Deuterated analogs of d-serine and uses thereof

Abstract

To provide pharmaceutical compositions for modulating N-methyl-D-aspartate receptor (NMDA receptor or NMDAR), and methods of use thereof.SOLUTION: Provided is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (in the formula, each of Y1, Y2a, and Y2b is independently H or D, provided that at least one of Y1, Y2a, and Y2b is D, and wherein each position designated specifically as deuterium has at least 50.1% incorporation of deuterium).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Background technology N-methyl-D-aspartate receptors (NMDA receptors or NMDARs) are neurotransmitters that bind to the Activation of NMDAR induces glutamate receptors and ion channels in the cytoplasm. NMDA receptors are involved in memory and mood. It plays a role in physiological processes that affect the brain. See, e.g., Nicholls et al., Neuron, 2008, 5 8(1):104-17. Agonists (N-methyl-D-aspartate or glutathione) mate (e.g., glutamate) and a co-agonist (e.g., glycine or D-serine) is required for NMDAR activation.

[0002] Agents that modulate NMDA receptors are believed to be useful in a variety of therapeutic applications. For example, memantine has been reported to treat Alzheimer's disease and dementia with Lewy bodies. However, treatment with NMDA modulators can cause side effects such as sedation and hallucinations. It may have side effects.

[0003] Anti-NMDAR encephalitis is characterized by the presence of antibodies against synaptic NMDARs It is an autoimmune encephalitis. Anti-NMDAR encephalitis (NMDA receptor antibody encephalitis or NMDAR encephalitis) (also known as inflammatory bowel disease) is the most common and best characterized antibody-mediated This resulted in a defined autoimmune neuronal disorder: encephalitis associated with antibodies against NMDAR. It primarily affects children and young adults, occurs with or without tumor complications, and is treatable. Although patients respond to anti-NMDAR encephalitis, relapses are possible. The exact incidence of anti-NMDAR encephalitis is unknown. Due to the rarity of the syndrome and the variety of clinical manifestations, anti-NMDAR syndrome is often misdiagnosed and overlooked. It can be easy to get carried away.

[0004] Schizophrenia is a chronic, devastating neurological disorder that ranks as the leading cause of disability worldwide. It is a mental disorder that afflicts almost 1% of the world's population, affects men and women equally, It affects all ethnic and socioeconomic groups with similar prevalence levels. sexual symptoms (hallucinations and delusional behavior), negative symptoms (anhedonia, social deficits and decreased motivation), and and three groups known as cognitive dysfunction (decreased ability to learn, remember, and executive function) Currently available antipsychotic drugs are effective in treating the positive symptoms. Although these drugs have shown efficacy for the symptoms, they have been limited in their ability to treat negative symptoms and cognitive deficits.

[0005] D-serine occurs naturally in the human body, but in much greater amounts than L-serine. Low. Only L-serine is found in proteins.

[0006] [ka] D-serine is an agonist of the NMDA receptor. Academic research has shown that oral administration of D-serine D2 antipsychotics (which bind to dopamine D2 receptors and inhibit the activity of dopamine D2 receptors) When added to antipsychotics (which inhibit or block neurotransmitter activity), positive and negative effects in schizophrenic patients demonstrated dose-dependent improvement in negative and cognitive symptoms. However, preclinical studies have It has been demonstrated that administration of D-serine can cause nephrotoxicity in rats. Furthermore, clinical findings suggesting renal dysfunction have been reported in some patients receiving high doses of D-serine. As a result, the clinical application of D-serine has been limited to date. It was.

[0007] NMDAR-mediated encephalitis and neurological diseases, including schizophrenia There remains a need for improved treatments for the condition.

[0008] Summary of the Invention In this study, the deuterated form of D-serine (DD-serine) was found to be reduced compared to D-serine. It has been found that deuterated steroids can have advantageous properties, including reduced nephrotoxicity. D-serine may restore NMDA receptor activity in key disease-related brain regions It has.

[0009] In one aspect, the present invention provides a deuterated form of D-serine, a pharmaceutically acceptable salt thereof, The present invention relates to analogs and prodrugs of, pharmaceutical compositions thereof, and methods of use.

[0010] In one aspect, the present invention provides a compound of formula I

[0011] [ka] [In the formula, R 1 -OH, -OD, -OC 1~4 alkyl, or amino acid residue, R 2 H, D, -C 1~4 Alkyl, -C(O)-C 1~6 Alkyl, or -C(O )-C 1~6 is hydroxyalkyl, R 3 is H, D, or an amino acid residue, R 4 is H or D, Y 1 , Y 2aand Y 2b are independently H or D, with the proviso that Y 1 , Y 2a and Y 2b is specifically designated as deuterium, provided that at least one of Deuterium incorporation at each designated position is at least 50.1%. or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; The present invention provides a pharmaceutical composition comprising:

[0012] In some embodiments, in compounds of Formula I, R 1 or R 3 DD-serine residue (deuterated D-serine residue).

[0013] In some embodiments, the compound is a compound of Formula II

[0014] [ka] [In the formula, Y 1 , Y 2a and Y 2b is independently H or D, with the proviso that Y 1 , Y 2a and Y 2b at least one of the following must be D] or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound is selected from Compound 100 and Compound 103. can be.

[0016] [ka]

[0017] The present invention provides such compounds and compositions, including N-methyl-D-aspartic acid (NM-DAS). Diseases that are beneficially treated by administering modulators of DA) receptor function and Also provided are uses in methods for treating conditions, including epilepsy, NMD, AR encephalitis, Parkinson's disease, cognitive deficits in Parkinson's disease, Alzheimer's disease, mild Cognitive impairment, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia (schizophrenia) positive, cognitive and / or negative symptoms, and prodromal schizophrenia), bipolar disorder, Bipolar mania, bipolar depression, treatment-resistant depression, cognitive deficits in depression, major depressive disorder disorders such as anxiety disorder, generalized anxiety disorder, major depressive disorder with mixed features, and Huntington's disease. Cognitive deficits associated with diseases or conditions, subjective cognitive decline, traumatic brain injury, Lewy body cognitive impairment 1. A method of treating a disease or condition selected from the group consisting of: Included are methods comprising the step of administering an effective amount of a compound or pharmaceutical composition of the present invention.

[0018] The present invention provides a method for treating schizophrenia (including the positive, negative and / or cognitive symptoms of schizophrenia). The method comprises administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the present invention. Also provided is a method comprising administering

[0019] Further aspects and embodiments of the invention are also disclosed herein. [Brief explanation of the drawings]

[0020] [Figure 1] 1 is a graph showing the concentration of Compound 100 in rat plasma, hippocampus, and cortex after administration of a single dose of 30 mg / kg. [Figure 2]1 is a graph showing the concentration of non-deuterated D-serine in rat plasma, hippocampus, and cortex after administration of a single dose of 300 mg / kg. [Figure 3] 1 is a graph showing the concentration of Compound 100 in rat plasma, hippocampus, and cortex after administration of a single dose of 150 mg / kg. [Figure 4] 1 is a graph showing urea nitrogen levels in rats after administration of a single 150 mg / kg dose of Compound 100 or non-deuterated D-serine. [Figure 5] 1 is a graph showing creatinine levels in rats after administration of a single 150 mg / kg dose of Compound 100 or non-deuterated D-serine. [Figure 6] 1 is a graph showing GGAT levels in rats after administration of a single 150 mg / kg dose of Compound 100 or non-deuterated D-serine. [Figure 7] FIG. 1 is a graph showing creatinine levels in rats after PO (oral) administration of non-deuterated and deuterated D-serine (Compound 100). [Figure 8] 1 is a graph showing the mean creatinine levels in rats after PO (oral) administration of non-deuterated and deuterated D-serine (Compound 100). [Figure 9] 1 is a graph showing urea nitrogen (BUN) levels in rats after PO (oral) administration of non-deuterated and deuterated D-serine (Compound 100). [Figure 10] 1 is a graph showing mean urea nitrogen (BUN) levels in rats after PO (oral) administration of non-deuterated and deuterated D-serine (Compound 100). [Figure 11] 1 is a graph showing urea nitrogen levels in rats after administration of various doses of non-deuterated D-serine. [Figure 12] 1 is a graph showing creatinine levels in rats after administration of various doses of non-deuterated D-serine. [Figure 13] 1 is a graph showing GGAT levels in rats after administration of various doses of non-deuterated D-serine. [Figure 14] 1 is a line graph showing NMDA receptor activity of non-deuterated ("protio") D-serine and Compound 100 using an automated patch clamp system. [Figure 15] 1 is a bar graph showing the accumulation of Compound 100 in the Sprague-Dawley rat brain. [Figure 16] 1 is a plot showing the concentration of Compound 100 in the brain of Sprague-Dawley rats after 4 days of dosing.

[0021] Detailed Description of the Invention In one aspect, the present invention provides a deuterated form of D-serine, a pharmaceutically acceptable salt thereof, The present invention relates to analogs and prodrugs of, pharmaceutical compositions thereof, and methods of use.

[0022] In one aspect, the present invention provides a compound of formula I

[0023] [ka] [In the formula, R 1 -OH, -OD, -OC 1~4 alkyl, or amino acid residue, R 2 H, D, -C 1~4 Alkyl, -C(O)-C 1~6 Alkyl, or -C(O )-C 1~6 is hydroxyalkyl, R 3 is H, D, or an amino acid residue, R 4 is H or D, Y 1 , Y 2a and Y 2b are independently H or D, with the proviso that Y 1 , Y 2a and Y 2bis specifically designated as deuterium, provided that at least one of Deuterium incorporation at each designated position is at least 50.1%. or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the deuterium intake at each position specifically designated as deuterium is The coverage is at least 90%.

[0025] In some embodiments, in compounds of Formula I, R 1 or R 3 DD-serine residue (deuterated D-serine residue). 1 or R 3 is a DD-serine residue When R 1 and R 3 Both are DD-serine residues. When the compound of formula I is a tripeptide.

[0026] In some embodiments of Formula I, Y 2a and Y 2b One of them is H and the other is D is.

[0027] In another aspect, the present invention provides a compound of formula I

[0028] [ka] [In the formula, R 1 -OH, -OD, -OC 1~4 alkyl, or amino acid residue, R 2 H, D, -C 1~4 Alkyl, -C(O)-C 1~6 Alkyl, or -C(O )-C 1~6 is hydroxyalkyl, R3 is H, D, or an amino acid residue, R 4 is H or D, Y 1 , Y 2a and Y 2b are independently H or D, with the proviso that Y 1 , Y 2a and Y 2b is specifically designated as deuterium, provided that at least one of Deuterium incorporation at each designated position is at least 50.1%. or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; The present invention provides a pharmaceutical composition comprising:

[0029] In some embodiments, the deuterium intake at each position specifically designated as deuterium is The coverage is at least 90%.

[0030] In some embodiments, in compounds of Formula I, R 1 or R 3 DD-serine residue (deuterated D-serine residue).

[0031] In some embodiments of the compositions of the present invention, the compound is a compound of Formula II

[0032] [ka] [In the formula, Y 1 , Y 2a and Y 2b is independently H or D, with the proviso that Y 1 , Y 2a and Y 2b at least one of the following must be D] or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, in compounds of Formula II, Y 1 is D.

[0034] In some embodiments, in compounds of Formula II, Y 2a and Y 2b are H is.

[0035] In some embodiments, in compounds of Formula II, Y 1 is D and Y 2a and Y 2b are H respectively.

[0036] In some embodiments, in compounds of Formula II, Y 2a and Y 2b are D In another embodiment of Formula II, Y 2a and Y 2b One of them is H and the other is It's D.

[0037] In some embodiments, the compound of formula II is selected from Compound 100 and Compound 103. are selected.

[0038] [ka]

[0039] In some embodiments, in compounds of Formula II, The deuterium incorporation at each position is at least 90%. In the compounds of Formula II, the incorporation of deuterium at each position specifically designated as deuterium is minimal. In some embodiments, the compound of Formula II contains at least 95% as deuterium. The deuterium incorporation at each position specifically designated in the formula is at least 97%.

[0040] In some embodiments, in compounds of Formula II, Y 1 is D and Y 2a and Y 2b are H and Y 1 The deuterium incorporation of the Both are 95%, or at least 97%.

[0041] In some embodiments, in compounds of Formula II, Every atom is present in its natural isotopic abundance.

[0042] In one aspect, the present invention provides a compound of formula Ia

[0043] [ka] [In the formula, R 1 is -OH, -OD, or -O-PG 1 , -OC 1~6 Cycloalkyl, also is an amino acid residue, R 2 H, D, -C 1~4 Alkyl, -C(O)-C 1~6 Alkyl, or -C(O )-C 1~6 is hydroxyalkyl, a)R 3 is H, D, or PG 2 and R 4 is H or D and deuterium incorporation at each position specifically designated as deuterium is at least 50.1% or b)R 3 and R 4 together with the nitrogen atom form a heterocyclic protecting group, Here, PG 1 and P.G. 2is a prodrug group] or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the deuterium intake at each position specifically designated as deuterium is In some embodiments, the concentration is at least 90%. The deuterium incorporation at each designated position is at least 95%. In each position specifically designated as deuterium, the deuterium incorporation is at least 9 It is 7%.

[0045] As used herein, the term "prodrug group" refers to a group that acts under physiological conditions (e.g., in vivo). cleaved to reveal the deprotected moiety (e.g., carboxylate or amino group) Therefore, PG 1 is cleaved under physiological conditions to Deprotecting the carboxylate group (i.e., the compound of formula Ia, where R 1 (is OH) Suitable PG groups include any group that provides 1 Examples of groups include -C 1~6 Alkyl (methyl, ethyl, isopropyl, tert-butyl, neopentyl, etc.), -C 3~6 cycloalkyl (including cyclohexyl), or amino acid residues. 2 teeth The cleavage group can be any group that is cleaved under physiological conditions to provide a deprotected amino group. Suitable PG 2 Examples of groups include amino acid residues or groups of the formula -C(O)OC(Z 1 Z 2 ) OR 5 wherein Z 1 and Z 2are independently selected from H, D, C1-C2 alkyl, or together with the carbon atoms to which they are attached form a C3-C5 carbocyclic ring, R 5 teeth , C 1~6 Aliphatic group (C 1~6 Alkyl or partially or fully unsaturated C 2~6 Aliphatic groups (including), C 3~6 Cycloalkyl, or C 4~6 Carbocyclyl (partially or fully unsaturated (possibly) and R 5 each is aryl or heterocycloalkyl and optionally (further substituted by R) 3 and R 4 Heterocyclic protection formed by The group has the following structure:

[0046] [ka] and R 6 However, methyl, ethyl, n-propyl, n-butyl, cyclohexyl, -CH It can be a group that is 2C6H5 or -CH2CH2C6H5.

[0047] In some embodiments, in compounds of Formula Ia, R 1 or R 3 DD-Seri The residue is a deuterated D-serine residue.

[0048] In some embodiments, the compound of Formula I or II has at least about 90% stereochemistry. For example, in the case of a compound of formula I, the compound is , at least 90% structure

[0049] [ka] and 10% or less

[0050] [ka] Includes.

[0051] In some embodiments, the compound of formula Ia has a stereoisomeric purity of at least about 90%. For example, in the case of a compound of formula Ia, the compound contains at least 90% of the structure .

[0052] Compounds of Formula I or II can exist as zwitterions (e.g., compounds of Formula II The compound has the structure

[0053] [ka] It is understood that such zwitterionic forms are included within the scope of the present invention. Let's solve it.

[0054] In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for intravenous administration.

[0055] In one aspect, the present invention provides a compound of formula A

[0056] [ka] [In the formula, R 1 -OH, -OD, -OC 1~4 alkyl, or amino acid residue, R 2 H, D, -C 1~4 Alkyl, -C(O)-C 1~6 Alkyl, or -C(O )-C 1~6 is hydroxyalkyl, R 3is H, D, or an amino acid residue, R 4 is H or D, Y 1 , Y 2a and Y 2b are independently H or D, with the proviso that Y 1 , Y 2a and Y 2b is specifically designated as deuterium, provided that at least one of Deuterium incorporation at each designated position is at least 50.1%. or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; a pharmaceutical composition comprising a therapeutically effective amount of a compound having a D-amino acid configuration; Pharmaceutical compositions are provided.

[0057] In some embodiments, the deuterium intake at each position specifically designated as deuterium is In some embodiments, the concentration is at least 90%. The deuterium incorporation at each designated position is at least 90%. In each position specifically designated as deuterium, the deuterium incorporation is at least 9 It is 5%.

[0058] R 1 or R 3 is an amino acid residue, the compounds of formula I may be It is a dipeptide in which the acid is DD-serine.

[0059] In some embodiments, the present invention provides a deuterated form of glycine, its pharmaceutically acceptable salts. The present invention relates to salts, analogs and prodrugs thereof, pharmaceutical compositions thereof, and methods of use thereof.

[0060] In some embodiments, the present invention provides a compound of formula III

[0061] [ka] [In the formula, X 1a , X 1b , and X 2 each is independently H or D; X 3 are H or D, However, X 1a and X 1b at least one of the following must be D] or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; The present invention provides a pharmaceutical composition comprising:

[0062] In some embodiments, in compounds of formula III, X 1a is D and X 1b is H is.

[0063] In some embodiments, in compounds of formula III, X 1a is H and X 1b is D is.

[0064] In some embodiments, in compounds of formula III, X 1a and X 1b are respectively It's D.

[0065] In some embodiments, the compound is a compound described in Table C (below) or a combination thereof. The compound is selected from any one of the physiologically acceptable salts.

[0066] [Table 1]

[0067] In some embodiments, the present invention provides a deuterated form of sarcosine, its pharmaceutically acceptable salts. The present invention relates to salts thereof, analogs and prodrugs thereof, pharmaceutical compositions thereof, and methods of use.

[0068] In some embodiments, the present invention provides a compound of formula IV

[0069] [ka] [In the formula, X 4a , X 4b , X 5 and X 6 each is independently H or D; R a are CH3, CH2D, CD2H or CD3, respectively; However, X 4a , X 4b and R a at least one of them must contain D] or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; The present invention provides a pharmaceutical composition comprising:

[0070] In some embodiments, in compounds of formula IV, X 4a is D and X 4b is H be.

[0071] In some embodiments, in compounds of formula IV, X 4a is H and X 4b is D be.

[0072] In some embodiments, in compounds of formula IV, X 4a and X 4b are D is.

[0073] In some embodiments, in compounds of formula IV, R ais CD3.

[0074] In some embodiments, the compound is a compound described in Table D (below) or a compound thereof. The compound is selected from any one of the physiologically acceptable salts.

[0075] [Table 2]

[0076] In some embodiments, the present invention provides deuterated forms of D-alanine, its pharmaceutically acceptable salts. The present invention relates to salts thereof, analogs and prodrugs thereof, pharmaceutical compositions thereof, and methods of use.

[0077] In some embodiments, the present invention provides a compound of formula V

[0078] [ka] [In the formula, X 7 and X 8 each is independently H or D; X 9 are H or D, R b are CH3, CH2D, CD2H or CD3, respectively; However, X 7 and R b at least one of them must contain D] or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; The present invention provides a pharmaceutical composition comprising:

[0079] In some embodiments, in compounds of formula V, X 7 is H and R b is CD3 do.

[0080] In some embodiments, in compounds of formula V, X 7 is D and R b is CD3 do.

[0081] In some embodiments, in compounds of formula V, X 7 is D and R b is CH3 do.

[0082] In some embodiments, the compound is a compound described in Table E (below) or a combination thereof. The compound is selected from any one of the physiologically acceptable salts.

[0083] [Table 3]

[0084] In some embodiments, the present invention provides deuterated forms of D-aspartic acid, its pharmaceutically acceptable salts. Acceptable salts, analogs and prodrugs thereof, pharmaceutical compositions thereof, and methods of use do.

[0085] In some embodiments, the present invention provides a compound of formula VI

[0086] [ka] [In the formula, X 10 , X 11 , X 12a , X 12b , and X 13 Each of the is independently H or D and X 14 are H or D, However, X 10 , X 12a and X 12b At least one of the following must be D: ] or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; The present invention provides a pharmaceutical composition comprising:

[0087] In some embodiments, in the compound of formula VI, X 10 is H and X 12a is H and X 12b is D.

[0088] In some embodiments, in the compound of formula VI, X 10 is H and X 12a is D and X 12b is D.

[0089] In some embodiments, in the compound of formula VI, X 10 is D and X 12a is H and X 12b is H.

[0090] In some embodiments, in the compound of formula VI, X 10 is D and X 12a is H and X 12b is D.

[0091] In some embodiments, in the compound of formula VI, X 10 is D and X 12a is D and X 12b is D.

[0092] In some embodiments, the compound is a compound described in Table F (below) or a combination thereof. The compound is selected from any one of the physiologically acceptable salts.

[0093] [Table 4]

[0094] In some embodiments, the compound is one described in Table C, Table D, Table E, or Table F (above). or a pharmaceutically acceptable salt thereof (wherein the compound is not designated as deuterium Any atom present in its natural isotopic abundance is selected from any one of:

[0095] In some embodiments, in compounds of formula III, IV, V, or VI, deuterium and The deuterium incorporation at each position specifically designated as a nucleotide is at least 90%.

[0096] In some embodiments, in compounds of formula III, IV, V, or VI, deuterium and Any atom not designated as an atom is present in its natural isotopic abundance.

[0097] In some embodiments, the compound of formula V or VI has at least about 90% stereochemistry. It has isomeric purity.

[0098] In some embodiments, one or more compounds of formula III, IV, V, and VI In some embodiments, the pharmaceutical composition is suitable for oral administration. The composition contains 0.1 g to 60 g of a compound of formula III, IV, V or VI.

[0099] In some embodiments, one or more compounds of formula III, IV, V, and VI In some embodiments, the pharmaceutical composition is suitable for intravenous administration. The composition contains 0.1 g to 60 g of a compound of formula III, IV, V or VI.

[0100] Another aspect of the present invention is a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof: It is a unit dosage form containing the compound together with a pharmaceutically acceptable carrier or diluent. In the form, the amount of the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof is 1 In some embodiments, the amount of the compound of formula I or The amount of the compound of formula II or a pharmaceutically acceptable salt thereof is about 1 g, about 2 g, about 3 g, about 4 g, or about 5 g, about 8 g, about 10 g, or in the range of about 5 g to about 10 g. In some embodiments, a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof The amount is 1g, 2g, 3g, 4g, 5g, 8g, 10g, or in the range of 5-10g. In some embodiments, the unit dose form is a tablet. Thus, the unit dosage form is a sachet.

[0101] Another aspect of the present invention is a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof: It is a packaged pharmaceutical preparation containing the pharmaceutical preparation together with a container or package. In this case, the amount of the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is 1 g to 10 g, or in the range of 1 g to 5 g. In some embodiments, the compound of Formula I or Formula II The amount of the compound or a pharmaceutically acceptable salt thereof may be about 1 g, about 2 g, about 3 g, about 4 g, or Or about 5 g, about 8 g, about 10 g, or in the range of about 5 g to about 10 g. In embodiments, the amount of the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof is: 1g, 2g, 3g, 4g, 5g, 8g, 10g, or in the range of 5-10g. In some embodiments, the packaged pharmaceutical formulation comprises a tablet. , packaged pharmaceutical formulations include sachets.

[0102] In another aspect, the present invention provides a method of treatment.

[0103] In one embodiment, the present invention provides a method for treating NMDAR encephalitis in a patient in need thereof. The present invention provides a method for treating a rheumatoid arthritis comprising administering to a subject an effective amount of a pharmaceutical composition of the present invention.

[0104] In another embodiment, the present invention provides a method for treating epilepsy, NMDAR encephalitis, Parkinson's disease, parkinsonism, Cognitive deficits in Son's disease, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (AL) S), Huntington's disease, schizophrenia (positive, cognitive and / or negative symptoms of schizophrenia, and prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression, treatment-resistant Depression, cognitive deficits in depression, major depressive disorder, generalized anxiety disorder, and mixed features Cognitive deficits, primarily associated with diseases or conditions such as major depressive disorder, and Huntington's disease A method for treating subjective cognitive decline, traumatic brain injury, and dementia with Lewy bodies, comprising: A method is provided for administering to a subject in need thereof an effective amount of a pharmaceutical composition of the present invention.

[0105] In another embodiment, the present invention provides a method for treating post-traumatic stress disorder (PTSD), ataxia, and seizures. Methods for treating additional diseases or conditions, including phosphorus deficiency disorders, including The method includes administering to a subject an effective amount of a pharmaceutical composition of the present invention.

[0106] In another embodiment, the present invention provides a method for treating depression in a patient in need thereof. A method is provided that includes the step of administering to a subject an effective amount of a pharmaceutical composition of the invention.

[0107] In another aspect, the present invention provides a method for increasing NMDA receptor function, comprising: The pharmaceutical composition of the present invention is contacted with a cell so as to increase NMDA receptor function in the cell. The present invention provides a method including the steps of:

[0108] In another aspect, the present invention provides a method for treating schizophrenia (positive, negative and / or cognitive impairment of schizophrenia). A method for treating a condition, including a cognitive impairment, comprising administering to a subject in need thereof an effective amount of a compound of the present invention. The present invention provides a method for treating a rheumatoid arthritis comprising administering a compound or pharmaceutical composition to a patient.

[0109] In some embodiments of any of the above-described compounds, compositions or methods, Administration of compounds (e.g., Compound 100) has been shown to reduce nephrotoxicity in the absence of (non-deuterated) D-serine. reduced compared to administration of an equivalent dose.

[0110] definition The term "treating" refers to treating a disease (e.g., a disease or disorder delineated herein) that is caused by or associated with a disease or disorder. Reduce, inhibit, attenuate, decrease, arrest, or stabilize the growth or progression of a disease "To reduce the severity of or ameliorate the symptoms associated with a disease" means to reduce the severity of or ameliorate the symptoms associated with a disease.

[0111] A "disease" is any condition that damages or interferes with the normal function of a cell, tissue, or organ. It means a condition or disorder.

[0112] As used herein, the term "subject" includes human and non-human mammals. Examples of the species include, but are not limited to, mice, rats, guinea pigs, rabbits, dogs, Examples include cats, monkeys, apes, pigs, cows, sheep, horses, etc. In this study, the subject is a human suffering from schizophrenia.

[0113] The term "alkyl" refers to a monovalent saturated hydrocarbon group. C1-C4 alkyl refers to a monovalent saturated hydrocarbon group. C1-C6 alkyl is an alkyl having 1 to 6 carbon atoms. In some embodiments, the alkyl is linear or branched. In some embodiments, alkyl can be primary, secondary, or tertiary. The alkyl group is not limited to, but may be, for example, methyl; ethyl; ;Propyl, including n-propyl and isopropyl;n-butyl, isobutyl, se Butyl, including c-butyl, and t-butyl; e.g., n-pentyl, isopentyl, and pentyl, including neopentyl; and, for example, n-hexyl and 2-methyl Examples of primary alkyl groups include, but are not limited to, hexyl, including pentyl. However, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n- The secondary alkyl group includes, but is not limited to, isopropyl, hexyl, and the like. Tertiary alkyl groups include propyl, sec-butyl, and 2-methylpentyl. Examples of C1-C6 hydroxy groups include, but are not limited to, t-butyl. An "alkyl" group is a C1-C6 alkyl group substituted with one to three hydroxyl groups. do.

[0114] In synthetic compounds, slight variations in natural isotope abundances occur depending on the chemicals used in the synthesis. It is recognized that this occurs depending on the source of the material. Therefore, preparations of Compound 1 may contain small amounts of Naturally contains deuterated isotopologues. Naturally abundant stable isotopologues of hydrogen and carbon. Despite this variation, the concentration of stable isotopes is comparable to the degree of stable isotope substitution in the compounds of the present invention. For example, Wada, E et al., Seikagaku, 1994, 66:15; See Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725. That is what I mean.

[0115] The term "DD-serine" refers to a deuterated analog of the amino acid serine in the (D)-configuration. DD-serine refers to the structure of formula II

[0116] [ka] [In the formula, Y 1 , Y 2a and Y 2b is independently H or D, with the proviso that Y 1 , Y 2a and Y 2b at least one of the following must be D] It can be expressed as:

[0117] The term "amino acid residue" refers to a residue of the general formula -C(O)-CHR-NH or -HO-C( The group -C(O)-CHR-NH- and its N-alkylated derivatives (-C(O)-CHR-N (alkyl)-) (wherein R is an amino acid side chain), and refers to (D)-, (L)- or It includes natural and synthetic amino acids in the racemic (D,L) configuration. Variable element R of I 1 or R 2 is an amino acid residue, the amino acid residue has an amide bond It will be understood that the amino acid is linked to the remainder of the molecule via an amino acid. Exemplary amino acids include any naturally occurring amino acid. Amino acid residues are included, including their deuterated forms. It can be a residue of substituted D-serine (DD-serine).

[0118] In the compounds of the present invention, any atom not specifically designated as a particular isotope is It is intended to represent any stable isotope of that atom. When is specifically designated as "H" or "hydrogen", that position replaces the hydrogen with its natural It is understood that the abundance is determined by the isotopic composition. In embodiments, when a position is specifically designated as "H" or "hydrogen" , the position is at least 80%, at least 90%, at least 95%, at least 9 6%, at least 97%, at least 98%, or at least 99% hydrogen. In some embodiments specifically described, a position may be designated as "H" or "hydrogen." When specifically designated by the ', the position may be ≦20% deuterium, ≦10% deuterium, ≦ 5% deuterium, ≤4% deuterium, ≤3% deuterium, ≤2% deuterium, or ≤1% heavy water Additionally, unless otherwise noted, if a position is marked with "D" or "deuterium" ", the position is designated as ... have an abundance at least 3340 times greater than 0.015% (i.e., at least 50 This is understood to be a deuterium uptake of 0.1%.

[0119] As used herein, the term "isotopic enrichment factor" refers to the ratio of the isotopic abundance of a specified isotope to the natural abundance of a specified isotope. It means the ratio to the natural abundance.

[0120] In other embodiments, the compounds of the present invention contain the isotopic enrichment of each designated deuterium atom. A contraction factor of at least 3500 (52.5% deuterium at each designated deuterium atom) deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 ( 67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least At least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466 0.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or or at least 6633.3 (99.5% deuterium incorporation).

[0121] In some embodiments, the compounds of the present invention contain deuterium atoms at each designated deuterium atom. In some embodiments, the compound of the present invention has a cytotoxicity of at least 52.5%. has a deuterium incorporation of at least 60% for each designated deuterium atom. In embodiments, the compounds of the present invention include deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the present invention have a specific In some embodiments, the deuterium incorporation of each of the deuterium atoms is at least 75%. In the compounds of the present invention, the deuterium incorporation at each designated deuterium atom is small. In some embodiments, the compounds of the present invention have a specified weight ratio of at least 82.5%. In some embodiments, the deuterium incorporation of each hydrogen atom is at least 90%. In the compounds of the present invention, the deuterium incorporation of each designated deuterium atom is at least 9 In some embodiments, the compounds of the present invention have a designated deuterium atom and a corresponding deuterium atom. In some embodiments, the deuterium incorporation of each is at least 97.5%. In this compound, the deuterium incorporation of each designated deuterium atom is at least 99%. In some embodiments, the compounds of the present invention have the designated weight of each deuterium atom. The hydrogen uptake is at least 99.5%.

[0122] Deuterium incorporation in the compounds of the present invention can be measured using a variety of techniques. Some of the various techniques are known in the art. For example, 1 Using H NMR (e.g., to a non-deuterated position(s), e.g., to a deuterated position (by measuring the absence or decrease of the proton signal corresponding to It is possible to measure the load.

[0123] The term "isotopologue" refers to a compound whose chemical structure is identical to that of a specific compound of the present invention and its isotopic composition. It refers to a species that differs only in its structure.

[0124] The term "compound" when referring to a compound of the present invention means that there are no isotopic groups between the constituent atoms of the molecule. It refers to a group of molecules that have the same chemical structure except for the possibility of somatic variants. The compound represented by the chemical structure It contains a molecule with deuterium in one or more of the designated deuterium positions in its structure. It will be apparent to one skilled in the art that the present invention may include isotopologues having hydrogen atoms in their numbers. The relative amounts of such isotopologues in the compounds of the invention may vary depending on the amount of isotopologue used to make the compound. The isotopic purity of the deuteration reagents used and the various synthesis methods used to prepare the compounds The efficiency of deuterium incorporation during the synthesis step depends on several factors.

[0125] The present invention also provides salts of the compounds of the present invention.

[0126] A salt of a compound of the present invention may be formed between an acid and a basic group, such as an amino functional group of the compound, or between a base and an amine functional group. and an acidic group, such as a carboxyl functional group, of the compound. The compound is a pharmaceutically acceptable acid addition salt. In one embodiment, the acid addition salt is a deuterium oxide salt. It may be an acid addition salt.

[0127] As used herein, the term "pharmaceutically acceptable" means that, within the scope of sound medical judgment, Can be used in contact with human and other mammalian tissues without significant toxicity, irritation, or allergic response "Pharmaceutical" refers to an ingredient that is suitable for use in a pharmaceutical product and is commensurate with a reasonable benefit / risk ratio. "Salts that are directly or indirectly acceptable to the compounds of the present invention after administration to a recipient" are intended to mean compounds that are directly or indirectly acceptable to the "Pharmaceutically acceptable counterion" means any non-toxic salt that can be provided by is the ionic portion of the salt that is non-toxic when released from the salt after administration to a recipient. do.

[0128] Acids commonly used to form pharmaceutically acceptable salts include hydrogen disulfide, hydrochloric acid, , inorganic acids such as hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and para-toluene Sulfonic 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, ethane Sulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, Organic acids such as carbonic, succinic, citric, benzoic and acetic acids, as well as related inorganic and Such pharmaceutically acceptable salts include sulfates, organic acids, etc. Pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, phosphoric acid Dihydrogen salt, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate Phosphate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate , heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l, 6-diazolate salts, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, Hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates Salt, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate , citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartaric acid Salt, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthyl Salts include talen-2-sulfonate, mandelate and other salts. Pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid. In particular, those formed with organic acids such as maleic acid. In this context, acids commonly used to form pharmaceutically acceptable salts include at least These include the above inorganic acids in which one hydrogen has been replaced by deuterium.

[0129] Pharmaceutically acceptable salts include salts of compounds of the invention having an acidic functional group, such as a carboxylic acid functional group. Exemplary bases include sodium, potassium, and hydroxides of alkali metals, including lithium; alkali metals such as calcium and magnesium hydroxides of other metals such as aluminum and zinc, ammonia, non-substituted substituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexyl Tributylamine; Pyridine; N-methyl, N-ethylamine; Diethylamine amine; triethylamine; N,N-dimethyl-N-(2-hydroxyethyl)amine or is a mono-, bis-, or tris-(2-hydroxyethyl)amine, such as tri-(2-hydroxyethyl)amine. OH-(C1-C6)-alkylamine;N-methyl-D-glucamine;morpholine; Organic amines such as thiomorpholine, piperidine, and pyrrolidine, as well as arginine, lysine, and Examples of amino acids include, but are not limited to, amino acids such as riboflavin.

[0130] Some compounds of the present invention (e.g., compounds of Formula I, II, V, or VI) have an asymmetric carbon atom. A hydrogen atom (i.e., —NH or NR in compounds of Formula I or II) 3 R 4 and Y 1 It contains one or more additional asymmetric carbon atoms. In some embodiments, the compounds of Formula I or II substantially disperse other possible stereoisomers. For example, the compound of formula I is a compound of the structure

[0131] [ka] and the compound of formula II is substantially free of a compound of the structure

[0132] [ka] As used herein, the term "substantially free of other stereoisomers" , less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably is present in less than 5% of other stereoisomers, most preferably in less than 2% of other stereoisomers It means that for a given compound, individual stereoisomers (e.g., enantiomers or Methods for obtaining or synthesizing diastereomers are known in the art, and most It can be applied to final compounds or starting materials or intermediates as operable.

[0133] Unless otherwise indicated, the disclosed compounds may contain one or more chiral centers, the stereochemistry of which is not specified. When named or depicted by a structure that has more than one, all possible It is understood to represent stereoisomers.

[0134] As used herein, the term "stable compound" refers to a compound that is sufficiently stable to allow its manufacture. The quality and integrity of the compound may be verified for the purposes detailed herein (e.g., as a therapeutic agent). Therapeutic compounds, isolatable or storable intermediate compounds, which treat the responsive disease or condition. sufficient to be useful for formulation into therapeutic products, intermediates for use in the production This refers to a compound that lasts for a certain period of time.

[0135] "Stereoisomer" refers to both enantiomers and diastereomers. "sec" or "s-" respectively refer to second class. "n-" refers to normal. "i-" refers to iso. "US" refers to the United States. .

[0136] "Deuterium substituted" means that one or more hydrogen atoms have been replaced with a corresponding number of deuterium atoms. This means that it has been replaced by

[0137] Throughout this specification, variables may be referred to collectively (e.g., "each R "), or may be specifically referred to (e.g., R 1 , R 2 , R 3 etc.) Unless otherwise specified Unless otherwise indicated, when variables are referred to generically, the specific embodiment of that particular variable is The term "individual" is intended to encompass all aspects of life.

[0138] As used herein, the term "schizophrenia" refers to a mental disorder that includes at least two of the following: Harm: delusions, hallucinations, disorganized speech, severely disorganized behavior, or catatonia sexual behavior, or negative symptoms. Diagnose the patient as schizophrenic using DSM-IV criteria. (APA, 2013, Diagnostic and Statistical Manual of Mental Disorders ( Fifth Edition), Washington, DC).

[0139] The "negative" symptoms of schizophrenia include blunted affect, anergy, allopathic behavior, and social withdrawal. and SANS (Scales for the Assessment of Negative Symptoms; Andreasen, 1983). (See SANS, Iowa City, Iowa) Cut.

[0140] The "positive" symptoms of schizophrenia include delusions and hallucinations, and are measured by the PANSS (Positive and Negative Symptom Scale). (see Kay et al., 1987, Schizophrenia Bulletin 13:261-276) and can be measured.

[0141] The "cognitive" symptoms of schizophrenia include disorders of the acquisition, organization, and use of intellectual knowledge, and can be classified as positive or negative. Personal Injury Symptom Scale-Cognitive Subscale (PANSS-Cognitive Subscale) ( Lindenmayer et al., 1994 , J. Nerv. Ment. Dis. 182:631-638) or by Wisconsin Card It can be measured using cognitive tasks such as the Sorting Test.

[0142] therapeutic composition In some aspects or embodiments, the present invention provides a compound of formula I

[0143] [ka] [In the formula, R 1 -OH, -OD, -OC 1~4 alkyl, or amino acid residue, R 2 H, D, -C 1~4 Alkyl, -C(O)-C 1~6 Alkyl, or -C(O )-C 1~6 is a hydroxyalkyl, R 3 is H, D, or an amino acid residue, R 4 is H or D, Y 1 , Y 2a and Y 2b are independently H or D, with the proviso that Y 1 , Y 2a and Y 2b at least one of the following must be D] or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; The present invention provides a pharmaceutical composition comprising:

[0144] In some embodiments of the compound of Formula I, R1 or R 3 is a DD-serine residue (the compound is a dipeptide).

[0145] In another aspect, the present invention provides a compound of formula Ia or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutical agent and a physiologically acceptable carrier.

[0146] In some embodiments, the compound is a compound of Formula II

[0147] [ka] [In the formula, Y 1 , Y 2a and Y 2b is independently H or D, with the proviso that Y 1 , Y 2a and Y 2b at least one of the following must be D] or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments of the compounds of Formula I or Formula II, Y 1 is D.

[0149] In some embodiments of the compounds of Formula I or Formula II, Y 2a and Y 2b is that They are all H.

[0150] In some embodiments of the compounds of Formula I or Formula II, Y 2a and Y 2b is that They are all D.

[0151] In some embodiments, the compound of formula II is selected from Compound 100 and Compound 103. are selected.

[0152] [ka]

[0153] In some embodiments of compounds of Formula I or Formula II, The deuterium incorporation at each designated position is at least 90%.

[0154] In some embodiments, in compounds of Formula II, Y 1 is D and Y 2a and Y 2b are H and Y 1 The deuterium incorporation of the Both are 95%, or at least 97%.

[0155] In some embodiments of compounds of Formula I or Formula II, Any atom not present is present at its natural isotopic abundance.

[0156] In some embodiments of the compound of Formula I or Formula II, the compound has a molecular weight of at least about 9 It has a stereoisomeric purity of 0%.

[0157] In some embodiments, the compound is a compound described in Table A (below) or a compound thereof. The compound is selected from any one of the physiologically acceptable salts.

[0158] [Table 5]

[0159] In a specific embodiment, the compound is Compound 100.

[0160] [ka]

[0161] In another specific embodiment, the compound is Compound 103.

[0162] [ka]

[0163] In some embodiments, the compound is a compound (Cmpd) described in Table B (below). or any one of the pharmaceutically acceptable salts thereof.

[0164] [Table 6]

[0165] In some embodiments, the compound is a compound described in Table A or Table B (above). or a pharmaceutically acceptable salt thereof (wherein any atom not designated as deuterium and at their natural isotopic abundances).

[0166] In some embodiments of the compounds of the present invention, Y 1 When is deuterium, Y 1 Heavy in The level of hydrogen uptake should be at least 52.5%, at least 75%, at least 82. 5%, at least 90%, at least 95%, at least 97%, or at least 99 %.

[0167] In some embodiments of the compounds of the present invention, Y 2a or Y 2b When is deuterium, Y designated as deuterium 2a or Y 2b The level of deuterium incorporation in each of is at least 52.5%, at least 75%, at least 82.5%, at least 90 %, at least 95%, at least 97%, or at least 99%.

[0168] In another group of embodiments, any of the embodiments described herein may be combined with deuterium. Any atom not designated as an atom is present in its natural isotopic abundance.

[0169] In some embodiments of the compounds of the present invention, the weight of each designated deuterium atom Hydrogen uptake is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99% .

[0170] In some embodiments of the compounds of the present invention, Y 1 , Y 2a , and Y 2b At least One is hydrogen.

[0171] The present invention is useful, for example, in the preparation of compounds of formula I, as set forth in the exemplary schemes Deuterated intermediates are also provided.

[0172] The synthesis of compounds of Formula I can be carried out by a synthetic chemist of ordinary skill in accordance with the exemplary methods disclosed herein. This can be readily achieved by reference to the synthesis and examples. Related procedures similar to those useful for the preparation of the compounds and intermediates thereof are described, for example, in U.S. Pat. No. 82,931.

[0173] The synthesis of compounds of formula III, IV, V and VI is readily accomplished by a synthetic chemist of ordinary skill. Using appropriate starting materials and reagents, the present invention may be practiced with reference to the exemplary syntheses and examples disclosed herein. This can be easily achieved by illuminating the

[0174] Such methods include the steps of: Other isotopically-containing reagents and / or intermediates may be utilized to synthesize the compounds depicted herein. or by carrying out standard synthetic protocols known in the art. The molecule can be introduced into the chemical structure and implemented.

[0175] Exemplary Synthesis A convenient method for synthesizing compounds of Formula I or II is shown in Scheme 1.

[0176] [ka]

[0177] As shown in Scheme 1 and further detailed in U.S. Pat. No. 4,582,931, As shown, esterification of dl-serine (1) forms serine ester (2), which is Cyclization using a benzoimidate to form oxazoline (3) The oxazoline (3) can then be deprotonated with a strong base (such as butyllithium). Deuterated by tonation and quenched with a deuterium source (e.g., acetic acid 0D). , to generate a deuterated intermediate (4) (e.g., d-α-bromocamphorsulfonic acid, etc.) or by using SMB (simulated moving bed) chromatography. Separation of the enantiomers provides intermediate (5) (as a salt). After the reaction, the oxazoline (5) is then hydrolyzed to provide the compound of formula II (Ski Figure 1 shows the preparation of compound 100).

[0178] By use of an appropriately deuterated reagent, Y of a compound of formula I or II can be obtained.1 , Y 2a ,oh Yobi Y 2b Deuterium incorporation at the position of, e.g., Y 1 , Y 2a , and Y 2b Smell This allows for deuterium incorporation of about 90%, about 95%, about 97%, or about 99%. For example, in the general procedure of Scheme 1, 2-amino-2,3,3-trideuterio-3- Hydroxy-propanoic acid (e.g., commercially available from Sigma-Aldrich) Compound 103 can be prepared by using as a starting material. In this case, the deuteration step in Scheme 1 is not necessary and is omitted.

[0179] Some compounds of formula III and IV are known and in some cases commercially available. Compounds of formula III and IV may be prepared according to methods known in the art. It can be manufactured.

[0180] Some compounds of formula V and VI are commercially available in high enantiomeric purity, and was purchased as a mixture of enantiomers and was prepared as described above or in the art. The separation can be carried out by using separation methods well known in the art or by methods known in the art. It can be prepared in accordance with known methods.

[0181] The specific procedures and compounds shown above are not intended to be limiting. Chemical structures in the schemes in the specification are identified by the same variable names (i.e., R 1 , R 2 , R 3 etc.), the corresponding positions in the compound formulae herein indicates variables defined herein in correspondence with the definitions of chemical groups (moieties, atoms, etc.) of The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the skill of the art. It is within the scope of knowledge.

[0182] The compounds of formulas I-VI and their synthetic precursors are illustrated in the schemes herein. Additional methods of synthesis, including those within the pathways not covered herein, are within the skill of a chemist in the art. Synthetic chemical transformations and protection techniques useful in synthesizing applicable compounds are within the means of the person skilled in the art. Methods of protection (protection and deprotection) are known in the art and are described, for example, in Larock R, Co. mprehensive Organic Transformations, VCH Publishers (1989);Greene, TW et al., Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999);Fie ser, L et al., Fieser and Fieser's Reagents for Organic Synthesis, John Wiley a nd Sons (1994); and Paquette, L, ed., Encyclopedia of Reagents for Organic Syn thesis, John Wiley and Sons (1995), and its subsequent editions. Includes.

[0183] Combinations of substituents and variables envisioned by this invention are those that are necessary to form stable compounds. Only what brings good.

[0184] composition The present invention provides a method for treating a brain disorder characterized by the inability to tolerate an effective amount of a compound of Formula I or II (e.g., any of the formulae herein). or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation. and in the case of a pharmaceutically acceptable carrier, the amount used in the pharmaceutical product. is not harmful to the recipient.

[0185] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula Ia.

[0186] The present invention provides a compound of formula III, IV, V, or VI (e.g., as described herein) in an effective amount. or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable salt thereof. and a carrier comprising:

[0187] The present invention provides a method for treating a brain tumor by administering to a subject a subject a therapeutically effective amount of a compound of Formula I, II, III, IV, V, and VI (e.g., a compound of Formula I, II, III, IV, V, or VI) of the present invention. or two or more compounds selected from the group consisting of A pharmaceutical preparation comprising each of the pharmaceutically acceptable salts in combination with a pharmaceutically acceptable carrier. Compositions are further provided.

[0188] The present invention provides an effective amount of (i) a compound of formula I or II, or a pharmaceutically acceptable salt thereof and (ii) glycine, sarcosine, (non-deuterated) D-alanine and (non-deuterated) one or more compounds selected from the group consisting of hydroxylated D-aspartic acid and pharmaceutically acceptable salts thereof; Further provided is a pharmaceutical composition comprising an acceptable salt in combination with a pharmaceutically acceptable carrier. do.

[0189] The present invention provides a method for treating a brain disorder characterized by the inability to tolerate an effective amount of a compound of formula III, IV, V, or VI (e.g., a compound of formula III, IV, V, or VI herein) and (non-deuterated) D-serine. Or a pharmaceutically acceptable salt of each of the above compounds in combination with a pharmaceutically acceptable carrier. Further provided is a pharmaceutical composition comprising:

[0190] The present invention provides a method for treating a brain disorder characterized by the inability to tolerate an effective amount of a compound of formula III, IV, V, or VI (e.g., a compound of formula III, IV, V, or VI herein) and D-serine, or two or more compounds selected from the group consisting of and a pharmaceutical composition comprising a pharmaceutically acceptable salt of each of the compounds in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions are further provided.

[0191] In certain embodiments, the present invention provides a method for treating atopic dermatitis by combining an effective amount of a compound of Formula I with sarcosine. In another embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of Compound 10. In another embodiment, the present invention provides a pharmaceutical composition comprising 0 in combination with sarcosine. The invention provides a pharmaceutical composition comprising an effective amount of Compound 103 in combination with sarcosine. .

[0192] A pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention, ajuba The materials and vehicles include ion exchangers, alumina, aluminum stearate, Serum proteins such as cytin, human serum albumin, and phosphate Buffer substances, glycine, sorbic acid, potassium sorbate, partial glycerides of saturated vegetable fatty acids Lid mixture, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate Salts or electrolyte solutions such as sodium chloride, zinc salts, colloidal silica, magnesium trisilicate Nesium, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, Sodium carboxymethylcellulose, polyacrylate, wax , polyethylene-polyoxypropylene-block polymer, polyethylene glycol and Examples of suitable cellulose derivatives include, but are not limited to, wool grease and wool fat.

[0193] If necessary, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be improved. The tea can be enhanced by methods well known in the art. , including the use of lipid excipients in formulations. the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences,” David J. Hauss, ed. Informa Healthcare, 2007; and “Role of Lipi d Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles an See "Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006. and.

[0194] Another known method of enhancing bioavailability is the use of LUTROL™ and PLU poloxamers such as RONIC™ (BASF Corporation) or Optionally formulated with block copolymers of ethylene oxide and propylene oxide The use of amorphous forms of the compounds of the present invention is also disclosed in U.S. Patent No. 7,014,866. and U.S. Patent Application Publication Nos. 20060094744 and 200600 See US Pat. No. 79502.

[0195] The pharmaceutical compositions of the present invention may be administered orally, rectally, nasally, topically (including buccal and sublingually), or intravenously. , suitable for vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration In some embodiments, the delivery system may be a transdermal patch or an iontophoretic technique. The compounds of the formulae herein are administered transdermally (using methods similar to those described above). The formulations may be presented in unit dosage forms, e.g., tablets, sustained release capsules, and in liposomes. They may be prepared by any of the methods well known in the pharmaceutical art. For example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & W ilkins, Baltimore, MD (20th ed. 2000). The unit dosage form may comprise a compound of Formula I or II. The compound may be contained in an amount of, for example, 100 mg to 1 g, or 500 mg to 2 g. may be administered with one or more second therapeutic agents, such as an antipsychotic or other agent for the treatment of schizophrenia. The unit dosage form can be administered once per day or multiple times per day (e.g., For example, two times per day, three times per day, or four times per day. In some embodiments, the unit dosage form is administered once per day. In another embodiment, the unit dosage form is administered twice daily. In other embodiments, the unit dosage form is administered four times per day. can be.

[0196] Such preparations may comprise administering ingredients such as a carrier which constitutes one or more accessory ingredients. Generally, the composition comprises an active ingredient, a liquid carrier, a liposome, and a liposome-containing molecule. The mixture is then homogeneously and intimately associated with the carrier or finely divided solid support, or both, and then, if necessary, the product is further processed. It is prepared by shaping the product.

[0197] In some embodiments, the compound is administered orally. The compositions may be in the form of capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient; powders may also be used. or granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water liquid emulsions as a water-in-oil liquid emulsion; encapsulated in liposomes; or as a discrete unit such as a bolus Soft gelatin capsules have been found to be useful for containing such suspensions. This can beneficially increase the rate of absorption of the compound.

[0198] In the case of tablets for oral use, common carriers include lactose and corn. Lubricants such as magnesium stearate are also typically added. When administered orally in capsule form, useful diluents include lactose and When an aqueous suspension is administered orally, the active ingredient is added to milk. and optionally, some sweetening and / or flavoring agents. and / or coloring agents may be added.

[0199] Compositions suitable for oral administration include those in which the ingredients are combined with a flavoring base, usually sucrose and akaashi. Lozenges containing the active ingredient in gelatin or tragacanth, and gelatin and glycerin or pastilles in an inert base such as sucrose and acacia.

[0200] Compositions suitable for parenteral administration may contain antioxidants, buffers, bacteriostats and formulations as desired. Aqueous and non-aqueous sterile injections that can contain solutes to make them isotonic with the recipient's blood. Solutions, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials. It can be presented in a liquid form, stored in a freeze-dried (lyophilized) state, and The sterile liquid carrier, e.g., water for injection, need only be added immediately prior to use. Liquids can be prepared from sterile powders, granules and tablets.

[0201] Such injectable solutions can be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. The suspension may be added to a liquid containing a suitable dispersing or wetting agent (such as, for example, Tween 80) and Suspending agents can be used and formulated according to techniques known in the art. The sterile injectable preparation is a sterile injectable solution in a non-toxic diluent or solvent that is acceptable for parenteral administration. Alternatively, it can be a suspension, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and In addition, sterile, fixed oils are commonly used as solvents or suspending media. 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. In this regard, pharmaceutically acceptable natural oils such as olive oil or castor oil are particularly preferred. These oil solutions or suspensions are useful in the form of long chain alkyl esters. An alcohol diluent or dispersant may also be included.

[0202] In another embodiment, the compositions of the present invention further comprise one or more additional therapeutic agents. Additional therapeutic agents may be effective when administered with a compound that has the same mechanism of action as D-serine. from any compound or therapeutic agent known or demonstrating beneficial properties. Such agents may be selected from those known to be useful in combination with D-serine. These include those shown in U.S. Pat. Nos. 9,040,581 and 9,687, Examples include, but are not limited to, those described in the specification of US Pat. No. 460.

[0203] In some embodiments, the additional therapeutic agent is a therapeutic agent for treating epilepsy, NMDAR encephalitis, Parkinson's disease, or other conditions. cognitive deficits in Parkinson's disease, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis Sclerosis (ALS), Huntington's disease, schizophrenia (positive for schizophrenia, cognitive and / or (including negative symptoms and prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression Illness, Treatment-Resistant Depression, Cognitive Deficits in Depression, Major Depressive Disorder, Generalized Anxiety Disorder, Mixed associated with diseases or conditions such as major depressive disorder with sexual characteristics, and Huntington's disease Cognitive deficit, subjective cognitive decline, traumatic brain injury, dementia with Lewy bodies, etc. It is an agent useful in the treatment of a disease or condition.

[0204] In some embodiments, a patient suffering from schizophrenia is administered a deuterated analog of D-serine. A pharmaceutical composition containing the compound (or other compounds described herein) can be administered to a patient in need of treatment for schizophrenia. Additional therapeutic agents known in the art for the treatment of rheumatoid arthritis (e.g., olanzapine, clozapine, haloperidol, Such pharmaceutical compositions can be administered together with or sequentially to other drugs, such as ridol. are included within the scope of the present invention. In general, antipsychotic medications typically range from 0.25 to 50 00 mg / day (e.g., 5-1000 mg / day). The drugs for the treatment of myocardial infarction include phenothiazines, butyrophenones, thioxanthenes, dibenzoxazepines, Dihydroindolone, and diphenylbutylpiperidine are common antipsychotics. "Atypical" antipsychotics generally act at dopamine D2 and 5HT2 serotonin receptors. and newer drugs with high levels of efficacy and a benign extrapyramidal side effect profile. It is a generation of antipsychotic drugs. Examples of typical antipsychotic drugs are chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, trifluoperazine, thiothixene haloperidol, loxapine, molindone, acetophenazine, chlorprothixene Examples of atypical antipsychotics include bromocriptine, droperidol, and pimozide. Nanserin, clozapine, risperidone, olanzapine, cariprazine, asenapine, Rasidone, brexpiprazole, lumateperone, aripiprazole, aripiprazole These include lauroxyl, iloperidone, paliperidone, ziprasidone, and quetiapine. Depot antipsychotics, e.g., haloperidol decanoate, fluphenazine Fluphenazine enanthate and fluphenazine enanthate may also be used. Additional antipsychotics include butaperazine, carphenazine, remoxipride, and piperacetate. Examples include phenytoin, phenytoin, and sulpiride.

[0205] In some embodiments, a patient experiencing symptoms of schizophrenia is administered deuterated D-serine. A pharmaceutical composition containing an analog (or other compound described herein) is administered to one or more drugs known in the art for treating schizophrenia (antipsychotics, e.g., olanzapine, clozapine) , haloperidol, quetiapine, risperidone, chlorpromazine, etc.) In certain embodiments, the pharmaceutical composition can be administered intravenously or sequentially. It is intended for administration for at least one year to patients with a DSM-V diagnosis of schizophrenia. In this embodiment, the pharmaceutical composition is administered to a patient with a PANSS total score of 70 to 110. In another embodiment, the pharmaceutical composition satisfies additional PANSS criteria. It is intended for administration to patients. a. PANSS score ≤ 5 based on the positive scale items for conceptual integration disorder and hostility b. PANSS score ≥ 4 based on at least two of the following items: i.Delusion ii. Hallucinations iii. Suspicion / Persecution iv. Unnatural thoughts In another embodiment, the pharmaceutical composition is administered without hospitalization or medication changes for at least 3 months. In another embodiment, the present invention is for administration to patients with clinically stable disease, defined as: In this study, patients were treated with one first-line atypical antipsychotic at the highest dose and one second-line atypical antipsychotic at a low dose. Diabetic medications (such as low-dose Seroquel® for sleep or low-dose mood stabilizers) currently being treated with risperidone, with a combined first- and second-line antipsychotic dose of ≤6 mg each or 600 mg chlorpromazine equivalent, and the antipsychotic dose was 4 weeks. Remain stable. In general, antipsychotic medications typically range from 0.25 to 5000 mg / day. "Typical" antipsychotics are administered at a dose of 500 mg / day (e.g., 5-1000 mg / day). Enothiazine, butyrophenone, thioxanthene, dibenzoxazepine, dihydroin These are conventional antipsychotics such as benzodiazepines, benzodiazepines, and diphenylbutylpiperidine. Antipsychotic drugs generally act on dopamine D2 and 5HT2 serotonin receptors, causing high levels of Newer generation antipsychotics with the efficacy and benign extrapyramidal side effect profile Examples of typical antipsychotics are chlorpromazine, thioridazine, and mesothelioma. azine, fluphenazine, perphenazine, trifluoperazine, thiothixene, haloperazine Dhol, loxapine, molindone, acetophenazine, chlorprothixene, droperilide Examples of atypical antipsychotics include blonanserin, Clozapine, risperidone, olanzapine, cariprazine, asenapine, lurasidone, Lexpiprazole, lumateperone, aripiprazole, aripiprazole lauroxyl , iloperidone, paliperidone, ziprasidone, and quetiapine. - Antipsychotics, such as haloperidol decanoate and fluphenazine decanoate Fluphenazine enanthate and fluphenazine benzoate may also be used. Medications include butaperazine, carphenazine, remoxipride, piperacetazine, and Examples include sulpiride.

[0206] In another embodiment, the present invention provides a compound of the present invention and an additional therapeutic agent as described above in separate dosage forms. and any one or more of the therapeutic agents, the compounds being associated with each other and the additional As used herein, the term "associated with each other" refers to the association of separate agents. The dosage forms are packaged together or otherwise sold together and are separated (24 It is easy to understand that it is intended to be administered (sequentially or simultaneously) within less than an hour. This means that they are attached to each other as is apparent from the diagram.

[0207] In the pharmaceutical compositions of the present invention, the compounds of the present invention are present in an effective amount. The term "amount" refers to an amount sufficient to treat the target disorder when administered in a proper manner. As noted above, the regimen may include one or more additional therapeutic agents (e.g., When a compound or composition of the invention is used in combination (e.g., a compound or composition of the invention when the composition is used as an adjunctive treatment).

[0208] The term "subject in need thereof" includes, but is not limited to, 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 (schizophrenia positive, cognitive and / or negative) symptoms, and prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression, Treatment-resistant depression, cognitive deficits in depression, major depressive disorder, generalized anxiety disorder, mixed characteristics cognitive deficits associated with diseases or conditions such as major depressive disorder with symptoms of depression, and Huntington's disease Diseases selected from the following: cognitive impairment, subjective cognitive decline, traumatic brain injury, dementia with Lewy bodies, etc. refers to a subject who has been or will be diagnosed with a disease or condition.

[0209] Dosages for animals and humans (based on milligrams per square meter of body surface) (The interrelationship is described, for example, in Freireich et al., Cancer Chemother. Rep., 1966, 50: 219. Body surface area can be approximately determined from the subject's height and weight. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 1970, 537. That is what I mean.

[0210] In some embodiments, the pharmaceutical composition is administered in an effective amount ranging from 0.1 g to 60 g. In some embodiments, an effective amount of a compound of Formula I or Formula II is provided. Compound I ranges from 1 to 60 g / day, or 5 to 30 g / day, or 10 to 20 g / day In some embodiments, an effective amount of a compound of Formula I or Formula II is 100mJ In some embodiments, an effective amount of a compound of Formula I or Formula II is in the range of 1 g to 1 g / day. In some embodiments, an effective amount of the compound of Formula I or or the compound of formula II in the range of 1 to 8 g / day.

[0211] In some embodiments, an effective amount of Compound 100 ranges from 1 g / day to 10 g / day. , or in the range of 1g / day to 5g / day, or in the range of 2g / day to 4g / day. In one embodiment, the pharmaceutical composition comprises 1 g of Compound 100, 2 g of Compound 100, and 3g of Compound 100, 5g of Compound 100, 8g of Compound 100, or 10g of Compound 100 include.

[0212] In some embodiments, an effective amount of a compound of Formula I or Formula II is administered per kilogram of body weight. 30 milligrams per kg / day (mg / kg / day) to 900 mg / kg / day, or 60mg / kg / day to 300mg / kg / day, or 150mg / kg / day to 300mg In some embodiments, an effective amount of a compound of Formula I or Formula II is administered in the range of 1 / kg / day. The combination ranges from 30 mg / kg / day to 120 mg / kg / day. In the present invention, an effective amount of the compound of formula I or formula II is 10 mg / kg / day to 150 mg / kg / day. g / day, or 10 mg / kg / day to 120 mg / kg / day, or 10 mg / kg / day The range is ~90 mg / kg / day.

[0213] In some embodiments, an effective amount of a compound of Formula III, IV, V, or VI is The range is ~60g / day, or 5-30g / day, or 10-20g / day.

[0214] In some embodiments, an effective amount of a compound of Formula III, IV, V, or VI is 3 0 mg / kg / day to 900 mg / kg / day, or 60 mg / kg / day to 300 mg / kg g / day, or in the range of 150 mg / kg / day to 300 mg / kg / day.

[0215] Effective doses will also vary depending on the disease being treated, the severity of the disease, the administration, and the dosage, as will be appreciated by those skilled in the art. route, sex, age and general health of the subject, use of excipients, use of other agents, etc. The possibility of co-use with other therapeutic treatments and the judgment of the treating physician will vary. Guidance for selecting an effective dose can be determined by reference to the prescribing information for Compound 1. This can be done.

[0216] In pharmaceutical compositions containing one or more additional therapeutic agents, an effective amount of the additional therapeutic agent(s) is / are Approximately 20% to 10% of the dose typically used in monotherapy regimens using only the active agent. 0%. Preferably, the effective amount is about 70% to 100% of the usual monotherapeutic dose. Typical monotherapeutic doses of these additional therapeutic agents are well known in the art. Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, S. tamford, Conn. (2000);PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, De Luxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000). Each of the references is incorporated herein by reference in its entirety.

[0217] Some of the additional therapeutic agents identified above may act synergistically with the compounds of the present invention. When acting synergistically with the compounds of the invention, the effective administration of additional therapeutic agents and / or compounds of the invention The amount can be reduced from the effective dose required in monotherapy. The compounds of the present invention minimize the toxic side effects of additional therapeutic agents, synergistically improve efficacy, and improve the ease of administration or use and / or reduce the overall cost of compound preparation or formulation There is an advantage in reducing

[0218] Treatment method In another aspect, the present invention provides a method for modulating the activity of an NMDAR in a cell. a cell and one or more compounds of formula I or II herein, or In some embodiments, the method comprises contacting a compound selected from the group consisting of hydroxybenzoates, ... In some embodiments, the cells are contacted in vitro. In some embodiments, the cells are contacted ex vivo.

[0219] In another aspect, the present invention provides a method for treating a disease or condition that is beneficially treated with D-serine. A method of treating a subject in need of such treatment, comprising administering to said subject a disease or condition that is treatable. an effective amount of a compound of formula I or II or a compound of formula I or II In another aspect, the present invention provides a method for treating a rheumatoid arthritis, the method comprising administering to a subject a pharmaceutical composition comprising the compound of formula (I). The present invention relates to a method for treating a disease or condition that is beneficially treated by D-serine. A method of such treatment comprises administering an effective amount of the formula: Administering to a subject a compound of formula Ia or a pharmaceutical composition comprising a compound of formula Ia. Provide the law.

[0220] Such diseases include epilepsy, NMDAR encephalitis, Parkinson's disease, and Cognitive deficits in Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), Chinton's disease, schizophrenia (positive, cognitive and / or negative symptoms of schizophrenia, and (including prodromal schizophrenia), bipolar disorder, bipolar mania, bipolar depression, treatment-resistant depression , cognitive deficits in depression, major depressive disorder, generalized anxiety disorder, major depression with mixed features cognitive deficits, subjective cognition, and cognitive disorders associated with diseases or conditions such as Huntington's disease These include, but are not limited to, cognitive decline, traumatic brain injury, and dementia with Lewy bodies. Additional diseases or conditions include post-traumatic stress disorder (PTSD), ataxia, and seizures. Examples include phosphorus deficiency disorders.

[0221] In some embodiments, the methods of the present invention are used to treat epilepsy and NMDAR encephalitis. and administering to a subject in need thereof a disease or condition selected from the group consisting of: The method provides a subject in need of treatment for a disease or condition with an effective administering an effective amount of a compound of formula I or II or a pharmaceutical composition containing a compound of formula I or II The method includes the step of providing the

[0222] The present invention provides a method for treating schizophrenia (including the positive, negative and / or cognitive symptoms of schizophrenia). The method comprises administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the present invention. (e.g., a compound of formula I or II or a compound of formula Ia; or a compound of formula I or II or a pharmaceutical composition comprising a compound of formula Ia In some embodiments, the method includes the step of administering an antipsychotic therapeutic agent to the subject. In some embodiments, the method further comprises administering a second therapeutic agent to the subject. wherein the second agent is an antipsychotic therapeutic agent.

[0223] In some embodiments, negative and / or positive and / or cognitive tests for schizophrenia are Symptoms of the condition can be measured before and after treatment in a subject or patient. indicates that the patient's condition has improved. The PANSS symptom rating scale can be used to assess improvement in schizophrenia symptoms. (e.g., Andreasen, 1983, Scales for the Assessment of Negative Symptoms (SAN S), Iowa City, Iowa, and Kay et al., 1987, Schizophrenia Bulletin 13:261-276. Similarly, the incidence of other neuropsychiatric disorders in patients treated by the methods of the present invention may be increased. In some embodiments, the positive symptoms of schizophrenia are: In some embodiments, the symptoms of schizophrenia are improved after treatment compared to pre-treatment symptoms. In some embodiments, the sexual symptoms are improved after treatment compared to the symptoms before treatment. Cognitive symptoms of ataxia improve after treatment compared to pre-treatment symptoms.

[0224] In some embodiments, the method of treating schizophrenia comprises administering to a patient suffering from schizophrenia a pharmaceutical comprising a deuterated analog of D-serine (or other compound described herein) The composition may be administered with any of the drugs known in the art for treating schizophrenia (antipsychotics, e.g., olanzapine, chlorpheniramine ... The method includes administering the drug together with or sequentially to a patient receiving a steroid drug (including rosapine, haloperidol, etc.). In some embodiments, patients suffering from schizophrenia may benefit from the treatments described herein. are stable on a prior antipsychotic treatment, i.e., on an existing antipsychotic treatment (e.g., a compound of Formula I or Compounds of formula II are used as adjunctive therapy with additional antipsychotic agents. Antipsychotic medications typically range from 0.25 to 5000 mg / day (e.g., 5 to 1000 mg / day). g / day). "Typical" antipsychotics include phenothiazines, butyrophenones, Non-, thioxanthene, dibenzoxazepine, dihydroindolone, and diphenyl butylpiperidine. "Atypical" antipsychotics are generally It acts on the D2 and 5HT2 serotonin receptors, resulting in high levels of efficacy and benign extrapyramidal effects. It is a newer generation of antipsychotics with a symptomatic side effect profile. Examples of drugs include chlorpromazine, thioridazine, mesoridazine, fluphenazine, and penicillin. Ruphenazine, trifluoperazine, thiothixene, haloperidol, loxapine, molybdenum These include acetaminophen, acetophenazine, chlorprothixene, droperidol, and pimozide. Examples of atypical antipsychotics include blonanserin, clozapine, and risperidone. , olanzapine, cariprazine, asenapine, lurasidone, brexpiprazole, luma Teperon, Aripiprazole, Aripiprazole Lauroxyl, Iloperidone, Paliperidone Depot antipsychotics, such as halothane, ziprasidone, and quetiapine. Peridol decanoate, fluphenazine decanoate, and fluphenazine Enanthate esters can also be used. Additional antipsychotics include butaperazine , carphenazine, remoxipride, piperacetazine, and sulpiride.

[0225] In some embodiments, the method of treating schizophrenia comprises administering to a patient with symptoms of schizophrenia. The patient is administered a deuterated analog of D-serine (or other compound described herein). The pharmaceutical composition may be administered in combination with one or more art-known drugs for treating schizophrenia (antipsychotics, e.g., For example, olanzapine, clozapine, haloperidol, quetiapine, risperidone, chlor Specific embodiments include administering the compound or compound(s) in combination with or sequentially to the patient. In one embodiment, the pharmaceutical composition is administered to a patient with a DSM-V diagnosis of schizophrenia for at least one year. In another embodiment, the pharmaceutical composition is for administration to a patient with a PANSS total score. In another embodiment, the pharmaceutical composition is for administration to a patient having 70 to 110 mg of the active ingredient. The product is intended for administration to patients who meet additional PANSS criteria. c. PANSS score based on the positive scale items for conceptual integration disorder and hostility ≤ 5 d. PANSS score ≥ 4 based on at least two of the following items: i.Delusion ii. Hallucinations iii. Suspicion / Persecution iv. Unnatural thoughts In another embodiment, the pharmaceutical composition is administered without hospitalization or medication changes for at least 3 months. In another embodiment, the present invention is for administration to patients with clinically stable disease, defined as: In this study, patients were treated with one first-line atypical antipsychotic at the highest dose and one second-line atypical antipsychotic at a low dose. Diabetic medications (such as low-dose Seroquel® for sleep or low-dose mood stabilizers) currently being treated with risperidone, with a combined first- and second-line antipsychotic dose of ≤6 mg each or 600 mg chlorpromazine equivalent, and the antipsychotic dose was 4 weeks. Remain stable. In general, antipsychotic medications typically range from 0.25 to 5000 mg / day. "Typical" antipsychotics are administered at a dose of 500 mg / day (e.g., 5-1000 mg / day). Enothiazine, butyrophenone, thioxanthene, dibenzoxazepine, dihydroin These are conventional antipsychotics such as benzodiazepines, benzodiazepines, and diphenylbutylpiperidine. Antipsychotic drugs generally act on dopamine D2 and 5HT2 serotonin receptors, causing high levels of Newer generation antipsychotics with the efficacy and benign extrapyramidal side effect profile Examples of typical antipsychotics are chlorpromazine, thioridazine, and mesothelioma. azine, fluphenazine, perphenazine, trifluoperazine, thiothixene, haloperazine Dhol, loxapine, molindone, acetophenazine, chlorprothixene, droperilide Examples of atypical antipsychotics include blonanserin, Clozapine, risperidone, olanzapine, cariprazine, asenapine, lurasidone, Lexpiprazole, lumateperone, aripiprazole, aripiprazole lauroxyl , iloperidone, paliperidone, ziprasidone, and quetiapine. - Antipsychotics, such as haloperidol decanoate and fluphenazine decanoate Fluphenazine enanthate and fluphenazine benzoate may also be used. Medications include butaperazine, carphenazine, remoxipride, piperacetazine, and Examples include sulpiride.

[0226] In some embodiments, the degree or extent of nephrotoxicity in a subject is determined by administering an equivalent amount of D-serotonin to a subject. Nephrotoxicity is reduced compared to treatment with phosphate (e.g., molar equivalent D-serine). Measuring levels of markers such as creatinine levels or blood urea nitrogen (BUN) BUN can be monitored by measuring approximately 7 to 20 mg / dL (2.5 to 7. A range of 1 mmol / L is considered normal. Approximately 0.6 to 1.2 milligrams (mg) per deciliter (dL) in adult women A range of 0.5 to 1.1 milligrams per deciliter is considered normal. In some embodiments, serum creatinine and / or BUN levels are maintained throughout treatment and and maintained within the normal range afterward.

[0227] In some embodiments, the method for treating schizophrenia comprises administering to a subject in need thereof , comprising a compound of formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Administering a pharmaceutical composition comprising a compound of formula I or II administered per day. The dose ranges from 10 mg / kg to 120 mg / kg (i.e., 1 kg of subject body weight). (10 mg per kilogram to 120 mg per kilogram of subject's body weight) and the subject's serum clear Maintain normal blood urea (BUN) or blood urea (BUN) levels (or both) (as above) It includes steps that can be performed.

[0228] In some embodiments, a compound of Formula I or II or a compound of Formula I or II In some embodiments, the pharmaceutical composition containing the compound is administered once per day. Compound 100 or a pharmaceutical composition containing Compound 100 is administered once per day. In embodiments, a compound of Formula I or II or a medicament comprising a compound of Formula I or II The composition is administered twice daily. In some embodiments, Compound 100 or In yet another embodiment, the pharmaceutical composition comprising Compound 100 is administered twice daily. wherein the compound of formula I or II or a pharmaceutical composition comprising a compound of formula I or II is In some embodiments, Compound 100 or Compound 100 is administered three times daily. In yet another embodiment, the pharmaceutical composition comprising: A compound of Formula I or II or a pharmaceutical composition comprising a compound of Formula I or II may be administered daily. In some embodiments, Compound 100 or Compound 100 is administered four times per day. The pharmaceutical composition containing the compound is administered four times per day.

[0229] In some embodiments, the effective amount of a compound of Formula I or Formula II is 1 to 60 g / day. In some embodiments, the range is 5-30 g / day, or 10-20 g / day. In this case, the effective amount of the compound of formula I or formula II is in the range of 100 mg to 1 g / day. In some embodiments, the effective amount of a compound of Formula I or Formula II ranges from 1 to 10 g / day. It is an enclosure.

[0230] In some embodiments, the effective amount of a compound of Formula I or Formula II is 30 mg / kg / day to 900 mg / kg / day, or 60 mg / kg / day to 300 mg / kg / day, or In some embodiments, the dose ranges from 150 mg / kg / day to 300 mg / kg / day. In this case, an effective amount of the compound of Formula I or Formula II is 10 mg / kg / day to 150 mg / kg / day. days, or 10 mg / kg / day to 120 mg / kg / day, or 10 mg / kg / day to 9 The range is 0 mg / kg / day.

[0231] Identification of subjects requiring such treatment should be at the discretion of the subject or healthcare professional. can be subjective (e.g., opinion) or objective (e.g., measured by tests or diagnostic methods) possible).

[0232] In another embodiment, any of the above methods of treatment may be administered to a subject in need thereof using one or more The method includes a further step of co-administering multiple additional therapeutic agents. The additional therapeutic agents are Any additional therapeutic agents known to be useful for co-administration with the co-agonist The choice of additional therapeutic agent will also depend on the particular disease or condition being treated. Examples of additional therapeutic agents that can be used in the methods of the present invention are as described above for use in a combination composition comprising the compound and an additional therapeutic agent. .

[0233] In some embodiments, the combination treatment of the present invention comprises administering to a subject in need thereof a compound of formula I or II and one selected from compounds of formula III, IV, V and VI, or and co-administration of multiple additional therapeutic agents to treat any of the diseases or conditions described herein. In certain embodiments, the method comprises administering an effective amount of a compound of Formula I and a monkey. In another embodiment, the method comprises administering in combination with cosine. In another embodiment, the method comprises administering a combined amount of Compound 100 and sarcosine. wherein the method comprises administering an effective amount of Compound 103 in combination with sarcosine. Includes flops.

[0234] In some embodiments, the method further comprises administering to the subject an antipsychotic therapeutic agent. This includes:

[0235] In some embodiments, the combination therapy of the present invention is stable during antipsychotic therapy. The method comprises co-administering a compound of formula I or II to a patient suffering from schizophrenia. In an embodiment, the method comprises combining an effective amount of a compound of Formula I or II with a "typical" antipsychotic agent. In another particular embodiment, the method comprises administering an effective amount of The method comprises administering a compound of Formula I or II in combination with an "atypical" antipsychotic agent. In another embodiment, the method comprises combining an effective amount of Compound 100 with an antipsychotic agent. In another embodiment, the method comprises administering an effective amount of Compound 103 to an anti-cancer agent. This includes administering it in combination with a psychotropic agent.

[0236] As used herein, the terms "co-administered" or "administered in combination" refer to additional The therapeutic agents may be combined with a compound of the invention as part of a single dosage form (e.g., a compound of the invention and the additional and a therapeutic agent) or as separate multiple dosage forms. Alternatively, the additional agent may be administered prior to administration of the compound of the present invention: Such combined therapeutic treatments may be administered sequentially or thereafter. In such cases, both the compounds of the invention and the additional therapeutic agent are administered by conventional methods. Administration of a composition of the invention to a subject that contains both a compound and an additional therapeutic agent does not result in the administration of that same therapeutic agent, either or any other additional therapeutic agent or compound of the invention administered to said subject at another time during the course of treatment. This does not preclude separate administration at different points.

[0237] Effective amounts of these additional therapeutic agents are well known to those skilled in the art, and guidance for administration is provided in the present disclosure. The patents and patent application publications referenced herein, as well as Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000);PDR Pharmacop oeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, L (2000), and other medical textbooks. However, additional treatment Determining optimal effective amount ranges for the agents is well within the purview of one skilled in the art.

[0238] In some embodiments of any of the above-described methods, a compound of the invention (e.g., Compound Administration of 100) of this compound resulted in less nephrotoxicity than administration of an equivalent dose of (non-deuterated) D-serine. Decrease.

[0239] In one embodiment of the invention, when an additional therapeutic agent is administered to a subject, an effective amount of the present invention The compound is administered at a dose below what would be its effective dose if no additional therapeutic agent were administered. In another embodiment, an effective amount of an additional therapeutic agent is administered in the absence of a compound of this invention. Thus, the effect of either agent at high doses is less than what would be expected if the dose were higher. Other potential benefits (use) Improvements in the method and / or reduction in drug costs (including but not limited to improvements in the method and / or reduction in drug costs) will be apparent to those skilled in the art. It is clear.

[0240] In yet another aspect, the present invention provides a method for treating the above-mentioned diseases, disorders or symptoms in a subject. In the manufacture of a medicament for the treatment of a patient having a condition characterized in that the patient is ... The present invention provides the use of the compound of formula I alone or in combination with one or more of the additional therapeutic agents described above. Another aspect of the present invention is the treatment of the diseases, disorders or conditions delineated herein in a subject. and a compound of Formula I or Formula II for use in

[0241] [Example 1] Evaluation of the pharmacokinetic profile of DD-serine (compound 100) Pharmacokinetic profile of Compound 100 in male Sprague-Dawley rats Evaluation of the effect of Compound 100 on the hippocampus, cortex, and periphery of male Sprague-Dawley rats. The quality and plasma concentration (92% D by mass spectrometry) of 1,2,3-trimethylbenzyl benzoate (BENZY) were investigated. Compound 100 was administered in an aqueous 0.5% methylcellulose solution at individual PO doses of 100 mg / kg. The hippocampus, cortex, and plasma were collected at 1 and 6 hours and the concentrations of Compound 100 were compared. The mean plasma, hippocampal, and cortical concentrations at 1 and 6 hours after administration are shown in Table 1 and Table 2. The mean plasma, hippocampal, and cortical concentrations at 1 hour were 19,200 ng / L, respectively. mL, 674 ng / g, and 754 ng / g. The serum and cortical concentrations were 1780 ng / mL, 1385 ng / g, and 936 ng / mL, respectively. Similar concentrations of Compound 100 were found in the hippocampus and cortex at 1 and 6 hours. Compound 100 concentrations in plasma, hippocampus, and cortex were within 2-fold of each other at 6 hours. It was.

[0242] [Table 7]

[0243] [Example 2] Evaluation of the pharmacokinetics and nephrotoxicity of non-deuterated D-serine: Nephrotoxicity of non-deuterated D-serine was evaluated in male Sprague-Dawley rats. Fasted rats were given individual PO doses of 300 mg / kg of 0.5% methylcellulose. Non-deuterated D-serine in a sucrose solution was administered. The hippocampus, cortex, and plasma were collected and analyzed. Additional blood was collected and analyzed for a complete clinical chemistry profile. Urine was also collected and analyzed. Glucose and total protein were tested. Mean endogenous undeuterated D-serine Bell's control group had 155ng / mL of rat plasma, 8970ng / g of rat cortex, and 13,450 ng / g of rat hippocampus. Deuterated D-serine levels were only subtracted. Plasma pharmacokinetics of non-deuterated D-serine ( PK parameters are shown in Table 2. Non-deuterated D-serine was administered in the hippocampus, cortex, and The T of undeuterated D-serine and its plasma concentration are shown in Table 3 and Figure 2. max , T 1 / 2 , C m ax and AUC inf are 0.5 hours, 3.63 hours, and 268,000 ng / m L, and 500,000 hours * ng / mL. Mean plasma, hippocampal, and The cortical concentrations were 19200 ng / mL, 674 ng / g, and 754 ng / g, respectively. At 8 hours, mean plasma, hippocampal, and cortical concentrations were 11,250 ng / mL, 11,250 ng / mL, and 11,250 ng / mL, respectively. The concentrations of non-deuterated D-serine were 17,725 ng / g and 11,875 ng / g. Plasma, hippocampal, and cortical concentrations in the intervening period were within two-fold of each other. To evaluate the nephrotoxicity of 300 mg / kg non-deuterated D-serine in Dawley rats Blood urea nitrogen and creatinine levels were elevated. Elevated blood pressure suggests nephrotoxicity. The presence of glucose was detected in the urine.

[0244] [Table 8]

[0245] [Table 9]

[0246] [Example 3] Pharmacokinetic profile and nephrotoxicity assessment of Compound 100 and non-deuterated D-serine The pharmacokinetic profile of Compound 100 was determined in male Sprague-Dawley rats. The pharmacokinetic profile of deuterated D-serine was investigated in comparison with that of non-deuterated D-serine. The rats were administered individual PO doses of 150 mg / kg of the compound in 0.5% aqueous methylcellulose solution. 100 (92% D by mass spectrometry) and non-deuterated D-serine were administered. Plasma was collected. Additional blood was collected and analyzed for Compound 100 and non-deuterated D-serine. , analyzed for full clinical chemistry profile. Compound 100 and non-deuterated D-serine The PK parameters of Compound 100 at 4, 8, and 24 hours are shown in Table 4. The hippocampal, cortical, and plasma concentrations are shown in Table 5 and Figure 3. The clinical pathology data are shown in Figures 4, 5, and Shown in 6.

[0247] In rats administered a single individual PO dose of 150 mg / kg of each compound, 100 T max is the T of non-deuterated D-serine max Compound 100 C max and AUC inf The results were similar to those of non-deuterated D-serine. - Serin T max , C max and AUC inf are 0.333 hours and 180 000ng / mL, and 349000 hours * The T of Compound 100 was ng / mL. m ax , C max and AUC inf are 0.667 hours and 186000ng / m L, and 383,000 hours * ng / mL. At 4 hours, mean plasma, hippocampal, and Cortical concentrations were 23283 ng / mL, 6155 ng / g, and 5070 ng / g. At 8 hours, mean plasma, hippocampal, and cortical concentrations were 2038 ng / m L, 4335ng / g, and 4035ng / g. Mean plasma and hippocampal concentrations at 24 hours were , and cortical concentrations were 711ng / mL, 4200ng / g, and 2420n The concentrations of Compound 100 in plasma and cortex decreased within 24 hours. However, the concentration of Compound 100 in the hippocampus remained constant at 24 hours.

[0248] Compound 100 and non-deuterated D were administered in male Sprague-Dawley rats. The nephrotoxicity of 1-deuterated serine was evaluated in rats administered 150 mg / kg of Compound 100 or non-deuterated serine. Deuterated D-serine was administered PO for 8 and 24 hours. Elevated blood urea nitrogen (BUN) levels were observed in ocular serum samples. Serine increased creatinine and γ-glutamyltransferase activity in 24-hour serum samples. Increased levels of GGT, blood urea nitrogen, creatinine and GG were observed. In contrast, compound 100 showed elevated T levels, suggesting nephrotoxicity. Urea nitrogen, creatinine, and GGT levels at 1 and 24 hours were measured by Charles R Compared favorably with control and reference values ​​provided by Liver Laboratory Non-deuterated D-serine caused an increase in the levels of biomarkers of nephrotoxicity. However, administration of Compound 100 did not increase levels of biomarkers of nephrotoxicity.

[0249] [Table 10]

[0250] [Table 11]

[0251] Compound 100 (Compound 100) at doses of 150 mg / kg to 750 mg / kg and non- Additional experiments were performed to compare the nephrotoxicity of deuterated D-serine. The results are shown in Figures 7-10. As shown in Figures 7 to 10, in animals administered Compound 100, BUN or creatinine Minimal changes in BU were observed in animals given a comparable dose of non-deuterated D-serine. It can be seen that the AUC and creatinine levels increased with increasing dose. Call C max Although exposure as measured by β-glucan was greater for Compound 100, overall signs of nephrotoxicity were This was observed only in rats given undeuterated D-serine (not in Compound 100). (Could not be done).

[0252] [Example 4] Pharmacokinetics and bioavailability of undeuterated D-serine in male Sprague-Dawley rats and nephrotoxicity dose-response assessment Pharmacokinetics of undeuterated D-serine in male Sprague-Dawley rats The profiles were investigated. Fasting rats were given 30, 75, 100, 150, and 3 Non-deuterated D in 0.5% aqueous methylcellulose at a single individual PO dose of 0.00 mg / kg Plasma was collected and analyzed for non-deuterated D-serine. Fluid was collected and analyzed for complete clinical chemistry profile. The parameters are shown in Table 6. The clinical pathology data are shown in Figures 11, 12 and 13.

[0253] Non-deuterated single individual PO doses of 30, 75, 100, 150, and 300 mg / kg In rats administered hydroxylated D-serine, T max is 0.3 to 0.5 at all doses. C max and AUC inf The increase in exposure, expressed as a function of dose, is / kg. kg C max are 24300, 54300, 96100, 180000, and and 216,000 ng / mL. 30, 75, 100, 150, and 300 mg / kcal AUC of g inf are 50600, 148000, 246000, and 349000 respectively. , and 911000ng * h / mL.

[0254] Nephrotoxicity of undeuterated D-serine in male Sprague-Dawley rats Dose response was assessed at 30, 75, 100, 150, and 300 mg / kg PO. Control values ​​and references provided by Rivers River Laboratory urea nitrogen, creatine, and gamma-glucose (markers of nephrotoxicity) compared with normal values. Increased glutamyltransferase (GGT) levels were observed at 150 and 300 mg / kg was seen in the 24 hour sample at the dose of

[0255] [Table 12]

[0256] [Example 5] Deuterated and non-deuterated D-serine in male Sprague-Dawley rats Pharmacokinetic evaluation of

[0257] [ka] Non-deuterated and deuterated D-serine (compound 100) were administered to male Sprague-Dawley rats. e-Dawley rats were given 5 mg / kg intravenously (IV) in phosphate-buffered saline (PBS). g; and orally (PO), 10 mg / kg, 0.5% methylcellulose solution) Three rats were used in each group. Blood was collected at the following time points: before administration, after administration, for IV administration, 0.05, 0.167, 0.5, 1, 2, 4, 6, 8, and 12 hours after administration; The measurements were taken before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours after PO administration. LC was collected pre-dose (minimum 12 hours), 0-6, 6-12, and 12-24 hours. Plasma samples were analyzed and quantified for the administered compounds by -MS / MS.

[0258] The results are shown in Table 7.

[0259] [Table 13]

[0260] Deuterated D-serine (compound 100) has a half-life (T 1 / 2 ) is non-deuterated D-serine The half-life of the deuterated and non-deuterated compounds was found to be approximately 1.5 times longer than that of the undeuterated compounds. Mr. T max The C of deuterated D-serine (compound 100) max is non-deuterated D-serine C max The AUC was approximately 1.3 times higher than inf is the A of non-deuterated D-serine UC inf It was about 1.6 times larger than

[0261] In a separate experiment, non-deuterated D-serine and two deuterated D-serine analogs ( Compound 100 and Compound 103 (96% D) were administered to male Sprague-Dawley rats. The drug was administered to the rats.

[0262] [ka]

[0263] The results show that Compound 100 and Compound 103 have similar PK parameters. did.

[0264] [Example 6] Exemplary Formulations of DD-Serine A modified release tablet formulation of DD-Serine is prepared using the materials shown in the table below. Tablet Content: 500 mg DD-Serine (e.g., Compound 100) Total tablet weight: 855mg

[0265] [Table 14]

[0266] [Example 7] (2R)-2-Amino-2-deutero-3-hydroxy-propanoic acid (Compound 100) Racemic 2-amino-2-deutero-3-hydroxy-propanoic acid was synthesized and then separated. Cleavage was carried out to obtain (2R)-2-amino-2-deutero-3-hydroxy-propanoic acid ( The details of obtaining compound 100 with high ee (enantiomeric excess) and high D% are given in the following table. This is shown in Scheme 2.

[0267] [ka]

[0268] Compound 100 was prepared from non-deuterated D,L-serine as shown in Scheme 2. Proton NMR and mass spectral data are consistent with the structure shown above for compound 100. The results matched those of the compound shown in Table 1. MS(M+H): 107.2; MS(MH): 105.2; 1 H-NMR (400MHz,D2O):δ3.90(dd,J1=12.4Hz,J2=19.2H z, 2H). Deuterium incorporation was determined to be approximately 96% by proton NMR. SFC(Supercritical Fluid Chromatography) of the Benzyloxycarbonylamino Derivative of Compound 100 Analysis revealed no trace of the S-enantiomer.

[0269] [Example 8] (2R)-2-amino-2,3,3-trideutero-3-hydroxy-propanoic acid (chemical Compound 103) Commercially available racemic 2-amino-2,3,3-trideutero-3-hydroxypropane The acid is resolved to give (2R)-2-amino-2,3,3-tri-deutero-3-hydroxy The details of obtaining propanoic acid (compound 103) with high ee and high D% are shown in Scheme 3 below. Shown below.

[0270] [ka] As shown in Scheme 3, commercially available racemic 2-amino-2,3,3-trideutero-3 Compound 103 was obtained by cleavage of -hydroxy-propanoic acid. The R and mass spectral data were consistent with the structure shown above for compound 103. MS(M+H):109.2; 1 H-NMR (400 MHz, DO): Deuterium uptake The proton NMR of the precursor and derivatives revealed that the methyl group was approximately 96% at the methinyl position. The deuterium incorporation at the methylenyl position was determined (based on the purity of the precursors described). ) about 98%. Critical fluid chromatography (CFC) analysis shows no trace of the S-enantiomer It was revealed that:

[0271] [Example 9] Compound 100 was measured using an automated patch clamp system (ScreenPatch ©). Evaluation of the pharmacology of deuterated and non-deuterated D-serine An automated patch clamp system (ScreenPatch®) was used to record human NMDA HEK293 cells expressing the DAR subunits GluN1 and GluN2A were used. The activation of NMDA receptors by Compound 100 and D-serine was evaluated.

[0272] Treat cells with increasing concentrations of Compound 100 or d-serine (0.003–10 μM) Peak and steady-state currents were measured. Activity at the NMDA receptor was determined by two chemical reactions. The receptor binding and activation by D-serine and Compound 100 were indistinguishable. The deuterium activation was similar in all cases measured. Compared to the non-deuterated compound, compound 100 , which exhibit nearly identical in vitro binding affinities for the glycine modulator site of the NMDAR. The activity of Compound 100 on the glycine site of the NMDA receptor derived from rat brain cortical membranes was shown. For binding affinity, the average K i The average value of D-serine was 0.91 μM. Average K i was 0.95 μM.

[0273] A representative graph is shown in FIG.

[0274] [Example 10] Evaluation of the brain distribution of Compound 100 in Sprague-Dawley rats after PO administration Price Distribution profile of Compound 100 in male Sprague-Dawley rats Rats (4 animals) were administered a single dose of Compound 100 at 100 mg / kg (oral PO). At 24 hours after administration, perfused brain and plasma-derived tissues were collected and analyzed by LC- The concentration of Compound 100 in the cortex (the intended target location) was analyzed by MS. was found to be higher than in other brain locations.

[0275] Plasma, cortex, brainstem, and cerebellum concentrations of Compound 100 at 24 hours are shown in Figure 15. vinegar.

[0276] At 24 hours, the mean concentrations in plasma, cortex, brainstem, and cerebellum were 880 ng / m L, 4660ng / g, 721ng / g, and 290ng / g.

[0277] [Example 11] Compound 10 in Sprague-Dawley rat cortex versus plasma after 4 days of PO administration Evaluation of the concentration of 0 Three groups of four male Sprague-Dawley rats were given 100 mg / kg of A single dose of Compound 100 was administered per day (orally (PO)) for a total of 4 days. After 4 days, perfused brain and plasma-derived tissues were collected at 24 hours (Group 1), 72 hours (Group 2) and 1 hour (Group 3) after administration. At 20 hours (group 3) samples were collected and analyzed by LC-MS.

[0278] Figure 1 shows the concentration of Compound 100 in rat cortex versus time after 4 days of administration of 100 mg / kg. Shown in 16.

[0279] Based on the concentration versus time data, the cortical (target location) half-life (T 1 / 2) has a much shorter plasma T that was shown to be less than 12 hours. 1 / 2 In contrast to about 4 This result indicates that systemic PK is uncoupled from brain PK, and the compound 100 has been shown to be surprising in the treatment of diseases that would benefit from NMDAR activation (or increased D-serine). Explain that the more a compound is synthesized, the more valuable it becomes.

[0280] Without further explanation, one of ordinary skill in the art can, using the preceding description and specific examples, prepare compounds of the present invention. It is believed that the above-mentioned inventions can be made and used to practice the claimed methods. The observations and examples are merely intended to provide a detailed description of some preferred embodiments. It should be understood that various modifications and equivalents may be made without departing from the spirit and scope of the present invention. It will be apparent to those skilled in the art that equivalents can be made.

Claims

1. Compounds of Formula I 【Chemical 1】 [In the formula, R １ is -OH, -OD, -OC １～４ alkyl, or amino acid residue, R ２ are H, D, and -C １～４ Alkyl, —C(O)—C １～６ alkyl, or —C(O )-C １～６ is a hydroxyalkyl, R ３ is H, D, or an amino acid residue, R ４ is H or D, Y １ , Y ２ａ and Y ２ｂ are independently H or D, with the proviso that Y １ , Y ２ａ and Y ２ｂ Specifically designated as deuterium, provided that at least one of The deuterium incorporation at each designated position is at least 50.1%. or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; 10. A pharmaceutical composition comprising:

2. R １ or R ３ The pharmaceutical composition of claim 1, wherein is a DD-serine residue.

3. The compound is a compound of formula II 【Chemistry 2】 [In the formula, Y １ , Y ２ａ and Y ２ｂ is independently H or D, with the proviso that Y １ , Y ２ａ and Y ２ｂ provided that at least one of is D. or a pharmaceutically acceptable salt thereof.

4. Y １ The pharmaceutical composition of claim 3, wherein is D.

5. Y ２ａ and Y ２ｂ The pharmaceutical composition according to any one of claims 1 to 4, wherein each of composition.

6. Y ２ａ and Y ２ｂ and each is D. composition.

7. 2. The method of claim 1, wherein the compound is selected from Compound 100 and Compound 103. Pharmaceutical composition. 【Chemistry 3】

8. 2. The pharmaceutical composition of claim 1, wherein the compound is compound 100. 【Chemistry 4】

9. Deuterium incorporation at each position specifically designated as deuterium is at least 90%. The pharmaceutical composition according to any one of claims 1 to 8.

10. Any atom not designated as deuterium is present in its natural isotopic abundance.

10. The pharmaceutical composition according to any one of claims 1 to 9.

11. 1. The compound of formula I according to claim 1, wherein the compound has a stereoisomeric purity of at least about 90%.

10. The pharmaceutical composition of any one of claims 1 to 8.

12. 12. A pharmaceutical composition according to any one of claims 1 to 11, suitable for oral administration.

13. 13. The method of claim 1, comprising 0.1 g to 60 g of the compound of formula I. Pharmaceutical compositions.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, further comprising an antipsychotic drug.

15. 1. A method for treating NMDAR encephalitis, comprising administering to a subject in need thereof an effective amount of claim 1 14. A method comprising administering a pharmaceutical composition according to any one of claims 1 to 13.

16. Epilepsy, NMDAR encephalitis, Parkinson's disease, cognitive deficits in Parkinson's disease, Alzheimer's disease Immer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia , bipolar disorder, bipolar mania, bipolar depression, treatment-resistant depression, cognitive deficits in depression , major depressive disorder, generalized anxiety disorder, major depressive disorder with mixed features, and huntington syndrome Cognitive deficits associated with Tony disease, subjective cognitive decline, traumatic brain injury, or Lewy body dementia 14. A method for treating dementia, comprising administering to a subject in need thereof an effective amount of any of claims 1 to 13. A method comprising the step of administering the pharmaceutical composition described in any one of claims 1 to 4.

17. 13. A method for treating depression, comprising administering to a subject in need thereof an effective amount of any one of claims 1 to 13.

2. A method comprising administering the pharmaceutical composition of any one of claims 1 to 11.

18. 14. A method for increasing NMDA receptor function, comprising administering to a cell a compound selected from the group consisting of a compound of claim 1 and ... The pharmaceutical composition according to the item 1 is contacted with the cells so as to increase the NMDA receptor function in the cells. The method includes the step of:

19. 1. A method for treating schizophrenia, comprising administering to a subject in need thereof an effective amount of any one of claims 1 to 10.

15. A method comprising administering a pharmaceutical composition according to any one of claims 14.

20. 20. The method of claim 19, further comprising administering to the subject an antipsychotic therapeutic agent. 。

Images