] ^< +>.

Step 2: 3-Butylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. To the reaction flask was added 3-butylamino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester (509 mg, 1.346 mmol), acetonitrile (4 mL) and N, N-dimethylformamide dimethyl acetal (0.19 mL, 1.413 mmol). And stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting rubbery residue was triturated with ice-cold water to give a white solid. The solid was filtered and dried to give the product (473 mg). MS m / z: 434 [M + 1] ^< +>.

Step 3: 3- (acetyl-butyl-amino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. To a round bottom flask was added 3-butylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (100 mg, 0.230 mmol), acetyl chloride (0.018 mL, 0.254 mmol), diisopropylethylamine. (0.05 mL), THF (5 mL) was charged and the reaction was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a colorless oil (110 mg). MS m / z: 476 [M + 1] ^< +>.

Step 4: 3- (Butyl-ethyl-amino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. A round bottom flask was charged with 3- (acetyl-butyl-amino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (110 mg, 0.23 mmol), THF (3 mL), and BH. ₃ · THF (THF in 1.0M) (4.6mL, 4.6mmol) was added slowly. The reaction was stirred at room temperature for 1 hour. The reaction was quenched by the dropwise addition of water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a colorless oil (53 mg). MS m / z: 462 [M + 1] ^< +>.

Step 5: 3- (Butyl-ethyl-amino) -4-phenoxy-5-sulfamoyl-benzoic acid (NTP-4001). In a reaction vial, 3- (butyl-ethyl-amino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (50 mg, 0.11 mmol), 2N NaOH (3 mL), methanol (3 mL) ) And the reaction was heated to 40 ° C. for 3 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the desired product (20.3 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.30 (bs, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 2.18 Hz) , 1H), 7.39 (s, 2H), 7.21 (t, J = 7.5 Hz, 2H), 6.97 (t, J = 7.2 Hz, 1H), 6.76 (d , J = 7.8 Hz, 2H), 3.06 (q, J = 6.9 & 7.2 Hz, 2H), 2.94 (t, J = 6.9 Hz, 2H), 1.17 -1.08 (m, 2H), 1.00-0.88 (m, 2H), 0.76-0.68 (m, 6H). MS m / z: 391 [M-1] ^- .

(Example 2)
3- (Butyl (propyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ａに従って、ステップ３における適当な酸塩化物から開始して調製し、生成物を白色の固体として得た。ＭＳ ｍ／ｚ：４０５［Ｍ−１］⁻。

The title compound was prepared according to General Method A starting from the appropriate acid chloride in Step 3 to give the product as a white solid. MS m / z: 405 [M-1] ^- .

(Example 3)
3- (Benzyl (butyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

一般方法Ｂ

General method B

ステップ１：メチル３−（ベンジル（ブチル）アミノ）−５−（Ｎ−（（ジメチルアミノ）メチレン）スルファモイル）−４−フェノキシベンゾエート。メチル３−（ブチルアミノ）−５−（Ｎ−（（ジメチルアミノ）メチレン）スルファモイル）−４−フェノキシベンゾエート（一般方法Ａ、０．１４ｇ、０．２８６ｍｍｏｌ）、臭化ベンジル（０．０４ｍＬ、０．３４３ｍｍｏｌ）、炭酸カリウム（６０ｍｇ、０．４２９ｍｍｏｌ）、およびアセトニトリル（４ｍＬ）を、フラスコに充填した。混合物を一晩加熱還流させた。過剰な炭酸カリウムを、セライト上の濾過によって除去した。濾液を蒸発させ、クロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝１／１）によって精製し、０．１０６ｇの表題化合物を白色の固体として得た。

Step 1: Methyl 3- (benzyl (butyl) amino) -5- (N-((dimethylamino) methylene) sulfamoyl) -4-phenoxybenzoate. Methyl 3- (butylamino) -5- (N-((dimethylamino) methylene) sulfamoyl) -4-phenoxybenzoate (General Method A, 0.14 g, 0.286 mmol), benzyl bromide (0.04 mL, 0 .343 mmol), potassium carbonate (60 mg, 0.429 mmol), and acetonitrile (4 mL) were charged to the flask. The mixture was heated to reflux overnight. Excess potassium carbonate was removed by filtration over celite. The filtrate was evaporated and purified by chromatography (n-hexane / ethyl acetate = 1/1) to give 0.106 g of the title compound as a white solid.

Step 2: 3- (Benzyl (butyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid. Methyl 3- (benzyl (butyl) amino) -5- (N-((dimethylamino) methylene) sulfamoyl) -4-phenoxybenzoate (0.106 g, 0.203 mmol), 2N aqueous solution of sodium hydroxide (0. 3 mL, 0.6 mmol), and methanol (2 mL) were charged into the flask. The mixture was heated to 70 ° C. overnight and then cooled to room temperature. An aqueous solution of 1N hydrochloric acid (1 mL) is added to adjust the pH to 2-3, the mixture is extracted with ethyl acetate (3 × 2 mL), dried over magnesium sulfate and evaporated to give 0.071 g of the title compound. Obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.36-7. 26 (m, 2H), 7.18-7.06 (m, 4H), 6.92-6.86 (m, 2H), 6.80-6.72 (m, 2H), 2.97 ( t, J = 7.4 Hz, 2H), 1.36-1.20 (m, 2H), 1.10-0.96 (m, 2H), 0.75 (t, J = 7.4 Hz) , 3H). MS m / z: 453 [M -1] -.

Example 4
3- (Butyl (3-chlorobenzyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ａに従って調製したが、ステップ２において適当な臭化ベンジルから開始して、生成物を白色の固体として得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤ_３ＯＤ） δ ８．２９ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ）， ７．９５ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ）， ７．３８−７．２６ （ｍ， ２Ｈ）， ７．１８−７．０６ （ｍ， ３Ｈ）， ６．９２−６．８４ （ｍ， ２Ｈ）， ６．８０−６．７１ （ｍ， ２Ｈ）， ２．９６ （ｔ， Ｊ ＝ ７．４ Ｈｚ， ２Ｈ）， １．３８−１．２０ （ｍ， ２Ｈ）， １．１０−０．９８ （ｍ， ２Ｈ），
０．７５ （ｔ， Ｊ ＝ ７．４ Ｈｚ， ３Ｈ）．ＭＳ ｍ／ｚ：４８７［Ｍ−１］⁻。

The title compound was prepared according to General Method A but starting with the appropriate benzyl bromide in Step 2, the product was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.29 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.38-7. 26 (m, 2H), 7.18-7.06 (m, 3H), 6.92-6.84 (m, 2H), 6.80-6.71 (m, 2H), 2.96 ( t, J = 7.4 Hz, 2H), 1.38-1.20 (m, 2H), 1.10-0.98 (m, 2H),
0.75 (t, J = 7.4 Hz, 3H). MS m / z: 487 [M-1] ^- .

(Example 5)
3- (Butyl (4-fluorobenzyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ａに従って調製したが、ステップ２において適当な臭化ベンジルから開始して、生成物を白色の固体として得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤ_３ＯＤ） δ ８．２６ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ）， ７．８７ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ）， ７．３６−７．２８ （ｍ， ２Ｈ）， ７．１８−７．１６ （ｍ， １Ｈ）， ６．９２−６．６８ （ｍ， ６Ｈ）， ２．９８ （ｔ， Ｊ ＝ ７．４ Ｈｚ， ２Ｈ）， １．３３−１．２０ （ｍ， ２Ｈ）， １．１０−０．９８ （ｍ， ２Ｈ）， ０．７６ （ｔ， Ｊ ＝ ７．４ Ｈｚ， ３Ｈ）．ＭＳ ｍ／ｚ：４７４［Ｍ＋１］^＋。

The title compound was prepared according to General Method A but starting with the appropriate benzyl bromide in Step 2, the product was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.26 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.36-7. 28 (m, 2H), 7.18-7.16 (m, 1H), 6.92-6.68 (m, 6H), 2.98 (t, J = 7.4 Hz, 2H), 1 .33-1.20 (m, 2H), 1.10-0.98 (m, 2H), 0.76 (t, J = 7.4 Hz, 3H). MS m / z: 474 [M + 1] ^< +>.

(Example 6)
3- (Dimethylamino) -4-phenoxy-5-sulfamoylbenzoic acid

一般方法Ｃ

General method C

ステップ１：３−ニトロ−４−フェノキシ−５−スルファモイル安息香酸。丸底フラスコに、４−クロロ−３−ニトロ−５−スルファモイル−安息香酸（２．０ｇ、７．１２ｍｍｏｌ）、炭酸水素ナトリウム（２．４５ｇ、２９．２ｍｍｏｌ）、フェノール（１．４７ｇ、１５．６ｍｍｏｌ）および水（２０ｍＬ）を充填し、８５℃で一晩加熱した。反応混合物を室温に冷却し、３ＮのＨＣｌで酸性化した。生成物が沈殿し、これを濾過し、乾燥させ、生成物を黄色の固体（１．９ｇ）として得た。ＭＳ ｍ／ｚ：３３７［Ｍ−１］⁻。

Step 1: 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid. In a round bottom flask was added 4-chloro-3-nitro-5-sulfamoyl-benzoic acid (2.0 g, 7.12 mmol), sodium bicarbonate (2.45 g, 29.2 mmol), phenol (1.47 g, 15. 6 mmol) and water (20 mL) were charged and heated at 85 ° C. overnight. The reaction mixture was cooled to room temperature and acidified with 3N HCl. The product precipitated and was filtered and dried to give the product as a yellow solid (1.9 g). MS m / z: 337 [M-1] ^- .

  Step 2: 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid methyl ester. A round bottom flask was charged with 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid (1.9 g, 5.637 mmol) and methanol (50 mL). Thionyl chloride (2.012 g, 16.91 mmol) was added slowly at room temperature and the reaction mixture was heated to 50 ° C. overnight. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a pale yellow solid (1.72 g).

Step 3: 3- (Dimethylaminomethylene-sulfamoyl) -5-nitro-4-phenoxy-benzoic acid methyl ester. To the reaction flask was added 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid methyl ester (1.65 g, 4.68 mmol), acetonitrile (20 mL) and N, N-dimethylformamide dimethyl acetal (0.65 mL, 4.917 mmol). ) And stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting rubbery residue was treated with ice cold water to give a yellow solid. The solid was filtered and dried to give the product (1.9 g). MS m / z: 408 [M + 1] ^< +>.

Step 4: 5-amino-3- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. A round bottom flask was charged with 3- (dimethylaminomethylene-sulfamoyl) -5-nitro-4-phenoxy-benzoic acid methyl ester (1.0 g, 2.457 mmol), ethanol (50 mL), and the reaction mixture was 85 ° C. Heated. Ammonium chloride (1.3 g, 24.57 mmol) in water (25 mL) was added. Iron powder (541 mg, 9.828 mmol) was added in 3 portions every 3 minutes. Heating was continued for an additional hour. The reaction mixture was cooled to 600 C and poured into dichloromethane (150 mL). The organic layer was separated, washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give the product as an off-white solid (690 mg). MS m / z: 378 [M + 1] ^< +>.

Step 5: 3-Dimethylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. In a pressure vial, 5-amino-3- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (200 mg, 0.530 mmol), potassium carbonate (440 mg, 3.18 mmol), methyl iodide (753 mg, 5.305 mmol), acetonitrile (10 mL) was charged and the reaction was heated at 77 ° C. overnight. The reaction was cooled, filtered and washed with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a white solid (70 mg). MS m / z: 406 [M + 1] ^< +>.

Step 6: 3-Dimethylamino-4-phenoxy-5-sulfamoyl-benzoic acid (NTP-4006). A reaction vial was charged with 3-dimethylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (70 mg, 0.17 mmol), 2N NaOH (1 mL), methanol (2 mL), The reaction was heated to 50 ° C. for 2 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a white solid (49 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.30 (bs, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 1.8 Hz) , 1H), 7.39 (s, 2H), 7.23 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.76 (d , J = 8.4 Hz, 2H), 2.65 (s, 6H). MS m / z: 337 [M + 1] ^< +>.

(Example 7)
3- (Diethylamino) -4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｃに従って調製したが、ステップ５において適当なヨウ化アルキルから開始して、生成物を白色の固体（２１ｍｇ）として得た。ＭＳ ｍ／ｚ：３６５［Ｍ＋１］^＋。

The title compound was prepared according to General Method C, but starting with the appropriate alkyl iodide in Step 5, the product was obtained as a white solid (21 mg). MS m / z: 365 [M + 1] ^< +>.

(Example 8)
3- (Butyl (cyclopropylmethyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｂに従って調製したが、ステップ２における適当な臭化アルキルおよびヨウ化カリウム（１当量）から開始し、ステップ２の反応物を密封した管中で１００℃に３日間加熱した。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ− ｄ_６） δ
１３．２８ （ｂｓ， １Ｈ）， ８．０３ （ｄ， Ｊ＝１．８ Ｈｚ， １Ｈ），
７．７８ （ｄ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ７．３８ （ｓ， ２Ｈ）， ７．２１ （ｔ， Ｊ＝７．５ Ｈｚ， ２Ｈ）， ６．９８ （ｔ， Ｊ＝７．２ Ｈｚ， １Ｈ）， ６．７６ （ｄ， Ｊ＝７．５ Ｈｚ， ２Ｈ）， ３．０８ （ｔ， Ｊ＝６．９ Ｈｚ， ２Ｈ）， ２．９０ （ｄ， Ｊ＝６．６ ＨＺ， ２Ｈ）， １．１６−１．１１ （ｍ， ２Ｈ）， ０．９６−０．８９ （ｍ ， ２Ｈ）， ０．７０ （ｔ， Ｊ＝７．５ Ｈｚ， ３Ｈ），０．５９ （ｍ， １Ｈ）， ０．３０−０．２４ （ｍ， ２Ｈ）， ０．０６−０．０１ （ｍ， ２Ｈ）．ＭＳ ｍ／ｚ：４１９［Ｍ＋１］^＋。

The title compound was prepared according to General Method B but starting with the appropriate alkyl bromide and potassium iodide (1 equivalent) in Step 2, and the Step 2 reaction was heated to 100 ° C. in a sealed tube for 3 days. . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ
13.28 (bs, 1H), 8.03 (d, J = 1.8 Hz, 1H),
7.78 (d, J = 2.1 Hz, 1H), 7.38 (s, 2H), 7.21 (t, J = 7.5 Hz, 2H), 6.98 (t, J = 7 .2 Hz, 1H), 6.76 (d, J = 7.5 Hz, 2H), 3.08 (t, J = 6.9 Hz, 2H), 2.90 (d, J = 6.6 HZ, 2H), 1.16-1.11 (m, 2H), 0.96-0.89 (m, 2H), 0.70 (t, J = 7.5 Hz, 3H), 0.59 (M, 1H), 0.30-0.24 (m, 2H), 0.06-0.01 (m, 2H). MS m / z: 419 [M + 1] ^< +>.

Example 9
3- (Bis (cyclopropylmethyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

一般方法Ｄ

General method D

ステップ１：３−（ビス−シクロプロピルメチル−アミノ）−５−（ジメチルアミノメチレン−スルファモイル）−４−フェノキシ−安息香酸メチルエステル。圧力管に、３−アミノ−５−（ジメチルアミノメチレン−スルファモイル）−４−フェノキシ安息香酸メチルエステル（２５０ｍｇ、０．６６３ｍｍｏｌ）、炭酸カリウム（５４９ｍｇ、３．９７８ｍｍｏｌ）、シクロプロピルメチルブロミド（２６９ｍｇ、１．９８９ｍｍｏｌ）、ヨウ化カリウム（１１０ｍｇ、０．６６３ｍｍｏｌ）、アセトニトリル（４ｍＬ）を充填し、１００℃で３日間加熱した。反応によって、ＬＣ／ＭＳによりモノアルキル化およびジアルキル化された生成物の混合物を得た。反応物を冷却し、セライト上で濾過し、溶媒を減圧下で除去した。残渣をフラッシュクロマトグラフィーによって精製し、生成物（８０ｍｇ）を得た。ＭＳ ｍ／ｚ：４８６．１［Ｍ＋１］^＋。

Step 1: 3- (Bis-cyclopropylmethyl-amino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. To the pressure tube, 3-amino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxybenzoic acid methyl ester (250 mg, 0.663 mmol), potassium carbonate (549 mg, 3.978 mmol), cyclopropylmethyl bromide (269 mg, 1.989 mmol), potassium iodide (110 mg, 0.663 mmol), and acetonitrile (4 mL) were charged and heated at 100 ° C. for 3 days. The reaction gave a mixture of products mono- and dialkylated by LC / MS. The reaction was cooled, filtered over celite and the solvent removed under reduced pressure. The residue was purified by flash chromatography to give the product (80 mg). MS m / z: 486.1 [M + l] ^< +>.

Step 2: 3- (Bis (cyclopropylmethyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid. In a reaction vial, 3- (bis-cyclopropylmethyl-amino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (75 mg, 0.15 mmol), 2N NaOH (1 mL), methanol (3 mL) was charged and the reaction was heated to 50 ° C. for 2 h. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a white solid (35 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.28 (bs, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 2.1 Hz) , 1H), 7.37 (s, 2H), 7.21 (t, J = 7.5 Hz, 2H), 6.97 (t, J = 7.2 Hz, 1H), 6.79 (d , J = 7.5 Hz, 2H), 2.95 (d, J = 6.3 Hz, 4H), 0.61 (m, 1H), 0.28-0.22 (m, 2H), 0 .09-0.04 (m, 2H). MS m / z: 417 [M + 1] ^< +>.

(Example 10)
4-phenoxy-3- (piperidin-1-yl) -5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｃに従って、ステップ５におけるヨウ化メチルの代わりに１，５−ジヨードペンタンを使用して調製した。ＭＳ ｍ／ｚ：３７７［Ｍ＋１］^＋。

The title compound was prepared according to general method C using 1,5-diiodopentane instead of methyl iodide in step 5. MS m / z: 377 [M + 1] ^< +>.

(Example 11)
3- (Dibenzylamino) -4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｄに従って、ステップ１における（ブロモメチル）シクロプロパン（ｃｙｃｌｏｐｒｏｐｏａｎｅ）の代わりに臭化ベンジルを使用して調製した。ＭＳ
ｍ／ｚ：４８９［Ｍ＋１］^＋。

The title compound was prepared according to general method D using benzyl bromide instead of (bromomethyl) cyclopropane in step 1. MS
m / z: 489 [M + 1] ⁺ .

(Example 12)
3-morpholino-4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｃに従って、ステップ５におけるヨウ化メチルの代わりに１−ヨード−２−（２−ヨードエトキシ）エタンを使用して調製した。ＭＳ ｍ／ｚ：３７９［Ｍ＋１］^＋。

The title compound was prepared according to General Method C using 1-iodo-2- (2-iodoethoxy) ethane instead of methyl iodide in Step 5. MS m / z: 379 [M + 1] ^< +>.

(Example 13)
3- (Butyl (pentyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

一般方法Ｅ

General method E

ステップ１：３−（ブチル−ペンチル−アミノ）−５−（ジメチルアミノメチレン−スルファモイル）−４−フェノキシ−安息香酸メチルエステル。丸底フラスコに、３−ブチルアミノ−５−（ジメチルアミノメチレン−スルファモイル）−４−フェノキシ−安息香酸メチルエステル（一般方法Ａ、ステップ２、２５０ｍｇ、０．５７７ｍｍｏｌ）、炭酸カリウム（２３９ｍｇ、１．７３２ｍｍｏｌ）、ヨードペンタン（２２８ｍｇ、１．１５４ｍｍｏｌ）、アセトニトリル（５ｍＬ）を充填し、反応物を１５０℃でマイクロ波反応器において３時間加熱した。反応物を室温に冷却し、濾過した。溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、生成物を淡黄色の固体（１４０ｍｇ）として得た。ＭＳ ｍ／ｚ：５０４［Ｍ＋１］^＋。

Step 1: 3- (Butyl-pentyl-amino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. In a round bottom flask was added 3-butylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (General Method A, Step 2, 250 mg, 0.577 mmol), potassium carbonate (239 mg, 1.. 732 mmol), iodopentane (228 mg, 1.154 mmol), acetonitrile (5 mL) was charged and the reaction was heated at 150 ° C. in a microwave reactor for 3 h. The reaction was cooled to room temperature and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a pale yellow solid (140 mg). MS m / z: 504 [M + 1] ^< +>.

Step 2: 3- (Butyl-pentyl-amino) -4-phenoxy-5-sulfamoyl-benzoic acid (NTP-4014). In a reaction vial, 3- (butyl-pentyl-amino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (135 mg, 0.27 mmol), 2N NaOH (2 mL), methanol (4 mL) ) And the reaction was heated to 50 ° C. for 2 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a yellow solid (78 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.28 (bs, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 2.1 Hz) , 1H), 7.34 (s, 2H),
7.20 (t, J = 7.5 Hz, 2H), 6.97 (t, J = 7.2 Hz, 1H), 6.72 (d, J = 7.5 Hz, 2H), 01-2.95 (m, 4H), 1.15-1.07 (m, 6H), 0.97-0.89
(M. 4H), 0.76-0.69 (m, 6H). MS m / z: 435 [M + 1] ^< +>.

(Example 14)
3-dipentylamino-4-phenoxy-5-sulfamoylbenzoic acid

一般方法Ｆ

General method F

ステップ１：３−（ジメチルアミノメチレン−スルファモイル）−５−ジペンチルアミノ−４−フェノキシ−安息香酸メチルエステル。

Step 1: 3- (Dimethylaminomethylene-sulfamoyl) -5-dipentylamino-4-phenoxy-benzoic acid methyl ester.

In a microwave vial, 3-amino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxybenzoic acid methyl ester (175 mg, 0.501 mmol), potassium carbonate (415 mg, 3.008 mmol), iodopentane (397 mg, 2 .01 mmol) and acetonitrile (4 mL) were charged and the reaction was heated in the microwave at 150 ° C. for 5 h. By LC / MS, there was a mixture of monoalkylated and dialkylated products. The reaction was cooled to room temperature, filtered and washed with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a pale yellow solid. The reaction was cooled, filtered over celite and the solvent removed under reduced pressure. The residue was purified by flash chromatography to give the product (80 mg). MS m / z: 518 [M + 1] ^< +>.

Step 2: 3- (Dipentylamino) -4-phenoxy-5-sulfamoylbenzoic acid (NTP-4015). A reaction vial was charged with 3- (dipentylamino) -5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (93 mg, 0.18 mmol), 2N NaOH (1 mL), methanol (2 mL). And the reaction was heated to 50 ° C. for 2 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a yellow solid (60 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.99 (d, J = 1.5 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.37 (s , 2H), 7.20 (t, J = 7.5 Hz, 2H), 6.97 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 7.5 Hz, 2H) ), 2.99 (t, J = 7.5 HZ, 4 H), 1.23-1.07 (m, 8H), 0.95-0.91 (m. 4H), 0.75 (t , J = 7.2 Hz, 6H). MS m / z: 449 [M + 1] ^< +>.

(Example 15)
3- (Diphenethylamino) -4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｆに従って、ステップ１におけるヨードペンタンの代わりに（２−ヨードエチル）ベンゼンを使用して調製した。ＭＳ ｍ／ｚ：５１７［Ｍ＋１］^＋。

The title compound was prepared according to General Method F using (2-iodoethyl) benzene instead of iodopentane in Step 1. MS m / z: 517 [M + 1] ^< +>.

(Example 16)
3- (Butyl (phenethyl) amino) -4-phenoxy-5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｅに従って、ステップ５におけるヨードペンタンの代わりに（２−ヨードエチル）ベンゼンを使用して調製した。ＭＳ ｍ／ｚ：４６９［Ｍ＋１］^＋。

The title compound was prepared according to General Method E using (2-iodoethyl) benzene instead of iodopentane in Step 5. MS m / z: 469 [M + 1] ^< +>.

  The following examples were prepared using the appropriate benzyl bromide in step 1 according to procedures familiar to those skilled in the art, with general modifications D or with minor modifications thereof.

（実施例２２）
３−（ヘプタン−４−イルアミノ）−４−フェノキシ−５−スルファモイル安息香酸

(Example 22)
3- (Heptane-4-ylamino) -4-phenoxy-5-sulfamoylbenzoic acid

ステップ１：３−アミノ−４−フェノキシ−５−スルファモイル安息香酸。

Step 1: 3-amino-4-phenoxy-5-sulfamoylbenzoic acid.

In a round bottom flask was added 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid (0.400 g, 0.00118 mol), ammonium chloride (0.553 g, 0.01035 mol), and THF-MeOH (1: 1 10 mL). Zinc (0.676 g, 0.01035 mol) was added under nitrogen and the reaction mixture was stirred overnight at room temperature. TLC and LC / MS showed the reaction was complete. The reaction mixture was filtered through celite and the filter cake was washed with THF-MeOH (1: 1). The filtrate was concentrated under reduced pressure to give a beige solid (360 mg). MS m / z: 307.0 [M + 1] ^< +>.

Step 2: 3- (Heptan-4-ylamino) -4-phenoxy-5-sulfamoylbenzoic acid Stirred 3-amino-4-phenoxy-5-sulfamoylbenzoic acid (70.0 mg, 0.00023 mol) of acetic acid ( To the solution, heptan-4-one (0.95 ml, 0.00681 mol) and sodium sulfate (645 mg, 0.00454 mol) were added and the mixture was stirred at 70 ° C. for 4 hours. After cooling to room temperature, sodium triacetoxyborohydride (0.481 g, 0.00227 mol) was added and the reaction was stirred at 40 ° C. overnight. LC-MS showed that only a trace amount of starting material remained. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column (0-80% EtOAc / hexanes) to give the product as a white foam (30 mg, 38%). MS m / z: 407.0 [M + 1] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.00 (s, 1H), 7.60 (s, 1H), 7.33 (t, 2H , J = 8.1 Hz), 7.12 (d, 1H, J = 7.5 Hz), 6.96 (d, 2H, J = 8.4 Hz), 4.99 (s, 2H), 3.74 (d, 1H, J = 7.5 Hz), 3.42 (m, 1H), 1.50-1.00 (m, 8H), 0.83 (t, 6H, J = 7. 2 Hz).

(Examples 23 and 24)
4-Chloro-3- (dimethylamino) -5-sulfamoylbenzoic acid and 4-chloro-3- (methylamino) -5-sulfamoylbenzoic acid

一般方法Ｇ

General method G

ステップ１：４−クロロ−３−ニトロ−５−スルファモイル安息香酸メチルエステル。丸底フラスコに、４−クロロ−３−ニトロ−５−スルファモイル安息香酸（３．０ｇ、１０．６８９ｍｍｏｌ）およびメタノール（５０ｍＬ）を充填した。塩化チオニル（３．８２ｇ、３２．０６ｍｍｏｌ）を室温でゆっくりと加え、反応混合物を５０℃に一晩加熱した。溶媒を減圧下で除去し、残渣を酢酸エチルに再溶解し、飽和炭酸水素ナトリウム溶液、水およびブラインで洗浄した。有機溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、生成物を淡黄色の固体（３．１ｇ）として得た。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ− ｄ_６） δ ８．７２ （ｄ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ８．６５ （ｄ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ８．１４ （ｓ，
２Ｈ）， ３．９３ （ｓ， ３Ｈ）。

Step 1: 4-Chloro-3-nitro-5-sulfamoylbenzoic acid methyl ester. A round bottom flask was charged with 4-chloro-3-nitro-5-sulfamoylbenzoic acid (3.0 g, 10.687 mmol) and methanol (50 mL). Thionyl chloride (3.82 g, 32.06 mmol) was added slowly at room temperature and the reaction mixture was heated to 50 ° C. overnight. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a pale yellow solid (3.1 g). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.72 (d, J = 2.1 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.14 (s ,
2H), 3.93 (s, 3H).

Step 2: 4-Chloro-3- (dimethylaminomethylene-sulfamoyl) -5-nitrobenzoic acid methyl ester. To the reaction flask was added 4-chloro-3-nitro-5-sulfamoylbenzoic acid methyl ester (500 mg, 1.696 mmol), acetonitrile (5 mL) and N, N-dimethylformamide dimethyl acetal (0.24 mL, 1.781 mmol). Filled and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting rubbery residue was treated with ice cold water to give a yellow solid. The solid was filtered and dried to give the product (520 mg). MS m / z: 350 [M + 1] ^< +>.

Step 3: 3-Amino-4-chloro-5- (dimethylaminomethylene-sulfamoyl) -benzoic acid methyl ester. A round bottom flask was charged with 4-chloro-3- (dimethylaminomethylene-sulfamoyl) -5-nitrobenzoic acid methyl ester (500 mg, 1.428 mmol), ethanol (20 mL) and the reaction mixture was heated to 85 ° C. . Ammonium chloride (756 mg, 14.28 mmol) in water (10 mL) was added. Iron powder (314 mg, 5.71 mmol) was added in 3 portions every 3 minutes. Heating was continued for another 2 hours. The reaction mixture was cooled to 60 ° C. and poured into dichloromethane (150 mL). The organic layer was separated, washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give the product as an off-white solid (340 mg). MS m / z: 320 [M + 1] ^< +>.

Step 4: 4-chloro-3-dimethylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester and 4-chloro-3- (methylamino) -5-sulfamoylbenzoic acid. A pressure tube was charged with 3-amino-4-chloro-5- (dimethylaminomethylene-sulfamoyl) -benzoic acid methyl ester (150 mg, 0.469 mmol), potassium carbonate (389 mg, 2.814 mmol), methyl iodide (400 mg, 2.8 mmol), acetonitrile (15 mL) was charged and the reaction was heated at 75 ° C. overnight. Both monoalkylated and dialkylated products were present by LC / MS. The reaction was cooled, filtered and washed with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give 4-chloro-3-dimethylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid as a pale yellow solid (88 mg) And 4-chloro-3- (methylamino) -5-sulfamoylbenzoic acid as a yellow solid (35 mg). MS m / z: 348 [M + 1] ⁺ and MS m / z: 334 [M + 1] ⁺ .

Step 5: 4-Chloro-3-dimethylamino-5-sulfamoyl-benzoic acid (NTP-5001). In a reaction vial, 4-chloro-3-dimethylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (85 mg, 0.247 mmol), 2N NaOH (2 mL), methanol (4 mL) And the reaction was heated to 50 ° C. for 2 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a white solid (49 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.51 (bs, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.81 (d, J = 1.8 Hz) , 1H), 7.70 (s, 2H), 2.79 (s,
6H). MS m / z: 279 [M + 1] ^< +>.

Step 6: 4-Chloro-3-methylamino-5-sulfamoyl-benzoic acid (NTP-5002). Following the procedure described for Step 5, starting from 4-chloro-3- (methylamino) -5-sulfamoylbenzoic acid, the product was obtained to give the title compound as a white solid (16 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.51 (bs, 1H), 8.45 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 1.8 Hz) , 1H), 7.34 (s, 2H), 5.69 (m, 1H), 2.80 (d, J = 5.1 Hz, 3H). MS m / z: 263 [M-1] ^- .

(Examples 25 and 26)
4-Chloro-3- (diethylamino) -5-sulfamoylbenzoic acid and 4-chloro-3- (ethylamino) -5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｇに従って、ステップ４における適当なヨウ化アルキルを使用して調製した。４−クロロ−３−（ジエチルアミノ）−５−スルファモイル安息香酸：ＭＳ ｍ／ｚ：３０７［Ｍ＋１］^＋。４−クロロ−３−（エチルアミノ）−５−スルファモイル安息香酸：ＭＳ ｍ／ｚ：２７９［Ｍ＋１］^＋。

The title compound was prepared according to General Method G using the appropriate alkyl iodide in Step 4. 4-Chloro-3- (diethylamino) -5-sulfamoylbenzoic acid: MS m / z: 307 [M + 1] ^< +>. 4-Chloro-3- (ethylamino) -5-sulfamoylbenzoic acid: MS m / z: 279 [M + 1] ^< +>.

(Example 27)
3- (Butylamino) -4-chloro-5-sulfamoylbenzoic acid

一般方法Ｈ

General method H

ステップ１：３−ブチリルアミノ−４−クロロ−５−（ジメチルアミノメチレン−スルファモイル）−安息香酸メチルエステル。丸底フラスコに、３−アミノ−４−クロロ−５−（ジメチルアミノメチレン−スルファモイル）−安息香酸メチルエステル（方法Ｇ、ステップ３、５００ｍｇ、１．５６ｍｍｏｌ）、塩化ブチリル（０．２０ｍＬ、１．８７６ｍｍｏｌ）、ジイソプロピルエチルアミン（０．１ｍＬ）、ＴＨＦ（５ｍＬ）を充填し、反応物を室温で２時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、生成物を薄茶色の油状物（６５０ｍｇ）として得た。ＭＳ ｍ／ｚ：３９０．２［Ｍ＋１］^＋。

Step 1: 3-Butyrylamino-4-chloro-5- (dimethylaminomethylene-sulfamoyl) -benzoic acid methyl ester. In a round bottom flask was added 3-amino-4-chloro-5- (dimethylaminomethylene-sulfamoyl) -benzoic acid methyl ester (Method G, Step 3, 500 mg, 1.56 mmol), butyryl chloride (0.20 mL, 1.. 876 mmol), diisopropylethylamine (0.1 mL), THF (5 mL) were charged and the reaction was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a light brown oil (650 mg). MS m / z: 390.2 [M + 1] ^< +>.

Step 2: 3-Butylamino-4-chloro-5- (dimethylaminomethylene-sulfamoyl) -benzoic acid methyl ester: In a round bottom flask, add 3-butyrylamino-4-chloro-5- (dimethylaminomethylene-sulfamoyl)- Benzoic acid methyl ester (600 mg, 1.539 mmol), THF (10 mL) was charged and BH ₃ .THF (1.0 M in THF) (7.69 mL, 7.69 mmol) was added slowly. The reaction was stirred at room temperature for 1 hour. The reaction was quenched by the dropwise addition of water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a pale yellow solid (340 mg). MS m / z: 376.3 [M + l] ^< +>.

  Step 3: 3-Butylamino-4-chloro-5-sulfamoyl-benzoic acid (NTP-5005).

A reaction vial was charged with 3-butylamino-4-chloro-5- (dimethylaminomethylene-sulfamoyl) -benzoic acid methyl ester (340 mg, 0.90 mmol), 2N NaOH (5 mL), methanol (5 mL), The reaction was heated to 50 ° C. for 2 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a white solid (105 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.34 (bs, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.59 (s, 2H), 7.33 (D, J = 1.8 Hz, 1H) 5.99 (t, J = 5.4 Hz, 1H), 3.20 (t, J = 6.3 Hz, 2H), 1.59-1. 52 (m, 2H), 1.40-1.1.33 (m, 2H), 0.92 (t, J = 6.6 Hz, 3H). MS m / z: 307.1 [M + 1] ^< +>.

(Example 28)
4-Chloro-3- (dibutylamino) -5-sulfamoylbenzoic acid

表題化合物を、一般方法Ｇに従って、ステップ４における適当なヨウ化アルキルを使用して調製した。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＣＤ_３ＯＤ） δ ８．３４ （ｍ， １Ｈ）， ７．９６ （ｍ， １Ｈ）， ３．１４ （ｔ， Ｊ＝５．７ Ｈｚ， ４Ｈ）， １．４８−１．４５（ｍ， ４Ｈ）， １．３８−１．３１ （ｍ， ４Ｈ）， ０．９０ （ｔ， Ｊ＝６．９ Ｈｚ， ６Ｈ）．ＭＳ ｍ／ｚ：３６３［Ｍ＋１］^＋。

The title compound was prepared according to General Method G using the appropriate alkyl iodide in Step 4. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.34 (m, 1H), 7.96 (m, 1H), 3.14 (t, J = 5.7 Hz, 4H), 1.48− 1.45 (m, 4H), 1.38-1.31 (m, 4H), 0.90 (t, J = 6.9 Hz, 6H). MS m / z: 363 [M + 1] ^< +>.

(Example 29)
2- (Dibutylamino) -6-sulfamoylbiphenyl-4-carboxylic acid

一般方法Ｉ

General method I

ステップ１：２−（ジメチルアミノメチレン−スルファモイル）−６−ニトロ−ビフェニル−４−カルボン酸メチルエステル。反応バイアルに、４−クロロ−３−（ジメチルアミノメチレン−スルファモイル）−５−ニトロ安息香酸メチルエステル（方法Ｇ、ステップ２、２２０ｍｇ、０．６３０ｍｍｏｌ）、フェニルボロン酸（１１５ｍｇ、０．９４５ｍｍｏｌ）、炭酸カリウム（２６１ｍｇ、１．８９ｍｍｏｌ）、［（ｔ−Ｂｕ）_２Ｐ（ＯＨ）］_２ＰｄＣｌ_２（ＰＯＰｄ）（３ｍｇ、０．００６３ｍｍｏｌ）および１，４−ジオキサン（３ｍＬ）を充填した。バイアルを真空で排気し、窒素でフラッシュした。次いで、反応物を９０℃で一晩加熱した。反応混合物を室温に冷却し、酢酸エチルで希釈し、水で洗浄した。溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、生成物を６０％純度で得て、これを次のステップにそれ以上精製することなく使用した（９０ｍｇ）。ＭＳ ｍ／ｚ：３９２［Ｍ＋１］^＋。

Step 1: 2- (Dimethylaminomethylene-sulfamoyl) -6-nitro-biphenyl-4-carboxylic acid methyl ester. In a reaction vial, 4-chloro-3- (dimethylaminomethylene-sulfamoyl) -5-nitrobenzoic acid methyl ester (Method G, Step 2, 220 mg, 0.630 mmol), phenylboronic acid (115 mg, 0.945 mmol), Charged with potassium carbonate (261 mg, 1.89 mmol), [(t-Bu) ₂ P (OH)] ₂ PdCl ₂ (POPd) (3 mg, 0.0063 mmol) and 1,4-dioxane (3 mL). The vial was evacuated with vacuum and flushed with nitrogen. The reaction was then heated at 90 ° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product in 60% purity, which was used in the next step without further purification (90 mg). MS m / z: 392 [M + 1] ^< +>.

Step 2: 6-amino-2- (dimethylaminomethylene-sulfamoyl) -biphenyl-4-carboxylic acid methyl ester. A round bottom flask was charged with 2- (dimethylaminomethylene-sulfamoyl) -6-nitro-biphenyl-4-carboxylic acid methyl ester (90 mg, 0.229 mmol), ethanol (10 mL) and the reaction mixture was heated to 85 ° C. did. Ammonium chloride (122 mg, 2.29 mmol) in water (3 mL) was added. Iron powder (51 mg, 0.917 mmol) was added in 3 portions every 3 minutes. Heating was continued for another 2 hours. The reaction mixture was cooled to 60 ° C. and poured into dichloromethane (100 mL). The organic layer was separated, washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as an off-white solid (60 mg). MS m / z: 362 [M + 1] ^< +>.

Step 3: 6-Dibutylamino-2- (dimethylaminomethylene-sulfamoyl) -biphenyl-4-carboxylic acid methyl ester. A pressure tube was charged with 6-amino-2- (dimethylaminomethylene-sulfamoyl) -biphenyl-4-carboxylic acid methyl ester (60 mg, 0.166 mmol), potassium carbonate (138 mg, 0.996 mmol), butyl iodide (122 mg, 0.664 mmol), acetonitrile (5 mL) was charged and the reaction was heated at 120 ° C. overnight. The reaction gave a mixture of monoalkylated and dialkylated products. The reaction was cooled, filtered and washed with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product (28 mg). MS m / z: 474 [M + 1] ^< +>.

Step 4: 6-Dibutylamino-2-sulfamoyl-biphenyl-4-carboxylic acid (NTP-5007). A reaction vial was charged with 6-dibutylamino-2- (dimethylaminomethylene-sulfamoyl) -biphenyl-4-carboxylic acid methyl ester (28 mg, 0.059 mmol), 2N NaOH (1 mL), methanol (3 mL), The reaction was heated to 50 ° C. for 2 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a yellow solid (16 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.41 (bs, 1H), 8.25 (d, J = 1.5 Hz, 1H), 7.83 (d,
J = 1.5 Hz, 1H), 7.38-7.28 (m, 3H), 7.19 (d, J = 6.9, 2H), 7.00 (s, 2H), 2.68. (M, 4H), 1.05-1.03 (m, 8H), 0.74 (t, J = 6.6 Hz, 6H). EI MS m / z: 405 [M + 1] ⁺ .

(Example 30)
3- (Dibutylamino) -4- (3-fluorophenoxy) -5-sulfamoylbenzoic acid

一般方法Ｊ

General method J

ステップ１：４−（４−フルオロフェノキシ）−３−ニトロ−５−スルファモイル安息香酸。撹拌した４−クロロ−３−ニトロ−５−スルファモイル安息香酸（１ｇ、３．５６ｍｍｏｌ）の水溶液に、４−フルオロフェノール（０．８ｇ、７．１２ｍｍｏｌ）およびＮａＨＣＯ_３（１．２ｇ、１４．２４ｍｍｏｌ）を０℃で加えた。混合物を１００℃で１２時間撹拌し、次いでこれを室温に冷却した。混合物を６ＮのＨＣｌで酸性とした。薄黄色の固体が現れ、次いで濾過し、粗４−（４−フルオロフェノキシ）−３−ニトロ−５−スルファモイル−安息香酸を得て、これを次の反応においてそれ以上精製することなく使用した。

Step 1: 4- (4-Fluorophenoxy) -3-nitro-5-sulfamoylbenzoic acid. To a stirred aqueous solution of 4-chloro-3-nitro-5-sulfamoylbenzoic acid (1 g, 3.56 mmol), 4-fluorophenol (0.8 g, 7.12 mmol) and NaHCO ₃ (1.2 g, 14.24 mmol). ) Was added at 0 ° C. The mixture was stirred at 100 ° C. for 12 hours, then it was cooled to room temperature. The mixture was acidified with 6N HCl. A pale yellow solid appeared and was then filtered to give crude 4- (4-fluorophenoxy) -3-nitro-5-sulfamoyl-benzoic acid, which was used in the next reaction without further purification.

Step 2: Methyl 4- (4-fluorophenoxy) -3-nitro-5-sulfamoylbenzoate. A methanolic solution of 4- (4-fluorophenoxy) -3-nitro-5-sulfamoylbenzoic acid (0.97 g, 2.72 mmol) was added dropwise to acetyl chloride (0.42 g, 5.38 mmol) at 0 ° C. . The mixture was stirred at 60 ° C. for 12 hours. When all starting material disappeared, water was slowly added at 0 ° C. Methanol was removed and the aqueous solution was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgSO ₄ and evaporated. The residue was purified by flash chromatography (n-hexane / ethyl acetate = 1/1) to give methyl 4- (4-fluorophenoxy) -3-nitro-5-sulfamoylbenzoate (0.37 g).

Step 3: Methyl 3- (N-((dimethylamino) methylene) sulfamoyl) -4- (4-fluorophenoxy) -5-nitrobenzoate. To an acetonitrile solution of methyl 4- (4-fluorophenoxy) -3-nitro-5-sulfamoylbenzoate (0.37 g, 1 mmol) was added N, N-dimethylformamide dimethyl acetal (DMF / DMA, 0.178 g, 1 0.5 mmol) was added at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then quenched with water. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with 0.1M HCl, dried over anhydrous MgSO ₄ and evaporated. The residue was purified by flash chromatography (n-hexane / ethyl acetate = 5/1) to obtain the title compound (0.27 g).

Step 4: Methyl 3-amino-5- (N-((dimethylamino) methylene) sulfamoyl) -4- (4-fluorophenoxy) benzoate. 3- (N-((dimethylamino) methylene) sulfamoyl) -4- (4-fluorophenoxy) -5-nitrobenzoate (190 mg, 0.447 mmol) and 10% Pd / C (19 mg, 10%) in ethyl alcohol The mixture of w / w) was stirred at 60 ° C. under H ₂ atmosphere. After 3 hours, the mixture was passed through celite to remove the catalyst. The filtered catalyst was washed with ethyl alcohol (2 × 10 mL). The combined filtrate was washed with H ₂ O (2 × 30 mL) and brine (30 mL), dried over anhydrous MgSO 4 and evaporated under reduced pressure. The residue was purified by flash chromatography (n-hexane / ethyl acetate = 1/1) to obtain the title compound (30 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.91 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.18-7.11 (m, 2H), 6.74-6.71 (m, 2H), 5.37 (s, 2H), 3.86 (s, 3H), 2.92 (s, 3H), 2.55 (s, 3H) ).

Step 5: 3-Dibutylamino-5- (dimethylaminomethylene-sulfamoyl) -4- (4-fluoro-phenoxy) -benzoic acid methyl ester. To a pressure tube, 3-amino-5 (dimethylaminomethylene-sulfamoyl) -4- (4-fluorophenoxy) -benzoic acid methyl ester (140 mg, 0.352 mmol), potassium carbonate (292 mg, 2.115 mmol), iodide Butyl (259 mg, 1.408 mmol), acetonitrile (5 mL) was charged and the reaction was heated at 100 ° C. for 4 days. The reaction gave a mixture of monoalkylated and dialkylated products. The reaction was cooled, filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography to give the product (51.5 mg). MS m / z: 508 [M + 1] ^< +>.

Step 6: 3-Dibutylamino-4- (4-fluoro-phenoxy) -5-sulfamoyl-benzoic acid (NTP-5209). A reaction vial was charged with 3-dibutylamino-5- (dimethylaminomethylene-sulfamoyl) -4- (4-fluoro-phenoxy) -benzoic acid methyl ester (51 mg, 0.101 mmol), 2N NaOH (1 mL), methanol ( 3 mL) and the reaction was heated to 50 ° C. for 2 h. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a pale yellow solid (37 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.30 (bs, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 2.1 Hz) , 1H), 7.42 (s, 2H), 7.08-7.03 (m, 2H), 6.78-6.73 (m, 2H), 3.00 (t, J = 7.2) Hz, 4H), 1.21-1.11 (m, 4H), 1.01-0.91 (m, 4H), 0.73 (t, J = 7.2 Hz, 6H). MS m / z: 439 [M + 1] ^< +>.

  The following examples were prepared from commercially available reagents according to procedures familiar to those skilled in the art according to General Method J or with minor modifications thereof.

（実施例４３）
３−（ジブチルアミノ）−５−（Ｎ，Ｎ−ジメチルスルファモイル）−４−フェノキシ安息香酸

(Example 43)
3- (Dibutylamino) -5- (N, N-dimethylsulfamoyl) -4-phenoxybenzoic acid

一般方法Ｋ

General method K

ステップ１：４−クロロ−３−ジメチルスルファモイル−５−ニトロ−安息香酸。丸底フラスコに、４−クロロ−３−クロロスルホニル−５−ニトロ−安息香酸（５００ｇ、１．６６ｍｍｏｌ）、ジメチルアミン（ＴＨＦ中２．０Ｍ、１ｍＬ、１．９９ｍｍｏｌ）、ジイソプロピルエチルアミン（０．３６ｍＬ、１．９９ｍｍｏｌ）およびＴＨＦ（３ｍＬ）を充填し、反応物を４５℃で一晩撹拌した。溶媒を減圧下で除去し、残渣を酢酸エチルに溶解し、水、ブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させた。溶媒を減圧下で除去し、生成物を黄色の固体（３６０ｍｇ）として得て、これを次の反応においてそれ以上精製することなく使用した。ＭＳ ｍ／ｚ：３０７［Ｍ−１］⁻。

Step 1: 4-Chloro-3-dimethylsulfamoyl-5-nitro-benzoic acid. In a round bottom flask was added 4-chloro-3-chlorosulfonyl-5-nitro-benzoic acid (500 g, 1.66 mmol), dimethylamine (2.0 M in THF, 1 mL, 1.99 mmol), diisopropylethylamine (0.36 mL). 1.99 mmol) and THF (3 mL) were charged and the reaction was stirred at 45 ° C. overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with water, brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the product as a yellow solid (360 mg) that was used in the next reaction without further purification. MS m / z: 307 [M-1] ^- .

  Step 2: 4-Chloro-3-dimethylsulfamoyl-5-nitro-benzoic acid methyl ester. A round bottom flask was charged with 4-chloro-3-dimethylsulfamoyl-5-nitro-benzoic acid (360 mg, 1.16 mmol) and methanol (10 mL). Thionyl chloride (152 mg, 1.283 mmol) was added slowly at room temperature and the reaction mixture was heated to 50 ° C. overnight. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a yellow solid, which was used directly in the next reaction (340 mg).

Step 3: 3-Dimethylsulfamoyl-5-nitro-4-phenoxy-benzoic acid methyl ester. In a round bottom flask was added 4-chloro-3-dimethylsulfamoyl-5-nitro-benzoic acid methyl ester (340 mg, 1.054 mmol), sodium bicarbonate (354 mg, 4.217 mmol), phenol (198 mg, 2.108 mmol). ) And DMSO (10 mL) and the reaction mixture was heated to 80 ° C. overnight. The reaction was cooled to room temperature and quenched with water. The precipitated product was filtered, dissolved in ethyl acetate and washed with brine. The solvent was removed under reduced pressure to give the product as a pale yellow solid (340 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.71 (d, J = 1.8 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 7.32 (t , J = 5.7 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 3.95 (s, 3H ), 2.79 (s, 6H).

Step 4: 3-amino-5-dimethylsulfamoyl-4-phenoxy-benzoic acid methyl ester. A round bottom flask was charged with 3-dimethylsulfamoyl-5-nitro-4-phenoxy-benzoic acid methyl ester (340 mg, 0.894 mmol), ethanol (10 mL) and the reaction mixture was heated to 85 ° C. Ammonium chloride (475 mg, 8.94 mmol) in water (5 mL) was added. Iron powder (197 mg, 3.578 mmol) was added in 3 portions every 3 minutes. Heating was continued for an additional hour. The reaction mixture was cooled to 60 ° C. and poured into dichloromethane (150 mL). The organic layer was separated, washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give the product as a pale yellow solid (300 mg). MS m / z: 351 [M + 1] ^< +>.

Step 5: 3-Butyrylamino-5-dimethylsulfamoyl-4-phenoxy-benzoic acid methyl ester. To a round bottom flask was added 3-amino-5-dimethylsulfamoyl-4-phenoxy-benzoic acid methyl ester (330 mg, 0.942 mmol), butyryl chloride (0.12 mL, 1.13 mmol), diisopropylethylamine (0.1 mL). ), THF (5 mL) was charged and the reaction was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a light brown oil (400 mg). MS m / z: 421 [M + 1] ^< +>.

Step 6: 3-Butylamino-5-dimethylsulfamoyl-4-phenoxy-benzoic acid methyl ester. A round bottom flask was charged with 3-butyrylamino-5-dimethylsulfamoyl-4-phenoxy-benzoic acid methyl ester (330 mg, 0.785 mmol), THF (3 mL), and BH3.THF (1.0 M in THF). (4 mL, 3.928 mmol) was added slowly. The reaction was stirred at room temperature for 1 hour. The reaction was quenched by the dropwise addition of water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a pale yellow solid (160 mg). MS m / z: 407 [M + 1] ^< +>.

Step 7: 3-Dibutylamino-5-dimethylsulfamoyl-4-phenoxy-benzoic acid (NTP-6001). A reaction vial was charged with 3-butylamino-5-dimethylsulfamoyl-4-phenoxy-benzoic acid methyl ester (30 mg, 0.073 mmol), THF (2 mL), sodium hydride (95%) (3.5 mg, 0 .147 mmol) and butyl bromide (16 mg, 0.147 mmol) were charged and the reaction was stirred at 50 ° overnight. The reaction was quenched with water, acidified with 3N HCl and extracted with ethyl acetate. The solvent was removed under reduced pressure to give the product as a colorless viscous oil (17 mg). ¹ H NMR
(300 MHz, DMSO-d ₆ ) δ 7.94 (d, J = 1.8 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.23 (t, J = 7.5 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 7.5 Hz, 2H), 3.02 (t, J = 7. 2 Hz, 4H), 2.70 (s, 6H), 1.23-1.1.11 (m, 4H),
0.98-0.93 (m, 4H), 0.72 (t, J = 7.5 Hz, 6H). MS m / z: 449 [M + 1] ^< +>.

(Example 44)
3- (Dibutylamino) -5- (morpholinosulfonyl) -4-phenoxybenzoic acid

一般方法Ｋに従って、またはその僅かな修正をして、当業者が精通している手順に従って、表題化合物を市販の試薬から調製した。ＭＳ ｍ／ｚ：４９１［Ｍ＋１］^＋。

The title compound was prepared from commercially available reagents according to General Method K, or with minor modifications thereof, following procedures familiar to those skilled in the art. MS m / z: 491 [M + 1] ^< +>.

(Example 45)
3- (Butylamino) -5- (N, N-dimethylsulfamoyl) -4-phenoxybenzoic acid

反応バイアルに、３−ブチルアミノ−５−ジメチルスルファモイル−４−フェノキシ−安息香酸メチルエステル（一般方法Ｋ、ステップ６、１３０ｍｇ、０．３１９ｍｍｏｌ）、メタノール（２ｍＬ）、ＴＨＦ（１ｍＬ）および１ＮのＬｉＯＨ（１ｍＬ）を充填し、反応物を室温で２時間撹拌した。溶媒を減圧下で除去し、水層を３ＮのＨＣｌで酸性化した。混合物を酢酸エチルで抽出し、溶媒を減圧下で除去し、生成物を白色の固体（９３ｍｇ）として得た。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ− ｄ_６） δ １３．２５ （ｂｓ， １Ｈ）， ７．６０ （ｄ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ７．４６ （ｄ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ７．２７ （ｔ， Ｊ＝７．５ Ｈｚ， ２Ｈ）， ７．０１ （ｔ， Ｊ＝７．２ Ｈｚ， １Ｈ）， ６．７５ （ｄ， Ｊ＝７．５ Ｈｚ， ２Ｈ）， ５．１８ （ｔ， Ｊ＝ ５．４ Ｈｚ， １Ｈ）， ３．０９−３．０３（ｍ， ２Ｈ）， １．３９−１．３４ （ｍ， ２Ｈ）， ０．７７ （ｔ， Ｊ＝７．２ Ｈｚ， ６Ｈ）．ＭＳ ｍ／ｚ：３９３［Ｍ＋１］^＋。

In a reaction vial, 3-butylamino-5-dimethylsulfamoyl-4-phenoxy-benzoic acid methyl ester (General Method K, Step 6, 130 mg, 0.319 mmol), methanol (2 mL), THF (1 mL) and 1N Of LiOH (1 mL) was charged and the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the aqueous layer was acidified with 3N HCl. The mixture was extracted with ethyl acetate and the solvent was removed under reduced pressure to give the product as a white solid (93 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.25 (bs, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 2.1 Hz) , 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 7.5 Hz, 2H) ), 5.18 (t, J = 5.4 Hz, 1H), 3.09-3.03 (m, 2H), 1.39-1.34 (m, 2H), 0.77 (t, J = 7.2 Hz, 6H). MS m / z: 393 [M + 1] ^< +>.

(Example 46)
3- (Butylamino) -5- (morpholinosulfonyl) -4-phenoxybenzoic acid

表題化合物を、実施例３３を調製するために使用したものと同様の態様で調製した。ＭＳ ｍ／ｚ：４３５．１［Ｍ＋１］^＋。

The title compound was prepared in a manner similar to that used to prepare Example 33. MS m / z: 435.1 [M + 1] ^< +>.

(Example 47)
3- (N-acetylsulfamoyl) -5- (dibutylamino) -4-phenoxybenzoic acid

メチル３−（ジブチルアミノ）−４−フェノキシ−５−スルファモイルベンゾエート（０．１６ｇ、０．３７ミリモル）、およびＥｔ_３Ｎ（０．１ｍＬ、０．７４ミリモル）、Ａｃ_２Ｏ（０．０４ｍＬ、０．４４ミリモル）、およびＣＨ_２Ｃｌ_２（２ｍＬ）を、フラスコに充填した。混合物を室温で２時間撹拌した。反応溶液を水（１０ｍＬ）でクエンチした。メタノールをｒｏｔａｖａｐｏｒ上で除去し、水溶液をＥｔＯＡｃ（２×１０ｍＬ）で抽出した。有機層を合わせ、ＭｇＳＯ_４上で乾燥させ、蒸発させた。残渣をフラッシュカラム（ｎ−ヘキサン／ＥｔＯＡｃ：１／１）によって精製し、０．１１ｇの白色の固体を得た。固体（０．１０５ｇ、０．２２１ｍｍｏｌ）、２ＮのＮａＯＨ（０．２２ｍＬ、０．４４２ｍｍｏｌ）、およびＭｅＯＨ（２ｍＬ）を、フラスコに充填した。混合物を４０℃に２時間加熱した。反応溶液を１ＮのＨＣｌ（１ｍＬ）で中和し、混合物をＥｔＯＡｃで抽出し、ＭｇＳＯ_４上で乾燥させ、蒸発させ、０．０４ｇの表題化合物を白色の固体として得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤ_３ＯＤ） δ ８．２８ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ）， ７．９４ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ）， ７．３５−７．２０ （ｍ， ２Ｈ）， ７．１０−７．０２ （ｍ， １Ｈ）， ６．８０−６．７０ （ｍ， １Ｈ）， ３．２０−３．０２ （ｍ， ４Ｈ）， １．５４ （ｓ， ３Ｈ）， １．４０−１．１５ （ｍ， ４Ｈ）， １．１０−１．０９ （ｍ， ４Ｈ）， ０．７９ （ｔ， Ｊ ＝ ７．２ Ｈｚ， ６Ｈ）．ＭＳ ｍ／ｚ：４６３［Ｍ＋１］^＋。

Methyl 3- (dibutylamino) -4-phenoxy-5-sulfamoylbenzoate (0.16 g, 0.37 mmol), and Et ₃ N (0.1 mL, 0.74 mmol), Ac ₂ O (0. 04 mL, 0.44 mmol), and CH ₂ Cl ₂ (2 mL) were charged to the flask. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with water (10 mL). Methanol was removed on rotavapo and the aqueous solution was extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried over MgSO ₄ and evaporated. The residue was purified by flash column (n-hexane / EtOAc: 1/1) to give 0.11 g of white solid. Solid (0.105 g, 0.221 mmol), 2N NaOH (0.22 mL, 0.442 mmol), and MeOH (2 mL) were charged to the flask. The mixture was heated to 40 ° C. for 2 hours. The reaction solution was neutralized with 1N HCl (1 mL) and the mixture was extracted with EtOAc, dried over MgSO ₄ and evaporated to give 0.04 g of the title compound as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.28 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.35-7. 20 (m, 2H), 7.10-7.02 (m, 1H), 6.80-6.70 (m, 1H), 3.20-3.02 (m, 4H), 1.54 ( s, 3H), 1.40-1.15 (m, 4H), 1.10-1.09 (m, 4H), 0.79 (t, J = 7.2 Hz, 6H). MS m / z: 463 [M + 1] ^< +>.

Examples 48 and 49
3- (Dibutylamino) -5- (N-ethylsulfamoyl) -4-phenoxybenzoic acid and 3- (dibutylamino) -5- (N, N-diethylsulfamoyl) -4-phenoxybenzoic acid

一般方法Ｌ

General method L

丸底フラスコに、３−ジブチルアミノ−４−フェノキシ−５−スルファモイル−安息香酸（１．０ｇ、２．３８ｍｍｏｌ）、水素化ナトリウム（９５％）（１７１ｍｇ、７．１３４ｍｍｏｌ）およびＴＨＦ（１５ｍＬ）を充填した。反応混合物を室温で１５分間撹拌し、ヨウ化エチル（１．１２ｇ、７．１３４ｍｍｏｌ）を加え、反応混合物を５０℃に一晩加熱した。反応混合物は、ＬＣＭＳによってジエチル、モノエチルおよびエチルエステル生成物を示した。水を加えることによって反応混合物をクエンチし、酢酸エチルで抽出した。次いで、有機層を３ＮのＨＣｌ、水、ブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させた。溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、３−（ジブチルアミノ）−５−（Ｎ−エチルスルファモイル）−４−フェノキシ安息香酸（２８ｍｇ）および３−（ジブチルアミノ）−５−（Ｎ，Ｎ−ジエチルスルファモイル）−４−フェノキシ安息香酸（１３２ｍｇ）を白色の固体として得た。
３−（ジブチルアミノ）−５−（Ｎ−エチルスルファモイル）−４−フェノキシ安息香酸：ＭＳ ｍ／ｚ：４４９［Ｍ＋１］^＋。
３−（ジブチルアミノ）−５−（Ｎ，Ｎ−ジエチルスルファモイル）−４−フェノキシ安息香酸：ＭＳ ｍ／ｚ：４７７．２［Ｍ＋１］^＋。

In a round bottom flask was added 3-dibutylamino-4-phenoxy-5-sulfamoyl-benzoic acid (1.0 g, 2.38 mmol), sodium hydride (95%) (171 mg, 7.134 mmol) and THF (15 mL). Filled. The reaction mixture was stirred at room temperature for 15 minutes, ethyl iodide (1.12 g, 7.134 mmol) was added and the reaction mixture was heated to 50 ° C. overnight. The reaction mixture showed diethyl, monoethyl and ethyl ester products by LCMS. The reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was then washed with 3N HCl, water, brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give 3- (dibutylamino) -5- (N-ethylsulfamoyl) -4-phenoxybenzoic acid (28 mg) and 3- (dibutylamino) -5- (N, N-diethylsulfamoyl) -4-phenoxybenzoic acid (132 mg) was obtained as a white solid.
3- (Dibutylamino) -5- (N-ethylsulfamoyl) -4-phenoxybenzoic acid: MS m / z: 449 [M + 1] ⁺ .
3- (Dibutylamino) -5- (N, N-diethylsulfamoyl) -4-phenoxybenzoic acid: MS m / z: 477.2 [M + 1] ⁺ .

  The following examples were prepared from commercially available reagents according to procedures familiar to those skilled in the art according to general method L or with minor modifications thereof.

（実施例５９）
３−（ジブチルアミノ）−５−（モルホリン−４−カルボニル）−２−フェノキシベンゼンスルホンアミド

(Example 59)
3- (Dibutylamino) -5- (morpholine-4-carbonyl) -2-phenoxybenzenesulfonamide

一般方法Ｍ

General method M

３−（ジブチルアミノ）−４−フェノキシ−５−スルファモイル安息香酸（１００ｍｇ、０．２３８ｍｍｏｌ）のジクロロメタン溶液に、モルホリン（４１ｍｇ、０．４７６ｍｍｏｌ）、トリエチルアミン（４８ｍｇ、０．４７６ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（５４．７ｍｇ、０．２８６ｍｍｏｌ）、および１−ヒドロキシベンゾトリアゾール（４８ｍｇ、０．３５７ｍｍｏｌ）を０℃で加えた。次いで、反応物を５０℃で１．５時間撹拌し、炭酸水素ナトリウムの飽和水溶液でクエンチした。このように得られた混合物をジクロロメタンで抽出した。合わせた有機抽出物を０．１Ｍの塩酸溶液および炭酸水素ナトリウムの飽和水溶液で洗浄し、次いで無水ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。粗生成物をフラッシュクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝５／１）によって精製し、表題化合物（７０ｍｇ）を得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤ_３ＯＤ−ｄ_４） δ ７．５４ （ｓ， １Ｈ）， ７．３０ （ｓ， １Ｈ）， ７．２２ （ｔ， Ｊ ＝ ８．０ Ｈｚ， ２Ｈ）， ７．００ （ｔ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ）， ６．８３ （ｄ， Ｊ ＝ ８．０ Ｈｚ， ２Ｈ）， ３．８１−３．４３ （ｍ， ８Ｈ）， ３．０８ （ｔ， Ｊ ＝ ７．２ Ｈｚ， ４Ｈ）， ２．２６−１．８６ （ｍ， ４Ｈ）， １．０７−１．００ （ｍ， ４Ｈ）， ０．７７ （ｔ， Ｊ ＝ ７．２ Ｈｚ， ６Ｈ）．ＭＳ ｍ／ｚ：４９０［Ｍ＋１］^＋。

To a dichloromethane solution of 3- (dibutylamino) -4-phenoxy-5-sulfamoylbenzoic acid (100 mg, 0.238 mmol), morpholine (41 mg, 0.476 mmol), triethylamine (48 mg, 0.476 mmol), 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (54.7 mg, 0.286 mmol) and 1-hydroxybenzotriazole (48 mg, 0.357 mmol) were added at 0 ° C. The reaction was then stirred at 50 ° C. for 1.5 hours and quenched with a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with dichloromethane. The combined organic extracts were washed with 0.1 M hydrochloric acid solution and a saturated aqueous solution of sodium bicarbonate, then dried over anhydrous MgSO ₄ and concentrated in vacuo. The crude product was purified by flash chromatography (n-hexane / ethyl acetate = 5/1) to give the title compound (70 mg). ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 7.54 (s, 1H), 7.30 (s, 1H), 7.22 (t, J = 8.0 Hz, 2H), 7 .00 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 3.81-3.43 (m, 8H), 3.08 (t, J = 7.2 Hz, 4H), 2.26-1.86 (m, 4H), 1.07-1.00 (m, 4H), 0.77 (t, J = 7.2 Hz, 6H) ). MS m / z: 490 [M + 1] ^< +>.

(Example 60)
3- (Dibutylamino) -N- (2-hydroxyethyl) -4-phenoxy-5-sulfamoylbenzamide

一般手順Ｎ

General procedure N

３−（ジブチルアミノ）−４−フェノキシ−５−スルファモイル安息香酸（１００ｍｇ、０．２４ｍｍｏｌ）および乾燥ジクロロメタン（３ｍＬ）を、磁気撹拌子を有する２５ｍＬの丸底フラスコ中に入れた。塩化チオニル（０．０５ｍＬ、０．７１３ｍｍｏｌ）を、上記の溶液に０°にて滴下した。混合物を室温で１時間撹拌した。溶媒および過剰な塩化チオニルを、ロータリーエバポレーター上で除去した。ジクロロメタン（３ｍＬ）および２−アミノエタノール（２９ｍｇ、０．４８ｍｍｏｌ）を、残渣に０℃で加えた。溶液を室温で１時間撹拌し続けた。溶媒を除去し、粗生成物をフラッシュクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝５／１）によって精製し、表題化合物（４０ｍｇ）を得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤ_３ＯＤ−ｄ_４） δ ８．０２ （ｄ， Ｊ＝３．２ Ｈｚ， １Ｈ）， ７．７５ （ｄ， Ｊ＝３．２ Ｈｚ， １Ｈ）， ７．２４ （ｔ， Ｊ ＝ ８．０ Ｈｚ， ２Ｈ）， ７．００ （ｔ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ）， ６．８３ （ｄ， Ｊ ＝ ８．０ Ｈｚ， ２Ｈ）， ３．７２ （ｔ， Ｊ＝７．６ Ｈｚ， ２Ｈ）， ３．５２ （ｔ， Ｊ＝８．０ Ｈｚ， ２Ｈ）， ３．０９ （ｔ， Ｊ＝ ８．０ Ｈｚ， ４Ｈ）， １．２７−１．２０ （ｍ， ４Ｈ）， １．０６−０．９６ （ｍ， ４Ｈ）， ０．７７ （ｔ， Ｊ ＝
７．２ Ｈｚ， ６Ｈ）．ＭＳ ｍ／ｚ：４６４［Ｍ＋１］^＋。

3- (Dibutylamino) -4-phenoxy-5-sulfamoylbenzoic acid (100 mg, 0.24 mmol) and dry dichloromethane (3 mL) were placed in a 25 mL round bottom flask with a magnetic stir bar. Thionyl chloride (0.05 mL, 0.713 mmol) was added dropwise to the above solution at 0 °. The mixture was stirred at room temperature for 1 hour. Solvent and excess thionyl chloride were removed on a rotary evaporator. Dichloromethane (3 mL) and 2-aminoethanol (29 mg, 0.48 mmol) were added to the residue at 0 ° C. The solution was kept stirring at room temperature for 1 hour. The solvent was removed and the crude product was purified by flash chromatography (n-hexane / ethyl acetate = 5/1) to give the title compound (40 mg). ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.02 (d, J = 3.2 Hz, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7.24 (T, J = 8.0 Hz, 2H), 7.00 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 3.72 (t , J = 7.6 Hz, 2H), 3.52 (t, J = 8.0 Hz, 2H), 3.09 (t, J = 8.0 Hz, 4H), 1.27-1.20. (M, 4H), 1.06-0.96 (m, 4H), 0.77 (t, J =
7.2 Hz, 6H). MS m / z: 464 [M + 1] ^< +>.

(Example 61)
3- (Dibutylamino) -N- (1-hydroxypropan-2-yl) -4-phenoxy-5-sulfamoylbenzamide

一般方法Ｏ

General method O

反応バイアルに、３−ジブチルアミノ−４−フェノキシ−５−スルファモイル−安息香酸（７０ｍｇ、０．１６６ｍｍｏｌ）、２−アミノ−１−プロパノール（１５ｍｇ、０．１９９９ｍｍｏｌ）、Ｏ−（７−アザベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ，Ｎ−テトラメチルウラニウムヘキサフルオロホスフェート（７６ｍｇ、０．１９９ｍｍｏｌ）、Ｎ，Ｎ−ジイソプロピルエチルアミン（３３μＬ、０．１９９ｍｍｏｌ）、ＤＭＦ（２ｍＬ）を充填し、混合物を室温で一晩撹拌した。反応物を酢酸エチルで希釈し、水、ブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させた。溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、生成物を白色の固体（６９ｍｇ）として得た。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ− ｄ_６） δ ８．２９ （ｄ， Ｊ＝８．１ Ｈｚ， １Ｈ）， ７．９４ （ｄ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ７．６７
（ｄ， Ｊ＝１．８ Ｈｚ， １Ｈ）， ７．２５ （ｓ， ２Ｈ）， ７．２０ （ｔ， Ｊ ＝ ７．２ Ｈｚ， ２Ｈ）， ６．９６ （ｔ， Ｊ ＝ ７．２ Ｈｚ， １Ｈ）， ６．７３ （ｄ， Ｊ ＝ ８．１ Ｈｚ， ２Ｈ）， ４．７５ （ｔ， Ｊ＝６．００ Ｈｚ， １Ｈ）， ４．０６−４．４．０１ （ｍ， １Ｈ）， ３．５１−３．２２ （ｍ， ６Ｈ）， ３．００ （ｔ， Ｊ＝ ７．２ Ｈｚ， ４Ｈ）， １．１９−１．０９ （ｍ， ４Ｈ）， １．０１−０．８９ （ｍ， ４Ｈ），
０．７２ （ｔ， Ｊ ＝ ７．５ Ｈｚ， ６Ｈ）．ＭＳ ｍ／ｚ：４７８［Ｍ＋１］^＋。

In a reaction vial, 3-dibutylamino-4-phenoxy-5-sulfamoyl-benzoic acid (70 mg, 0.166 mmol), 2-amino-1-propanol (15 mg, 0.1999 mmol), O- (7-azabenzotriazole). -1-yl) -N, N, N, N-tetramethyluranium hexafluorophosphate (76 mg, 0.199 mmol), N, N-diisopropylethylamine (33 μL, 0.199 mmol), DMF (2 mL), The mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate, washed with water, brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a white solid (69 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.67
(D, J = 1.8 Hz, 1H), 7.25 (s, 2H), 7.20 (t, J = 7.2 Hz, 2H), 6.96 (t, J = 7.2 Hz) , 1H), 6.73 (d, J = 8.1 Hz, 2H), 4.75 (t, J = 6.00 Hz, 1H), 4.06-4.4.01 (m, 1H) , 3.51-3.22 (m, 6H), 3.00 (t, J = 7.2 Hz, 4H), 1.19-1.09 (m, 4H), 1.01-0.89 (M, 4H),
0.72 (t, J = 7.5 Hz, 6H). MS m / z: 478 [M + 1] ^< +>.

  Benzoic acid which can be prepared according to General Methods A to P according to General Methods M to O, or with minor modifications thereof, according to procedures familiar to those skilled in the art, and commercially available reagents Prepared from

（実施例１５８）
３−ジブチルアミノ−５−ヒドロキシメチル−２−フェノキシ−ベンゼンスルホンアミド

(Example 158)
3-Dibutylamino-5-hydroxymethyl-2-phenoxy-benzenesulfonamide

一般方法Ｐ

General method P

ステップ１：３−ジブチルアミノ−４−フェノキシ−５−スルファモイル−安息香酸メチルエステル。丸底フラスコに、３−ジブチルアミノ−４−フェノキシ−５−スルファモイル安息香酸（１．８２ｇ、４．３３ｍｍｏｌ）およびメタノール（５０ｍＬ）を充填した。塩化チオニル（１．５０ｇ、１２．９９ｍｍｏｌ）を室温でゆっくりと加え、反応混合物を５０°に一晩加熱した。溶媒を減圧下で除去し、残渣を酢酸エチルに再溶解し、飽和炭酸水素ナトリウム溶液、水およびブラインで洗浄した。有機溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、生成物を白色の固体（１．７５ｇ）として得た。ＭＳ ｍ／ｚ：４３５［Ｍ＋１］^＋。

Step 1: 3-Dibutylamino-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester. A round bottom flask was charged with 3-dibutylamino-4-phenoxy-5-sulfamoylbenzoic acid (1.82 g, 4.33 mmol) and methanol (50 mL). Thionyl chloride (1.50 g, 12.99 mmol) was added slowly at room temperature and the reaction mixture was heated to 50 ° overnight. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a white solid (1.75 g). MS m / z: 435 [M + 1] ^< +>.

Step 2: 3-Dibutylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester. To the reaction flask was added 3-dibutylamino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester (1.75 g, 4.032 mmol), acetonitrile (25 mL) and N, N-dimethylformamide dimethyl acetal (0.56 mL, 4. 233 mmol) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the resulting rubbery residue was treated with ice-cold water to give a pale yellow solid. The solid was filtered and dried to give the product (2.1 g). MS m / z: 490 [M + 1] ^< +>.

Step 3: 3-dibutylamino-5-hydroxymethyl-2-phenoxy-benzenesulfonamide (NTP-100001). To a round bottom flask was added 3-dibutylamino-5- (dimethylaminomethylene-sulfamoyl) -4-phenoxy-benzoic acid methyl ester (200 mg, 0.41 mmol), THF (5 mL) and lithium aluminum hydride (2M in THF). (0.25 mL, 0.49 mmol) was charged and the reaction was stirred at room temperature for 1 hour. A further portion of lithium aluminum hydride (2M in THF) (0.25 mL, 0.49 mmol) was added and the reaction was heated to 50 ° C. for 1 hour. The reaction was cooled, quenched with cold water and diluted with ether. The reaction was filtered and the filtrate was removed under reduced pressure. The residue was then purified by flash chromatography to give the product as a white solid (33 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.41 (d, J = 1.8 Hz, 1H), 7.21-7.16 (m, 3H) 7.13
(S, 2H), 6.93 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.7 Hz, 2H), 5.35 (t, J = 5.7 Hz) , 1H), 4.51 (d, J = 5.7 Hz, 2H), 2.97 (t, J = 7.2 Hz, 4H), 1.17-1.1.10 (m, 4H) 1.02-0.94 (m, 4H), 0.73 (t, J = 7.5 Hz, 6H). MS m / z: 407 [M + 1] ^< +>.

(Example 159)
3- (Bis (3-chloro-4-fluorobenzyl) amino) -5- (hydroxymethyl) -2-phenoxybenzenesulfonamide

一般方法Ｑ

General method Q

３−（ビス（３−クロロ−４−フルオロベンジル）アミノ）−５−（ヒドロキシメチル）−２−フェノキシベンゼンスルホンアミド：反応バイアルに、３−（ビス（３−クロロ−４−フルオロベンジル）アミノ）−４−フェノキシ−５−スルファモイル−安息香酸（７５ｍｇ、０．１２６ｍｍｏｌ）、テトラヒドロフラン（４ｍＬ）を充填し、ＢＨ_３・ＴＨＦ錯体（テトラヒドロフラン中１．０Ｍ）を滴下した。反応混合物を室温で１時間撹拌した。水を加え、反応混合物を酢酸エチルで抽出し、ブラインで洗浄し、ＭｇＳＯ_４上で乾燥させた。溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、表題生成物（４８ｍｇ）を得た。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ−ｄ_６） δ ７．５２ （ｄ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ７．３４ （ｔ， Ｊ＝７．５ Ｈｚ， ２Ｈ）， ７．２６ （ｓ， ２Ｈ）， ７．２２−７．１１ （ｍ，
４Ｈ）， ６．９１ （ｄｄ， Ｊ＝７．５ ＆２．１ Ｈｚ， ２Ｈ）， ６．８３−６．７７ （ｍ， ４Ｈ）， ５．３４ （ｔ， Ｊ＝ ５．７ Ｈｚ， １Ｈ）， ４．４４ （ｄ， Ｊ＝５．７ Ｈｚ， ２Ｈ）， ４．１１ （ｓ， ４Ｈ）．ＭＳ ｍ／ｚ：５８０．９［Ｍ＋１］^＋。

3- (Bis (3-chloro-4-fluorobenzyl) amino) -5- (hydroxymethyl) -2-phenoxybenzenesulfonamide: In a reaction vial, 3- (bis (3-chloro-4-fluorobenzyl) amino ) -4-phenoxy-5-sulfamoyl-benzoic acid (75 mg, 0.126 mmol) and tetrahydrofuran (4 mL) were charged and BH ₃ .THF complex (1.0 M in tetrahydrofuran) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Water was added and the reaction mixture was extracted with ethyl acetate, washed with brine and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the title product (48 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.52 (d, J = 2.1 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.26 (s , 2H), 7.22-7.11 (m,
4H), 6.91 (dd, J = 7.5 & 2.1 Hz, 2H), 6.83-6.77 (m, 4H), 5.34 (t, J = 5.7 Hz, 1H) 4.44 (d, J = 5.7 Hz, 2H), 4.11 (s, 4H). MS m / z: 580.9 [M + 1] ^< +>.

(Example 160)
3- (Butylamino) -5- (hydroxymethyl) -2-phenoxybenzenesulfonamide

表題化合物を、ステップ１におけるブメタニドから開始して、一般方法Ｐによって作製する。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ−ｄ_６） δ ７．２５−７．１９
（ｍ， ２Ｈ）， ７．０７ （ｂｓ， ２Ｈ）， ７．０５ （ｄ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ６．９５ （ｔ， Ｊ＝７．５ Ｈｚ， １Ｈ）， ６．８６ （ｓ， １Ｈ）， ６．８１ （ｄ， Ｊ＝７．５ Ｈｚ， ２Ｈ）， ５．２８ （ｔ， Ｊ＝ ５．７ Ｈｚ， １Ｈ）， ４．６７ （ｔ， Ｊ＝５．７ Ｈｚ， １Ｈ）， ４．４８ （ｄ， Ｊ＝６．０ Ｈｚ， ２Ｈ）， ３．０４−２．９７ （ｍ． ２Ｈ）， １．３７−１．３０ （ｍ， ２Ｈ）， １．１４−１．０６ （ｍ， ２Ｈ），
０．７６ （ｔ， Ｊ＝７．５ Ｈｚ， ３Ｈ）．ＭＳ ｍ／ｚ：３５１．０［Ｍ＋１］^＋。

The title compound is made by general method P starting from bumetanide in step 1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.25-7.19
(M, 2H), 7.07 (bs, 2H), 7.05 (d, J = 2.1 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.86 (S, 1H), 6.81 (d, J = 7.5 Hz, 2H), 5.28 (t, J = 5.7 Hz, 1H), 4.67 (t, J = 5.7 Hz) , 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.04-2.97 (m. 2H), 1.37-1.30 (m, 2H), 1.14 1.06 (m, 2H),
0.76 (t, J = 7.5 Hz, 3H). MS m / z: 351.0 [M + 1] ^< +>.

(Example 161)
3- (Dibutylamino) -N, N-diethyl-5- (hydroxymethyl) -2-phenoxybenzenesulfonamide

表題化合物を、適当な安息香酸誘導体から開始して、一般手順Ｑによって作製する。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ−ｄ_６） δ ７．４２ （ｄ， Ｊ＝１．２ Ｈｚ， １Ｈ）， ７．２０ （ｔ， Ｊ＝７．８ Ｈｚ， ３Ｈ）， ６．９４ （ｔ， Ｊ＝７．５ Ｈｚ， １Ｈ）， ６．６３ （ｄ， Ｊ＝７．８ Ｈｚ， ２Ｈ）， ５．３５ （ｔ， Ｊ＝ ５．７ Ｈｚ， １Ｈ）， ４．５２ （ｄ， Ｊ＝６．０ Ｈｚ， ２Ｈ）， ３．２４−３．１３ （ｍ， ４Ｈ）， ２．９５ （ｔ， Ｊ＝７．２ Ｈｚ， ４Ｈ）， １．１８−１．０８ （ｍ， ４Ｈ）， １．０１−０．９０ （ｍ， １０Ｈ）， ０．７０ （ｔ， Ｊ＝７．２ Ｈｚ， ６Ｈ）．ＭＳ ｍ／ｚ：４６３．３［Ｍ＋１］^＋。

The title compound is made by general procedure Q starting from the appropriate benzoic acid derivative. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.42 (d, J = 1.2 Hz, 1H), 7.20 (t, J = 7.8 Hz, 3H), 6.94 (t , J = 7.5 Hz, 1H), 6.63 (d, J = 7.8 Hz, 2H), 5.35 (t, J = 5.7 Hz, 1H), 4.52 (d, J = 6.0 Hz, 2H), 3.24-3.13 (m, 4H), 2.95 (t, J = 7.2 Hz, 4H), 1.18-1.08 (m, 4H) 1.01-0.90 (m, 10H), 0.70 (t, J = 7.2 Hz, 6H). MS m / z: 463.3 [M + 1] ^< +>.

(Example 162)
Additional Aryl Sulfonamide Compounds Additional aryl sulfonamide compounds can be synthesized using standard methods. The following examples can be prepared from commercially available reagents according to general methods A to P, or with slight modifications thereof, according to procedures familiar to those skilled in the art.

（実施例１６３）
ベンジル型アルコールおよびアミン化合物
さらなるアリールスルホンアミド化合物は、標準的な方法を用いて合成し得る。Ｒ_１〜８は、本明細書に定義されている通りである。上記の実施例に加えて、式の化合物

(Example 163)
Benzyl Alcohol and Amine Compounds Additional arylsulfonamide compounds can be synthesized using standard methods. R _1-8 are as defined herein. In addition to the above examples, compounds of the formula

を、一般方法Ｑに従って、またはその僅かな修正をして、当業者が精通している手順に従って調製することができ、下記の実施例を、市販の試薬から調製することができる。

Can be prepared according to General Method Q, or with minor modifications thereof, according to procedures familiar to those skilled in the art, and the following examples can be prepared from commercially available reagents.

  General method Q

方法Ｐに従って、またはその僅かな修正をして、本発明の安息香酸から出発して作製することができる本発明の第一級アルコール（Ａ）は、当業者が精通している手順（の存在下で第一級アルコールとメタンスルホニルクロリドと反応させるなど）を使用して、適切な脱離基（メシレート、トシレートまたはトリフレートなど）を有する化合物に変換することができる。次いで、変換されたアルコールを、適切な塩基（トリエチルアミンまたはジイソプロピルエチルアミンなど）の存在下で適切な溶媒（ジクロロメタンまたはＮ，Ｎ−ジメチルホルムアミドなど）中、適切なアルコールまたは第一級もしくは第二級アミンと反応させて、一般式の化合物を提供することができる。

The primary alcohols (A) of the present invention, which can be made starting from the benzoic acids of the present invention according to Method P, or with minor modifications thereof, are present in procedures familiar to those skilled in the art. Can be converted to compounds with an appropriate leaving group (such as mesylate, tosylate or triflate) using a primary alcohol and methanesulfonyl chloride, for example). The converted alcohol is then converted to a suitable alcohol or primary or secondary amine in a suitable solvent (such as dichloromethane or N, N-dimethylformamide) in the presence of a suitable base (such as triethylamine or diisopropylethylamine). To provide a compound of the general formula.

  Instead, compounds of general formula

は、一般方法Ｒに従って、またはその僅かな修正をして、当業者が精通している手順に従って調製することができる。

Can be prepared according to General Procedure R, or with minor modifications thereof, according to procedures familiar to those skilled in the art.

  General method R

方法ＭからＯに従って、またはその僅かな修正をして、当業者が精通している手順に従って調製することができる本発明のアミド化合物は、適切な溶媒（テトラヒドロフランなど）中で適切な還元剤（ボラン−テトラヒドロフランなど）による反応によって、第一級アミンおよび第二級アミンに変換することができる。

The amide compounds of the present invention, which can be prepared according to procedures familiar to those skilled in the art, according to methods M to O, or with minor modifications thereof, are prepared in a suitable solvent (such as tetrahydrofuran) with a suitable reducing agent ( Can be converted to primary and secondary amines by reaction with borane-tetrahydrofuran and the like.

  The following examples can be prepared from commercially available reagents according to general methods Q to R, or with slight modifications thereof, according to procedures familiar to those skilled in the art.

（実施例１６４）
４−クロロ−２−（ジブチルアミノ）−５−スルファモイル安息香酸

(Example 164)
4-Chloro-2- (dibutylamino) -5-sulfamoylbenzoic acid

一般方法Ｓ

General method S

マイクロ波バイアルに、２，４−ジクロロ−５−スルファモイル−安息香酸（２００ｍｇ、０．７４１ｍｍｏｌ）、トリエチルアミン（０．４ｍＬ）、ジブチルアミン（３４１ｍｇ、１．８５ｍｍｏｌ）およびジメトキシエタン（２ｍＬ）を充填し、反応混合物をマイクロ波反応器中で１５０°にて４時間加熱した。反応物を室温に冷却し、酢酸エチルで希釈し、水およびブラインで洗浄した。有機溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィーによって精製し、生成物を白色の固体（１２０ｍｇ）として得た。^１Ｈ
ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ−ｄ_６）： δ ８．１８ （ｓ， １Ｈ），
７．４９ （ｓ， ２Ｈ）， ７．４２ （ｓ，１Ｈ）， ３．２２ （ｔ， Ｊ＝７．５ Ｈｚ， ４Ｈ）， １．４４ − １．３８ （ｍ， ４Ｈ）， １．２７−１．１８ （ｍ， ４Ｈ）， ０．８３ （ｔ， Ｊ＝７．２ Ｈｚ， ６Ｈ）．ＭＳ ｍ／ｚ：３６３（Ｍ＋１）^＋。

A microwave vial is charged with 2,4-dichloro-5-sulfamoyl-benzoic acid (200 mg, 0.741 mmol), triethylamine (0.4 mL), dibutylamine (341 mg, 1.85 mmol) and dimethoxyethane (2 mL). The reaction mixture was heated in a microwave reactor at 150 ° for 4 hours. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the product as a white solid (120 mg). ¹ H
NMR (300 MHz, DMSO-d ₆ ): δ 8.18 (s, 1H),
7.49 (s, 2H), 7.42 (s, 1H), 3.22 (t, J = 7.5 Hz, 4H), 1.44-1.38 (m, 4H), 1.27 -1.18 (m, 4H), 0.83 (t, J = 7.2 Hz, 6H). MS m / z: 363 (M + 1) ^<+> .

  The following examples were prepared from commercially available reagents according to General Method S or with slight modifications thereof, following procedures familiar to those skilled in the art.

上記の実施例に加えて、式の化合物

In addition to the above examples, compounds of the formula

（式中、Ｒ_５は、アリールオキシである）は、一般方法Ｔに従って、またはその僅かな修正をして調製することができ、当業者が精通している手順に従って、下記の実施例を、市販の試薬から調製することができる。

(Wherein R ₅ is aryloxy) can be prepared according to General Method T or with minor modifications thereof, according to procedures familiar to those skilled in the art, It can be prepared from commercially available reagents.

  General method T

一般方法Ｕに従って、またはその僅かな修正をして、当業者が精通している手順に従って調製することができる芳香族クロリド（Ａ）は、塩基（炭酸カリウムまたは水素化ナトリウムなど）の存在下で適切な溶媒（水またはＮ，Ｎ−ジメチルホルムアミドなど）中、置換または非置換の芳香族フェノールとさらに反応させ、式の化合物を生成することができる。一般方法ＳおよびＴに従って、下記の化合物を、市販の試薬から調製することができる。

The aromatic chloride (A), which can be prepared according to General Method U, or with minor modifications thereof, according to procedures familiar to those skilled in the art, is prepared in the presence of a base (such as potassium carbonate or sodium hydride). Further reaction with a substituted or unsubstituted aromatic phenol in a suitable solvent (such as water or N, N-dimethylformamide) can yield a compound of formula. According to general methods S and T, the following compounds can be prepared from commercially available reagents.

このような実施例から開始して、および一般方法Ｌ、ＭからＯ、ＰおよびＳに従って、またはその僅かな修正をして、当業者が精通している手順に従って、下記の実施例を、市販の試薬から調製することができる。

Starting with such examples and following the procedures familiar to those skilled in the art according to general methods L, M to O, P and S, or with minor modifications thereof, the following examples are commercially available: From the following reagents.

（実施例１７１）
ＣＮＳを標的とする薬物のための製剤
経口調製物。本明細書に記載の化合物は、経口投与のために製剤し得る。例示的経口調製物は、ゼラチンカプセル中に含有された、様々な非活性成分（微結晶性セルロースおよび他の添加剤など）と一緒に、約１０〜６０ｍｇの範囲の薬物物質の本明細書に記載されている化合物を含む。代わりに、活性薬物物質は、微結晶性セルロース、ヒドロキシプロピルセルロース、ステアリン酸マグネシウムおよび他の添加剤と共に、約１０〜６０ｍｇの薬物物質を含む錠剤形態において提供し得る。

(Example 171)
Formulations for drugs targeting CNS Oral preparations. The compounds described herein can be formulated for oral administration. Exemplary oral preparations are described herein for drug substances ranging from about 10-60 mg, along with various inactive ingredients (such as microcrystalline cellulose and other additives) contained in gelatin capsules. Including the compounds described. Alternatively, the active drug substance may be provided in a tablet form containing about 10-60 mg of drug substance along with microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate and other additives.

  In addition, for oral administration, the compounds described herein can be about 10 to 10 together with various inactive ingredients (such as microcrystalline cellulose and other additives) contained in gelatin capsules. It can be used in the range of 100 mg / kg. Alternatively, the compounds described herein can be provided in a tablet form containing about 10-100 mg / kg with microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate and other additives.

  Intravenous preparation. The compounds described herein can be formulated for intravenous administration. In an exemplary intravenous formulation, each milliliter of sterile solution is about 20-40% propylene glycol, about 0-10% ethyl alcohol, optional water, buffer (eg, about 5% as buffer). Sodium benzoate and benzoic acid), and a preservative (eg, about 1.5% benzyl alcohol as a preservative) can include about 1-25 mg of a compound described herein.

  Also, for intravenous administration, each milliliter of sterile solution may contain about 20-40% propylene glycol, about 0-10% ethyl alcohol, optional water, buffer (eg, about 5 as buffer). % Sodium benzoate and benzoic acid), and about 1 to 25 mg / kg of a compound described herein formulated with a preservative (eg, about 1.5% benzyl alcohol as a preservative). it can.

(Example 172)
In Vitro Pharmacology: Na ⁺ K ⁺ Cl ⁻ Cotransporter Assay The effects of selected compounds were evaluated for their effects on Na ⁺ K ⁺ Cl ⁻ cotransporter in vitro. Gamba (2005), Physiol. Rev. 85: 423-493.

material. Normal human skin fibroblasts (NHDF), fibroblast basal medium (FBM), and FGM-2 bullet kit were purchased from LONZA (C-2511). For the experiment, the following three buffers were made. Buffer A: 5 mM KCl, 0.8 mM MgSO ₄ , 5 mM glucose, 25 mM HEPES / TRIS (pH 7, 4). Buffer B: 127.3mM choline chloride, CaCl ₂ of 1.63 mm, a buffer having a bFGF ouabain (ouabaine) (Sigma, O3125) and 1 ng / ml of 0.9 mM A. Buffer C: Buffer A with 140 mM NaCl, 1.8 mM CaCl ₂ , 1 mM ouabain, 1 ng / mL bFGF and 5 μCi / mL [ ⁸⁶ Rb] (Perkin Elmer, NEZ072).

Method. After 2 weeks of cell culture in reconstituted cell culture medium (FBM with FGM-2 bullet kit), cells were seeded at 3000 cells per well in white 96-well cell culture plates and overnight at 37 ° C. incubated (5% _CO 2). The next day, the cell culture medium was replaced with medium with 0.2% FCS (low serum) and incubated for 48 hours at 37 ° C. (5% CO ₂ ). BFGF was then added to each well at a final concentration of 1 ng / mL and the cells were incubated at 37 ° C. for 1 hour (5% CO ₂ ). The cells were then washed in buffer B for 15 minutes at 37 ° C. Buffer B was then replaced with the compound diluted in Buffer C. After a 20 minute incubation at 37 ° C., each well was washed with a cold MgCl ₂ (0.1 M) solution. Subsequently, 40 μL of scintillation fluid (Microscint-40, Camberra Packard) was added to each well. The plate was sealed and incubated overnight at room temperature. Radioactivity was counted in a 96 well plate counter. Uptake was measured as a percentage of bumetanide sensitive ⁸⁶ Rb influx. All experiments were performed in duplicate. Chassande et al. (1988), Eur. J. et al. Biochem. 171: 425-433.

Specific activity was established using bumetanide (30 μM) as a positive control compound. Results were obtained in the presence of a compound herein and listed in Table 18, the control ratio percent [100 × activity ^{(86 Rb} influx by the compound - ^{86 Rb} influx by bumetanide) / buffer C in ⁸⁶ Rb influx- ⁸⁶ Rb influx with bumetanide], and percent inhibition of control specific activity [100- (percent / control specific activity)]. These results were expressed as% inhibition at 10 μM.

２０〜５０％の「対照値の抑制％」を示す化合物は、ＮＫＣＣ活性の弱い抑制から中等度の抑制を示した。２０％未満の「対照値の抑制％」を示す化合物は、本明細書に記載の化合物とビヒクル対照値との間に有意差がないことを示した。化合物の多くはＮＫＣＣの抑制を殆ど示さず、または示さず、一方、いくつかは中等度の抑制を示す。これらの化合物は、ブメタニドに匹敵する利尿活性を有することは予想されない。

Compounds exhibiting “% inhibition of control value” of 20-50% showed moderate to moderate inhibition of NKCC activity. Compounds showing a “% inhibition of control value” of less than 20% showed no significant difference between the compounds described herein and the vehicle control value. Many of the compounds show little or no inhibition of NKCC, while some show moderate inhibition. These compounds are not expected to have diuretic activity comparable to bumetanide.

(Example 173)
Test compounds for diuretic effects (including cumulative urine output, sodium excretion, and potassium excretion) Renal function assessment, including cumulative urine output, sodium excretion, and potassium excretion, is measured over 6 hours post-dose in animals receiving compound and vehicle control.

  Method. Animals are fasted overnight prior to dosing without access to drinking water prior to any pretreatment. If applicable, leave food and water undisturbed until after the last sample collection or for the first 6 hours of blood sample collection. Prior to test compound administration, all animals are pre-treated with a single IP dose of PBx. Approximately 5-6 minutes prior to administration, all animals can be given a single oral (PO) nutritional dose of 0.9% sodium chloride for injection (USP) at a dose volume of 15 mL / kg. Vehicle, diuretic (control) [(eg, bumetanide, furosemide, piretanide, azosemide, and torsemide)], DMSO, and test compound are administered in a single IP dose at a dose volume of 1 mL / kg. Cumulative urine output, sodium excretion, and potassium excretion can be measured.

  Test compounds that exhibit lower cumulative urine volume, sodium excretion, and / or potassium excretion compared to diuretic controls may exhibit fewer diuretic side effects when used clinically.

(Example 174)
In Vitro Molecular Testing of Selected Bumetanide Derivatives against GABA _A Receptor Isoforms Experimental Design for Selective Screening Addition of GABA to GABAergic cells activates the recombinantly expressed GABA _A receptor and GABA _A It causes the movement of ions through the ion channel at the receptor. The current generated by the transfer of chloride ions into the cell can be quantified.

Experiments are conducted to test the activity of α ₄ -subunit containing GABA _A receptors activated by 10 μM GABA in the presence and absence of 10 μM test compound. HEK-293T cells are transiently transfected with rat or human GABA _A receptor subunits. Unless otherwise indicated, whole cell patch clamp recordings are made at -50 mV. Test compounds are diluted in DMSO from freshly made stock and GABA is prepared from frozen stock. For each experiment, GABA or GABA + test compound is applied for 5 seconds, the current generated by the transfer of chloride ions to the cells is measured and recorded as a current versus time trace.

4-8, a 100% response to GABA indicates no inhibition of GABA _A receptor. Any value less than 100% indicated inhibition of GABA _A receptor by the test compound. The compounds described herein are directed against the α ₁ GABA _A receptor isoform, the α ₄ GABA _A receptor isoform, the α ₅ GABA _A receptor isoform, and the α ₆ GABA _A receptor isoform. Tested at a GABA concentration of 10 μM. Many of the compounds described herein exhibit α ₄ GABA _A receptor activity, α ₅ GABA _A receptor activity, and inhibition of α ₆ GABA _A receptor activity, but α ₁ GABA _A receptor activity. Not shown. Accordingly, the compounds described herein exhibit activity as selective α ₄ -subunit containing GABA _A receptor inhibitors.

Classic GABAergic Drugs Classic GABAergic drugs (eg, benzodiazepines) are non-selective agonists that increase both the amplitude and time course of inhibitory currents at GABA _A receptors. As shown in (A) FRISIUM (anticonvulsant), (B) AMBIEN (zolpidem) (sleep aid), and (C) VALIUM (diazepam) (anxiolytics) in FIG. Increases both the amplitude and time course of inhibitory currents at GABA _A receptors. GABA _A receptor agonists are effective at activating GABA _A receptors at low GABA concentrations, while also having CNS side effects (including sedation, decreased breathing, cognitive decline, and impaired motor function) Trigger.

Acylsulfonamide Derivatives Compounds described herein can be synthesized from a plurality of GABA _A receptor isoforms (eg, α ₁ β ₃ γ ₂ , α ₄ β ₃ γ ₂ , α ₅ β ₃ γ ₂ , α ₆ β ₃ γ ₂ ) was tested at a GABA concentration of 10 μM. Some of the compounds described herein selectively antagonize alpha ₄ GABA _A receptor isoform by inhibitory currents in alpha ₄ GABA _A receptor isoform. Some of the compounds can act as non-competitive inhibitors. The compounds described herein can inhibit current in the near-synaptic α ₄ GABA _A receptor isoform in GABAergic interneurons. The compounds described herein can inhibit the α ₄ GABA _A receptor presynaptically. Furthermore, the preferred compounds described herein do not activate the α ₁ GABA _A receptor post-synapse.

α ₁ β ₃ γ ₂ GABA _A Receptor Isoform The α ₁ subunit is the predominant α subunit in the GABA _A receptor of the adult brain. α ₁ -containing receptors did not show significant activation in response to many of the compounds described herein. In general, the amplitude of current associated with GABA activation of these receptors is unaffected by the preferred compounds, with a mixture of increased decay time and decreased amplitude seen at the highest concentration (10 μM), but at lower concentrations No change is seen. This is in contrast to the significantly increased positive modulation seen in the action of benzodiazepines and other classic GABAergic agents.

α ₁ / α ₄ / α ₅ / α ₆ GABA _A receptor isoforms In cells transfected with GABA _A receptor isoforms containing the α ₅ subunit subtype, 10 μM NTP-3032, NTP-3033, NTP-3034, NTP-6002, and NTP-6008 inhibited the receptor in the presence of 10 μM GABA alone compared to control conditions. The results are shown in FIG.

α ₄ / α ₆ GABA _A Receptor Isoform Receptor containing α ₄ and α ₆ subunits is inhibited at 10 μM by NTP-3032, NTP-3033, NTP-3034, NTP-6002, and NTP-6008 The These results are shown in FIG. These compounds showed marked inhibition of these receptor isoforms in the presence of 10 μM GABA alone compared to control conditions. Furthermore, these compounds had little effect on the postsynaptic α ₁ -containing GABA _A receptor under the same experimental conditions.

Some of the compounds described herein (eg, 3032, 3033, 3034, 4012, 4015, 5007, 5008, 5009, 5010, 5011, 5013, 5016, 6001, 6002, 6006, 6008, 6009, 6011) , 6012, 7021, and 10001) show selective inhibition against the α ₄ GABA _A receptor isoform and the α ₆ GABA _A receptor isoform.

The compounds described herein appear to have a different mechanism of action for GABA _A receptors than traditional GABA agonist drugs. The main effect is the suppression of chloride current, which reduces the overall GABA “drive”. This is most commonly seen in α ₄ and α ₆ , α ₅ and inhibition is consistent with non-competitive antagonism, ie open channel blockade.

The activity of the compounds described herein can exhibit two characteristics. Particular subunit, e.g., lack of inhibition of the receptor containing the alpha _4, and alpha positive modulation of receptor containing ₁ (e.g., traditional GABA agonistic mechanisms such as benzodiazepines). Increased effects due to increased GABA release at the synapse are expected to result in increased suppression due to presynaptic mechanisms and thus reduced anxiety and seizure frequency. Compounds whose activity exhibits these characteristics can also reduce pain, particularly neuropathic pain. Suppression, alpha ₄ containing receptors, the only effect observed in alpha ₅ containing receptors and alpha ₆ containing receptors. Both of these actions may require a γ subunit. This is because δ-containing receptors are believed not to be affected by the compounds described herein.

(Examples 175 to 179)
Assessment of therapeutic potential of compounds in reducing anxiety (Example 175)
An astonishing paradigm enhanced by fear. To assess the effect of test compounds in the rat anxiety model, the test compounds are evaluated in a fear-enhanced startle paradigm (FPS) anxiety model.

  FPS design. The FPS model is a commonly used assessment of the therapeutic value of anxiolytic compounds in rats. Rats can be habituated to the FPS instrument for 30 minutes. After 24 hours, baseline startle amplitude is collected. Rats are divided into two corresponding groups based on baseline startle amplitude. Following the collection of baseline startle amplitude, 20 light / shock pairings are given in 2 sessions over 2 consecutive days (ie 10 light / shock pairings per day). On the last day, one group of rats may receive an injection (iv) of the test compound and the other group may receive vehicle alone. Immediately after injection, startle amplitude is evaluated during startle alone and startle plus fear (light followed by startle) trials. Fear-enhanced startle (light + startle amplitude-startle alone amplitude) is compared between treatment groups.

  Animals are trained and tested in four identical Med-Associates devices (Med-Associates). Briefly, each rat was placed in a small Plexiglas cylinder. Each sway meter floor consists of four 6 mm diameter stainless steel bars spaced 18 mm apart through which shocks can be applied. Cylinder movement results in accelerometer displacement, and the resulting voltage is proportional to the rate of cage displacement. The startle amplitude is defined as the maximum accelerometer voltage that occurs during the first 0.25 seconds after the startle stimulus is applied. The accelerometer analog output is amplified, digitized to a scale of 0-4096 units, and stored in a microcomputer. Each sway meter is housed in a ventilated box that attenuates light and sound. All sound levels are measured with a Precision Sound Level Meter. The sound of the ventilation fan attached to the side wall of each wooden box gives an overall background noise level of 64 dB. The startle stimulus is a 50 ms burst of white noise (5 ms rise-decay time) generated by a white noise generator. The visual conditioned stimulus used (“CS”) is the illumination of the bulb adjacent to the source of white noise. The unconditioned stimulus is a 0.6 mA foot shock with a 0.5 second period caused by four constant current shockers located outside the chamber. The presentation and sequencing of all stimuli is under microcomputer control.

  The FPS procedure consists of a 5-day test. Baseline startle responses were collected on days 1 and 2, light / shock pairings were given on days 3 and 4, and a test for fear-enhanced startle on day 5. went.

  matching. During the first 2 days, all rats are placed in a Plexiglas cylinder and after 30 minutes, 30 startle stimuli are given at a 30 second stimulation interval. Use an intensity of 105 dB. Rats are assigned to treatment groups with similar averages using the average startle amplitude over 30 startle stimuli on day 2.

  Training. In the next 2 days, the rats are placed in a Plexiglas cylinder. On each day, 10 CS-shock pairings are given 3 minutes after entry. Shocks are given at a 4-minute average trial interval (range, 3-5 minutes) during the last 0.5 seconds of a 3.7 second CS.

  test. Rats are placed in the same startle box where they are trained and given 18 startle-inducing stimuli (all 105 dB) after 3 minutes. These initial startle stimuli are used to re-habituate the rat to auditory startle stimuli. After the last 30 seconds of these stimuli, each animal may receive 60 startle stimuli, half of the stimulus given alone (startle alone trial) and the other half of the start of the 3.7 second CS. 3. Give after 2 seconds (CS-startle trial). All startle stimuli are delivered with an average 30 second stimulus interval that randomly varies between 20 and 40 seconds.

  Measurement. Treatment groups are compared between CS-startle and startle-single trials based on differences in startle amplitude (enhancement of fear). In general, the compounds described herein can affect startle amplitude. The greater the fear-reduced startle reduction, the more anxiolytic the test compound. Thus, as shown in US Patent Application Publication Nos. 2006/0089350; 2007/0149526; and 2009/0215754, the compounds described herein can be used in methods of treating anxiety. Can be used.

(Example 176)
Conditional fear conditioning model To assess the potential of the compounds described herein to relieve strong anxiety in conditioning the contextual fear of rats.

  design. Contextual fear conditioning involves pairing an aversive event, in this case a moderate foot shock, with a specific environment. The intensity of fear memory is assessed using a freezing feature characterized by complete immobility, excluding breathing, a species-specific protective response in rats. If a rat is placed in a unique environment and immediately shocked, the rat does not learn to fear the situation. However, if a rat is allowed to explore a unique environment for some time before an immediate shock, the rat exhibits strong anxiety and fear when returned to the same environment. By learning the relationship between context and shock by progressively dividing contextual fear conditioning into two phases, or shock aversion (depending on emotional response circuit including amygdala) From experience, the effects of treatments on contextual memory (especially hippocampal processes) can be studied separately. Post-traumatic emergency syndrome (PTSD) in humans has been shown to be associated with an emotion response circuit in the amygdala. For this reason, contextual memory conditioning is a widely accepted model for PTSD.

  In a typical experiment, 24 rats can be used. Each rat can be given a single 5 minute episode of exploration in a small new environment. After 72 hours, the rat is placed in the same environment and the rat is immediately given a single moderate foot shock. After 24 hours, 12 rats can be given an injection (iv) of a test compound as described herein. The remaining 12 rats can be given vehicle injections. Each rat is again placed in the same environment for 8 minutes, during which time freezing can be measured as a Pavlovian conditioned fear index.

  Method. In a typical experiment, four identical chambers (20 × 20 × 15 cm) are used. All aspects of event timing and control are under microcomputer control. The freezing measurement is performed by an overhead video camera connected to a microcomputer and automatically scored using FreezeFrame, one of specialized software. In the first phase, rats are individually placed in the chamber for 5 minutes. The second phase begins after 72 hours and the rats are again individually placed in the same chamber, but the rats are immediately foot shocked (eg, 1 mA for 2 seconds). After 30 seconds, the rat is removed from the chamber. In the third phase, after 24 hours, the rats are returned to the chamber for 8 minutes, during which time freezing, an index of conditioning fear, is scored. Total freezing time is analyzed in a one-way ANOVA with drug dose as an intragroup factor.

  Compounds described herein that exhibit significant anxiolytic effects in this model system may be used in methods of treating anxiety or post-traumatic stress disorder. Exemplary uses of this model system are shown in US Patent Application Publication Nos. 2006/0089350 and 2009/0215754.

(Example 177)
Elevated cross maze design. The elevated plus maze (EPM) is commonly used to assess anxiety levels in rodents. EPM takes advantage of the fact that when a normal rat feels anxiety in a new environment, the rat can seek and hide the enclosed space. Normal rats can step into an open space in a new environment only when they feel less anxious. Drugs (such as diazepam and buspirone) show anxiolytic effects in this task, so rats treated with such drugs spend more time in the open area of the maze.

  This experiment may use two groups of rats. The first group of rats may be given an injection (iv) of the test compound and the second group may be given an injection of the vehicle. Each rat may be placed immediately on the elevated plus maze. The time spent in the open arm of the maze is recorded and compared between treatment groups. If the test compound reduces anxiety in the rat, the group receiving the test compound may spend more time in the open arm than the rat receiving the vehicle.

  The elevated plus maze may consist of two opposing open arms (50 × 10 cm) intersected with two opposing enclosed arms of the same dimensions (with a 40 cm high wall). Each of the four arms is connected to one side of a central square (10 × 10 cm), giving the instrument a cross symbol appearance. The maze is lifted 50 cm above the floor in a room that is usually exposed to light. Rats are individually placed in the central square of the cross maze and face the enclosed arm. All 3 minute sessions will be recorded on videotape and scored later. Record the time spent in the open and closed arms and the number of entries, and the number of round trips made to at least the middle of the open arm. Entry to the arm is defined as placing all four feet on the surface of the arm. This model is described in US Patent Application Publication No. 2006/0025387.

(Example 178)
Test to fill marbles in mice This method detects anxiolytic / calm activity, but is described in Broekkamp et al. (1986), Eur. J. et al. Pharmacol. 126: 223-229. Mice exposed to new objects (marbles) bury marbles in the sawdust floor covering. Anti-anxiety agents reduce the number of marbles buried with non-sedating doses.

  The mice are individually placed in a clear plastic cage (33 × 21 × 18 cm), 5 cm sawdust is placed on the floor, and 25 marbles are grouped in the center of the cage. Cover the cage with an inverted plastic cage. Each test cage is pre-impregnated with the scent of the mouse by leaving 10 mice in the cage for 15 minutes together with marbles. These mice then play no more role in the experiment.

  The number of marbles covered with sawdust (> 2/3) is counted at the end of the 30 minute test. Twelve mice are studied per group. The study is performed blinded. Each of the two test substances is i. p. Assess at 3 doses administered and compare to vehicle control group. Clobazam (8 mg / kg, ip) under the same experimental conditions is used as reference material. The experiment may include 8 groups.

本明細書に記載されている化合物は、非鎮静用量で埋められたビー玉の数を減少し得、したがって抗不安剤として有用であり得る。

The compounds described herein can reduce the number of marbles buried at non-sedating doses and can therefore be useful as anxiolytics.

(Example 179)
Light / dark box test This method detects anxiolytic activity and is described in Crawley (1981), Pharmacol. Biochem. Behav. 15: 695-699. Anti-anxiety agents increase the time spent in the bright compartment and decrease the number of crossings.

  Animals are placed in the light compartment of the two compartment box, half open and bright (25 x 27 x 27 cm) and the other half darkly enclosed (20 x 27 x 27 cm). The time spent in each compartment and the number of times the animal crosses from one side to the other is scored during the 3 minute test. Ten mice are studied per group. The study is partially blinded (apart from the positive control).

  30 minutes before the test i. p. The administered compound is evaluated at 3 doses and compared to the vehicle control group. Clobazam (16 mg / kg, ip) is administered as a reference substance 30 minutes before the test. The experiment can include 8 groups.

２つの選択した本明細書に記載されている化合物（例えば、２０１４および５００９）は、明るいコンパートメントにおいて過ごした時間を増加させ、横断の数を減少させる。したがって、本明細書に記載されている化合物は、不安障害の処置において抗不安剤として有用であり得る。

Two selected compounds described herein (eg, 2014 and 5009) increase the time spent in the bright compartment and decrease the number of crossings. Accordingly, the compounds described herein may be useful as anti-anxiety agents in the treatment of anxiety disorders.

(Examples 180 to 183)
Analgesic / Anti-inflammatory Activity Model Experimental Model of Pain Experimental model of pain includes response thresholds to high intensity stimuli (acute pain test) and changes in spontaneous or induced behavioral responses in animals with peripheral injury or inflammation ( Test of persistent pain model). Acute thermal pain can be modeled by a hot plate and tail flick test, while persistent pain can be modeled by a formalin test. For all three protocols of these studies, including the preparation of animals (rats or mice), administration of compounds to be tested for analgesic properties, and data collection, see Bannon and Malmberg, “Models of Nocipation: Hot-Plate. , Tail-Flick, and Formalin Tests in
Rodents ", Curr. Protoc. Neurosci. 41: 8.9.1-8.9.16.

(Example 180)
Formalin foot test (delayed phase)
The methods described herein are commonly used to detect analgesic / anti-inflammatory activity and test compounds for pain relief (particularly diabetic or nociceptive neuropathy). See Wheeler-Aceto et al. (1991), Psychopharmacology 104: 35-44.

  Mice are given an intraplantar injection of 5% formalin (25 μl) into the left hind paw. This treatment induces paw licking in control animals. The mice are observed briefly at 1 minute intervals 15-50 minutes after the formalin injection, and the number of occasions where the mouse was observed to lick the paw injected is recorded. There are 10 mice per group, and the test is performed in a “blind” manner.

  The compounds described herein can be administered i. 30 minutes prior to testing (ie, 15 minutes prior to formalin). p. Each dose administered is evaluated at 3 doses and compared to a general vehicle control group. Morphine (8 mg / kg, ip) or gabapentin (100 mg / kg, ip) or venlafaxine (32 mg / kg, ip) administered under the same experimental conditions is used as a reference substance To do. Data are analyzed by comparing treatment groups and vehicle controls using the unpaired Mann-Whitney U test.

  The data recorded for each animal is the time spent licking the affected hind paw over a period of 2 minutes. Take these 2 minute periods at 5 minute intervals and continue for 45 minutes. Plotting the time spent licking against time reveals a characteristic biphasic response. From this plot, the area under the curve (AUC) for each animal during both the acute and inflammatory phases is calculated. AUC for each phase is shown for both control and drug-treated animals. The AUC for each drug-treated animal is compared to the average result from the control group to obtain the average percent of control. A significant decrease in this number indicates a decrease in licking and a decrease in perceived pain.

Vehicle 1 control (0.2% HPMC in saline), gabapentin (100 mg / kg, ip) as reference, and vehicle 2 (5% dimethylacetamide / 50% PEG 400/45% H ₂ O) was used to test some of the compounds described in the formalin paw test at a dose of 250 μmol / kg.

本明細書に記載されているいくつかの化合物は、感知される疼痛の減少を示し、このように疼痛を処置および／または防止（予防）する方法において使用し得る。

Some of the compounds described herein exhibit a perceived decrease in pain and can thus be used in methods of treating and / or preventing (preventing) pain.

(Example 181)
Taxol-induced neuropathy model Peripheral neuropathy is a chronic condition that occurs when nerves are damaged by trauma, disease, metabolic failure, or by certain drugs and toxins. Sensory disturbances associated with chemotherapeutic agents such as paclitaxel (Taxol®) typically range from mild tingling to spontaneous scorching in the periphery (such as hands and feet). Symptoms become stronger with continuous therapy, resulting in weakness, ataxia, numbness and pain, and can limit administration and / or treatment with chemotherapeutic agents.

  Gabapentin (100 mg / kg, IP) can relax the mechanical allodynia seen as a result of Taxol-induced neuropathic pain. Similarly, rats treated with the compounds described herein are believed to show a significant improvement in allodynia when compared to the vehicle control group.

  The test article is administered intraperitoneally at a dose volume of 10 mL / kg body weight. On each day of administration, a new preparation is made.

  The reference article, gabapentin, is formulated in saline to a concentration of 100 mg / mL and delivered under the skin at a dose volume of 1 mL / kg body weight (for a dose concentration of 100 mg / kg). Male Sprague-Dawley rats are used.

  Assignment to treatment group. For inclusion in the study (first part), animals undergo a baseline thermal paw test that is measured prior to Taxol injection. Animals with a thermal paw score greater than 15 seconds are excluded from the study.

  All animals that can be administered Taxol® are tested for thermal hyperalgesia. Animals must have at least a 20% reduction from baseline to be included in the treatment segment of the study. All animals underwent a baseline pre-dose von Frey test (measured before Taxol injection). In order to be included in the study, animals needed to have a baseline von fly score greater than 12.

  All animals receiving Taxol® are tested for mechanical allodynia using von Frey. Animals with a score of 13 or less are assigned to treatment groups. Assess the mechanical allodynia score for each group to ensure that the mean and standard deviation are uniform. Rats are assigned to treatment groups.

  All animals are dosed with Taxol® (2 mg / kg, IP) at a dose volume of 1 mL / kg on days 1, 3, 5, and 7.

  All animals can receive a single intraperitoneal injection of the test compound. All animals can receive an IP injection of vehicle or test compound 30 minutes prior to the mechanical allodynia test. Animals are dosed at a volume of 10 mL / kg.

  Control animals can be given an IP injection of gabapentin 90 minutes prior to the mechanical allodynia test. Animals are dosed at a volume of 1 mL / kg.

  Behavioral testing-adaptation. Twice prior to baseline testing, the animals were acclimatized to mechanical allodynia equipment. This allowed the rat to become accustomed to the test apparatus so that it remained calm during the time of the test.

  Mechanical allodynia (von fried). All animals undergo a von Frey test for mechanical allodynia. On the day of testing, animals are returned to the chamber and allowed to explore around 15 minutes prior to testing. The filament is applied to the left hind paw.

  Group mean results are analyzed using a two-way ANOVA followed by Bonferroni post hoc test against the vehicle control group. Individual groups are tested before and after dosing using paired t-tests.

  Thus, the compounds described herein act near the synapse and treat neuropathic pain without the unwanted side effects normally associated with GABAergic compounds (eg, sedation from benzodiazepines). To be administered. Furthermore, treatment with the compounds described herein is expected to have similar effects.

(Example 182)
Summary of nociceptive tail flick test model. The mouse tail flick assay is a well-recognized model of acute thermal pain, and several clinically relevant opioid analgesics are moderate to complete for measurements involving several different pains. To produce effective. The mouse model also requires a lower amount of drug and is a faster initial screen for antinociceptive activity compared to the chronic pain model. This model of pain is also described in US Patent Application Publication Nos. 2006/0089550 and 2006/0025387.

  Test for antinociception. The effectiveness of the test compound may be assessed using a 52 ° C. hot water tail flick test. The latency to the first sign of rapid tail flick is the behavioral endpoint (Jansen et al., 1963). Each mouse's tail is first tested for baseline latency by immersing it in water and recording the time to response. Mice that do not respond within 5 seconds are excluded from further testing. The mice are then administered test compounds and tested for antinociception at various time points thereafter. Antinociception is calculated by the following formula:% antinociception = 100 × (test latency−control latency) / (10−control latency). The maximum score (100%) is assigned to animals that do not respond within 10 seconds to avoid tissue damage.

  Subject: Male CD-1 (25-35 g, Charles River) mice can be used for all studies. Mice are housed in groups of 5 in a Plexiglas chamber and food and water are freely available. All animals are maintained on a 12 hour light / dark cycle (light on at 7:00 AM) in temperature and humidity controlled animal colonies. Only animals in good health will be adapted to the laboratory conditions and used in the study. The period of adaptation to the animal facility is a minimum of 7 days. All animal experiments can be performed under approved protocols in accordance with institutional guidelines and in accordance with Guide for the Care and Use of Laboratory Animals adopted and published by the National Institutes of Health.

  Drugs and injections. Morphine sulfate (Mallinckrodt, St. Louis, MO) can be dissolved in saline. The injection is performed at a volume of 10 ml / kg body weight using a 1 mL syringe with a 30 gauge needle. Animals are weighed on the morning of the study. Grasp the mouse nape and pinch the tail between the technician's last two fingers and palm. Bend the mouse back slightly and expose the abdomen. A syringe needle is inserted through the skin and abdominal musculature into the peritoneal cavity (shifting the midline slightly). Mice are immediately returned to the holding cage until behavioral testing.

  Total number of animals: Each experimental group may consist of 8 mice and a total of approximately 260 mice are required to complete the proposed study (30 compounds x 1 dose / compound x 8 mice / group plus control).

  Containment: automatically controlled environmental conditions are: laboratory temperature 20-24 ° C, 30-70% relative humidity (RH), 12:12 hours light: dark cycle and 15-30 ventilations / hour Set to maintain. Monitor temperature and RH daily. During acclimatization and for the entire study period, animals are housed in a restricted-access rodent facility, and a group of 5 mice / polypropylene cage (23 × 17 × 14 cm) (with a hard bottom, litter It is held by filling the plank waste as material. Individual cages are suspended in a stainless steel rack system, and each cage has a tube and hood hopper that spills water on itself. Mice have free access to food (Harlan Teklad Global, 2018) and water except during formal drug administration and testing procedures.

  Overall experimental design: On the morning of day 1, mice are labeled and weighed, and then a baseline is obtained for the thermal latency in a 52 ° C. tail flick assay. The test compound is then injected and the mice are rested for thermal latencies at 10, 20, 30, 45, 60, 90, 120 and 180 minutes after injection (drug action is If the group mean falls below 20%, the study is discontinued for that group). All compounds may be dissolved in 0.2% hydroxypropylmethylcellulose (HPMC) in saline to obtain a final concentration of 5-20 mg / ml (pH about 7.4). Tween 80 (1-2 drops) may be added to help solubilize the compound. A similar vehicle is used as a control. Morphine sulfate can be dissolved in physiological saline.

  Evidence for the ability of the compounds described herein to relieve pain is seen as a higher pain threshold than the group that received the vehicle as tested. The results of selected compounds (eg, 4012, 4018, 5009, 5011, 6002, 6008, 6009, 7009, 10001) tested in the tail flick pain model are shown in FIG. An increase in the pain threshold of treated mice indicates that the compounds described herein may be useful as analgesics in the treatment of pain.

(Example 183)
Neuropathic Chung model design. Spinal nerve ligation is performed under isoflurane anesthesia, the animal is placed in the prone position, and the left L4-L6 spinal nerve is accessed. Under magnification, approximately one third of the lateral protrusions are removed. The L5 spinal nerve is identified and carefully cut from the adjacent L4 spinal nerve and then tightly ligated using 6-0 silk suture. The wound is treated with antiseptic solution, the muscle layer is sutured, and the incision is closed with a wound clip. Mechanical paw withdrawal threshold behavioral testing is performed within a period of 3-7 days after incision. Briefly, animals are placed in a Plexiglas chamber (20 × 10.5 × 40.5 cm) and allowed to acclimate for 15 minutes. The chamber is positioned at the top of the mesh screen so that mechanical stimulation can be applied to the plantar surface of both hind legs. Mechanical threshold measurements for each hind paw are obtained using the up / down method with 8 von Frey monofilaments (5 mN, 7 mN, 13 mN, 26 mN, 43 mN, 64 mN, 106 mN, and 202 mN). Each trial begins with a 13 mN von Frey force applied to the right hind paw and then to the left hind paw for approximately 1 second. If there is no withdrawal reaction, give the next stronger force. If there is a response, then give a weaker force. This procedure is performed until no response occurs at the strongest force (202 mN) or until the first response is followed by 4 stimuli. The 50% paw withdrawal threshold for each paw is calculated using the following formula: [Xth] log = [vFr] log + ky. Where [vFr] is the last used von Frey force, k = 0.268, which is the average spacing (in log) between von Frey monofilaments, and y is the pattern of the withdrawal reaction The value depends on. If the animal does not respond to the highest von Frey hair (202 mN), y = 1.00 and the 50% mechanical paw withdrawal response for this paw is calculated to be 340.5 mN. The mechanical paw withdrawal threshold test is performed three times and the 50% withdrawal value is averaged over three trials to determine the average mechanical paw withdrawal threshold for each animal's right and left paw. This model is described in US Patent Application Publication No. 2006/0025387.

(Examples 184 to 186)
Seizure model (Example 184)
Mouse model of medial temporal lobe epilepsy (MTLE). In order to test the anti-seizure properties of the compounds described herein, the compounds can be tested for their ability to deter seizures in the kainic acid model of epilepsy.

  Method. Intrahippocampal injections of kainic acid (1 nmole in 50 nl) are performed in adult mice (eg, C57 / B16) using a stereotaxic technique under general anesthesia. The mice can then be implanted with a bipolar electrode and three cortical monopolar electrodes in the dorsal hippocampus. Four weeks after kainic acid injection, the mice are injected with the test compound (eg twice injections per week). Drug conditions are balanced and animals are used as their own controls. Digital EEG recordings are made on freely moving animals for 20 minutes prior to injection and 20 minutes after 20-40 minutes of injection with freely moving animals. The effect of the injected compound is compared against the reference period. Several compounds described herein were tested in the MTLE model at a dose of at least about 20-75 mg / kg.

  Some compounds described herein reduce the cumulative duration and number of hippocampal firings in this model of medial temporal lobe epilepsy. Accordingly, the compounds described herein can be used in therapeutic methods for treating seizures.

(Example 185)
Epileptiform firing in hippocampal slices During these studies, spontaneous epileptiform activity can be triggered by various treatments. Sprague-Dawley rats (male and female; 25-35 days old) are decapitated, the upper part of the skull is quickly removed and the brain is cooled in ice-cold oxygen-rich slicing medium. The slicing medium used is sucrose consisting of 220 mM sucrose, 3 mM KCl, 1.25 mM NaH ₂ PO ₄ , 2 mM MgSO ₄ , 26 mM NaHCO ₃ , 2 mM CaCl ₂ , and 10 mM dextrose (295-305 mOsm). Is an artificial cerebrospinal fluid (sACSF) based on The brain hemisphere containing the hippocampus is blocked and adhered to the stage of Vibroslicer (Frederick Haer, Brunsick, ME) (cyanoacrylic adhesive). Horizontal or transverse slices (400 μm thick) are cut in slicing medium rich in oxygen (95% O ₂ ; 5% CO ₂ ) at 4 ° C. The slices were then immediately transferred to a holding chamber where 124 mM NaCl, 3 mM KCl, 1.25 mM NaH ₂ PO ₄ , 2 mM MgSO ₄ , 26 mM NaHCO ₃ , 2 mM CaCl ₂ , and 10 mM dextrose (29- Immerse in an immersion medium (ACSF) rich in oxygen consisting of 305 mOsm). Slices can be held at room temperature for at least 45 minutes before being transferred to the immersion recording chamber. In the recording chamber, slices are perfused at 34-35 ° C. with recording medium rich in oxygen. All animal procedures should be performed according to NIH animal care guidelines. In most slice experiments, simultaneous extracellular field electrode recordings are obtained from CA1 and CA3, as described in US Pat. Nos. 6,495,601 and 7,214,711.

  Hippocampal slices treated with test compounds may exhibit less epileptiform activity, which exhibits anti-seizure properties. The compounds described herein treat and / or prevent (prevent) seizures, seizure disorders, epilepsy, epilepsy seizures, and other neurodegenerative disorders (eg, those neurodegenerative disorders that involve seizures). Can be used in the method of

(Example 186)
In vitro hippocampal recording of microinhibitory post-synaptic currents and spontaneous inhibitory post-synaptic currents (mIPSC and sIPSC) Ionic flux in neurons is measured using standard techniques. See Kandel and Schwartz, Principles of Neural Science, 2nd edition (1985), eg, pages 128-131. Recording is performed in vitro in hippocampal slices (CA1 pyramidal cell layer). To record GABA _A- IPSC, glutamatergic and GABA _B transmission is blocked by adding DNOX (50 μM), AP-5 (50 μM), and SCH50911 (20 mM) into the medium. The intracellular fluid contained CsCl and OX314.

Compounds can be tested for their ability to increase GABA _A inhibitory drive, such as a significant increase in spontaneous IPSCs or micro-IPSCs in the hippocampal slice model, which compounds significantly reduce the time between inhibitory events (Eg, an increase in the frequency of events).

  Data showing that the interval between microinhibitory post-synaptic currents and / or spontaneous inhibitory post-synaptic current (mIPSC and sIPSC, respectively) events is substantially reduced in the presence of the compound It shows a very significant increase in frequency. Such data suggests that presynaptic mechanisms increase GABA release from neurons through the action of the compounds described herein.

  Hippocampal slice preparation-young adult male Sprague-Dawley rats weighing 220-250 g in use, housed in groups of four in an air-conditioned room with a 12 hour light / dark cycle, with free access to food and water It was. On the day of the experiment, the animals were anesthetized terminally using isofluorane, the cervical spine was removed, and the head was decapitated. The brain was removed and 300-400 μm thick hippocampal slices were cut using Leica VT1000S.

Electrophysiological recordings—Slices were maintained in artificial cerebrospinal fluid (aCSF) at room temperature for 1 hour after slicing before initiating electrophysiological recordings. After this period, individual slices were transferred to a custom chamber and continuously perfused with aCSF at a rate of 4-10 ml / min with the following composition (mM): NaCl, 127; KCl, 1.9; _{KH 2 PO 4, 1.2; CaCl} 2, 2.4; MgCl 2, 1.3; NaHCO 3, 26; D- glucose, 10; equilibrated with 95% O2-5% CO _2. Whole cell patch clamp recordings were performed from hippocampal cone CA1 neurons at room temperature (17-21 ° C.) using an Axoclamp 700B amplifier using a “visualized” version of the patch clamp method. The patch pipette had a resistance of 3-8 MΩ when filled with an intracellular solution of the following composition (mM): cesium chloride, 150; EGTA-Na; HEPES, 10; Na 2 ATP. All experiments were performed in the presence of tetrodotoxin (TTX, 1 μM), NBQX (10 μM), D-AP-5 (10 μM) and CGP55845 (GABA _B antagonist, 200 nM) to eliminate action potential-dependent synaptic activity, _A GABA _A receptor-dependent synaptic response was isolated.

Test compounds (3034, 6008, 6009, and 7049) were prepared as 5 mM stocks in DMSO and serially diluted to the required concentration in aCSF just prior to use. TTX (1 mM), bicuculline (10 mM), NBQX (10 mM), CGP55845 (10 mM) and AP5 (10 mM) were all obtained from Ascent Scientific and prepared as stock solutions in DMSO or ddH ₂ O as needed. All compounds were stored at −20 ° C. before use. Test compounds were applied cumulatively for a minimum of 10 minutes.

  Analyzes—All analyzes were performed using Excel (Microsoft), Clampfit (MDS Technologies), and Lavasoft software. mIPSC analysis was performed on a 60 s trace using a threshold of about 10 pA and an area of about 150 fC / s for synaptic current.

  Three selected compounds (eg, 3034, 6009, 7049) were tested for in vitro synaptic transmission in adult rat hippocampal neurons. See Figures 10-12. Compounds 3034, 6009 increased mIPSC frequency in a concentration dependent manner. Compounds 3034, 6008, 6009, and 7049 reduced the interval between mIPSC events in a concentration manner. Compounds 3034, 6008, 6009, and 7049 had no effect on mIPSC amplitude. These data show an increase in presynaptic inhibition corresponding to increased mIPSC frequency. The compound did not increase mIPSC amplitude, indicating that the compound does not affect post-synaptic inhibition. Furthermore, this data indicates that these compounds increase GABA inhibitory drive.

  The compounds described herein that act in the vicinity of synapses are high doses (eg, 100 mg / kg) without the undesirable side effects normally associated with GABAergic compounds (eg, sedation from benzodiazepines). Can be administered. The compounds may exhibit anticonvulsant activity and may be useful as therapeutics for treating seizure disorders without these unwanted side effects.

(Example 187)
6 Hz psychomotor test in mice The 6 Hz psychomotor test detects anticonvulsant activity and is described in Brown et al. (1953), J. MoI. Pharmacol. Exp. Ther. 107: 273-283. The mouse is given a rectangular current (eg, 32 mA, rectangular pulse: 0.2 ms pulse width, 3 s period, 6 Hz) via a corneal electrode connected to a constant current shock generator. The results for the number of seizures reflected by forelimb clonus and strobing are recorded for 30 seconds after current administration. Forelimb clonus is scored as absent (0), mild (1) and strong (2), while Stroub tail is rated as absent (0) or present (1).

  The test substance is administered i. 30 minutes before the test. p. Assess at 1 dose administered and compare to vehicle control group. Fifteen mice are studied per group. The study is performed blinded. Diazepam (2 mg / kg, ip) is administered under the same experimental conditions and used as a reference substance. A compound that reduces the number of seizures experienced by a mouse refers to a compound having anticonvulsant activity that may be useful in the treatment of seizures.

(Example 188)
Amphetamine Hyperactivity Test in Mice This method detects antipsychotic and anti-Parkinson disease activity and is described in Costall et al. (1977) Brain Res. 123: 89-111, Boissier and Simon (1965), Arch. Int. Pharmacodyn. 158: 212-221, an activity meter similar to that described by is used.

  Amphetamine induces hyperactivity in this test state. Hyperactivity is antagonized by classical and atypical antipsychotics that act on the dopaminergic system at the limbic level and is enhanced by antiparkinsonian drugs. Mice are injected with d-2014 mphetamine (3 mg / kg, ip) and immediately placed in an activity meter. The activity meter may consist of 24 covered Plexiglas cages (20.5 × 10.5 × 18 cm) contained in a dark cabinet and connected to a silent electronic counter. In order to measure the number of movements of each animal (one per cage) in the horizontal plane, each cage is equipped with four photocell assemblies (two at each end of the cage) 2.5 cm above the floor. It was. Seven additional photocell assemblies are placed evenly spaced 9.5 cm above the floor along the long wall and the rise is recorded. The number of (horizontal) crossings by each animal (one per cage) from one photocell to the other is recorded by a computer for 30 minutes at 10 minute intervals. A similar procedure is used for start-up recording, except for recording individual photo beam breaks. Scores for activity and rise are recorded by the computer over a 10 minute interval and accumulated over a 30 minute period. Ten mice were studied per group. The test was performed in a blinded manner.

  Each compound was i.p. 30 minutes prior to amphetamine. p. Evaluated at a dose of 50 mg / Kg administered and compared to the vehicle control group. The experiment can also include a control group that is not treated with amphetamine. Haloperidol (0.25 mg / kg, ip) can be administered under the same experimental conditions as the reference substance. The experiment can include 9 groups.

本明細書に記載されている選択された化合物を、アンフェタミンによって誘発される多動試験において試験し、横断の数および立ち上がりの数の減少を示す。したがって、本明細書に記載されている化合物は、抗精神病および抗パーキンソン病活性を示し、不安障害、ＡＤＨＤ、およびパーキンソン病、ならびに運動緩慢が関与する他の運動障害（ハンチントン病など）の処置において有用であり得る。

Selected compounds described herein are tested in the hyperactivity test induced by amphetamine and show a decrease in the number of crossings and rises. Accordingly, the compounds described herein exhibit antipsychotic and anti-Parkinson disease activity and in the treatment of anxiety disorders, ADHD, and Parkinson's disease, and other movement disorders that involve slow movement (such as Huntington's disease). Can be useful.

(Example 189)
Animal model of amphetamine sensitization (addiction). The usefulness of compound therapy in the treatment of behavioral disorders can be examined by measuring the compound's ability to reverse the symptoms of amphetamine sensitization in rats.

  Method. Amphetamine sensitization is induced in animals. Following sensitization, rats are divided into two equal groups. One group is given treatment with compounds and the other half is given vehicle. All rats may then be given a challenge injection of amphetamine. Monitor open field motor activity. If the compound reduces or blocks amphetamine sensitization, the group that received the compound prior to amphetamine challenge shows a shorter distance and less total rise.

  Following 3 days of handling, animals are given an intraperitoneal (ip) injection of 1.5 mg / kg amphetamine hydrochloride (injection volume 1.0 ml / kg) daily for 5 days (amphetamine-amphetamine). group). Amphetamine can be freshly diluted with daily breakfast saline (0.9%) (injection between 10:00 and 12:00). A 48-hour withdrawal is performed after the fifth day of treatment with amphetamine. Following 48 hours withdrawal, 8 rats are given compound injections (iv) and 8 are given vehicle injections (iv). Rats are then given an amphetamine challenge injection (1.5 mg / kg) and monitored for locomotor activity in the open field. All injections except challenge injections are administered in the rat's home cage.

  Following amphetamine loading, locomotor activity is measured for 120 minutes in the open field. The total distance moved and the number of rises are automatically recorded and compared between groups using a one-way analysis of variance. This model is described in US Patent Application Publication No. 2006/0025387.

  Although the invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Modifications of the above described modes for carrying out the invention which are obvious to those skilled in medicine, pharmacology, microbiology, and / or related fields are intended to be within the scope of the following claims .

  All published materials (eg, non-patent literature), patent application publications, and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention belongs. All such published materials (eg, non-patent literature), patent application publications, and patent applications are specifically and individually incorporated by reference with each individual published material, patent, patent application publication, or patent application. Are incorporated herein by reference to the same extent.

Claims (43)

Compounds of formula I

Or a pharmaceutically acceptable salt thereof, wherein
Z is oxygen or nitrogen;
R ₁ and R ₂ are each independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or R ₁ and R ₂ are the atoms to which they are attached. Together, they form a 4-7 membered heterocyclic ring that can have one or more additional heteroatoms and can have one or more substituents, provided that Z is oxygen In some cases, R ₂ is not present,
R ₃ and R ₄ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or R ₃ and R ₄ are bonded to each other. Together with the atoms to form a 4- to 7-membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents,
R ₅ is alkoxy, halo, aryl, aryloxy, alkaryloxy, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio;
R ₆ and R ₇ are each independently hydrogen, acyl, alkyl, cycloalkylalkyl, aryl or arylalkyl, or R ₆ and R ₇ together with the atoms to which they are attached, Forming a 4 to 7 membered heterocyclic ring which may have one or more additional heteroatoms and may have one or more substituents). The compound of claim 1, wherein Z is nitrogen and R ₅ is aryloxy. The compound of claim 2, wherein R ₆ and R ₇ are hydrogen. The compound of claim 1, wherein Z is oxygen and R ₁ is hydrogen. The compound according to claim 4, wherein R ₆ and R ₇ are hydrogen. _5. A compound according to claim 4, wherein R5 is aryloxy or halo. The compound of claim 1, wherein neither R ₃ nor R ₄ is hydrogen. R ₄ is alkyl, preferably n- butyl, compound according to any one of claims 2 6. Compound of formula II

Or a pharmaceutically acceptable salt thereof, wherein
Z is oxygen or nitrogen;
R ₁ and R ₂ are each independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or R ₁ and R ₂ are the atoms to which they are attached. Together, they form a 4-7 membered heterocyclic ring that can have one or more additional heteroatoms and can have one or more substituents, provided that Z is oxygen In some cases, R ₂ is not present,
R ₃ and R ₄ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or R ₃ and R ₄ are bonded to each other. Together with the atoms to form a 4- to 7-membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents,
R ₅ is halo, aryl, aryloxy, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio;
R ₆ and R ₇ are each independently hydrogen, acyl, alkyl, cycloalkylalkyl, aryl or arylalkyl, or R ₆ and R ₇ together with the atoms to which they are attached, Forming a 4 to 7 membered heterocyclic ring which may have one or more additional heteroatoms and may have one or more substituents). Compound of formula III

Or a pharmaceutically acceptable salt thereof, wherein
Z is oxygen or nitrogen;
R ₁ and R ₂ are each independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or R ₁ and R ₂ are the atoms to which they are attached. Together, they form a 4-7 membered heterocyclic ring that can have one or more additional heteroatoms and can have one or more substituents, provided that Z is oxygen In some cases, R ₂ is not present,
R ₃ and R ₄ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or R ₃ and R ₄ are bonded to each other. Together with the atoms to form a 4- to 7-membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents,
R ₅ is alkoxy, halo, aryl, aryloxy, alkaryloxy, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio;
R ₆ and R ₇ are each independently hydrogen, acyl, alkyl, cycloalkylalkyl, aryl or arylalkyl, or R ₆ and R ₇ together with the atoms to which they are attached, Forming a 4-7 membered heterocycle, which may have one or more additional heteroatoms and may have one or more substituents;
R ₈ and R ₉ are each independently hydrogen, alkyl, or R ₈ and R ₉ together with the atoms to which they are attached, are 3 to 6 membered substituted or unsubstituted cyclo Forming an alkyl ring or a heterocycloalkyl ring). Compound of formula IV

Or a pharmaceutically acceptable salt thereof, wherein
Z is oxygen or nitrogen;
R ₁ and R ₂ are each independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or R ₁ and R ₂ are the atoms to which they are attached. Together, they form a 4-7 membered heterocyclic ring that can have one or more additional heteroatoms and can have one or more substituents, provided that Z is oxygen In some cases, R ₂ is not present,
R ₃ and R ₄ are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or R ₃ and R ₄ are bonded to each other. Together with the atoms to form a 4- to 7-membered heterocycle that can have one or more additional heteroatoms and can have one or more substituents,
R ₅ is alkoxy, halo, aryl, aryloxy, alkaryloxy, arylamino, heteroarylamino, heterocycloalkyl, heteroaryl, heteroaryloxy, heterocycloalkoxy, or alkylthio;
R ₆ and R ₇ are each independently hydrogen, acyl, alkyl, cycloalkylalkyl, aryl or arylalkyl, or R ₆ and R ₇ together with the atoms to which they are attached, Forming a 4-7 membered heterocycle, which may have one or more additional heteroatoms and may have one or more substituents;
R ₈ and R ₉ are each independently hydrogen, alkyl, or R ₈ and R ₉ together with the atoms to which they are attached, are 3 to 6 membered substituted or unsubstituted cyclo Forming an alkyl ring or a heterocycloalkyl ring).   A pharmaceutical composition comprising the compound according to any one of claims 1 to 11.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable additive.   12. A method of treating a condition involving NKCC comprising administering an effective amount of a composition comprising a compound according to any one of claims 1-11.   The condition is addictive disorder, Alzheimer's disease, anxiety disorder, ascites, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar disorder, cancer, cognitive improvement, cognitive function Disorder, cognitive dysfunction, depression, corneal endothelial dystrophy, edema, epilepsy, glaucoma, Huntington's disease, inflammatory pain, insomnia, ischemia, migraine, migraine with aura, migraine without aura, neuropathic Pain, nociceptive neuralgia, nociceptive pain, eye disease, pain, Parkinson's disease, periodic limb movement disorder (PLMD), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, 15. The method of claim 14, wherein the method is selected from the group consisting of seizure disorder, spasticity, tinnitus, and withdrawal syndrome. Wherein the compound is bumetanide sensitive basolateral ^Na + ^K + Cl ^- inhibit cotransporter the (NKCC1) preferentially method of claim 14.   The method according to claim 16, wherein the inhibition of NKCC2 is 50% or less, preferably 25% or less, more preferably 15% or less of the action on NKCC1.   15. The method of claim 14, wherein the compound has increased lipophilicity as compared to a loop diuretic selected from the group consisting of bumetanide, furosemide, piretanide, azosemide, and torsemide.   The method of claim 18, wherein the lipophilicity is measured by a partition coefficient. 12. _A method of treating a condition involving GABA _A receptor comprising administering an effective amount of a composition comprising a compound according to any one of claims 1-11.   The condition is addictive disorder, Alzheimer's disease, anxiety disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar disorder, cognitive improvement, cognitive dysfunction, cognitive dysfunction , Depression, epilepsy, Huntington's disease, inflammatory pain, insomnia, migraine, migraine with aura, migraine without aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, pain, Parkinson's disease Selected from the group consisting of: periodic limb movement disorder (PLMD), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, seizure disorder, spasticity, tinnitus, and withdrawal syndrome. The method of claim 20.   21. The method of claim 20, wherein the compound has a reduced diuretic effect as compared to a loop diuretic selected from the group consisting of bumetanide, furosemide, piretanide, azosemide, and torsemide. Compound is an antagonist to GABA _A receptor comprising the alpha ₄ subunit The method of claim 20. The antagonism of GABA _A receptor comprising α ₁ subunit is 50% or less, preferably 25% or less, more preferably 15% or less of the effect on GABA _A receptor comprising α ₄ subunit. The method described in 1. The effective concentration (EC ₅₀ ) of said compound for GABA _A receptor comprising α ₄ subunit is 50% or less, preferably 25% or less of EC ₅₀ of the same compound for GABA _A receptor comprising α ₁ subunit, more 21. The method of claim 20, preferably 15% or less. Compound is an antagonist to GABA _A receptors, including alpha ₅ subunit The method of claim 20. The antagonism of a GABA _A receptor comprising an α ₁ subunit is 50% or less, preferably 25% or less, more preferably 15% or less of the effect on a GABA _A receptor comprising an α ₅ subunit. The method described in 1. The effective concentration (EC ₅₀ ) of said compound for GABA _A receptor comprising α ₅ subunit is 50% or less, preferably 25% or less of EC ₅₀ of the same compound for GABA _A receptor comprising α ₁ subunit, more 21. The method of claim 20, preferably 15% or less. Compound is an antagonist to GABA _A receptors, including alpha ₆ subunit The method of claim 20. The antagonism of GABA _A receptor comprising α ₁ subunit is not more than 50%, preferably not more than 25%, more preferably not more than 15% of the action on GABA _A receptor comprising α ₆ subunit. The method described in 1. The effective concentration (EC ₅₀ ) of said compound for GABA _A receptor comprising α ₆ subunit is 50% or less, preferably 25% or less of EC ₅₀ of the same compound for GABA _A receptor comprising α ₁ subunit, more 21. The method of claim 20, preferably 15% or less.   12. A composition for treating a condition involving NKCC comprising administering an effective amount of a composition comprising a compound according to any one of claims 1-11.   The condition is addictive disorder, Alzheimer's disease, anxiety disorder, ascites, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar disorder, cancer, cognitive improvement, cognitive function Disorder, cognitive dysfunction, depression, corneal endothelial dystrophy, edema, epilepsy, glaucoma, Huntington's disease, inflammatory pain, insomnia, ischemia, migraine, migraine with aura, migraine without aura, neuropathic Pain, nociceptive neuralgia, nociceptive pain, eye disease, pain, Parkinson's disease, periodic limb movement disorder (PLMD), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, 33. The composition of claim 32, selected from the group consisting of seizure disorder, spasticity, tinnitus, and withdrawal syndrome. _A composition for treating a condition involving GABA _A receptor, comprising administering an effective amount of a composition comprising a compound according to any one of claims 1 to 11.   The condition is addictive disorder, Alzheimer's disease, anxiety disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar disorder, cognitive improvement, cognitive dysfunction, cognitive dysfunction , Depression, epilepsy, Huntington's disease, inflammatory pain, insomnia, migraine, migraine with aura, migraine without aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, pain, Parkinson's disease Selected from the group consisting of: periodic limb movement disorder (PLMD), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, seizure disorder, spasticity, tinnitus, and withdrawal syndrome. 35. The composition of claim 34.   Use of a compound of formula I, II, III or IV for the manufacture of a medicament for treating a condition involving NKCC comprising administering a composition comprising an effective amount of a.   The condition is addictive disorder, Alzheimer's disease, anxiety disorder, ascites, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar disorder, cancer, cognitive improvement, cognitive function Disorder, cognitive dysfunction, depression, corneal endothelial dystrophy, edema, epilepsy, glaucoma, Huntington's disease, inflammatory pain, insomnia, ischemia, migraine, migraine with aura, migraine without aura, neuropathic Pain, nociceptive neuralgia, nociceptive pain, eye disease, pain, Parkinson's disease, periodic limb movement disorder (PLMD), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, 37. Use according to claim 36, selected from the group consisting of paroxysmal disorder, spasticity, tinnitus, and withdrawal syndrome. Formula I, II, III or for the manufacture of a medicament for treating a condition involving GABA _A receptor comprising administering an effective amount of a composition comprising a compound of Formula I, II, III or IV Use of compounds of IV.   The condition is addictive disorder, Alzheimer's disease, anxiety disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (autism), bipolar disorder, cognitive improvement, cognitive dysfunction, cognitive dysfunction , Depression, epilepsy, Huntington's disease, inflammatory pain, insomnia, migraine, migraine with aura, migraine without aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, pain, Parkinson's disease Selected from the group consisting of: periodic limb movement disorder (PLMD), personality disorder, postherpetic neuralgia, psychosis, restless leg syndrome (RLS), schizophrenia, seizure disorder, spasticity, tinnitus, and withdrawal syndrome. 40. Use according to claim 38.   12. A method for improving cognition comprising administering an effective amount of a composition comprising a compound according to any one of claims 1-11.   12. A method of treating cognitive dysfunction comprising administering an effective amount of a composition comprising a compound according to any one of claims 1-11.   A composition for improving cognition, comprising an effective amount of a compound according to any one of claims 1-11.   A composition for treating cognitive impairment comprising an effective amount of a compound according to any one of claims 1-11.

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