Patent Description:
Agents that modulate NMDA receptors have been reported to be useful in a variety of therapeutic applications. For example, memantine is used to treat Alzheimer's disease and Lewy Body Dementia. However, treatment with NMDA modulators can have side effects such as sedation and hallucinations.

Anti-NMDAR encephalitis is an autoimmune encephalitis characterized by the presence of antibodies against synaptic NMDAR. Anti-NMDAR encephalitis (also known as NMDA receptor antibody encephalitis or NMDAR encephalitis) has become the most common and best characterized antibody-defined autoimmune neuronal disorder. The encephalitis associated with antibodies against NMDAR predominantly affects children and young adults, occurs with or without tumor association, responds to treatment, but can relapse. The exact incidence of anti-NMDAR encephalitis is unknown. Due to the rareness of the syndrome and the varied clinical presentations, anti-NMDAR syndrome may be misdiagnosed and under-recognized.

Schizophrenia is a chronic and devastating neuropsychiatric disorder that is ranked as a leading cause of disability worldwide. The disease afflicts nearly <NUM>% of the world's population, affecting both men and women equally, and striking all ethnic and socioeconomic groups with a similar level of prevalence. The illness is characterized by multiple symptoms that are categorized into three clusters known as positive symptoms (hallucinations and delusional behaviors), negative symptoms (anhedonia, social withdrawal and apathy), and cognitive dysfunction (diminished capacity for learning, memory, and executive function). Currently available antipsychotic drugs exhibit efficacy for positive symptoms, but have been limited in their capacity to treat negative symptoms and cognitive deficits.

D-serine occurs naturally in the human body, although in much smaller amounts than L-serine. Only L-serine is found in proteins.

D-serine is an agonist of NMDA receptors. Academic studies have demonstrated that oral dosing of D-serine can result in dose-dependent improvement in positive, negative, and cognitive symptoms in schizophrenic patients when added to D2 antipsychotics (antipsychotic drugs that bind to and inhibit or block the activation of dopamine D2 receptors). However, preclinical studies have demonstrated that administration of D-serine can cause nephrotoxicity in rats. In addition, in some patients who received high doses of D-serine, clinical findings suggesting renal impairment were observed. As a result, the clinical development of D-serine has historically been limited.

<NPL>) relates to a bioanalytical method for determining endogenous D-serine levels in the mouse brain using a surrogate analyte and liquid chromatography-tandem mass spectrometry (LC-MS/MS). [<NUM>,<NUM>,<NUM>-<NUM>H]D-serine and [<NUM>N]D-serine were used as a surrogate analyte and an internal standard, respectively.

<NPL>) relates to the role of Zn<NUM>+ ions in the mechanism of D-serine dehydration by DsdSC. The dehydration reaction of D-[α-<NUM>H]serine was monitored by <NUM>H NMR to identify the catalytic step(s) in which Zn<NUM>+ is involved.

<CIT> discloses preparation of deutero-D-serine and its use as an intermediate to prepare a fluorodeuteroalanine.

<NPL>) relates to stereospecifically labelled samples of D-serine, D-cystine and β-chloro-D-alanine, prepared by a chemicoenzymic synthesis.

<NPL>) relates to the evaluation of the efficacy and safety of D-serine at doses ><NUM>/kg/day; a <NUM>-week, open-label trial of adjunctive D-serine (<NUM>, <NUM> or <NUM>/kg/day).

<CIT> relates to a method of enhancing NMDAR-mediated neurotransmission in a disease associated with NMDAR antibody production and a method of mitigating the severity of, mitigating the pathogenesis of, lowering the incidence of or treating a disease associated with NMDAR antibody production, said methods comprising administering an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor or a combination thereof to said subject.

<CIT> provides methods for treating neuropsychiatric disorders such as schizophrenia, Alzheimer's Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder a pharmaceutical composition containing (i) a therapeutically effective amount of D-alanine (or a modified form thereof), provided that the composition is substantially free of D-cycloserine, and/or (ii) D-serine (or a modified form thereof), and/or (iii) <NUM> to <NUM> of D-cycloserine (or a modified form thereof), and/or (iv) N-methylglycine (or a modified form thereof).

<CIT> discloses a pharmaceutical composition, medical food, dietary supplement or micronutrient for the treatment of a movement disorder comprising an NMDAR agonist or partial agonist as active ingredient therein in combination with a pharmaceutically acceptable carrier.

There remains a need for improved treatments for NMDAR encephalitis and neurological conditions mediated by the NMDAR, including schizophrenia.

It has now been found that deuterated forms of D-serine (D-D-serine) may have advantageous properties, including reduced nephrotoxicity, relative to D-serine. Further, deuterated D-serine has the potential to restore NMDA receptor activity in key disease-related areas of the brain.

In one aspect, this invention relates to pharmaceutical compositions comprising Compound <NUM>, pharmaceutically acceptable salts thereof, and such compositions for use in treating a number of disorders.

The invention provides a pharmaceutical composition comprising Compound <NUM>:
<CHM>
wherein.

This invention also provides a pharmaceutical composition for use in treating diseases and conditions that are beneficially treated by administering a modulator of N-methyl-D-aspartate (NMDA) receptor function. The invention also provides a pharmaceutical composition for use in treating a disease or condition selected from epilepsy, NMDAR encephalitis, Parkinson's disease, cognitive deficits in Parkinson's disease, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia (including positive, cognitive, and/or negative symptoms of schizophrenia, as well as prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression, treatment-refractory depression, cognitive deficits in depression, major depressive disorder, generalized anxiety disorder, major depressive disorder with mixed features, and cognition deficits associated with diseases or conditions such as Huntington's disease, subjective cognitive decline, traumatic brain injury, Lewy Body Dementia, the use comprising the step of administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Compound <NUM>:
<CHM>
wherein.

This invention also provides a pharmaceutical composition for use in treating schizophrenia (including positive, negative, and/or cognitive symptoms of schizophrenia), the use comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Compound <NUM>:
<CHM>
wherein.

Further aspects and embodiments of the invention are also disclosed herein.

The dependent claims depict other embodiments of the invention. Any embodiment not falling under the scope of the appended claims does not form part of the invention.

In certain embodiments, in Compound <NUM>, each position designated specifically as deuterium has at least <NUM>% incorporation of deuterium. In certain embodiments, in Compound <NUM>, each position designated specifically as deuterium has at least <NUM>% incorporation of deuterium. In certain embodiments, in Compound <NUM>, each position designated specifically as deuterium has at least <NUM>% incorporation of deuterium.

In certain embodiments, in Compound <NUM>, any atom not designated as deuterium is present at its natural isotopic abundance.

Compound <NUM> may exist as a zwitterion (e.g., Compound <NUM> can be represented by the structure:
<CHM>
). It will be understood that such zwitterionic forms are included within the scope of this invention.

In certain embodiments, the pharmaceutical composition is suitable for oral administration. In certain embodiments, the pharmaceutical composition is suitable for intravenous administration.

As described in more detail below, Compound <NUM> may be co-administered together with and one or more additional therapeutic agents selected from a compound of Formula III, IV, V and VI, as defined below. In certain aspects, there is provided a pharmaceutical composition comprising Compound <NUM>, as defined herein, and a compound of Formula III:
<CHM>
wherein.

In certain aspects, there is provided a pharmaceutical composition comprising Compound <NUM>, as defined herein, and a compound of Formula IV:
<CHM>
wherein.

In certain aspects, there is provided a pharmaceutical composition comprising Compound <NUM>, as defined herein, and a compound of Formula V:
<CHM>
wherein.

In certain aspects, there is provided a pharmaceutical composition comprising Compound <NUM>, as defined herein, and a compound of Formula VI:
<CHM>
wherein.

Another aspect of the invention is a unit dose form comprising Compound <NUM>, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. In certain embodiments, the amount of Compound <NUM>, or a pharmaceutically acceptable salt thereof, is in the range of <NUM> to <NUM>, or <NUM> to <NUM>. In certain embodiments, the amount of Compound <NUM>, or a pharmaceutically acceptable salt thereof, is about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>, about <NUM>, about <NUM>, or in the range of about <NUM> to about <NUM>. In certain embodiments, the amount of Compound <NUM>, or a pharmaceutically acceptable salt thereof, is <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or in the range of <NUM> to <NUM>. In certain embodiments, the unit dose form is a tablet. In certain embodiments, the unit dose form is a sachet.

Another aspect of the invention is a packaged pharmaceutical formulation comprising Compound <NUM>, or a pharmaceutically acceptable salt thereof, together with a container or package. In certain embodiments, the amount of Compound <NUM>, or a pharmaceutically acceptable salt thereof, is in the range of <NUM> to <NUM>, or <NUM> to <NUM>. In certain embodiments, the amount of Compound <NUM>, or a pharmaceutically acceptable salt thereof, is about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>, about <NUM>, about <NUM>, or in the range of about <NUM> to about <NUM>. In certain embodiments, the amount of Compound <NUM>, or a pharmaceutically acceptable salt thereof, is <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or in the range of <NUM> to <NUM>. In certain embodiments, the packaged pharmaceutical formulation comprises a tablet. In certain embodiments, the packaged pharmaceutical formulation comprises a sachet.

In one embodiment, the invention provides a pharmaceutical composition for use in treating NMDAR encephalitis, the use comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Compound <NUM>
<CHM>
wherein.

In another embodiment, the invention provides a pharmaceutical composition for use in treating epilepsy, NMDAR encephalitis, Parkinson's disease, cognitive deficits in Parkinson's disease, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia (including positive, cognitive, and/or negative symptoms of schizophrenia, as well as prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression, treatment-refractory depression, cognitive deficits in depression, major depressive disorder, generalized anxiety disorder, major depressive disorder with mixed features, and cognition deficits in associated with diseases or conditions such as Huntington's disease, subjective cognitive decline, traumatic brain injury, Lewy Body Dementia, the use comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Compound <NUM>
<CHM>
wherein.

In another embodiment, the invention provides a pharmaceutical composition for use in treating Additional diseases or conditions include post-traumatic stress disorder (PTSD), ataxia, and serine deficiency disorders, the use comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Compound <NUM>
<CHM>
wherein.

In another embodiment, the invention provides a pharmaceutical composition for use in treating depression, the use comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Compound <NUM>
<CHM>
wherein.

In another aspect, the invention provides a pharmaceutical composition for use in treating schizophrenia (including positive, negative, and/or cognitive symptoms of schizophrenia), the use comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Compound <NUM>
<CHM>
wherein.

In certain embodiments of any of the foregoing compositions or uses, administration of Compound <NUM> results in reduced nephrotoxicity compared to administration of an equivalent dose of (non-deuterated) D-Serine.

The term "treat" means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

"Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

As used herein, the term "subject" includes humans and non-human mammals. Non-limiting examples of non-human mammals include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, apes, pigs, cows, sheep, horses, etc. In certain embodiments, the subject is a human suffering from schizophrenia.

The term "alkyl" refers to a monovalent saturated hydrocarbon group. A C<NUM>-C<NUM> alkyl is an alkyl having from <NUM> to <NUM> carbon atoms; a C<NUM>-C<NUM> alkyl is an alkyl having from <NUM> to <NUM> carbon atoms. In some embodiments, an alkyl may be linear or branched. In some embodiments, an alkyl may be primary, secondary, or tertiary. Non-limiting examples of alkyl groups include methyl; ethyl; propyl, including n-propyl and isopropyl; butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl; pentyl, including, for example, n-pentyl, isopentyl, and neopentyl; and hexyl, including, for example, n-hexyl and <NUM>-methylpentyl. Non-limiting examples of primary alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Non-limiting examples of secondary alkyl groups include isopropyl, sec-butyl, and <NUM>-methylpentyl. Non-limiting examples of tertiary alkyl groups include t-butyl. A "C<NUM>-C<NUM> hydroxyalkyl" group is a C<NUM>-C <NUM> alkyl group substituted with one to three hydroxyl groups.

It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of Compound <NUM> will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, <NPL>; <NPL>.

The term "D-D-serine" refers to a deuterated analog of the amino acid serine in the (D)-configuration. D-D-serine can be represented by the structure of Formula II:
<CHM>
wherein each of Y<NUM>, Y2a and Y2b is independently H or D, provided that at least one of Y<NUM>, Y2a and Y2b is D.

In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. However, in certain embodiments, where specifically stated, when a position is designated specifically as "H" or "hydrogen", the position has at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, or at least <NUM>% hydrogen. In some embodiments, where specifically stated, when a position is designated specifically as "H" or "hydrogen", the position incorporates ≤<NUM>% deuterium, ≤<NUM>% deuterium, ≤<NUM>% deuterium, ≤<NUM>% deuterium, ≤<NUM>% deuterium, ≤<NUM>% deuterium, or ≤<NUM>% deuterium. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least <NUM> times greater than the natural abundance of deuterium, which is <NUM>% (i.e., at least <NUM>% incorporation of deuterium).

The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

In other embodiments, a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least <NUM> (<NUM>% deuterium incorporation at each designated deuterium atom), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), at least <NUM> (<NUM>% deuterium incorporation), or at least <NUM> (<NUM>% deuterium incorporation).

In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least <NUM>%.

Deuterium incorporation in a compound of the invention can be measured using a variety of techniques, some of which are known in the art. For example, <NUM>H NMR can be used to measure deuterium incorporation (e.g., by measuring the absence of or decrease in proton signals corresponding to deuterated positions, e.g., relative to a non-deuterated position or positions).

The term "isotopologue" refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.

The term "compound," when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure will contain molecules having deuterium at each of the positions designated as deuterium in the chemical structure, and may also contain isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to one embodiment, the compound is a pharmaceutically acceptable acid addition salt. In one embodiment the acid addition salt may be a deuterated acid addition salt.

The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-<NUM>,<NUM>-dioate, hexyne-l,<NUM>-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-<NUM>-sulfonate, naphthalene-<NUM>-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In one embodiment, the acids commonly employed to form pharmaceutically acceptable salts include the above-listed inorganic acids, wherein at least one hydrogen is replaced with deuterium.

The pharmaceutically acceptable salt may also be a salt of a compound of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or trialkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(<NUM>-OH-(C<NUM>-C<NUM>)-alkylamine), such as N,N-dimethyl-N-(<NUM>-hydroxyethyl)amine or tri-(<NUM>-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

Compound <NUM> contains an asymmetric carbon atom (i.e., the carbon bearing the -NH<NUM> and Y<NUM> groups in a compound of Formula II shown below). In certain embodiments, Compound <NUM> is a deuterated D-serine analog substantially free from other possible stereoisomers, e.g., a compound of Formula II (such as Compound <NUM>) is substantially free of a compound of the structure:
<CHM>
The term "substantially free of other stereoisomers" as used herein means less than <NUM>% of other stereoisomers, preferably less than <NUM>% of other stereoisomers, more preferably less than <NUM>% of other stereoisomers and most preferably less than <NUM>% of other stereoisomers are present. Methods of obtaining or synthesizing an individual stereoisomer (e.g., enantiomer or diastereomer) for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named or depicted by a structure having one or more chiral centers of unspecified stereochemistry, it is understood to represent all possible stereoisomers of the compound.

The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

"Stereoisomer" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to tertiary. "Sec" or "s-" each refer to secondary. "n-" refers to normal. "i-" refers to iso. "US" refers to the United States of America.

"Substituted with deuterium" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

Throughout this specification, a variable may be referred to generally (e.g.,"each R") or may be referred to specifically (e.g., R<NUM>, R<NUM>, R<NUM>, etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.

As used herein, the term "schizophrenia" refers to a psychiatric disorder that includes at least two of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms. Patients may be diagnosed as schizophrenic using the DSM-IV criteria (<NPL>.

"Negative" symptoms of schizophrenia include affect blunting, anergia, alogia and social withdrawal, which can be measured using SANS (the Scales for the Assessment of Negative Symptoms; see Andreasen, <NUM>, Scales for the Assessment of Negative Symptoms (SANS), Iowa City, Iowa).

"Positive" symptoms of schizophrenia include delusion and hallucination, which can be measured using PANSS (the Positive and Negative Syndrome Scale; see <NPL>).

"Cognitive" symptoms of schizophrenia include impairment in obtaining, organizing, and using intellectual knowledge which can be measured by the Positive and Negative Syndrome Scale-cognitive subscale (PANSS-cognitive subscale) (<NPL>) or with cognitive tasks such as the Wisconsin Card Sorting Test.

In certain aspects or embodiments, the present invention provides a pharmaceutical composition comprising Compound <NUM>:
<CHM>
wherein.

In certain embodiments of Compound <NUM>, each position designated specifically as deuterium has at least <NUM>% incorporation of deuterium.

In certain embodiments, Compound <NUM> has at least <NUM>% incorporation of deuterium, or at least <NUM>% incorporation of deuterium, or at least <NUM>% incorporation of deuterium.

In certain embodiments of Compound <NUM>, any atom not designated as deuterium is present at its natural isotopic abundance.

In certain embodiments of Compound <NUM>, the compound is at least about <NUM>% stereomerically pure.

In another set of embodiments, any atom not designated as deuterium in any of the embodiments set forth herein is present at its natural isotopic abundance.

In some embodiments of a compound of this invention, deuterium incorporation at each designated deuterium atom is at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, or at least <NUM>%.

The present invention also provides deuterated intermediates useful, e.g., in the preparation of Compound <NUM>, and as provided in the Exemplary Schemes.

The synthesis of Compound <NUM> may be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis and Examples disclosed herein. Relevant procedures analogous to those of use for the preparation of Compound <NUM> and intermediates thereof are disclosed, for instance in <CIT>.

The synthesis of compounds of Formula III, IV, V and VI may be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis and Examples disclosed herein, using appropriate starting materials and reagents.

Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

A convenient method for synthesizing Compound <NUM> is depicted in Scheme <NUM>.

As depicted in Scheme <NUM>, and as described in more detail in <CIT>, esterification of dl-serine (<NUM>) results in formation of the serine ester (<NUM>), which can be cyclized to the oxazoline (<NUM>) using benzoimidate. Oxazoline (<NUM>) is then deuterated by deprotonation with a strong base (such as butyllithium) and quenching with a deuterium source (such as acetic acid O-D) to produce deuterated intermediate (<NUM>), which is resolved (e.g., using a chiral salt such as d-α-bromocamphorsulfonic acid or separating the enantiomers using SMB (simulated moving bed) chromatography) to provide intermediate (<NUM>) (as the salt). After neutralizing the salt, the oxazoline (<NUM>) is then hydrolyzed to provide Compound <NUM>.

Use of appropriately deuterated reagents allows deuterium incorporation in Compound <NUM>, e.g., about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>% deuterium.

Certain compounds of Formulae III and IV are known and in some cases may be commercially available. Compounds of Formula III and IV may be prepared according to methods known in the art.

Certain compounds of Formulae V and VI are commercially available at high enantiomeric purity, or may be purchased as a mixture of enantiomers and resolved as shown above or by using resolution methods well-known in the art, or may be prepared according to methods known in the art.

The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (i.e., R<NUM>, R<NUM>, R<NUM>, etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the knowledge of one of ordinary skill in the art.

Additional methods of synthesizing Compound <NUM> and compounds of Formula III-VI and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in <NPL>);<NPL>);<NPL>); and <NPL>) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

The invention provides pharmaceutical compositions comprising Compound <NUM> , wherein the pharmaceutical composition comprises <NUM> to <NUM> of the compound; and wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

The invention still further provides pharmaceutical compositions comprising in combination an effective amount of (i) Compound <NUM>, or a pharmaceutically acceptable salt thereof, and (ii) one or more compounds selected from glycine, sarcosine, (nondeuterated) D-alanine and (nondeuterated) D-aspartic acid, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In a particular embodiment, the invention provides a pharmaceutical composition comprising in combination an effective amount of Compound <NUM> and sarcosine.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

If required, the solubility and bioavailability of Compound <NUM> in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "<NPL>; and "<NPL>.

Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See <CIT>; and <CIT> and <CIT>.

The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, <NPL>). A unit dosage form can comprise, e.g., <NUM> to <NUM>, or <NUM> to <NUM>, of Compound <NUM>. A unit dosage form can further include one or more second therapeutic agents, e.g., an antipsychotic agent or other agent for the treatment of schizophrenia. A unit dosage form can be administered once per day, or multiple times per day (e.g., twice per day, three times per day, or four times per day). In certain embodiments, the unit dosage form is administered once per day. In other embodiments, the unit dosage form is administered twice per day. In other embodiments, the unit dosage form is administered three times per day. In other embodiments, the unit dosage form is administered four times per day.

Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween <NUM>) and suspending agents. 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 <NUM>,<NUM>-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

In another embodiment, a composition of this invention further comprises one or more additional therapeutic agents. The additional therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as D-serine. Such agents include those indicated as being useful in combination with D-serine, including but not limited to, those described in <CIT>and <CIT>.

In certain embodiments, the additional therapeutic agent is an agent useful in the treatment of a disease or condition selected from epilepsy, NMDAR encephalitis, Parkinson's disease, cognitive deficits in Parkinson's disease, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia (including positive, cognitive, and/or negative symptoms of schizophrenia, as well as prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression, treatment-refractory depression, cognitive deficits in depression, major depressive disorder, generalized anxiety disorder, major depressive disorder with mixed features, and cognition deficits in associated with diseases or conditions such as Huntington's disease, subjective cognitive decline, traumatic brain injury, Lewy Body Dementia, and the like.

In certain embodiments, a pharmaceutical composition containing Compound <NUM> can be administered to a patient suffering from schizophrenia along with, or in sequence with, an art-known additional therapeutic agent for treating schizophrenia (e.g., olanzapine, clozapine, haloperidol, and the like). Such pharmaceutical compositions are included within the invention. In general, the antipsychotic therapeutic typically is administered at a dosage of <NUM>-<NUM>/day (e.g., <NUM>-<NUM>/day)). "Typical" antipsychotics are conventional antipsychotics such as phenothiazine, butryophenones, thioxantheses, dibenzoxazepines, dihydroindolones, and diphenylbutylpiperidines. "Atypical" antipsychotics are a newer generation of antipsychotics which generally act on the dopamine D<NUM> and 5HT<NUM> serotonin receptor and have high levels of efficacy and a benign extrapyramidal symptom side effect profile. Examples of typical antipsychotics include chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, trifluoperazine, thiothixene, haloperidol, loxapine, molindone, acetophenazine, chlorprothixene, droperidol, and pimozide. Examples of atypical antipsychotics include bolanserin, clozapine, risperidone, olanzapine, cariprazine, asenapine, lurasidone, brexpiprazole, lumateperone, aripiprazole, aripiprazole lauroxil, iloperidone, paliperidone, ziprasidone, and quetiapine. Depot antipsychotics also can be used, e.g., haloperidol decanoate, fluphenazine decanoate, and fluphenazine enanthate. Additional antipsychotics include butaperazine, carphenazine, remoxipride, piperacetazine, and sulpiride.

In certain embodiments, a pharmaceutical composition containing Compound 100can be administered to a patient with symptoms of schizophrenia together with, or in sequence with, one or more art-known drugs for treating schizophrenia (including antipsychotic agents, e.g., olanzapine, clozapine, haloperidol, quetiapine, risperidone, chlorpromazine and the like). In a particular embodiment, the pharmaceutical composition is for administration to a patient with a DSM-V diagnosis of schizophrenia for at least one year. In a further embodiment, the pharmaceutical composition is for administration to a patient with a PANSS total score of <NUM>-<NUM>. In a further embodiment, the pharmaceutical composition is for administration to a patient meeting the additional PANSS criteria:.

In a further embodiment, the pharmaceutical composition is for administration to a patient with clinically stable disease, defined as no hospitalization and no change in medications, for at least <NUM> months. In a further embodiment, the patient is currently being treated with a maximum of one primary atypical antipsychotic and one low-dose atypical antipsychotic (such as low-dose Seroquel® for sleep or low-dose mood stabilizer) where the sum of primary and secondary antipsychotics is ≤ <NUM> of risperidone equivalents or <NUM> of chlorpromazine equivalents, respectively, wherein the dose of the antipsychotic medications remain stable for <NUM> weeks In general, the antipsychotic therapeutic typically is administered at a dosage of <NUM>-<NUM>/d (e.g., <NUM>-<NUM>/d)). "Typical" antipsychotics are conventional antipsychotics such as phenothiazine, butryophenones, thioxantheses, dibenzoxazepines, dihydroindolones, and diphenylbutylpiperidines. "Atypical" antipsychotics are a newer generation of antipsychotics which generally act on the dopamine D<NUM> and 5HT<NUM> serotonin receptor and have high levels of efficacy and a benign extrapyramidal symptom side effect profile. Examples of typical antipsychotics include chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, trifluoperazine, thiothixene, haloperidol, loxapine, molindone, acetophenazine, chlorprothixene, droperidol, and pimozide. Examples of atypical antipsychotics include bolanserin, clozapine, risperidone, olanzapine, cariprazine, asenapine, lurasidone, brexpiprazole, lumateperone, aripiprazole, aripiprazole lauroxil, iloperidone, paliperidone, ziprasidone, and quetiapine. Depot antipsychotics also can be used, e.g., haloperidol decanoate, fluphenazine decanoate, and fluphenazine enanthate. Additional antipsychotics include butaperazine, carphenazine, remoxipride, piperacetazine, and sulpiride.

In another embodiment, the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described additional therapeutic agents, wherein the compound and additional therapeutic agent are associated with one another. The term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than <NUM> hours of one another, consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder. As described above, the dosing regimen can include one or more additional therapeutic agents (e.g., where the compound or composition of the invention is used in a combination (e.g., when a compound or composition of the invention is used as an adjunctive therapy).

The term "subject in need thereof," refers to a subject having or being diagnosed with a disease or condition selected from epilepsy, NMDAR encephalitis, Parkinson's disease, cognitive deficits in Parkinson's disease, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia (including positive, cognitive, and/or negative symptoms of schizophrenia, as well as prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression, treatment-refractory depression, cognitive deficits in depression, major depressive disorder, generalized anxiety disorder, major depressive disorder with mixed features, and cognition deficits associated with diseases or conditions such as Huntington's disease, subjective cognitive decline, traumatic brain injury, Lewy Body Dementia, and the like.

The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in, e.g.,<NPL>. Body surface area may be approximately determined from height and weight of the subject. See, e.g., <NPL>.

The pharmaceutical composition comprises an effective amount of Compound 100that is in the range from <NUM> to <NUM>. In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM> to <NUM>/day, or from <NUM> to <NUM>/day, or from <NUM> to <NUM>/day. In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM> to <NUM>/day. In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM> to <NUM>/day. In certain embodiments, an effective amount of a compound of Compound <NUM> is in the range from <NUM> to <NUM>/day.

In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM>/day to <NUM>/day, or in the range from <NUM>/day to <NUM>/day, or in the range from <NUM>/day to <NUM>/day. In certain embodiments, the pharmaceutical composition comprises <NUM> of Compound <NUM>, <NUM> of Compound <NUM>, <NUM> of Compound <NUM>, <NUM> of Compound <NUM>, <NUM> of Compound <NUM>, or <NUM> of Compound <NUM>.

In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM> milligrams per kilogram body weight per day (mg/kg/day) to <NUM>/kg/day, or from <NUM>/kg/day to <NUM>/kg/day, or from <NUM>/kg/day to <NUM>/kg/day. In certain embodiments, an effective amount of Compound 100is in the range from <NUM>/kg/day to <NUM>/kg/day. In certain embodiments, an effective amount of a compound of Compound <NUM> is in the range from <NUM>/kg/day to <NUM>/kg/day, or <NUM>/kg/day to <NUM>/kg/day, or <NUM>/kg/day to <NUM>/kg/day.

Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for Compound <NUM>.

For pharmaceutical compositions that comprise one or more additional therapeutic agents, an effective amount of the additional therapeutic agent is between about <NUM>% and <NUM>% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about <NUM>% and <NUM>% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these additional therapeutic agents are well known in the art. See, e.g., <NPL>); <NPL>).

Some of the additional therapeutic agents referenced above may act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the additional therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the additional therapeutic agent of a compound of this invention, synergistically improving efficacy, improving ease of administration or use and/or reduced overall expense of compound preparation or formulation.

In another aspect, the invention provides a pharmaceutical composition for use in treating a disease or condition in a subject in need thereof, the use comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising Compound <NUM>, such that the disease or condition is treated, the disease being selected from the group consisting of epilepsy, NMDAR encephalitis, Parkinson's disease, cognitive deficits in Parkinson's disease, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia (including positive, cognitive, and/or negative symptoms of schizophrenia, as well as prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression, treatment-refractory depression, cognitive deficits in depression, major depressive disorder, generalized anxiety disorder, major depressive disorder with mixed features, and cognition deficits in associated with diseases or conditions such as Huntington's disease, subjective cognitive decline, traumatic brain injury, and Lewy Body Dementia.

In certain embodiments, a pharmaceutical composition is used to treat a disease or condition selected from epilepsy and NMDAR encephalitis in a subject in need thereof. The use comprises administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising Compound <NUM>, wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier such that the disease or condition is treated.

This invention also provides a pharmaceutical composition for use in treating schizophrenia (including positive, negative, and/or cognitive symptoms of schizophrenia), the use comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of Compound <NUM> wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In certain embodiments, the use further comprises administering an antipsychotic therapeutic agent to the subject. In certain embodiments, the use further comprises administering a second therapeutic agent to the subject, wherein the second agent is an antipsychotic therapeutic agent.

In certain embodiments, negative and/or positive and/or cognitive symptom(s) of schizophrenia can be measured before and after treatment of the subject or patient. A reduction in such a symptom(s) indicates that the patient's condition has improved. Improvement in the symptoms of schizophrenia can be assessed using the Scales for the Assessment of Negative Symptoms (SANS) or Positive and Negative Syndrome Scale (PANSS) (see, e.g., <NPL>, <NPL>). Likewise, one can measure improvement of other neuropsychiatric disorders in patients who have been treated by the use of the pharmaceutical composition of the invention. In certain embodiments, positive symptoms of schizophrenia are improved after treatment, relative to pre-treatment symptoms. In certain embodiments, negative symptoms of schizophrenia are improved after treatment, relative to pre-treatment symptoms. In certain embodiments, cognitive symptoms of schizophrenia are improved after treatment, relative to pre-treatment symptoms.

In certain embodiments, the use of treating schizophrenia includes administering a pharmaceutical composition comprising Compound <NUM> wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier to a patient suffering from schizophrenia along with, or in sequence with, an art-known drug for treating schizophrenia (including antipsychotic agents, e.g., olanzapine, clozapine, haloperidol, and the like). In some embodiments, the patient suffering from schizophrenia is stable on antipsychotic therapy, i.e., an existing antipsychotic therapy, prior to treatment as described herein (e.g., Compound <NUM> is used as adjunctive therapy, in conjunction with an additional antipsychotic therapeutic agent). In general, the antipsychotic therapeutic typically is administered at a dosage of <NUM>-<NUM>/d (e.g., <NUM>-<NUM>/d)). "Typical" antipsychotics are conventional antipsychotics such as phenothiazine, butryophenones, thioxantheses, dibenzoxazepines, dihydroindolones, and diphenylbutylpiperidines. "Atypical" antipsychotics are a newer generation of antipsychotics which generally act on the dopamine D<NUM> and 5HT<NUM> serotonin receptor and have high levels of efficacy and a benign extrapyramidal symptom side effect profile. Examples of typical antipsychotics include chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, trifluoperazine, thiothixene, haloperidol, loxapine, molindone, acetophenazine, chlorprothixene, droperidol, and pimozide. Examples of atypical antipsychotics include bolanserin, clozapine, risperidone, olanzapine, cariprazine, asenapine, lurasidone, brexpiprazole, lumateperone, aripiprazole, aripiprazole lauroxil, iloperidone, paliperidone, ziprasidone, and quetiapine. Depot antipsychotics also can be used, e.g., haloperidol decanoate, fluphenazine decanoate, and fluphenazine enanthate. Additional antipsychotics include butaperazine, carphenazine, remoxipride, piperacetazine, and sulpiride.

In certain embodiments, the use of treating schizophrenia includes administering a pharmaceutical composition comprising Compound <NUM> wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier to a patient with symptoms of schizophrenia along with, or in sequence with, one or more art-known drugs for treating schizophrenia (including antipsychotic agents, e.g., olanzapine, clozapine, haloperidol, quetiapine, risperidone, chlorpromazine and the like). In a particular embodiment, the pharmaceutical composition is for administration to a patient with a DSM-V diagnosis of schizophrenia for at least one year. In a further embodiment, the pharmaceutical composition is for administration to a patient with a PANSS total score of <NUM>-<NUM>. In a further embodiment, the pharmaceutical composition is for administration to a patient meeting the additional PANSS criteria:.

In certain embodiments, the degree or extent of nephrotoxicity in the subject is reduced compared to treatment with an equivalent amount of D-serine (e.g., a molar equivalent amount of D-serine). Nephrotoxicity can be monitored by measuring levels of markers such as serum creatinine levels or blood urea nitrogen (BUN). A range of about <NUM> to <NUM>/dL (<NUM> to <NUM> mmol/L) is considered normal for BUN. A range of approximately <NUM> to <NUM> milligrams (mg) per deciliter (dL) in adult males and <NUM> to <NUM> milligrams per deciliter in adult females is considered normal for serum creatinine. In certain embodiments, the serum creatinine and/or the BUN level is maintained in a normal range during and after treatment.

In certain embodiments, a use of treating schizophrenia comprises administering to subject in need thereof a pharmaceutical composition comprising Compound <NUM> wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the amount of Compound <NUM> administered per day is in the range of <NUM>/kg to <NUM>/kg (i.e., <NUM> per kilogram of body weight of the subject to <NUM> per kilogram of body weight of the subject), and wherein the serum creatinine level or the BUN level (or both) of the subject is maintained in the normal range (as described above).

In certain embodiments, a pharmaceutical composition comprising Compound <NUM> wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier is administered once per day. In certain embodiments, a pharmaceutical composition comprising Compound <NUM> wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier is administered twice per day. In certain embodiments, a pharmaceutical composition comprising Compound <NUM> wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier is administered three times per day. In certain embodiments, a pharmaceutical composition comprising Compound <NUM> wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier is administered four times per day.

In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM> to <NUM>/day, or from <NUM> to <NUM>/day, or from <NUM> to <NUM>/day. In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM> to <NUM>/day. In certain embodiments, an effective amount of a compound of Compound <NUM> is in the range from <NUM> to <NUM>/day.

In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM>/kg/day to <NUM>/kg/day, or from <NUM>/kg/day to <NUM>/kg/day, or from <NUM>/kg/day to <NUM>/kg/day. In certain embodiments, an effective amount of Compound <NUM> is in the range from <NUM>/kg/day to <NUM>/kg/day, or <NUM>/kg/day to <NUM>/kg/day, or <NUM>/kg/day to <NUM>/kg/day.

Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above uses comprises the further step of coadministering to the subject in need thereof one or more additional therapeutic agents. The choice of additional therapeutic agent may be made from any additional therapeutic agent known to be useful for co-administration with a co-agonist of the NMDAR. The choice of additional therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of additional therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and an additional therapeutic agent.

In certain embodiments, the use of a combination of this invention include coadministering Compound <NUM> and one or more additional therapeutic agents selected from a compound of Formula III, IV, V and VI to a subject in need thereof for treatment of any of the diseases or conditions described herein. In a further embodiment, the use comprises administering in combination an effective amount of Compound <NUM> and sarcosine.

In certain embodiments, the use further comprises administering an antipsychotic therapeutic agent to the subject.

In certain embodiments, the combination therapies of this invention include coadministering Compound <NUM> to a patient suffering from schizophrenia who is stable on antipsychotic therapy. In a further embodiment, the method comprises administering in combination an effective amount of Compound <NUM> and an antipsychotic agent.

The term "co-administered" or "administering in combination" as used herein means that the additional therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an additional therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the additional therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and an additional therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other additional therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.

Effective amounts of these additional therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in <NPL>); <NPL>), and other medical texts. However, it is well within the skilled artisan's purview to determine the additional therapeutic agent's optimal effective-amount range.

In certain embodiments of any of the foregoing uses, administration of Compound <NUM> results in reduced nephrotoxicity compared to administration of an equivalent dose of (non-deuterated) D-Serine.

In one embodiment of the invention, where an additional therapeutic agent is administered to a subject, the effective amount of Compound <NUM> is less than its effective amount would be where the additional therapeutic agent is not administered. In another embodiment, the effective amount of the additional therapeutic agent is less than its effective amount would be where Compound <NUM> is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides Compound <NUM> for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.

Evaluation of the Pharmacokinetic Profile of Compound <NUM> in Male Sprague-Dawley Rats: The hippocampus, cortex and plasma concentration of Compound <NUM> (<NUM>% D by mass spectroscopy) was investigated in male Sprague Dawley rats. The rats were administered a discrete <NUM>/kg PO dose of Compound <NUM> in <NUM>% methylcellulose in water, in the fasted state. The hippocampus, cortex and plasma were collected at <NUM> hour and <NUM> hours and analyzed for Compound <NUM> concentration. The mean plasma, hippocampus and cortex concentration at <NUM> hour and <NUM> hours post dose are shown in Table <NUM> and <FIG>. The mean plasma, hippocampus, and cortex concentrations at <NUM> hour were <NUM> ng/mL, <NUM> ng/g, and <NUM> ng/g, respectively. The mean plasma, hippocampus, and cortex concentrations at <NUM> hours were <NUM> ng/mL, <NUM> ng/g, and <NUM> ng/g, respectively. Similar concentrations of Compound <NUM> were seen in hippocampus and cortex at <NUM> hour and <NUM> hours. Concentrations of Compound <NUM> in plasma, hippocampus, and cortex were within <NUM>-fold of each other at <NUM> hour.

The nephrotoxicity of non-deuterated D-serine was investigated in Male Sprague-Dawley Rats. The rats were administered a discrete dose of <NUM>/kg PO dose of non-deuterated D-serine in <NUM>% methylcellulose in water, in the fasted state. The hippocampus, cortex and plasma were collected and analyzed. Additional blood was collected and were analyzed for the full clinical chemistry profile. Urine was also collected and examined for glucose and total protein. The average endogenous level of the non-deuterated D-serine was <NUM> ng/mL in rat plasma, <NUM> ng/g in rat cortex, and <NUM> ng/g in rat hippocampus from control group. The endogenous level of non-deuterated D-serine was only subtracted from the reported plasma concentration. The plasma pharmacokinetic (PK) parameters for non-deuterated D-serine are shown in Table <NUM>. The hippocampus, cortex, and plasma concentration at <NUM> hr for the non-deuterated D-serine are shown in Table <NUM> and <FIG>. The Tmax, T½, Cmax and AUCinf for non-deuterated D-serine were <NUM> hr, <NUM> hr, <NUM> ng/mL, and <NUM> hr*ng/mL; respectively. The mean plasma, hippocampus, and cortex concentration at <NUM> hour are <NUM> ng/mL, <NUM> ng/g, and <NUM> ng/g; respectively. The mean plasma, hippocampus, and cortex concentrations at <NUM> hours were <NUM> ng/mL, <NUM> ng/g, and <NUM> ng/g, respectively. Concentrations of non-deuterated D-serine in plasma, hippocampus, and cortex were within <NUM>-fold of each other at <NUM> hours. Nephrotoxicity of the non-deuterated D-serine at <NUM>/kg in Male Sprague-Dawley Rats was evaluated. Blood urea nitrogen and creatinine levels were elevated. Elevated levels of urea nitrogen and creatinine are suggestive of nephrotoxicity. The presence of glucose was observed in urine.

The pharmacokinetic profile of Compound <NUM> was investigated in male Sprague-Dawley rats compared with that of non-deuterated D-serine. The rats were administered discrete <NUM>/kg PO doses of Compound <NUM> (<NUM>% D by mass spectroscopy) in <NUM>% methylcellulose in water and non-deuterated D-serine, in the fasted state. Plasma was collected and analyzed for Compound <NUM> and non-deuterated D-Serine. Additional blood was collected and analyzed for the full clinical chemistry profile. The PK parameters for Compound <NUM> and non-deuterated D-serine are shown in Table <NUM>. The hippocampus, cortex, and plasma concentration at <NUM> hr, <NUM> hr, and <NUM> hr for Compound <NUM> are shown in Table <NUM> and <FIG>. Clinical pathology data are shown in <FIG>, <FIG> and <FIG>.

In rats administered a single <NUM>/kg discrete PO dose of each compound, the Tmax for Compound <NUM> was <NUM>-fold greater than that of the non-deuterated D-serine. The Cmax and AUCinf for Compound <NUM> were similar to the non-deuterated D-serine. The Tmax, Cmax and AUCinf for non-deuterated D-serine were <NUM> hr, <NUM> ng/mL, and <NUM> hr*ng/mL; respectively. The Tmax, Cmax and AUCinf for Compound <NUM> were <NUM> hr, <NUM> ng/mL, and <NUM> hr*ng/mL, respectively. The mean plasma, hippocampus, and cortex concentrations at <NUM> hr were <NUM> ng/mL, <NUM> ng/g, and <NUM> ng/g, respectively. The mean plasma, hippocampus, and cortex concentrations at <NUM> hr were <NUM> ng/mL, <NUM> ng/g, and <NUM> ng/g, respectively. The mean plasma, hippocampus, and cortex concentrations at <NUM> hr were <NUM> ng/mL, <NUM> ng/g, and <NUM> ng/g, respectively. Compound <NUM> concentrations in plasma and cortex decreased within <NUM> hr; however, Compound <NUM> concentration in hippocampus remained steady at <NUM> hr.

The nephrotoxicity of Compound <NUM> and non-deuterated D-serine were evaluated in male Sprague-Dawley Rats. Rats received <NUM>/kg of either Compound <NUM> or non-deuterated D-serine (PO administration). Elevated levels of blood urea nitrogen (BUN) were seen in the non-deuterated D-serine at <NUM> hr and <NUM> hr serum samples. Elevated levels of creatinine and Gamma glutamyl transferase (GGT) were seen in the non-deuterated D-serine at <NUM> hr serum samples. Elevated levels of blood urea nitrogen, creatinine and GGT are suggestive of nephrotoxicity. In contrast, with Compound <NUM>, levels of urea nitrogen, creatinine, and GGT level at <NUM>, <NUM>, and <NUM> hours were similar in comparison to control values and reference values provided by Charles River Laboratory. While non-deuterated D-serine caused an increase in levels of biomarkers of nephrotoxicity, administration of Compound <NUM> did not increase levels of biomarkers of nephrotoxicity.

Additional experiments were performed to compare the nephrotoxicity of Compound <NUM> (Compound <NUM>) and non-deuterated D-serine at doses from <NUM>/kg to <NUM>/kg. The results are shown in <FIG>. It can be seen from <FIG> that minimal changes in BUN or creatinine were observed in animals dosed with Compound <NUM>, while animals receiving comparable doses of non-deuterated D-serine showed increasingly elevated levels of BUN and creatinine. During the dose escalation, the exposure as measured by AUC and Cmax were greater for Compound <NUM>, yet the gross signs of nephrotoxicity were only observed in rats receiving non-deuterated D-serine (not Compound <NUM>).

The pharmacokinetic profile of non-deuterated D-serine was investigated in male Sprague-Dawley rats. The rats were administered a single discrete <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg PO doses of non-deuterated D-serine in <NUM>% methylcellulose in water, in the fasted state. Plasma was collected and analyzed for the non-deuterated D-serine. Additional blood was collected and analyzed for the full clinical chemistry profile. The PK parameters for the non-deuterated D-Serine are shown in Table <NUM>. Clinical pathology data are shown in <FIG>, and <FIG>.

In rats administered a single discrete <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg PO dose of non-deuterated D-serine, the Tmax was from <NUM> to <NUM> for all doses. Increase in exposure in terms of Cmax and AUCinf was seen as the doses increased from <NUM> to <NUM>/kg. The Cmax for <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg are <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> ng/mL, respectively. The AUCinf for <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg are <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> ng*hr/mL; respectively.

The nephrotoxicity dose response of non-deuterated D-serine was evaluated in male Sprague-Dawley Rats at <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg PO. Elevated levels of urea nitrogen, creatine, and gamma glutamyl transferase (GGT) (which are markers indicative of nephrotoxicity) were seen in the <NUM> hr samples at the <NUM> and <NUM>/kg doses compared to control values and reference values provided by Charles River Laboratory.

Non-deuterated D-serine and deuterated D-serine (Compound <NUM>) were administered to male Sprague Dawley rats (intravenous (IV), <NUM>/kg in phosphate-buffered saline (PBS); and orally (PO), <NUM>/kg, <NUM>% methylcellulose in water). Three rats were used for each group. Blood was collected at the following time points: for IV dosing: pre-dose, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> hours post-dose; for PO dosing: pre-dose, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> hours post-dose PO. Urine was collected at pre-dose (minimum <NUM> hours), <NUM>-<NUM>, <NUM>-<NUM> and <NUM>-<NUM> hours. Plasma samples were analyzed and quantified for dosed compound LC-MS/MS.

It was found that deuterated D-serine (Compound <NUM>) had a half-life (T<NUM>/<NUM>) about <NUM>-fold longer than for the non-deuterated D-serine; the deuterated and non-deuterated compounds had a similar Tmax. Deuterated D-serine (Compound <NUM>) had a Cmax about <NUM>-fold greater than for the non-deuterated D-serine, and an AUCinf about <NUM>-fold greater than for the non-deuterated D-serine.

In a separate experiment, non-deuterated D-serine and two deuterated D-serine analogs (Compound <NUM> and Compound <NUM> (<NUM>% D)) were administered to male Sprague Dawley rats.

The results showed that Compound <NUM> and Compound <NUM> had similar PK parameters.

A modified-release tablet formulation of a D-D-serine is prepared using the materials shown in the table below:.

Tablet Strength: <NUM> D-D-serine (e.g., Compound <NUM>)
Total Tablet Wt: <NUM>.

The detailed synthesis of racemic <NUM>-amino-<NUM>-deutero-<NUM>-hydroxy-propanoic acid followed by resolution to obtain (<NUM>R)-<NUM>-amino-<NUM>-deutero-<NUM>-hydroxy-propanoic acid (Compound <NUM>) in high e. (enantiomeric excess) and with high % D is shown in Scheme <NUM> below.

As depicted in Scheme <NUM>, Compound <NUM> was prepared from non-deuterated D,L-serine. Proton NMR and mass spectral data were consistent with the structure shown above for Compound <NUM>: MS (M+H): <NUM>; MS (M-H): <NUM>; <NUM>H-NMR (<NUM>, D<NUM>O): δ <NUM> (dd, J<NUM>=<NUM>, J<NUM>=<NUM>, <NUM>). Deuterium incorporation was determined by proton NMR to be approximately <NUM>%. SFC (supercritical fluid chromatography) analysis of the benzyloxycarbonylamino derivative of Compound <NUM> revealed no trace of the S-enantiomer.

The details of the resolution of commercially available racemic <NUM>-amino-<NUM>,<NUM>,<NUM>-trideutero-<NUM>-hydroxy-propanoic acid to obtain (<NUM>R)-<NUM>-amino-<NUM>,<NUM>,<NUM>-tri-deutero-<NUM>-hydroxy-propanoic acid (Compound <NUM>) in high e. and with high % D are shown in Scheme <NUM> below.

As depicted in Scheme <NUM>, Compound <NUM> was obtained by resolution of commercially available racemic <NUM>-amino-<NUM>,<NUM>,<NUM>-trideutero-<NUM>-hydroxy-propanoic acid. Proton NMR and mass spectral data were consistent with the structure shown above for Compound <NUM>: MS (M+H): <NUM>; <NUM>H-NMR (<NUM>, D<NUM>O): deuterium incorporation was determined by proton NMR of a precursor and a derivative to be approximately <NUM>% at the methinyl position; deuterium incorporation at the methylenyl position is approximately <NUM>% (based on the stated purity of a precursor). SFC (supercritical fluid chromatography) analysis of the benzyloxycarbonylamino derivative of Compound <NUM> revealed no trace of the S-enantiomer.

The activation of the NMDA receptors by Compound <NUM> and by D-serine was assessed in an automated patch clamp system (ScreenPatch©) using HEK293 cells expressing human NMDAR subunits GluN1 and GluN2A.

Cells were treated with increasing concentrations of Compound <NUM> or d-serine (<NUM> to <NUM>). Peak current and steady state current were measured. The activity at the NMDA receptor was indistinguishable for the two compounds. The binding and activation of receptors by D-serine and Compound <NUM> were similar in all cases where measured. Compared to the non-deuterated compound, Compound <NUM> demonstrated nearly identical in vitro binding affinity for the glycine modulatory site of NMDAR. For the binding affinity of Compound <NUM> to the glycine site of NMDA receptor from rat cerebral cortical membranes, the average Ki for Compound <NUM> was <NUM> while the average Ki for D-serine was <NUM>.

A representative graph is depicted in <FIG>.

The distribution profile of Compound <NUM> was investigated in male Sprague-Dawley rats. The rats (<NUM>) were administered a single dose of Compound <NUM> (oral (PO)) at <NUM>/kg. At <NUM> hours after dosing, tissues from perfused brain and plasma were collected and analyzed by LC-MS. The concentration of Compound <NUM> in the cortex (location of the target of interest) was found to be greater than in plasma or other brain locations.

The plasma, cortex, brain stem, and cerebellum concentration at <NUM> hr for Compound <NUM> are shown in <FIG>.

The mean concentrations at <NUM> hr in the plasma, cortex, brain stem, and cerebellum were <NUM> ng/mL, <NUM> ng/g, <NUM> ng/g, and <NUM> ng/g, respectively.

Three groups each of <NUM> male Sprague-Dawley rats were administered a single dose per day of Compound <NUM> (oral (PO)) at <NUM>/kg for a total of <NUM> days. After <NUM> days, tissues from perfused brain and plasma were collected and analyzed by LC-MS at <NUM> hours (group <NUM>), <NUM> hours (group <NUM>) and <NUM> hours (group <NUM>) after dosing.

The concentration of Compound <NUM> in the rat cortex versus time after <NUM> days of dosing <NUM>/kg is shown in <FIG>.

Based on the concentration versus time data, the half-life (T<NUM>/<NUM>) of Compound <NUM> in the cortex (location of the target) was shown to be approximately <NUM> hours, in contrast to the much shorter plasma T<NUM>/<NUM> which was shown to be less than <NUM> hours. This result illustrates that the systemic PK is decoupled from the brain PK making Compound <NUM> a surprisingly valuable compound for the treatment of diseases that benefit from NMDAR activation (or increases in D-serine).

Claim 1:
A pharmaceutical composition comprising Compound <NUM>:
<CHM>
wherein
the pharmaceutical composition comprises <NUM> to <NUM> of the compound;
and
wherein each position designated specifically as deuterium has at least <NUM> % incorporation of deuterium;
or a pharmaceutically acceptable salt thereof;
and a pharmaceutically acceptable carrier.