KR20220103707A - Compositions that preferentially potentiate subtypes of GABAA receptors and methods of use thereof - Google Patents

Abstract

The present invention provides compositions containing neurosteroids in isomerically pure form which allow for preferential modulation of different subtypes of GABA _A receptors, such as preferential modulation of α4β3δ GABA _A receptors over α1β2γ2 GABA _A receptors. The present invention also provides methods of treating GABA _A disorders using such compositions.

Description

Compositions that preferentially potentiate subtypes of GABAA receptors and methods of use thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 62/907,763, filed on September 30, 2019, the contents of which are incorporated by reference.

field of invention

The present invention relates generally to compositions containing neurosteroids and methods of using the same to treat GABA _A disorders in a subject.

According to the World Health Organization (WHO), neurological disorders affect up to 1 billion people worldwide. Neurological disorders include a wide range of conditions, such as Alzheimer's disease, brain damage, epilepsy, headache, infection, multiple sclerosis, Parkinson's disease, and stroke. Many neurological disorders result from altered signaling by receptors for the neurotransmitter γ-aminobutyric acid (GABA). The GABA _A receptor is a pentameric transmembrane receptor comprising various combinations of 19 different subunit polypeptides. At least 15 GABA _A receptor subtypes are known, and certain subtypes are associated with different conditions. For example, altered activity of receptor subtypes comprising α ₂ or α ₃ subunits is associated with anxiety disorders, while α ₅ -containing subtypes appear to play a role in memory and cognition.

Neuroactive steroids that alter the activity of GABA _A receptors have been investigated as drug candidates for various neurological disorders. However, the therapeutic potential of these molecules remains largely unexplored. One reason for the shortage is the large number of chemical modifications that can be made from the steroid structural core, making it difficult to know whether the compound currently under investigation has better pharmacological properties than other molecules that have not yet been prepared or analyzed. that it is because Another problem is that the structural similarity of the different GABA _A receptor subtypes makes it challenging to identify molecules with the desired subtype specificity. As a result, millions of people continue to suffer from neurological conditions due to the limited arsenal of neuroactive steroids we can currently handle.

The present invention provides compositions containing an isomerically pure form of a selected neurosteroid. The present invention recognizes that the interaction between a neurosteroid and the GABA _A receptor is highly sensitive to the stereochemical structure of the neurosteroid and that certain neurosteroids exhibit strong GABA _A receptor subtype specificity when provided in a composition that is substantially free of isomeric contaminants. do. Because the compositions of the present invention selectively target specific GABA _A receptor subtypes, they have greatly improved pharmacological efficacy over previous compositions, including those containing biologically active compounds contaminated with less active isomers.

In certain embodiments, the present invention provides a composition containing an isomerically pure form of a compound of formula (I):

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The present invention includes the discovery that the isomerically pure composition of formula (I) is significantly more active on the α4β3δ GABA _A receptor than on the α1β2γ2 GABA _A receptor. As described herein, such compositions modulate the activity of the α4β3δ receptor with an EC ₅₀ that is at least 5-fold lower than that of the α1β2γ2 receptor. Without wishing to be bound by any particular theory, it is believed that the stereochemical configuration at both the chiral centers of the molecule and the pattern of atomic binding within the molecule are important in conferring GABA _A receptor subtype selectivity. Thus, mixtures containing a compound of formula (I) together with an isomer thereof, such as a regioisomer of formula (I) or a stereoisomer that differs structurally from formula (I) at only a single chiral center, lacks this selectivity. Because compositions containing the isomerically pure form of the compound of formula (I) preferentially target the α4β3δ GABA _A receptor, they are useful in therapeutic applications where altering the activity of this receptor is beneficial.

In one aspect, the present invention provides a pharmaceutical composition containing an isomerically pure form of a compound of formula (I):

wherein the compound of formula (I) is present in a therapeutically effective amount to preferentially potentiate the α4β3δ GABA _A receptor compared to the α1β2γ2 GABA _A receptor.

In another aspect, the present invention provides a method of treating a GABA _A disorder by providing to a subject a pharmaceutical composition comprising an isomerically pure form of a compound of formula (I):

wherein the compound of formula (I) is present in a therapeutically effective amount to preferentially potentiate the α4β3δ GABA _A receptor compared to the α1β2γ2 GABA _A receptor.

The composition may be chemically pure, ie, free of other molecules or chemical species. For example, different molecules or chemical species may have distinct formulas, structural formulas, empirical formulas, molecular formulas, or condensation formulas. The composition may have a defined level of chemical purity. For example, the compound of formula (I) may comprise at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight.

The composition may be isomerically pure to all isomers. A composition may be isomerically pure with respect to one or more specific types of isomers. The composition may be substantially free of structural isomers or specific types of structural isomers, such as regioisomers. A composition may be substantially free of stereoisomers or stereoisomers of a particular type, such as enantiomers or diastereomers.

The composition may contain the compound of formula (I) at any level of isomeric purity to achieve preferential modulation of the α4β3δ GABA _A receptor compared to the α1β2γ2 GABA _A receptor. For example, the compound of formula (I) may comprise at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, at least 99 wt% of the total amount of isomeric molecules comprising the compound of formula (I) and isomers thereof. % by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight.

The composition may contain a compound of formula (I) and may be substantially free of stereoisomers. Stereoisomers may differ from formula (I) at 1, 2, 3, 4, 5, 6, 7 or 8 chiral centers. Stereoisomers may be diastereomers or enantiomers. For example, a stereoisomer may be a compound of formula (II) or (III):

.

.

The composition comprises one or more stereoisomers of a compound of formula (I), such as a compound of formula (II) or (III), less than 5%, less than 4% of the total of the compound of formula (I) and one or more stereoisomers thereof. , less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.1%. The composition comprises a compound of formula (I) and one or more stereoisomers thereof at least 19:1, 20:1, 25:1, 30:1, 40:1, 50:1, 100:1, 200:1, 500 :1, or in a ratio of 1000:1.

The compounds may potentiate GABA _A receptors, GABA _A receptor subtypes, or a subset of GABA _A receptor subtypes by any mechanism. The compounds may potentiate GABA _A receptors, subtypes, or subsets by allosteric modulation, activation, or inhibition. Allosteric adjustment can be positive or negative.

The composition may preferentially potentiate the α4β3δ GABA _A receptor to any extent compared to the α1β2γ2 GABA _A receptor. The composition may preferentially potentiate the α4β3δ GABA _A receptor compared to the α1β2γ2 GABA _A receptor by any measure or parameter.

The composition may have an EC ₅₀ for the α4β3δ GABA _A receptor that is lower than the EC ₅₀ for the α1β2γ2 GABA _A receptor. The EC ₅₀ for the α4β3δ GABA _A receptor is about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 10 times, about the EC ₅₀ for the α1β2γ2 GABA _A receptors. It may be as low as about 20 times, about 50 times, about 100 times, about 200 times, about 500 times, or about 1000 times. The EC ₅₀ for the α4β3δ GABA _A receptor is less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, about 10 of the EC ₅₀ for the α1β2γ2 GABA _A receptor. %, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1%.

The composition may have a binding affinity for the α4β3δ GABA _A receptor (which can be expressed, for example, as the dissociation constant K _D ) that is lower than the binding affinity for the α1β2γ2 GABA _A receptor. The binding affinity for the α4β3δ GABA _A receptor is about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 10 times that of the binding affinity for the α1β2γ2 GABA _A receptors. It can be as low as a fold, about 20 times, about 50 times, about 100 times, about 200 times, about 500 times, or about 1000 times. The binding affinity for the α4β3δ GABA _A receptor is less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15% of the binding affinity for the α1β2γ2 GABA _A receptor; less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1%.

The composition may have an EC ₅₀ for the α4β3δ GABA _A receptor that is less than a defined value. The composition is less than about 1 μM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, about 5 nM have an EC ₅₀ for the α4β3δ GABA _A receptor that is less than, less than about 2.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, or less than about 0.1 nM.

The composition may have a binding affinity for the α4β3δ GABA _A receptor that is less than a defined value. The composition is less than about 1 μM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, about 5 nM have a binding affinity for the α4β3δ GABA _A receptor that is less than, less than about 2.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, or less than about 0.1 nM.

The composition may be effective for the treatment of a GABA _A disorder. A GABA _A disorder may be any disease, disorder, or condition associated with altered GABA _A receptor function or any disorder may be a disease, disorder, or condition that may be ameliorated by altered GABA _A receptor function. GABA _A disorders include acute pain, addiction disorder, Alzheimer's disease, Angelman's syndrome, antisocial personality disorder, anxiety disorder, attention deficit hyperactivity disorder (ADHD), attention disorder, deafness, autism, autism spectrum disorder, bipolar disorder. Disorders, chronic pain, cognitive impairment, obsessive-compulsive disorder, convulsive disorder, dementia, depression, dysthymia, epileptic disorder, essential tremor, epileptic mechanism, fragile X syndrome, generalized anxiety disorder (GAD), Huntington's disease, injury-related pain syndrome , insomnia, ischemia, Lewy body dementia, memory impairment, migraine, mood disorders, movement disorders, neurodegenerative disorders, neuropathic pain, obsessive compulsive disorder, pain, panic disorder, Parkinson's disease, personality disorder, post-traumatic stress disorder (PTSD) ), psychosis, Rett syndrome, schizoaffective disorder, schizophrenia, schizophrenia spectrum disorder, seizure disorder, sleep disorder, social anxiety disorder, status epilepticus, stress, stroke, tinnitus, traumatic brain injury (TBI), vascular disease, vascular malformation, vascular dementia movement disorder, Wilson's disease, or withdrawal syndrome.

The composition may be formulated for administration by a particular mechanism. The compositions may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical nasal, or pulmonary administration. The composition may be formulated for administration by injection or on an implantable medical device (eg, a stent or drug-eluting stent or balloon equivalent).

The composition may be formulated as a single daily dose. The composition may be formulated for multiple daily doses, eg, 2, 3, 4, 5, 6 or more daily doses.

The composition may be provided to a subject according to any dosing schedule. The composition may be given once a day. The composition may be given multiple times per day. The composition may be given twice, three times, four times, five times, six times or more per day.

The present invention provides compositions containing neurosteroids in isomerically pure form and methods of treating neurological and other disorders using such compositions. The present invention is based on the recognition that isomerically pure neurosteroids allow modulation of specific subtypes of the γ-aminobutyric acid (GABA) receptor. Because the compositions allow for selective modulation of subtypes of GABA receptors, they are useful for treating conditions in which alteration of such receptor subtypes provides a therapeutic benefit.

Justice

Definitions and chemical terms of specific functional groups are described in more detail below. Chemical elements are identified according to Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described in the literature. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989]; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

As used herein, a "pure isomer" compound or "isomerically pure" compound is substantially free of other isomers of the compound. The term "pure isomer" compound or "isomerically pure" means at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% by weight of the compound having the specified structure. % by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight. In certain embodiments, the weight is based on the total weight of all isomers of the compound.

As used herein, a “pure stereoisomeric” compound or a “stereomerically pure” compound is substantially free of other stereoisomers of the compound. Thus, the composition is substantially free of isomers that differ at any chiral center. When a compound has multiple chiral centers, a substantial majority of the composition contains a compound with the same stereochemistry at all of the chiral centers. The term "pure stereoisomeric" compound or "stereomerically pure" means at least 95%, at least 96%, at least 97%, at least 98%, at least 99% by weight of the compound having the specified stereochemistry. , at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight. In certain embodiments, the weight is based on the total weight of all stereoisomers of the compound.

As used herein, a pure enantiomer compound is substantially free (ie, in enantiomeric excess) of the other enantiomers or stereoisomers of the compound. In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and thus is an enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% by weight of the enantiomers, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

The compounds described herein may also include one or more isotopic substitutions. For example, H can be in any isotopic form, including ¹ H, ² H (D or deuterium), and ³ H (T or tritium); C can be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; N can be in any isotopic form, including ¹⁴ N and ¹⁵ N; O can be in any isotopic form, including ¹⁶ O and ¹⁸ O, and the like.

The article “a” may be used herein to refer to one or more than one (ie, at least one) of the grammatical objects of the article. For example, "analog" means one analog or more than one analog.

As used herein, the terms “modulation” and “enhancement” refer to inhibition or stimulation of GABA receptor function. A “modulator” or “potentiator” can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of a GABA receptor. A “modulator” or “potentiator” may act at the active site or the allosteric site of the GABA receptor. It may promote or inhibit ligand binding. It may promote or attenuate ligand-mediated, for example, GABA-mediated-signaling.

"Pharmaceutically acceptable" means that which has been approved or may be approved by a federal or state regulatory agency or an equivalent body outside the United States, or is recognized in the United States Pharmacopeia or other generally recognized for use in animals, and more particularly in humans. means listed in the pharmacopoeia.

“Pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts may be non-toxic inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid , cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor Sulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid , acid addition salts formed with hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or salts formed when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N methylglucamine, and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; When the compound contains a basic functional group, it includes salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations and the like. See, eg, Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79].

A “solvate” refers to a form of a compound that is associated with a solvent or water (also referred to as a “hydrate”), usually by a solvolysis reaction. This physical association involves hydrogen bonding. Typical solvents include water, ethanol, acetic acid and the like. The compounds of the present invention may be prepared, for example, in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. “Solvate” includes both solution phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

As used herein, the term “isotopic variant” refers to a compound that contains an unnatural proportion of isotopes at one or more of the atoms that make up such compounds. For example, an "isotopic variant" of a compound may contain one or more non-radioactive isotopes, such as, for example, deuterium ( ² H or D), carbon-13 ( ¹³ C), nitrogen-15 ( ¹⁵ N), and the like. can In compounds with such isotopic substitutions, the following atoms, if present, may vary, such that for example any hydrogen may be ² H/D, any carbon may be ¹³ C, or any nitrogen may be ¹⁵ N, and it will be understood that the presence and configuration of such atoms can be determined within the skill of the art. Likewise, the present invention may include the preparation of isotopic variants with radioactive isotopes, for example, where the resulting compound can be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and easy means of detection. Additionally, compounds substituted with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N can be prepared and will be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. . All isotopic variants of the compounds provided herein, whether radioactive or not, are intended to be included within the scope of this invention.

"Stereoisomers": Compounds that have the same molecular formula but differ in the bonding properties or order of their atoms or the arrangement of their atoms in space are to be understood as termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers", and those that are non-superimposable mirror images of one another are termed "enantiomers". For example, if a compound has an asymmetric center and an atom, such as a carbon atom, is bonded to four different groups, a pair of enantiomers are possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog or in which the molecule rotates the plane of polarization and is designated as a right or left rotation. are described by the way (ie (+) or (-)-isomers, respectively). Chiral compounds may exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture".

"Tautomers" refer to compounds which are interchangeable forms of the structure of a particular compound and which vary in the displacement of hydrogen atoms and electrons. Thus, the two structures can be in equilibrium through the transfer of n electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by acid or base treatment. Another example of tautomerism is the acid- and nitro-forms of phenylnitromethane, which are likewise formed by acid or base treatment. Tautomeric forms can be associated with the attainment of optimal chemical reactivity and biological activity of a compound of interest.

A "subject" contemplated for administration is a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged) adults or geriatric adults)) and/or non-human animals, such as mammals such as primates (eg cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and/or or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat”, “treating” and “treatment” refer to reducing the severity of, or delaying the progression of, a disease, disorder or condition. It contemplates actions that occur while a subject is afflicted with a specified disease, disorder or condition (“therapeutic treatment”), which causes or delays, and also takes action that occurs before the subject begins to suffer from a specified disease, disorder or condition ( "prophylactic treatment").

In general, an “effective amount” of a compound refers to an amount sufficient to treat the desired biological response, eg, to induce anesthesia or sedation, to treat a CNS-related disorder. As will be understood by one of ordinary skill in the art, an effective amount of a compound of the present invention will depend on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, the age, weight, health, and condition of the subject. may vary depending on An effective amount includes both therapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or delay or minimize one or more symptoms associated therewith. to be. A therapeutically effective amount of a compound means that amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term “therapeutically effective amount” may include an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. it is sheep A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term “prophylactically effective amount” may include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

composition

compound

The present invention provides a composition having a neurosteroid in an isomerically pure form.

In certain embodiments, the present invention provides pharmaceutical compositions containing an isomerically pure form of a compound of formula (I):

.

.

The composition may be chemically pure, ie, free of other molecules or chemical species. For example, different molecules or chemical species may have distinct formulas, structural formulas, empirical formulas, molecular formulas, or condensed formulas. The composition may have a defined level of chemical purity. For example, the compound of formula (I) may comprise at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight.

The composition may contain the compound of formula (I) at any level of isomeric purity, ie the composition may contain the compound of formula (I) at a level associated with the isomeric form of the compound. For example, the compound of formula (I) may comprise at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, at least 99 wt% of the total amount of isomeric molecules comprising the compound of formula (I) and isomers thereof. % by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight.

The composition may be isomerically pure to all isomers. A composition may be isomerically pure with respect to one or more specific types of isomers. The composition may be substantially free of structural isomers or specific types of structural isomers, such as regioisomers. A composition may be substantially free of stereoisomers or stereoisomers of a particular type, such as enantiomers or diastereomers.

The composition may contain the compound of formula (I) at any level of isomeric purity to achieve preferential modulation of the α4β3δ GABA _A receptor compared to the α1β2γ2 GABA _A receptor. For example, the compound of formula (I) may comprise at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, at least 99 wt% of the total amount of isomeric molecules comprising the compound of formula (I) and isomers thereof. % by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight,

The composition may contain a compound of formula (I) and may be substantially free of stereoisomers. Stereoisomers may differ from formula (I) at 1, 2, 3, 4, 5, 6, 7 or 8 chiral centers. Stereoisomers may be diastereomers or enantiomers. For example, a stereoisomer may be a compound of formula (II) or (III):

.

.

The composition comprises less than 5%, less than 4% of a compound of formula (I), such as one or more stereoisomers of a compound of formula (II) or (III), of the total of the compound of formula (I) and one or more stereoisomers thereof. , less than 3%, less than 2 % , less than 1%, less than 0.5%, or less than 0.1%. The composition comprises a compound of formula (I) and one or more stereoisomers thereof at least 19:1, 20:1, 25:1, 30:1, 40:1, 50:1, 100:1, 200:1, 500 :1, or in a ratio of 1000:1.

formulation

The present invention provides pharmaceutical compositions containing one or more of the compounds described above. Pharmaceutical compositions containing the compounds may be in a form suitable for oral use, for example, tablets, troches, lozenges, fast dissolving, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. can Compositions for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, which compositions may contain sweetening, flavoring, coloring and preservative agents, in order to provide a pharmaceutically orderly and palatable preparation. It may contain one or more agents selected from Tablets contain the compound in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binders, for example starch, gelatin or acacia, and lubricants, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption down the gastrointestinal tract, thereby providing a sustained action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. These also include US Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. The preparation and administration of the compounds are discussed in US Pat. No. 6,214,841 and US Publication No. 2003/0232877, the contents of which are incorporated herein by reference.

Formulations for oral use may also be prepared as hard gelatin capsules in which the compound is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the compound is mixed in water or an oil medium, such as peanut oil, liquid paraffin or olive oil. It may be provided as a soft gelatin capsule mixed with

An alternative oral formulation in which control of the gastrointestinal hydrolysis of a compound is sought can be achieved using a controlled-release formulation, wherein the compound of the present invention is encapsulated in an enteric coating.

Aqueous suspensions may contain the compounds in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols. For example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbate It is bitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. can

Oily suspensions may be formulated by suspending the compound in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for preparing aqueous suspensions by addition of water provide the compound in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring and coloring agents may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers include natural gums, such as gum acacia or gum tragacanth, natural phosphatides, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monoole ates and condensation products of ethylene oxide with said partial esters, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain emollients, preservatives, flavoring and/or coloring agents. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques using such suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend of fixed oils may be employed for this purpose, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

In certain embodiments, the formulation is not a sustained release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation does not contain particles having a D50 (volume weighted median diameter) of less than 10 microns. In certain embodiments, the formulation does not contain a polymeric surface stabilizer. In certain embodiments, the formulation is not an aqueous suspension.

The composition may be formulated for administration by a particular mechanism. The compositions may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical nasal, or pulmonary administration. The composition may be formulated for administration by injection or on an implantable medical device (eg, a stent or drug-eluting stent or balloon equivalent).

The composition may be formulated as a single daily dose. The composition may be formulated for multiple daily doses, eg, 2, 3, 4, 5, 6 or more daily doses.

The composition may be provided to a subject according to any dosing schedule. The composition may be given once a day. The composition may be given multiple times per day. The composition may be given twice, three times, four times, five times, six times or more per day.

GABA _A treatment of receptor disorders

The compositions of the present invention are useful for treating disorders that are associated with, or may be ameliorated by, altering the activity of the GABA _A receptor. The GABA _A receptor is a ligand-gated ion channel that allows Cl ⁻ ions to selectively pass through the plasma membrane immediately after GABA binding. GABA _A receptors are expressed in neurons throughout the central nervous system (CNS) and mediate most of the physiological activities of GABA in the CNS. Within neurons, the type and density of GABA _A receptors may vary depending on the cell body and dendrites. The GABA _A receptor is also expressed in other tissues, including Leedig cells, placenta, immune cells, liver, bone growth plates, and other endocrine tissues. Outside the CNS, GABA _A receptors can regulate cell proliferation and immune responses.

Structurally, the GABA _A receptor is a pentamer comprising five polypeptide subunits. Polypeptide subunits are encoded by 19 genes classified according to sequence similarity as follows: α(1-6), β(1-3), γ(1-3), δ, ε, θ, π , and ρ(1-3). Most subtypes contain two copies of one type of α subunit, two copies of one type of β subunit, and one type of γ, δ, ε, θ, or π is a heteropentamer comprising one copy of a subunit; Other subtypes are homopentamers or heteropentamers of the ρ subunit. GABA _A 수용체의 공지된 아형은 α1β1γ2, α1β2γ2, α1β3γ2, α2β1γ2, α2β2γ2, α2β3γ2, α3β1γ2, α3β2γ2, α3β3γ2, α4β1γ2, α4β3δ, α4β3γ2, α5β1γ2, α5β2γ2, α5β3γ2, α6β1γ2, α6β2γ2, 및 α6β3γ2를 포함한다. GABA _A receptor subtypes depend on the tissue type and anatomical region of the CNS, and subtypes may be associated with specific functions. Furthermore, GABA _A receptor subtypes may differ between normal and malignant cells of the same tissue type.

The active site of the GABA _A receptor is the binding site for GABA and drugs such as musimol, gaboxadol and bicuculin. The GABA _A receptor also has several allosteric binding sites that are targets of other drugs including benzodiazepines, nonbenzodiazepines, neuroactive steroids, barbiturates, ethanol, inhalation anesthetics, and picrotoxins. Thus, the activity of the GABA _A receptor is controlled by the binding of the molecule to both the active and allosteric binding sites. The structure, function, and modulation of GABA _A receptors are known in the art and are described, for example, in Sigel E., and Steinmann, ME, Structure, Function, and Modulation of GABA _A Receptors, J. Biol. Chem. 287:48 pp. 40224-402311 (2012), doi: 10.1074/jbc.R112.386664, the contents of which are incorporated herein by reference.

The isomerically pure compositions of the present invention preferentially potentiate the activity of selected GABA _A receptor subtypes. The compositions of the present invention may preferentially potentiate the activity of one or more GABA _A receptor subtypes, such as those described above, over one or more GABA _A receptor subtypes. In certain embodiments, the composition preferentially potentiates the activity of the α4β3δ receptor compared to the α1β2γ2 receptor.

The compositions of the present invention may potentiate one or more GABA _A receptors by any mechanism. For example, and without limitation, a compound in its isomerically pure form may potentiate the GABA _A receptor by allosteric modulation, activation, or inhibition. Allosteric adjustment can be positive or negative.

The preferential activity of a composition on one or more GABA _A receptors relative to one or more other GABA _A receptors may be measured by any suitable means. Activity can be measured using an in vitro assay or an in vivo assay. For example, and without limitation, methods of determining the effect of modulators on GABA _A receptor activity include anticonvulsant assays, binding assays, fluorophore potential assays, immune response assays, intracranial self-stimulation assay patch clamp assays, proliferation assay receptor occupancy. Assays seizure induction assays (eg using pentylenetetrazole (PTZ) or maximal electroshock (MES)) assays, and survival assays. Such assays are known in the art and are described, for example, in International Publication Nos. WO 2016/061527; Ghisdal P., et al., Determining the relative efficacy of positive allosteric modulators of the GABA _A receptor: design of a screening approach, J Biomol Screen. 2014 Mar;19(3):462-7. doi: 10.1177/1087057113501555, Epub 2013 Aug 29; Tian J., et al., Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication, Sci Rep. 2017 Mar 23;7(1):374. doi: 10.1038/s41598-017-00515-y; and Tian J., et al., A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA's Ability to Inhibit Inflammatory T Cells, J Diabetes Res. 2019 Feb 26;2019:5783545, doi: 10.1155/2019/5783545, the contents of each of which are incorporated herein by reference.

The preferential activity of the composition for one or more GABA _A receptors as compared to one or more other GABA _A receptors may be expressed by any suitable means. For example, and without limitation, preferential activity may be indicated by comparison of EC ₅₀ values or binding affinity values.

In certain embodiments, a composition of the invention has an EC ₅₀ for the α4β3δ GABA _A receptor that is lower than the EC ₅₀ for the α1β2γ2 GABA _A receptor. The EC ₅₀ for the α4β3δ GABA _A receptor is about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 10 times, about the EC ₅₀ for the α1β2γ2 GABA _A receptors. It may be as low as about 20 times, about 50 times, about 100 times, about 200 times, about 500 times, or about 1000 times.

In certain embodiments, compositions of the present invention comprise less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, about an EC ₅₀ for the α1β2γ2 GABA _A receptor. less than 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% for α4β3δ GABA _A receptors It has an EC ₅₀ .

In certain embodiments, a composition of the invention will have a binding affinity for the α4β3δ GABA _A receptor (which can be expressed, for example, as the dissociation constant K _D ) that is lower than the binding affinity for the α1β2γ2 GABA _A receptor. can The binding affinity for the α4β3δ GABA _A receptor is about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 10 times that of the binding affinity for the α1β2γ2 GABA _A receptors. It can be as low as a fold, about 20 times, about 50 times, about 100 times, about 200 times, about 500 times, or about 1000 times.

In certain embodiments, a composition of the invention comprises less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15% of the binding affinity for the α1β2γ2 GABA _A receptor; less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% of α4β3δ GABA _A receptors has a binding affinity for

In certain embodiments, a composition of the invention has an EC ₅₀ for the α4β3δ GABA _A receptor that is less than a defined value. For example and without limitation, a composition may be less than about 1 μM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, about 10 have an EC ₅₀ for the α4β3δ GABA _A receptor that is less than nM, less than about 5 nM, less than about 2.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, or less than about 0.1 nM.

In certain embodiments, a composition of the invention may have a binding affinity for the α4β3δ GABA _A receptor that is less than a defined value. For example and without limitation, the composition may be less than about 1 μM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, about less than 10 nM, less than about 5 nM, less than about 2.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 _nM , or less than about 0.1 nM.

The compositions and methods of the present invention may be effective in the treatment of GABA _A disorders. A GABA _A disorder may be any disease, disorder, or condition associated with altered GABA _A receptor function or any disorder may be a disease, disorder, or condition that may be ameliorated by altered GABA _A receptor function. GABA _A disorders include acute pain, addiction disorder, Alzheimer's disease, Angelman's syndrome, antisocial personality disorder, anxiety disorder, attention deficit hyperactivity disorder (ADHD), attention disorder, deafness, autism, autism spectrum disorder, bipolar disorder, chronic pain , cognitive impairment, obsessive compulsive disorder, convulsive disorder, dementia, depression, dysthymia, epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington's disease, injury-related pain syndrome, insomnia, ischemia , Lewy body dementia, memory impairment, migraine, mood disorders, movement disorders, neurodegenerative disorders, neuropathic pain, obsessive compulsive disorder, pain, panic disorder, Parkinson's disease, personality disorder, post-traumatic stress disorder (PTSD), psychosis, Rett Syndrome, Schizoaffective Disorder, Schizophrenia, Schizophrenia Spectrum Disorder, Seizure Disorder, Sleep Disorder, Social Anxiety Disorder, Persistent Epilepsy, Stress, Stroke, Tinnitus, Traumatic Brain Injury (TBI), Vascular Disease, Vascular Malformation, Vascular Type dementia movement disorder, Wilson's disease, or withdrawal syndrome.

A method of treating a subject comprises providing to the subject a composition of the invention as described above. Providing can include administering the composition to the subject. The compositions may be administered by any suitable means, such as oral, intravenous, enteral, parenteral, dermal, buccal, topical (including transdermal), injection, nasal, or pulmonary, and into an implantable medical device (eg, a stent or drug). -eluting stent or balloon equivalent) or on the device. Preferably the composition is given orally.

The composition may be provided under any suitable dosing regimen. For example, the composition may be provided as a single dose or as multiple doses. Multiple doses may be administered at intervals, such as 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. may be provided separately. Multiple doses may be given within a period of time. For example, multiple doses may be given over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. The composition may be given repeatedly for a specified period of time. For example and without limitation, the composition may be administered at 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months. or overtime.

Example

Example 1

The ability of CV-10155 and SPNC-019 to modulate the activity of GABA _A receptors of different GABA _A was analyzed. CV-10155 and SPNC-019 have the following structures:

.

.

Cells expressing the indicated GABA _A receptor subtypes were exposed to gamma-aminobutyric acid in the presence of varying concentrations of CV-10155 or SPNC-019, and calcium flux was measured using a fluorometric imaging plate reader (FLIPR), and the compound EC50 values were determined. The results are provided in Table 1.

<Table 1>

-- non-measurable value

CV-10155 showed some level of positive allosteric modulating activity in all GABA _A receptor subtypes tested. In contrast, SPNC-019 did not have any modulating activity in 15 of the 18 GABA _A receptor subtypes tested. The only structural difference between CV-10155 and SPNC-019 is the stereochemical configuration of the hydroxyl and methyl groups attached to the carbon atom at position 3 of the steroid core. Thus, the results indicate that changes in the stereochemistry of a single chiral center of steroidal compounds dramatically alter the ability of the molecule to modulate GABA _A receptor activity. The results further indicate that the isomeric purity of the neurosteroid composition greatly affects the usefulness of such compositions as therapeutic agents.

Example 2

The ability of various neurosteroids to compete with t-butylbicyclophosphorothionate (TBPS), a ligand for the picrotoxin binding site of the GABA _A receptor, was analyzed in International Publication No. WO 2016/061527. WO 2016/061527, pages 215-227. Compounds were assayed for binding to GABA receptors in membranes isolated from the cortex of rat brain. WO 2016/061527, page 216.

Among the neurosteroids analyzed was compound 10, which had the structure:

.

.

WO 2016/061527, page 106. Compound 10 has the same structure as formula (II) and is a stereoisomer of the structure of formula (I). Compound 10/formula (II) and formula (I) are stereoisomers that differ only in the configuration of the hydrogen atom bonded to the carbon atom at position 5: compound 10/formula (II) has the 5β configuration, while formula (I) has a 5α configuration.

Another neurosteroid analyzed in WO 2016/061527 was compound 121 having the structure:

.

.

WO 2016/061527, page 150. Compound 121 is a regioisomer of the structure of formula (I). Compound 121 and Formula (I) differ only in the positioning of the cyano substituent on the pyrazole ring: Compound 121 is substituted in the 3rd position of the pyrazole ring, while Formula (I) is in the 4th position of the pyrazole ring is substituted in

Compound 10 and Compound 121 are isomers with two structural differences: stereochemical configuration at carbon 5, and positioning of the cyano substituent on the pyrazole ring.

The analysis results are provided in Table 1 of WO 2016/061527. WO 2016/061527, pages 217-227. Compound 10 has an IC ₅₀ of <10 nM in the TBPS displacement assay, while compound 121 has an IC ₅₀ of 10-50 nM. WO 2016/061527, pages 217 and 221.

These results indicate that subtle structural differences in neurosteroids can dramatically affect the binding of molecules to GABA _A receptors.

Example 3

The pharmacological effects of various neurosteroids on the α1β2γ2 GABA _A receptor and the α4β3δ GABA _A receptor were analyzed in International Publication No. WO 2016/061527. WO 2016/061527, pages 227-231. Compounds were tested for their ability to modulate GABA-mediated currents at submaximal doses of agonists in LTK cells stably transfected with the α1β2γ2 subunit and CHO cells transiently transfected with the α4β3δ subunit WO 2016/061527, page 227 -228. Cells were incubated with GABA at 2 μM, EC ₂₀ for GABA, and 0.01 μM, 0.1 μM, 1 μM, or 10 μM neurosteroids. WO 2016/061527, pages 227-228.

The analysis results are provided in Table 2 of WO 2016/061527. WO 2016/061527, pages 229-231. Results are expressed as relative enhancement of GABA-mediated conductance in the presence of 10 μM neurosteroid compared to GABA-mediated conductance in the absence of neurosteroid. WO 2016/061527, page 228. Compound 121 at 10 μM exhibited an efficacy of >500% for both α1β2γ2 GABA _A receptors and α4β3δ GABA _A receptors. WO 2016/061527, page 229.

The results indicate that the regioisomer of formula (I) does not show any preferential modulation of the α4β3δ GABA _A receptor over the α1β2γ2 GABA _A receptor. In particular, compounds that differ from formula (I) only in the positioning of the cyano substituent on the pyrazole ring have comparable potencies against the two GABA _A receptor subtypes. Thus, the data indicate that a composition containing a compound of formula (I) can preferentially modulate the α4β3δ GABA _A receptor over the α1β2γ2 GABA _A receptor or at a concentration at which such a composition modulates the α4β3δ GABA _A receptor but not the α1β2γ2 GABA _A receptor. It does not provide any indication that it can be administered as Consequently, nothing from the above results suggests that a composition containing a compound of formula (I) would be useful for the treatment of conditions in which enhancement of the α4β3δ GABA _A receptor rather than the α1β2γ2 GABA _A receptor would be beneficial.

In contrast, the data presented in Example 1 indicate that the compound of formula (I) is substantially more active against the α4β3δ GABA _A receptor than it is against the α1β2γ2 GABA _A receptor. Taken together, the results of the Examples demonstrate that subtle structural differences in neurosteroids affect the ability of molecules to potentiate specific subtypes of GABA _A receptors. Therefore, it is concluded from the above results that the isomeric purity of the neurosteroid composition may affect the receptor subtype specificity and thus the usefulness of such a composition as a therapeutic agent.

INCLUDING BY REFERENCE

References and citations to other documents such as patents, patent applications, patent publications, journals, books, articles, and web content have been made throughout this disclosure. All such documents are incorporated herein by reference in their entirety for all purposes.

equivalent

In addition to those shown and described herein, various modifications of the present invention and many further embodiments thereof will be apparent to those skilled in the art from the text of this document, including reference to the scientific and patent literature cited herein. will be done The subject matter herein contains important information, examples, and guidance that may be adapted to the practice of the invention in various embodiments of the invention and equivalents thereof.

Claims (10)

A pharmaceutical composition comprising an isomerically pure form of a compound of formula (I):

wherein the compound of formula (I) is present in a therapeutically effective amount to preferentially potentiate the α4β3δ GABA _A receptor compared to the α1β2γ2 GABA _A receptor. The composition of claim 1 , wherein the compound of formula (I) preferentially positively modulates the α4β3δ GABA _A receptor compared to the α1β2γ2 GABA _A receptor. 3. The composition of claim 2, wherein the EC ₅₀ of the compound of formula (I) to the α4β3δ GABA _A receptor is less than 50% of the EC ₅₀ of the compound of formula (I) to the α1β2γ2 GABA _A receptor. The composition according to claim 3 , wherein the EC ₅₀ of the compound of formula (I) to the α4β3δ GABA _A receptor is less than 20% of the EC ₅₀ of the compound of formula (I) to the α1β2γ2 GABA _A receptor. The composition according to claim 1 , wherein the EC ₅₀ of the compound of formula (I) for the α4β3δ GABA _A receptor is less than 500 nM. The composition of claim 1 , which is effective for the treatment of a GABA _A disorder. 7. The method of claim 6, wherein the GABA _A disorder is acute pain, addiction disorder, Alzheimer's disease, Angelman's syndrome, antisocial personality disorder, anxiety disorder, attention deficit hyperactivity disorder (ADHD), attention disorder, deafness, autism, autism spectrum disorder, Bipolar disorder, chronic pain, cognitive impairment, obsessive compulsive disorder, convulsive disorder, dementia, depression, dysthymia, epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington's disease, injury-related pain syndrome, insomnia, ischemia, Lewy body dementia, memory impairment, migraine, mood disorders, movement disorders, neurodegenerative disorders, neuropathic pain, obsessive compulsive disorder, pain, panic disorder, Parkinson's disease, personality disorder, post-traumatic stress disorder ( PTSD); A composition selected from the group consisting of vascular malformations, vascular dementia movement disorders, Wilson's disease, and withdrawal syndrome. 8. The composition of claim 7, wherein the GABA _A disorder is an epileptic disorder, an epileptic mechanism, or a seizure disorder. The composition of claim 1 , wherein the composition is formulated for oral administration. The composition of claim 1 , formulated as a single daily dose.