阅读说明：本技术 环丝氨酸化合物的盐和其应用 (Salts of cycloserine compounds and uses thereof ) 是由 蔡果荃 王景正 T-M.石 于 2019-09-12 设计创作，主要内容包括：本文提供了式[A][B]的盐,其中[A]是环丝氨酸化合物的阳离子形式,并且[B]是式(I)的化合物的阴离子形式,其中所述环丝氨酸化合物与所述式(I)的化合物之间的比率范围为10:1到1:10。本文所描述的盐具有改善的性质,包含大大增加的稳定性和降低的吸湿性。本文还提供了用于治疗和/或降低神经精神病症和/或细菌感染疾病(例如,结核病)的风险的方法,包括向有需要的受试者施用包括本文所描述的式[A][B]的盐的组合物。(Provided herein are compounds of the formula [ A][B]A salt of [ A ]]Is a cationic form of a cyclic serine compound, and [ B]Is an anionic form of a compound of formula (I), wherein the ratio between the cycloserine compound and the compound of formula (I) ranges from 10:1 to 1: 10. The salts described herein have improved properties, including greatly increased stability and reduced hygroscopicity. Also provided herein are methods for treating and/or reducing the risk of a neuropsychiatric disorder and/or a bacterial infectious disease (e.g., tuberculosis) comprising administering to a subject in need thereof a composition comprising formula [ a ] described herein][B]Of saltsA composition is provided.)

1. A salt of the formula [ A ] [ B ],

wherein [ A ] is the cationic form of the cycloserine compound; and is

[B] Is an anionic form of a compound of formula (I):

wherein

X is-NH₂or-OH;

L₁and L₂Each of which is independently C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene, or L when valency permits₁And L₂One of which is N, O or S, and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6An alkynylene group;

is a single or double bond; and is

Wherein the ratio of [ A ] to [ B ] in the salt is in the range of 10:1 to 1: 10.

2. The salt of claim 1, wherein the cycloserine compound has the formula:

3. the salt of claim 1 or claim 2, wherein the compound of formula (I) has the formula:

wherein:

each of A and BExamples are independently-NH₂-OH or H;

and isis-C₁-C₂-or-C₂＝C₁-。

4. The salt of claim 3, wherein the compound of formula (Ia) has the formula:wherein each instance of A and B is independently-OH or-H.

5. The salt of claim 4, wherein the compound of formula (Ib) is selected from the group consisting of:and [ A]And [ B ]]In the range of 5:1 to 1: 1.

6. The salt of claim 5, wherein the compound of formula (Ib) isAnd [ A]And [ B ]]The ratio between is 4: 1.

7. The salt of claim 5, wherein the compound of formula (Ib) isAnd [ A]And [ B ]]The ratio between is 2: 1.

8. The salt of claim 5, wherein the compound of formula (Ib) isAnd [ A]And [ B ]]In betweenThe ratio was 1: 1.

9. The salt of claim 3, wherein the compound of formula (Ia) is a compound of formula (Ic):wherein A and B are independently-OH or-H.

10. The salt of claim 9, wherein the compound of formula (Ic) is selected from the group consisting of:

11. the salt of claim 10, wherein the compound of formula (Ic) isAnd [ A]And [ B ]]The ratio between is 1: 1.

12. A composition comprising a salt according to any one of claims 1 to 11 and a carrier.

13. The composition of claim 12, consisting essentially of the salt.

14. The composition of claim 12 or claim 13, wherein the composition is a pharmaceutical composition, a nutritional composition, a nutraceutical, or a medical food.

15. A method for treating a neuropsychiatric disorder or a bacterial infectious disease, comprising administering to a subject in need thereof an effective amount of a salt according to any one of claims 1 to 11 or a composition according to any one of claims 12 to 14.

16. The method of claim 15, wherein the subject has, is suspected of having, or is at risk for: neuropsychiatric disorders or bacterial infectious diseases.

17. The method of claim 16, wherein the neuropsychiatric disorder is selected from the group consisting of: schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive impairment, benign forgetfulness, closed brain injury, autistic spectrum disorder, Asperger's disorder, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive compulsive disorder, tic disorders, childhood learning disorders, premenstrual syndrome, depression, major depression, anorgasmia, suicidal ideation and/or behavior, bipolar disorders, anxiety disorders, panic disorders, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addiction disorders, personality disorders, Parkinson's disease (Parkinson's disease), Huntington's disease (Huntington's disease), multiple sclerosis, Alzheimer's disease, dementia with Lewy bodies, Alzheimer's dementia, mild cognitive disorders, benign forgetfulness disorders, attention deficit disorder, obsessive compulsive disorders, tic disorders, premenstrual syndrome, depression, major depression, mental depression, attention deficit disorder, schizophrenia, multiple sclerosis, Alzheimer's disease, dementia, Alzheimer's, Amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette's syndrome, nocturia, non-seizures, blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain, hyperalgesia, allodynia, diabetic polyneuropathy and chronic pain syndrome.

18. The method of claim 16, wherein the neuropsychiatric disorder is selected from the group consisting of: ataxia, spinocerebellar degeneration, autism, pervasive developmental disorder not otherwise specified (PDD-NOS), anorexia nervosa, phobia, agoraphobia, and claustrophobia.

19. The method of claim 16, wherein the bacterial infectious disease is tuberculosis.

20. The method of any one of claims 15-19, wherein the subject is a human.

21. The method of any one of claims 15-20, wherein the salt is administered to the human at a frequency of four times per day to once every three months.

22. The method of any one of claims 15-21, wherein the method further comprises administering to the human one or more additional agents for treating the neuropsychiatric disorder.

23. The method of claim 22, wherein the one or more additional agents are selected from the group consisting of: antipsychotics, antidepressants, mood stabilizers, anxiolytics, psychostimulants, or agents for the treatment of cognitive disorders or dementia.

24. The method of claim 23, wherein:

(a) the antipsychotic agent is butyrophenone (butyrophenone), phenothiazine (phenothizine), fluphenazine (fluphenazine), perphenazine (perphenazine), prochlorperazine (prochlorperazine), thioridazine (thioridazine), trifluoperazine (trifluoperazine), mesoridazine (mesoridazine), promazine (promazine), thioridazine (thioridazine), thiothixene (thiothixene), zuclopenthixol (zuclopenthixol), clozapine (olanzapine), risperidone (risperidone), quetiapine (tiaprazine), thioridone (tiaprazine), thioridazine (piperazinone), sulpridine (piperazinone), piperazinone (piperazinone), piperazinone (piperazinone), piperazinone (piperazin, Piperazines (piperacetazines), sulpiride (sulpiride), acamprosate (acamprosate) or tetrabenazine (tetrabenazine);

(b) the antidepressant or mood stabilizer is a monoamine oxidase inhibitor (MAOI), tricyclic antidepressant (TCA), tetracyclic antidepressant (TeCA), Selective Serotonin Reuptake Inhibitor (SSRI), noradrenergic and serotonergic-specific antidepressant (NASSA), noradrenaline (noradrenaline) reuptake inhibitor, noradrenaline-dopamine reuptake inhibitor, serotonin-noradrenaline-dopamine reuptake inhibitor (SNDRI), or serotonin-noradrenaline reuptake inhibitor (SNRI);

(c) the anxiolytic is hydroxyzine hydrochloride (hydroxazine hydrochloride), diphenhydramine (diphenylhydramine), azaspirone (azaspirone), benzodiazepine or beta blocker;

(d) the psychostimulant is an agent for treating ADD and/or ADHD, comprising amphetamine (amphetamine), modafinil (modafinil), norudin (desoxyn), methamphetamine (methamphetamine), cocaine, arecoline, dexmethylphenidate (dexmethylphenidate), dexamphetamine (dexamphetamine), methylphenidate (methylphenidate), lisdexamphetamine (lisdexfamide), atomoxetine hydrochloride (atomoxetine hydrochloride), guanfacine hydrochloride (guanfacine hydrochloride), arecoline or pemoline (pemoline); and is

(e) Agents for the treatment of cognitive disorders or dementia are tacrine (tacrine), rivastigmine (rivastigmine), donepezil (donepezil), physostigmine (physostigmine), nicotine, arecoline, huperzine a (huperzine alpha), selegiline (selegiline), riluzole (riluzole), memantine (memantine), vitamin C, vitamin E, carotenoids or ginkgo biloba.

25. The method of claim 22, wherein the one or more additional agents are selected from the group consisting of: 5-hydroxytryptophan (5-HTP), idebenone (idebenone), amantadine (amantadine), physostigmine, L-carnitine or derivatives, trimethoprim/sulfamethoxazole (trimethoprim/sulfamethoxazole), vigabatrin (vigabatrin), phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone, Q10, vitamin E, and N-acetyl-leucine.

26. The method according to any one of claims 15 to 21, wherein the method further comprises administering to the human one or more additional agents for treating and/or reducing the risk of tuberculosis.

27. The method of claim 26, wherein the additional agent is isoniazid (isoniazid), rifampin (rifampin), ethambutol (ethambutol), pyrazinamide (pyrazinamide), rifabutin (rifabutin), rifapentine (rifapentine), capreomycin (capreomycin), kanamycin (kanamycin), amikacin (amikacin), streptomycin (strepomycin), fluoroquinolone antibiotics (fluoroquinolone antibiotics), prothiocyanamide (prothiocyanamide), para-aminosalicylic acid (para-aminosalicylic acid), ethionamide (ethionamide), terizione (terizadone), clofazimine (clozimine), clarithromycin (clindamycin), rilazolidinium (azolidinium), victorin (amoxicillin), carbapenem (carbapenem-carbapenem), carbapenem (carbapenem) or carbapenem (carbapenem) antibiotics.

28. The method of any one of claims 15-18 and 20-25, wherein the human has been or is receiving another treatment for the neuropsychiatric disorder.

29. The method of claim 23, wherein the antidepressant or mood stabilizer is fluoxetine (fluoxetine), paroxetine (parooxetine), escitalopram (escitalopram), citalopram (citalopram), sertraline (sertraline), fluvoxamine (fluvoxamine), venlafaxine (venlafaxine), milnacipran (milnacipran), duloxetine (duloxetine), mirtazapine (mirtazapine), mianserin (mianserin), reboxetine (reboxetine), bupropion (bupropion), amitriptyline (amitriptyline), nortriptyline (nortriptyline), protriptyline (protriptyline), desipramine (desipramine), trimipramine (trimipramine), amoxapine (amphetamine), meproxypromine (chlorphenamine), pyrimethazine (propiram), pyribenzoepin (propiram), doxazone (propine), doxazone (propiram), doxazone (propine), doxazone (propiram), doxazone (, Gabapentin (gabapentin), carbamazepine (carbamazepine), oxcarbazepine (oxcarbazepine), valproic acid (valproate), maprotiline (maprotiline), brofaromine (brofaromine), gepirone (gepirone), moclobemide (moclobemide), isoniazide (isoniazide) or isoniazide (ipronizide).

Background

D-cycloserine (i.e., 4-amino-3-isoxazolone) is a natural product of Streptomyces orchidensis and Streptomyces leucissus as a competitive antagonist of D-alanine, a component of the bacterial cell wall. D-cycloserine inhibits alanine racemase and alanine synthetase, and accumulation of incomplete cell wall components leads to bacterial cell wall disruption. D-cycloserine has been called antibiotic drug since the end of the 50 s of the 20 th century and is under the trademarkAnd (5) selling. D-cycloserine, as a second-line drug for the treatment of multi-drug resistant tuberculosis (MDR-TB), is classified on the World Health Organization's List of Essential drugs.

In addition, D-cycloserine can penetrate into the Central Nervous System (CNS) and has the unique potential to target the glycine binding site of the human N-methyl-D-aspartate (NMDA) receptor. As a selective partial NMDA agonist, D-cycloserine was later shown to influence long-term potentiation (LTP), a neuronal mechanism of the learning process, in slice preparation. Interestingly, it acts as a positive modulator of NMDA receptors at low doses, but as a negative modulator at high doses. Thus, when the dose is inappropriate, the use of D-cycloserine is restricted due to side effects of D-cycloserine, including headache, somnolence, depression, dizziness, vertigo, confusion, paresthesia, dysarthria, irritability, psychosis, convulsion and vibration (tremor). Also, overdosing with D-cycloserine may lead to paresis, seizures and coma, and in addition, drinking may increase the risk of seizures.

Since LTP is important for cognitive function, D-cycloserine has been introduced into neuropsychiatric studies at appropriate doses to assess the therapeutic potential of D-cycloserine for neurological and psychiatric conditions such as Alzheimer's disease, schizophrenia, depression, obsessive compulsive disorder, autism, traumatic stress disorder and anxiety disorders.

Disclosure of Invention

The present disclosure is based, at least in part, on the following findings: the salts of the cycloserine compounds disclosed herein have improved qualities, e.g., unexpectedly high stability and significantly reduced hygroscopicity.

In one aspect, the present disclosure provides a salt of formula [ A ] [ B ]. [A] Is a cationic form of a cyclic serine compound; and [ B ] is an anionic form of the compound of formula (I):

wherein

X is-NH₂or-OH;

L₁and L₂Each of which is independently C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene, or L when valency permits₁And L₂One of which is N, O or S, and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6An alkynylene group;

is a single or double bond;

and the ratio between [ A ] and [ B ] in the salt is in the range of 10:1 to 1: 10.

In another aspect, the present disclosure provides a composition comprising a salt of formula [ a ] [ B ] described herein and a carrier. The composition may be a pharmaceutical composition, a nutritional composition, a health food or a medical food.

In yet another aspect, the present disclosure provides a method for treating a neuropsychiatric disorder or a bacterial infectious disease, comprising administering to a subject in need of treatment an effective amount of a salt of formula [ a ] [ B ] as described herein. In some embodiments, the subject has, is suspected of having, or is at risk for: neuropsychiatric disorders or bacterial infectious diseases (e.g., tuberculosis). Exemplary neuropsychiatric disorders include, but are not limited to, schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive disorder, benign forgetfulness, ataxia symptoms, spinocerebellar degeneration, closed brain injury, autism spectrum disorder, autism, Asperger's disorder, unspecified pervasive developmental disorder (PDD-NOS), fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive compulsive disorder, tic disorder, childhood learning disorder, premenstrual syndrome, depression, major depression, anhedonia, suicidal thoughts and/or behaviors, bipolar disorder, anxiety disorder, panic disorder, anorexia nervosa, phobia, anxiety disorder, and/or depression, Agoraphobia, claustrophobia, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addictive disorders, personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette's syndrome, nocturia, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain including hyperalgesia and allodynia, diabetic polyneuropathy and chronic pain syndrome.

Also provided herein are pharmaceutical compositions comprising any of the salts of any of the formulae [ a ] [ B ] disclosed herein for use in treating a neuropsychiatric disorder or a bacterial infectious disease (such as those disclosed herein), and the use of the salts of formula [ a ] [ B ] in the manufacture of a medicament for treating a target disease as disclosed herein.

The details of one or more embodiments of the disclosure are set forth herein. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims.

Definition of

Definitions of specific functional groups and chemical terms are described in more detail below. Chemical Elements are identified according to the Periodic Table of Elements (CAS version, Handbook of Chemistry and Physics, 75 th edition, enclosure) and specific functional groups are generally defined as described herein. In addition, the general principles of Organic Chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry (Organic Chemistry), University Science book publishers (University Science Books), Soxhlet (Sausalitio), 1999; smith and March, Advanced Organic Chemistry of March, 5 th edition, John Wiley & Sons, Inc, new york, 2001; larock, Comprehensive Organic Transformations (Comprehensive Organic Transformations), VCH Publishers Inc. (VCH Publishers, Inc.), New York, 1989; and Carruther, Some of the Modern Methods of Organic Synthesis (Some Modern Methods of Organic Synthesis), 3 rd edition, Cambridge University Press (Cambridge University Press), Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

The compounds described herein may include one or more asymmetric centers, and thus may exist in various isomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and enriched mixtures of one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al, "Enantiomers, Racemates and Resolutions (enertiomers, racemes and Resolutions) (willy international, new york, 1981); wilen et al, Tetrahedron (Tetrahedron) 33:2725 (1977); eliel, Stereochemistry of Carbon Compounds (Stereochemistry of Carbon Compounds) (McGraw-Hill, New York, 1962); and Wilen, Tables for resolution Agents and Optical resolution (Tables of resolution Agents and Optical resolution), page 268 (edited by E.L. Eliel, university of san Diego publishers (Univ. of Notre Dame Press), Nutta, Ind., 1972). The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

When a range of values is recited, it is intended to include each value and sub-range within the range. For example, "C_1-6"is intended to cover C₁、C₂、C₃、C₄、C₅、C₆、C_1-6、C_1-5、C_1-4、C_1-3、C_1-2、C_2-6、C_2-5、C_2-4、C_2-3、C_3-6、C_3-5、C_3-4、C_4-6、C_4-5And C_5-6。

The term "aliphatic" encompasses saturated and unsaturated, straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be understood by those of ordinary skill in the art, "aliphatic" is intended herein to encompass, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" encompasses linear, branched, and cyclic alkyl groups. Similar convention applies to other general terms such as "alkenyl", "alkynyl", and the like. Furthermore, the terms "alkyl", "alkenyl", "alkynyl", and the like encompass both substituted and unsubstituted groups. In certain embodiments, "lower alkyl" is used to denote those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-4 carbon atoms. Thus, exemplary aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH₂-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH₂-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH₂Cyclohexyl moieties and the like, which may bear one or more substituents again. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

The term "alkyl" refers to a group of straight or branched chain saturated hydrocarbon groups having from 1 to 10 carbon atoms ("C)_1-10Alkyl "). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C)_1-9Alkyl "). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C)_1-8Alkyl "). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C)_1-7Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C)_1-6Alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C)_1-5Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C)_1-4Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C)_1-3Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C)_1-2Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C)₁Alkyl "). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C)_2-6Alkyl "). C_1-6Examples of alkyl groups include methyl (C)₁) Ethyl (C)₂) Propyl group (C)₃) (e.g., n-propyl, isopropyl), butyl (C)₄) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C)₅) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C)₆) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C)₇) N-octyl (C)₈) And the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halo, such as F). In certain embodiments, alkyl is unsubstituted C_1-10Alkyl (e.g. unsubstituted C)_1-6Alkyl radicals, e.g., -CH₃). In certain embodiments, alkyl is substituted C_1-10Alkyl (e.g. substituted C)_1-6Alkyl radicals, e.g., -CF₃)。

"alkenyl" means a straight or branched chain hydrocarbyl ("C") group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds_2-20Alkenyl "). In some embodiments, alkenyl groups have 2 to 10 carbon atoms ("C)_2-10Alkenyl "). In some embodiments, alkenyl groups have 2 to 9 carbon atoms ("C)_2-9Alkenyl "). In some embodiments, alkenyl groups have 2 to 8 carbon atoms ("C)_2-8Alkenyl "). In some embodiments, alkenyl groups have 2 to 7 carbon atoms ("C)_2-7Alkenyl "). In some embodiments, alkenyl groups have 2 to 6 carbon atoms ("C)_2-6Alkenyl "). In some embodiments, alkenyl groups have 2 to 5 carbon atoms ("C)_2-5Alkenyl "). In some embodiments, alkenyl groups have 2 to 4 carbon atoms ("C)_2-4Alkenyl "). In some embodiments, alkenyl groups have 2 to 3 carbon atoms ("C)_2-3Alkenyl "). In some embodiments, alkenyl has 2 carbon atoms ("C)₂Alkenyl "). The one or more carbon-carbon double bonds may be internal (as in 2-butenyl) or terminal (as in 1-butenyl). C_2-4Examples of the alkenyl group include vinyl (C)₂) 1-propenyl (C)₃) 2-propenyl (C)₃) 1-butenyl (C)₄) 2-butenyl (C)₄) Butadienyl radical (C)₄) And the like. C_2-6Examples of alkenyl groups include the aforementioned C_2-4Alkenyl and pentenyl (C)₅) Pentadienyl (C)₅) Hexenyl (C)₆) And the like. Further examples of alkenyl groups include heptenyl (C)₇) Octenyl (C)₈) Octrienyl (C)₈) And the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl is unsubstituted C_2-10An alkenyl group. In certain embodiments, the alkenyl is substituted C_2-10An alkenyl group. In the alkenyl group, a stereochemically unspecified C ═ C double bond (e.g., -CH ═ CHCH)₃Or) May be an (E) -or (Z) -double bond.

"alkynyl" refers to a group of straight or branched hydrocarbon radicals having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds and optionally one or more double bonds ("C)_2-20Alkynyl "). In some embodiments, alkynyl has 2 to 10 carbon atoms ("C)_2-10Alkynyl "). In some embodiments, alkynyl has 2 to 9 carbon atoms ("C)_2-9Alkynyl "). In some embodiments, alkynyl has 2 to 8 carbon atoms ("C)_2-8Alkynyl "). In some embodiments, alkynyl has 2 to 7 carbon atoms ("C)_2-7Alkynyl "). In some embodiments, alkynyl has 2 to 6 carbon atoms ("C)_2-6Alkynyl "). In some embodiments, alkynesRadicals having 2 to 5 carbon atoms ("C)_2-5Alkynyl "). In some embodiments, alkynyl has 2 to 4 carbon atoms ("C)_2-4Alkynyl "). In some embodiments, alkynyl has 2 to 3 carbon atoms ("C)_2-3Alkynyl "). In some embodiments, alkynyl has 2 carbon atoms ("C)₂Alkynyl "). The one or more carbon-carbon triple bonds may be internal (as in 2-butynyl) or terminal (as in 1-butynyl). C_2–4Examples of alkynyl groups include, but are not limited to, ethynyl (C)₂) 1-propynyl (C)₃) 2-propynyl (C)₃) 1-butynyl (C)₄) 2-butynyl (C)₄) And the like. C_2-6Examples of alkenyl groups include the aforementioned C_2-4Alkynyl and pentynyl (C)₅) Hexynyl (C)₆) And the like. Further examples of alkynyl groups include heptynyl (C)₇) (C) octynyl group₈) And the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is unsubstituted C_2-10Alkynyl. In certain embodiments, the alkynyl group is substituted C_2-10Alkynyl.

Alkyl, alkenyl, and alkynyl groups that are divalent bridging groups are further referred to using the suffix-ene (e.g., alkylene, alkenylene, and alkynylene).

Unless otherwise specifically stated, an atom, moiety or group described herein may be unsubstituted or substituted where valency permits. The term "optionally substituted" refers to substituted or unsubstituted.

Unless explicitly specified otherwise, a group is optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). Generally, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that results in a stable compound upon substitution, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. It is contemplated that the term "substituted" encompasses substitution with all permissible substituents of organic compounds, any of the substituents described herein that result in the formation of stable compounds. The present disclosure contemplates any and all such combinations in order to obtain stable compounds. For the purposes of this disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent that satisfies the valence of the heteroatom and results in the formation of a stable moiety as described herein. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OR^aa、-ON(R^bb)₂、-N(R^bb)₂、-N(R^bb)₃ ⁺X^–、-N(OR^cc)R^bb、-SH、-SR^aa、-SSR^cc、-C(＝O)R^aa、-CO₂H、-CHO、-C(OR^cc)₂、-CO₂R^aa、-OC(＝O)R^aa、-OCO₂R^aa、-C(＝O)N(R^bb)₂、-OC(＝O)N(R^bb)₂、-NR^bbC(＝O)R^aa、-NR^bbCO₂R^aa、-NR^bbC(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-OC(＝NR^bb)R^aa、-OC(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-OC(＝NR^bb)N(R^bb)₂、-NR^bbC(＝NR^bb)N(R^bb)₂、-C(＝O)NR^bbSO₂R^aa、-NR^bbSO₂R^aa、-SO₂N(R^bb)₂、-SO₂R^aa、-SO₂OR^aa、-OSO₂R^aa、-S(＝O)R^aa、-OS(＝O)R^aa、-Si(R^aa)₃、-OSi(R^aa)₃、-C(＝S)N(R^bb)₂、-C(＝O)SR^aa、-C(＝S)SR^aa、-SC(＝S)SR^aa、-SC(＝O)SR^aa、-OC(＝O)SR^aa、-SC(＝O)OR^aa、-SC(＝O)R^aa、-P(＝O)(R^aa)₂、-P(＝O)(OR^cc)₂、-OP(＝O)(R^aa)₂、-OP(＝O)(OR^cc)₂、-P(＝O)(N(R^bb)₂)₂、-OP(＝O)(N(R^bb)₂)₂、-NR^bbP(＝O)(R^aa)₂、-NR^bbP(＝O)(OR^cc)₂、-NR^bbP(＝O)(N(R^bb)₂)₂、-P(R^cc)₂、-P(OR^cc)₂、-P(R^cc)₃ ⁺X^-、-P(OR^cc)₃ ⁺X^-、-P(R^cc)₄、-P(OR^cc)₄、-OP(R^cc)₂、-OP(R^cc)₃ ⁺X^-、-OP(OR^cc)₂、-OP(OR^cc)₃ ⁺X^-、-OP(R^cc)₄、-OP(OR^cc)₄、-B(R^aa)₂、-B(OR^cc)₂、-BR^aa(OR^cc)、C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups; wherein X^-Is a counter ion;

or two geminal hydrogens on a carbon atom are selected from the group consisting of O, ═ S, ═ NN (R)^bb)₂、＝NNR^bbC(＝O)R^aa、＝NNR^bbC(＝O)OR^aa、＝NNR^bbS(＝O)₂R^aa、＝NR^bbOr NOR^ccSubstitution;

R^aaeach instance of (A) is independently selected from C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, or two Raa groups joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

R^bbeach instance of (A) is independently selected from hydrogen, -OH, -OR^aa、-N(R^cc)₂、-CN、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、-P(＝O)(R^aa)₂、-P(＝O)(OR^cc)₂、-P(＝O)(N(R^cc)₂)₂、C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, or two R^bbThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups; wherein X^-Is a counter ion;

R^cceach instance of (A) is independently selected from hydrogen, C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, or two R^ccThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

R^ddeach instance of (A) is independently selected from halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OR^ee、-ON(R^ff)₂、-N(R^ff)₂、-N(R^ff)₃ ⁺X^–、-N(OR^ee)R^ff、-SH、-SR^ee、-SSR^ee、-C(＝O)R^ee、-CO₂H、-CO₂R^ee、-OC(＝O)R^ee、-OCO₂R^ee、-C(＝O)N(R^ff)₂、-OC(＝O)N(R^ff)₂、-NR^ffC(＝O)R^ee、-NR^ffCO₂R^ee、-NR^ffC(＝O)N(R^ff)₂、-C(＝NR^ff)OR^ee、-OC(＝NR^ff)R^ee、-OC(＝NR^ff)OR^ee、-C(＝NR^ff)N(R^ff)₂、-OC(＝NR^ff)N(R^ff)₂、-NR^ffC(＝NR^ff)N(R^ff)₂、–NR^ffSO₂R^ee、-SO₂N(R^ff)₂、-SO₂R^ee、-SO₂OR^ee、-OSO₂R^ee、-S(＝O)R^ee、-Si(R^ee)₃、-OSi(R^ee)₃、-C(＝S)N(R^ff)₂、-C(＝O)SR^ee、-C(＝S)SR^ee、-SC(＝S)SR^ee、-P(＝O)(OR^ee)₂、-P(＝O)(R^ee)₂、-OP(＝O)(R^ee)₂、-OP(＝O)(OR^ee)₂、C_1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, 3-10 membered heterocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by radicals, or two twin positions R^ddSubstituents may be joined to form ═ O or ═ S; wherein X^-Is a counter ion;

R^eeeach instance of (A) is independently selected from C_1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, C_6-10Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by groups;

R^ffeach instance of (A) is independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, 3-10 membered heterocyclyl, C_6-10Aryl and 5-10 membered heteroaryl, or two R^ffThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by groups; and is

R^ggEach instance of (A) is independently halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OC_1-6Alkyl, -ON (C)_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₃ ⁺X^–、-NH(C_1-6Alkyl radical)₂ ⁺X^–、-NH₂(C_1-6Alkyl radical)⁺X^–、-NH₃ ⁺X^–、-N(OC_1-6Alkyl) (C_1-6Alkyl), -N (OH) (C)_1-6Alkyl), -NH (OH), -SH, -SC_1-6Alkyl, -SS (C)_1-6Alkyl), -C (═ O) (C)_1-6Alkyl), -CO₂H、-CO₂(C_1-6Alkyl), -OC (═ O) (C)_1-6Alkyl), -OCO₂(C_1-6Alkyl), -C (═ O) NH₂、-C(＝O)N(C_1-6Alkyl radical)₂、-OC(＝O)NH(C_1-6Alkyl), -NHC (═ O) (C)_1-6Alkyl), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl), -NHCO₂(C_1-6Alkyl), -NHC (═ O) N (C)_1-6Alkyl radical)₂、-NHC(＝O)NH(C_1-6Alkyl), -NHC (═ O) NH₂、-C(＝NH)O(C_1-6Alkyl), -OC (═ NH) (C)_1-6Alkyl), -OC (═ NH) OC_1-6Alkyl, -C (═ NH) N (C)_1-6Alkyl radical)₂、-C(＝NH)NH(C_1-6Alkyl), -C (═ NH) NH₂、-OC(＝NH)N(C_1-6Alkyl radical)₂、-OC(NH)NH(C_1-6Alkyl), -OC (NH) NH₂、-NHC(NH)N(C_1-6Alkyl radical)₂、-NHC(＝NH)NH₂、-NHSO₂(C_1-6Alkyl), -SO₂N(C_1-6Alkyl radical)₂、-SO₂NH(C_1-6Alkyl), -SO₂NH₂、-SO₂C_1-6Alkyl, -SO₂OC_1-6Alkyl, -OSO₂C_1-6Alkyl, -SOC_1-6Alkyl, -Si (C)_1-6Alkyl radical)₃、-OSi(C_1-6Alkyl radical)₃、-C(＝S)N(C_1-6Alkyl radical)₂、C(＝S)NH(C_1-6Alkyl), C (═ S) NH₂、-C(＝O)S(C_1-6Alkyl), -C (═ S) SC_1-6Alkyl, -SC (═ S) SC_1-6Alkyl, -P (═ O) (OC)_1-6Alkyl radical)₂、-P(＝O)(C_1-6Alkyl radical)₂、-OP(＝O)(C_1-6Alkyl radical)₂、-OP(＝O)(OC_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, C_6-10Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two twin sites R^ggSubstituents may be joined to form ═ O or ═ S; wherein X^-Is a counter ion.

R^ggEach instance of (A) is independently halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OC_1-6Alkyl, -ON (C)_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₃ ⁺X^–、-NH(C_1-6Alkyl radical)₂ ⁺X^–、-NH₂(C_1-6Alkyl radical)⁺X^–、-NH₃ ⁺X^–、-N(OC_1-6Alkyl) (C_1-6Alkyl), -N (OH) (C)_1-6Alkyl), -NH (OH), -SH, -SC_1-6Alkyl, -SS (C)_1-6Alkyl), -C (═ O) (C)_1-6Alkyl), -CO₂H、-CO₂(C_1-6Alkyl), -OC (═ O) (C)_1-6Alkyl), -OCO₂(C_1-6Alkyl), -C (═ O) NH₂、-C(＝O)N(C_1-6Alkyl radical)₂、-OC(＝O)NH(C_1-6Alkyl), -NHC (═ O) (C)_1-6Alkyl), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl), -NHCO₂(C_1-6Alkyl), -NHC (═ O) N (C)_1-6Alkyl radical)₂、-NHC(＝O)NH(C_1-6Alkyl), -NHC (═ O) NH₂、-C(＝NH)O(C_1-6Alkyl), -OC (═ NH) (C)_1-6Alkyl), -OC (═ NH) OC_1-6Alkyl, -C (═ NH) N (C)_1-6Alkyl radical)₂、-C(＝NH)NH(C_1-6Alkyl), -C (═ NH) NH₂、-OC(＝NH)N(C_1-6Alkyl radical)₂、-OC(NH)NH(C_1-6Alkyl), -OC (NH) NH₂、-NHC(NH)N(C_1-6Alkyl radical)₂、-NHC(＝NH)NH₂、-NHSO₂(C_1-6Alkyl), -SO₂N(C_1-6Alkyl radical)₂、-SO₂NH(C_1-6Alkyl), -SO₂NH₂、-SO₂C_1-6Alkyl, -SO₂OC_1-6Alkyl, -OSO₂C_1-6Alkyl, -SOC_1-6Alkyl, -Si (C)_1-6Alkyl radical)₃、-OSi(C_1-6Alkyl radical)₃、-C(＝S)N(C_1-6Alkyl radical)₂、C(＝S)NH(C_1-6Alkyl), C (═ S) NH₂、-C(＝O)S(C_1-6Alkyl), -C (═ S) SC_1-6Alkyl, -SC (═ S) SC_1-6Alkyl, -P (═ O) (OC)_1-6Alkyl radical)₂、-P(＝O)(C_1-6Alkyl radical)₂、-OP(＝O)(C_1-6Alkyl radical)₂、-OP(＝O)(OC_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, C_6-10Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two twin sites R^ggSubstituents may be joined to form ═ O or ═ S; wherein X^-Is a counter ion.

To maintain electronic neutrality, a "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group. The anionic counter ion may be monovalent (i.e., contain a formal negative charge). The anionic counter-ion may also be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F)^–、Cl^–、Br^–、I^–)、NO₃ ^–、ClO₄ ^–、OH^–、H₂PO₄ ^–、HSO₄ ^–Sulfonate ion (e.g., methanesulfonate)Trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), a carboxylate ion (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF₄ ^–、PF₄ ^–、PF₆ ^–、AsF₆ ^–、SbF₆ ^–、B[3,5-(CF₃)₂C₆H₃]₄]^–、BPh₄ ^–、Al(OC(CF₃)₃)₄ ^–And carborane anions (e.g., CB)₁₁H₁₂ ^–Or (HCB)₁₁Me₅Br₆)^–). Exemplary counterions that can be multivalent include CO₃ ^2-、HPO₄ ^2-、PO₄ ^3-、B₄O₇ ^2-、SO₄ ^2-、S₂O₃ ^2-Carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, and the like) and carboranes.

"halo" or "halogen" refers to fluoro (fluoro, -F), chloro (chloro, -Cl), bromo (bromo, -Br), or iodo (iodo, -I).

"acyl" refers to a moiety selected from the group consisting of: -C (═ O) R^aa、-CHO、-CO₂R^aa、-C(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-C(＝O)NR^bbSO₂R^aa、-C(＝S)N(R^bb)₂、-C(＝O)SR^aaor-C (═ S) SR^aaWherein R is^aaAnd R^bbAs defined herein.

The nitrogen atoms may be substituted or unsubstituted as valency permits and include primary, secondary, tertiary and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR^aa、-N(R^cc)₂、-CN、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^bb)R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、-P(＝O)(OR^cc)₂、-P(＝O)(R^aa)₂、-P(＝O)(N(R^cc)₂)₂、C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, or two R attached to the nitrogen atom^ccThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddIs substituted by radicals, and wherein R^aa、R^bb、R^ccAnd R^ddAs defined above.

Exemplary oxygen atom substituents include, but are not limited to, -R^aa、-C(＝O)SR^aa、-C(＝O)R^aa、-CO₂R^aa、-C(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-S(＝O)R^aa、-SO₂R^aa、-Si(R^aa)₃、-P(R^cc)₂、-P(R^cc)₃ ⁺X^-、-P(OR^cc)₂、-P(OR^cc)₃ ⁺X^-、-P(＝O)(R^aa)₂、-P(＝O)(OR^cc)₂and-P (═ O) (N (R)^bb)₂)₂Wherein X is^-、R^aa、R^bbAnd R^ccAs defined herein.

The term "salt" refers to an ionic compound resulting from the neutralization of an acid and a base. A salt consists of one or more "cations" (positively charged ions) and one or more "anions" (negatively charged ions), and thus a salt is electrically neutral (without a net charge). The salts described herein may comprise those derived from suitable organic acids as disclosed herein, for example dicarboxylic acids. Examples of organic and inorganic acids include, but are not limited to, acetic acid, ascorbic acid, aspartic acid, benzoic acid, formic acid, fumaric acid, gallic acid, gluconic acid, lactic acid, lauric acid, methanesulfonic acid, nicotinic acid, oxalic acid, maleic acid, malonic acid, L-tartaric acid, D-tartaric acid, meso-tartaric acid, malic acid, citric acid, succinic acid, stearic acid, pentetic acid, propionic acid, p-toluenesulfonic acid, undecanoic acid, valeric acid, ethylenediaminetetraacetic acid, boric acid, hydrochloric acid, hydrobromic acid, chromic acid, nitric acid, phosphoric acid, phosphorous acid, hypophosphorous acid, sulfuric acid, and sulfonic acid.

The term "cycloserine compound" refers to cycloserine (racemic mixture in D-or L-form or DL-form) or a pharmaceutically acceptable salt or ester thereof or a functional derivative thereof. In some embodiments, the cycloserine compound may be nanocrystalline D-cycloserine. In some embodiments, the cycloserine compound may be nanocrystalline L-crystals. In other embodiments, the cycloserine compound is a racemic mixture of DL-cycloserine in nanocrystalline form. The chemical structure of cycloserine is provided below:

is contained inIn (1).

The functional derivative of cycloserine may be a compound having the same core structure as cycloserine, which has one or more substituents such as alkyl, alkenyl, alkynyl and/or halogen.

A "subject" contemplated for administration refers to a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, a middle aged adult, or an elderly adult) or a non-human animal.

The term "administration" refers to implanting, absorbing, ingesting, injecting, inhaling or otherwise introducing a salt of the formula [ a ] [ B ], wherein [ a ] is a cationic form of a cycloserine compound and [ B ] is an anionic form of or on a compound of formula (I) described herein.

The term "treating" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, the treatment can be administered in the absence of signs or symptoms of disease. For example, treatment can be administered to a susceptible subject prior to the onset of symptoms (e.g., based on a history of symptoms and/or based on exposure to a pathogen) to delay or prevent disease onset. After the symptoms subside, treatment may also be continued, e.g., to delay or prevent relapse.

The terms "condition," "disease," and "disorder" are used interchangeably.

An "effective amount" of a salt of formula [ A ] [ B ] as described herein refers to an amount sufficient to elicit the desired biological response, i.e., to treat the condition. As will be appreciated by those skilled in the art, the effective amounts of the salts of cycloserine and the compounds of formula (I) described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the salt of formula [ a ] [ B ], the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount of a salt of formula [ A ] [ B ] described herein in a single dose. In certain embodiments, the effective amount is an amount of a combination of multiple doses of a salt of formula [ A ] [ B ] described herein.

A "therapeutically effective amount" of a salt of formula [ a ] [ B ] described herein is an amount sufficient to provide a therapeutic benefit for treating a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a salt of formula [ a ] [ B ] means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating a condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a condition, and/or enhances the therapeutic efficacy of another therapeutic agent.

A "prophylactically effective amount" of a salt of formula [ A ] [ B ] described herein is an amount sufficient to prevent a condition or one or more symptoms associated with the condition or to prevent recurrence thereof. A prophylactically effective amount of a salt of formula [ a ] [ B ] means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

The term "neuropsychiatric disorder" encompasses neurological diseases or psychiatric disorders or CNS disorders, or refers to disorders involving psychotic symptoms or syndromes arising from organic brain disorders. The main properties of neuropsychiatric symptoms include various psychiatric symptoms, cognitive impairment, the occurrence of neurological symptoms or the likelihood of early brain development symptoms. For example, the neuropsychiatric disorder may include, but is not limited to, schizophrenia, psychotic disorders, alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with lewy bodies, senile dementia, mild cognitive impairment, benign forgetfulness, closed brain injury, autism spectrum disorder, asperger's disorder, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive compulsive disorder, tic disorder, childhood learning disorders, premenstrual syndrome, depression, major depression, anhedonia, suicidal thoughts and/or behaviors, bipolar disorders, anxiety disorders, panic disorders, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addictive disorders, personality disorders, parkinson's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, post-traumatic stress disorder, stress disorder, Friedreich's ataxia, tourette's syndrome, nocturia, non-epileptic seizures, blepharospasm, duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain involving hyperalgesia and allodynia, diabetic polyneuropathy and chronic pain syndrome.

The term "nutraceutical" or "nutraceutical product" refers to any type of liquid and solid/semisolid material used to nourish humans and animals for improving basic behavioral functions, hyperactivity, anxiety, depression, sensorimotor gating, pain threshold, memory and/or cognitive function, body weight, or for facilitating the treatment of any of the target disorders described herein. The term "nutritional composition" refers to a composition that contains components of food origin and imparts additional health benefits in addition to the essential nutritional value found in food.

The term "medical food" or "medical food product" refers to a food product formulated for enteral consumption or administration, including food products that are typically used under the direction of a physician for specific dietary management of a disease of interest, such as those described herein. A "medical food product" composition may refer to a composition specifically formulated and processed (as opposed to a naturally occurring food used in a natural state) for a patient in need of treatment (e.g., a human patient with a disease or a human patient in need of using the product as a primary active agent for alleviating a disease or condition through specific dietary management).

Drawings

FIG. 1 shows the preparation of D-cycloserine from Strides Shasun Ltd¹H-NMR spectrum.

FIG. 2 shows the preparation of succinic acid¹H-NMR spectrum.

FIG. 3 shows D-cycloserine succinate form¹H-NMR spectrum.

FIG. 4 shows an X-ray powder diffraction (XRPD) spectrum of D-cycloserine from Stellex Sassen GmbH.

Fig. 5 shows the XRPD spectrum of succinic acid.

FIG. 6 shows XRPD spectra of the D-cycloserine succinate (4:1) salt form, confirming salt formation.

FIG. 7 shows a thermogravimetric analysis (TGA) curve of D-cycloserine.

Fig. 8 shows the TGA profile of succinic acid.

FIG. 9 shows a TGA curve demonstrating the D-cycloserine succinate (4:1) salt form, which is different from D-cycloserine and succinate.

FIG. 10 shows the Differential Scanning Calorimetry (DSC) curve of D-cycloserine from Stelley Sassen GmbH.

Fig. 11 shows DSC curves for succinic acid.

FIG. 12 shows a DSC curve demonstrating the D-cycloserine succinate (4:1) salt form.

FIG. 13 shows the preparation of L-tartaric acid¹H-NMR spectrum.

FIG. 14 shows¹H-NMR spectrum confirmed the D-cycloserine L-tartaric acid (1:1) salt form.

Fig. 15 shows an XRPD spectrum of L-tartaric acid.

FIG. 16 shows an XRPD spectrum, confirming the D-cycloserine L-tartaric acid (1:1) salt form.

Fig. 17 shows a TGA profile of L-tartaric acid.

FIG. 18 shows a TGA curve demonstrating the D-cycloserine L-tartaric acid (1:1) salt form.

FIG. 19 shows a DSC curve of L-tartaric acid.

FIG. 20 shows a DSC curve demonstrating the D-cycloserine L-tartaric acid (1:1) salt form.

FIG. 21 shows the preparation of maleic acid¹H-NMR spectrum.

FIG. 22 shows¹H-NMR spectrum confirmed the D-cycloserine maleic acid (1:1) salt form.

Figure 23 shows an XRPD spectrum of maleic acid.

FIG. 24 shows an XRPD spectrum, confirming the D-cycloserine maleate (1:1) salt form.

Figure 25 shows a TGA profile of maleic acid.

FIG. 26 shows a TGA curve confirming the D-cycloserine maleic acid (1:1) salt form.

Figure 27 shows the DSC curve for maleic acid.

FIG. 28 shows a DSC curve demonstrating the D-cycloserine maleate (1:1) salt form.

FIG. 29 shows the preparation of D-tartaric acid¹H-NMR spectrum.

FIG. 30 shows¹H-NMR spectrum confirmed the D-cycloserine D-tartaric acid (2:1) salt form.

Figure 31 shows an XRPD spectrum of D-tartaric acid.

FIG. 32 shows an XRPD spectrum confirming the D-cycloserine D-tartaric acid (2:1) salt form.

Figure 33 shows a TGA profile of D-tartaric acid.

FIG. 34 shows a TGA curve demonstrating the D-cycloserine D-tartaric acid (2:1) salt form.

FIG. 35 shows a DSC curve of D-tartaric acid.

FIG. 36 shows a DSC curve demonstrating the D-cycloserine D-tartaric acid (2:1) salt form.

Fig. 37 shows HPLC analysis of (1) fresh D-cycloserine from milrod Pharmaceuticals Ltd. (Macleods Pharmaceuticals Ltd.), (2) D-cycloserine L-tartaric acid (1:1) salt form, (3) D-cycloserine from milrod Pharmaceuticals Ltd., and (4) D-cycloserine from sls sason Ltd. (60 days at 40/75% RH), as described in example 5. The results indicate that the D-cycloserine L-tartaric acid (1:1) salt is stable, while the rest is unstable.

Fig. 38 shows the results of HPLC analysis of (1) fresh D-cycloserine (t ═ 0 days) from miloude pharmaceuticals, inc and sley-sason, inc, (2) maleic acid, (3) D-cycloserine maleic acid (1:1) salt form, (4) D-cycloserine from miloude pharmaceuticals, inc, (5) D-cycloserine from sley-sason, inc (30 days at 40/75% RH), as described in example 5. After 30 days, the D-cycloserine maleate (1:1) salt was stable, while the rest were unstable.

Fig. 39 shows HPLC analysis of (1) fresh D-cycloserine (t ═ 0 days) and (2) D-tartaric acid from miloude pharmaceuticals limited and sley samson limited, (3) D-cycloserine D-tartaric acid (2:1) salt form, (4) D-cycloserine from miloude pharmaceuticals limited, and (5) D-cycloserine from sley samson limited (held at 40/75% RH for 30 days), as described in example 5. In this case, only the D-cycloserine D-tartaric acid (2:1) salt is stable.

FIG. 40 shows the results of hygroscopicity tests at room temperature/95% RH for 60 days in an open system of D-cycloserine from Stylece Sassen GmbH (top curve), D-cycloserine from McRod pharmaceuticals GmbH, L-tartaric acid and D-cycloserine L-tartaric acid (1:1) salt form (bottom curve), as described in example 6. The D-cycloserine L-tartaric acid (1:1) salt form is not hygroscopic, while the others are hygroscopic.

FIG. 41 shows the results of hygroscopicity tests for D-cycloserine from Stylece Sassen, Inc. (top curve), D-cycloserine from McRod pharmaceutical Co., Ltd., maleic acid and D-cycloserine maleic acid (1:1) salt form (bottom curve) in an open system for 30 days at room temperature/95% RH, as described in example 6. The D-cycloserine L-tartaric acid (1:1) salt form is not hygroscopic, while the others are hygroscopic.

FIG. 42 shows the results of hygroscopicity tests for D-cycloserine from Striesis Saseng, Inc. (top curve), D-cycloserine, D-tartaric acid and D-cycloserine D-tartaric acid (2:1) salt form (bottom curve) from McRod pharmaceuticals, Inc. in an open system for 30 days at room temperature/95% RH, as described in example 6. The D-cycloserine D-tartaric acid (2:1) salt form is not hygroscopic, while the others are hygroscopic.

Detailed Description

The present disclosure provides salts of formula [ A ] [ B ], wherein [ A ] is the cationic form of the cycloserine compound, and wherein [ B ] is the anionic form of the compound of formula (I) described herein. This salt or composition thereof may be used to treat a neuropsychiatric disorder or a bacterial infection in a subject.

Salts of cationic forms of cycloserine compounds and anionic forms of compounds of formula (I)

One aspect of the present invention provides a salt of formula [ A ] [ B ]. [A] Is a cationic form of a cyclic serine compound, and [ B ] is an anionic form of a compound of formula (I):

wherein X is-NH₂or-OH;

L₁and L₂Each of which is independently C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene, or L when valency permits₁And L₂One of which is N, O or S, and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6An alkynylene group;

is a single or double bond; and is

The ratio of [ A ] to [ B ] in the salt is in the range of 10:1 to 1: 10.

In some embodiments, X is-NH₂. In some embodiments, X is-OH.

In some embodiments, L when valency allows₁And L₂Each of which is independently C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene or L₁And L₂One of which is N, O or S, and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical. In some embodiments, L₁And L₂Each of which is independently C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene, wherein C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Each of the alkynylene groups. In some embodiments, L₁And L₂Each of which is independently C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical. In some embodiments, L when valency allows₁And L₂One of which is N, O or S, and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical. In some embodiments, L₁And L₂Is at least one of C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical. As disclosed herein, C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene may be unsubstituted or optionally substituted by halogen, -CN, -NO₂、-OH、-O(C_1-6Alkyl), -NH₂or-N₃And (4) substitution.

In some embodiments, L₁And L₂Is at least one of C_1-6Alkylene radical, C_1-6Alkylene may be substituted or unsubstituted C_1-6An alkylene group. In some embodiments, L₁And L₂Is a methylene group, which may be substituted or unsubstituted. In some embodiments, L₁And L₂Is methylene. As used herein, methylene may be unsubstituted or optionally substituted with halogen, -CN, -NO₂、-OH、-O(C_1-6Alkyl) or-NH₂And (4) substitution. In some embodiments, L₁And L₂Is methylene. In some embodiments, L₁And each of L2 is substituted by halogen, -CN, -NO₂、-OH、-O(C_1-6Alkyl) or-NH₂A substituted methylene group. In some embodiments, L₁And L₂Each of which is a methylene group substituted with-OH. In some embodiments, L₁And L₂Is unsubstituted methylene. In some embodiments, L₁And L₂Both are methylene groups, which may beThe substituted methylene groups may be unsubstituted methylene groups. In some embodiments, L₁And L₂Is at least one of C_2-6Alkenylene radical, C_2-6Alkylene may be substituted or unsubstituted C_2-6An alkenylene group. In some embodiments, L₁And L₂Is at least one of C_2-6Alkynylene, C_2-6Alkylene may be substituted or unsubstituted C_2-6Alkynylene radical.

In some embodiments, X is-OH; and isIs a single bond. In some embodiments, X is-OH;is a single bond; and L is₁And L₂Each of which is a methylene group substituted with-OH. In some embodiments, X is-OH;is a double bond; and L is₁And L₂Each of which is an optionally substituted methylene group.

In some embodiments, L when valency allows₁And L₂Is N, O or S, and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical. In some embodiments, L when valency allows₁And L₂Is N, and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical. In some embodiments, L when valency allows₁And L₂Is substituted N, and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical. In some embodiments, L when valency allows₁And L₂Is O and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical. In some embodimentsIn (1), L when allowed by valence₁And L₂Is S and the other is C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene radical.

In some embodiments of the present invention, the,is a single bond. In some embodiments of the present invention, the,is a double bond.

In some embodiments, [ A ] in the salt]And [ B ]]In a ratio range of 10:1 to 1:10, 9:1 to 1:9, 8:1 to 1:8, 7:1 to 1:7, 6:1 to 1:6, 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2 or 2:1 to 1:1, wherein [ A ] is]Is a cationic form of a cyclic serine compound, and [ B]Is an anionic form of a compound of formula (I):in some embodiments, [ A ] in the salt]And [ B ]]In the range of 10:1 to 1: 10. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 9:1 to 1: 9. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 8:1 to 1: 8. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 7:1 to 1: 7. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 6:1 to 1: 6. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 5:1 to 1: 5. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 4:1 to 1: 4. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 3:1 to 1: 3. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 2:1 to 1: 2. In some embodiments, [ A ] in the salt]And [ B ]]In the range of 2:1 to 1: 1. In some embodiments, [ A ] in the salt]And [ B ]]In a ratio of 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1: 1.

In some embodiments, the cycloserine compound has the formula:

in some embodiments, the cycloserine compound is:

in some embodiments, the cycloserine compound is:

in some embodiments, the compound of formula (I) has the formula:

wherein each of A and B is independently-NH₂-OH or H; and is

C₁ C₂Is C₁-C₂Or C₂＝C₁。

In some embodiments, at least one of A and B is-NH₂. In some embodiments, at least one of a and B is-OH. In some embodiments, a and B are both-OH. In some embodiments, the compound of formula (I) is succinic acid, D-tartaric acid, L-tartaric acid, meso-tartaric acid, fumaric acid, maleic acid, or malic acid.

In some embodiments, the compound of formula (Ia) has the formula:

wherein each of A and B is independently-OH or-H. In some embodiments, at least one of a and B is-OH. In some embodiments, a and B are both-OH.

In some embodiments, the compound of formula (Ib) is:

(succinic acid),(D-tartaric acid),

(L-tartaric acid) or(meso-tartaric acid).

In some embodiments, the compound of formula (Ib) is selected from the group consisting of: succinic acid, D-tartaric acid, L-tartaric acid. In some embodiments, the compound of formula (Ib) is selected from the group consisting of: succinic acid, D-tartaric acid, L-tartaric acid and meso-tartaric acid, and [ A]And [ B ]]In the range of 5:1 to 1: 1. In some embodiments, the compound of formula (Ib) isAnd [ A]And [ B ]]The ratio between is 4: 1. In some embodiments, the compound of formula (Ib) isAnd [ A]And [ B ]]The ratio between is 2: 1. In some embodiments, the compound of formula (Ib) isAnd [ A]And [ B ]]The ratio between is 1: 1.

In some embodiments, the compound of formula (Ia) is a compound of formula (Ic):

wherein each of A and B is independently-OH or-H. In some embodiments, at least one of a and B is-OH. In some embodiments, a and B are both-OH.

In some embodiments, the compound of formula (Ic) is selected from(fumaric acid) j or(maleic acid). In some embodiments, the compound of formula (Ic) is fumaric acid. In some embodiments, the compound of formula (Ic) is maleic acid. In some embodiments, the compound of formula (Ic) isAnd described herein [ A ]]And [ B ]]The ratio between is 1: 1.

Composition comprising a metal oxide and a metal oxide

Another aspect of the disclosure provides a composition comprising a salt of formula [ a ] [ B ] described herein and a carrier.

In some embodiments, the composition is a pharmaceutical composition, a nutritional composition, a nutraceutical, or a medical food.

In certain embodiments, the composition is a health food. In some embodiments, the compositions described herein can be a nutraceutical or nutraceutical product, which can be any type of liquid and solid/semi-solid material useful for nourishing humans and animals, for improving basic behavioral functions, hyperactivity, anxiety, depression, sensorimotor gating, pain threshold, memory and/or cognitive function, or for facilitating treatment of any of the target diseases described herein (e.g., neuropsychiatric disorders and/or bacterial infectious diseases (e.g., tuberculosis) including those described herein). The nutraceutical product can be a food product (e.g., tea-based beverages, juices, soft drinks, coffee, milk, jellies, cookies, cereals, chocolates, snack bars, herbal extracts, dairy products (e.g., ice cream and yogurt)), a food/dietary supplement, or a nutritional formulation.

The nutraceutical products described herein may include one or more edible carriers that impart one or more benefits to the products as described herein. Examples of edible carriers include starch, cyclodextrin, maltodextrin, methyl cellulose, carbomethoxy cellulose, xanthan gum, and aqueous solutions thereof. Other examples include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavorants, dyes, materials like this, and combinations thereof as known to one of ordinary skill in the art. In some examples, the nutraceutical products described herein can further comprise a neuroprotective food, such as fish oil, linseed oil, and/or benzoate.

In some examples, the health food product is a nutritional composition, which refers to a composition that contains food-derived components and imparts additional health benefits in addition to the basic nutritional value found in food. The nutritional compositions as described herein include any of the salts of formula [ a ] [ B ] as described herein and additional ingredients and supplements that promote good health and/or enhance the stability and biological activity of the salts of formula [ a ] [ B ].

The effect of the nutritional composition may be rapid and/or short-term or may help achieve long-term health goals as described herein, such as improving basic behavioral function, hyperactivity, anxiety, depression, sensorimotor gating, pain threshold, memory and/or cognitive function, in, for example, a human subject suffering from or at risk of a neuropsychiatric disorder. The nutritional composition may be included in an edible material, for example, as a dietary supplement or a pharmaceutical formulation. As a dietary supplement, additional nutrients may be included, such as vitamins, minerals or amino acids. The composition may also be a beverage or food product, such as tea, soft drinks, juices, milk, coffee, cookies, cereals, chocolates, and snack bars. If desired, the composition may be sweetened by adding sweeteners such as sorbitol, maltitol, hydrogenated glucose syrup and hydrogenated starch hydrolysates, high fructose corn syrup, sucrose, beet sugar, pectin or sucralose.

The nutritional compositions disclosed herein may be in the form of a solution. For example, the nutritional formulation may be provided in a medium such as a buffer, solvent, diluent, inert carrier, oil, or cream. In some examples, the formulation is present in an aqueous solution optionally containing a non-aqueous co-solvent such as an alcohol. The nutritional composition may also be in the form of a powder, paste, jelly, capsule, or tablet. Lactose and corn starch are commonly used as diluents for capsules and carriers for tablets. A lubricant, such as magnesium stearate, is typically added to form tablets.

The health food product can be formulated for suitable routes of administration, such as oral administration. For oral administration, the compositions may take the form of, for example, tablets, pills, capsules, lozenges, tablets, lozenges, capsules, lozenges, tablets, lozenges, or capsules, with acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or in the form of tablets or capsules prepared with a wetting agent (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Also included are sticks and other chewable formulations.

In some examples, the nutraceutical product can be in liquid form, and the one or more edible carriers can be a solvent or dispersion medium including, but not limited to, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), lipids (e.g., triglycerides, vegetable oils, liposomes), or combinations thereof. Proper fluidity can be maintained, for example, by: use of coatings such as lecithin; maintaining the desired particle size by dispersion in a carrier such as, for example, a liquid polyol or lipid; use of surfactants such as, for example, hydroxypropyl cellulose; or a combination thereof. In many cases, it will be desirable to include isotonic agents, such as, for example, sugars, sodium chloride or combinations thereof.

Liquid formulations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. In one embodiment, the liquid formulation may be formulated for administration with fruit juices. Such liquid formulations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl parabens, benzoates or sorbates).

In certain embodiments, the composition is a medical food. The medical food product is a food product formulated for enteral consumption or administration. Such food products are typically used under the supervision of a physician for specific dietary management of those target diseases as described herein. In some cases, such medical food compositions are specially formulated and processed (as opposed to naturally occurring foods used in a natural state) for patients in need of treatment (e.g., human patients with a disease or human patients in need of using the product as a primary active agent for alleviating a disease or condition through specific dietary management). In some examples, the medical food compositions described herein are not one of those that physicians would simply recommend as part of an overall diet to manage symptoms or reduce the risk of a disease or condition.

Any of the medical food compositions described herein comprising a salt of formula [ a ] [ B ] described herein and at least one carrier (e.g., those described herein) can be in a liquid solution; powders, sticks, wafers, suspensions in suitable liquids or suitable emulsions, as described in more detail below. At least one carrier, which may be naturally occurring or synthetic (non-naturally occurring), will confer one or more benefits, e.g., stability, bioavailability and/or bioactivity, to the salt of formula [ a ] [ B ] in the composition. Any of the carriers described herein can be used to prepare a medical food composition. In some embodiments, the medical food composition may further comprise one or more additional ingredients selected from the group comprising, but not limited to: natural flavors, artificial flavors, major trace and ultra trace minerals, vitamins, oats, nuts, spices, milk, eggs, salt, flour, lecithin, xanthan gum, and/or sweeteners. The medical food composition may be placed in a suitable container, which may further comprise at least one additional therapeutic agent, such as those described herein.

In some embodiments, the composition is a pharmaceutical composition comprising a salt of formula [ a ] [ B ] described herein and at least one pharmaceutically acceptable excipient and/or carrier.

In certain embodiments, the salt of formula [ a ] [ B ] described herein is provided in an effective amount in a pharmaceutical composition. In certain embodiments, an effective amount is a therapeutically effective amount (e.g., an amount effective for treating and/or reducing the risk of a neuropsychiatric disorder and/or a bacterial infectious disease (e.g., tuberculosis) in a subject in need thereof).

The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology. Typically, such preparative methods comprise bringing a salt of the formula [ a ] [ B ] (i.e., "the active ingredient") as described herein into association with a carrier or excipient and/or one or more other auxiliary ingredients, and then, where necessary and/or desired, shaping and/or packaging the product into the desired single or multiple dosage units.

The pharmaceutical compositions may be prepared, packaged and/or sold in bulk as a single unit dose and/or as a plurality of single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition that includes a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient to be administered to the subject and/or a convenient fraction of such dose, such as half or one third of such dose.

The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and/or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the identity, size, and/or condition of the subject being treated and further depending on the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrants, binding agents, preservatives, buffering agents and/or pH adjusting agents, lubricants, carriers, enhancers, slow-release and/or anti-settling agents, and/or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavoring agents, and flavoring agents may also be present in the composition.

Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may include inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are combined with a solubilizing agent, e.g., a solubilizerAlcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, U.S. p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable vehicle prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly water soluble. The rate of absorption of the drug then depends on its rate of dissolution, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily vehicle.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with: at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binding agents, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution retarding agents, such as paraffin; (f) absorption promoters, such as quaternary ammonium compounds; (g) humectants, such as cetyl alcohol and glycerol monostearate; (h) absorbents such as kaolin and bentonite clay; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may contain buffering agents. In the case of capsules, the active ingredient may be encapsulated in a capsule shell without any excipients or carriers.

Solid compositions of a similar type may be employed as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmacological arts. The solid dosage form may optionally include an opacifying agent and may be a composition that: the solid dosage form may release one or more active ingredients only or preferentially in a certain part of the digestive tract, optionally in a delayed manner. Examples of encapsulation compositions that may be used include polymeric materials and waxes. Solid compositions of a similar type may be employed as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active ingredient may be in microencapsulated form together with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may include, in addition to inert diluents, additional substances such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as is common practice. In the case of capsules, tablets and pills, the dosage forms may include buffering agents. The solid dosage form may optionally include an opacifying agent and may be a composition that: the solid dosage form may release one or more active ingredients only or preferentially in a certain part of the digestive tract, optionally in a delayed manner. Examples of encapsulating agents that may be used include, but are not limited to, polymeric substances and waxes.

All commercially available enteric materials can be applied to the compositions of the present invention. In some embodiments of the composition, the enteric material is selected from a polymethacrylate-based coating material, a phthalate-based coating material, a cellulose ester-based coating material, shellac, sodium alginate, or mixtures thereof.

In some embodiments of the composition, the polymethacrylate-based coating material is selected from the group consisting of poly (methacrylic acid-co-ethyl acrylate) (i.e., Eudragit L100-55, Eudragit L30D-55, Eastacryl 30D series, Kollicoat MAE 30DP, Kollicoat MAE 100P, Acryl-EZE 93 series, and Acryl-EZE MP series) in a ratio of 1:1, poly (methacrylic acid-co-methyl methacrylate) (i.e., Eudragit L100, Eudragit L12, 5P, and Opadry 94 series) in a ratio of 1:2, poly (methacrylic acid-co-methyl methacrylate) (i.e., Eudragit S100, Eudragit S12, 5P, and Opadry 95 series) in a ratio of 7:3:1, and poly (methyl acrylate-co-methyl methacrylate-co-ethyl acrylate) (i.e., Eudragit S100, Eudragit S12, 5, Eudragit S95 series) in a ratio of 7:3:1 FS 30D).

In some embodiments of the composition, the phthalate-based coating material is selected from the group consisting of polyvinyl acetate phthalate (i.e., Opadry 91 series and Sureteric series), hydroxypropyl methylcellulose phthalate (i.e., HPmcp-HP Grades series), diethyl phthalate, and cellulose acetate phthalate (i.e., Eastman' s^TMC-A-P)。

In some embodiments of the compositions, the cellulose ester-based coating material is selected from the group consisting of cellulose acetate trimellitate, cellulose acetate succinate, and hydroxypropyl methyl cellulose acetate succinate (i.e., AQOAT AS series and ENTERACT)^TMHPMCAS)。

In some embodiments of the composition, the enteric material comprises 90.5% -98.49% poly (methacrylic acid-co-ethyl acrylate), 0.5% -2% sodium lauryl sulfate, 0.01% -2.5% triethyl citrate, 0.5% -2.5% colloidal silicon dioxide, and 0.5% -2.5% talc in a 1:1 ratio.

In some embodiments of the composition, the composition further comprises 10mg to 50mg of a barrier material selected from hydroxypropyl methylcellulose-based coating materials. Specifically, hydroxypropylmethylcellulose has an average molecular weight of 50000 to 125000 and a solid content of 8%. Other commercially available barrier layers may be applied to the compositions of the present invention.

In certain embodiments, the one or more release materials are provided at 10mg to 50mg, 15mg to 45mg, 20mg to 35mg, or 25mg to 30 mg.

In some embodiments of the composition, the barrier layer material comprises 95.5% to 99.49% hydroxypropyl methylcellulose, 0.5% to 2.5% talc, and 0.01% to 2% triacetin.

In some embodiments of the composition, the composition further comprises one or more pharmaceutically acceptable excipients selected from fillers, binders, disintegrants, and/or lubricants.

In some embodiments of the composition, the filler is selected from the group consisting of starch, lactose, sucrose, glucose, mannitol, anhydrous dibasic calcium phosphate, microcrystalline cellulose, and mixtures thereof. In some embodiments of the composition, the microcrystalline cellulose is microcrystalline cellulose having a moisture content of, for example, 3% to 10% or 3% to 5% (e.g., microcrystalline cellulose pH 102).

In some embodiments of the composition, the binding agent is selected from the group consisting of carboxymethylcellulose, hydroxypropylcellulose, alginates, gelatin, polyvinylpyrrolidone, acacia, and mixtures thereof.

In some embodiments of the composition, the disintegrant is selected from the group consisting of agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, Sodium Starch Glycolate (SSG), cross-linked carboxymethylcellulose, cross-linked vitamin one, sodium carbonate, and mixtures thereof.

In some embodiments of the composition, the lubricant is selected from the group consisting of magnesium stearate, colloidal silicon dioxide, talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.

In some embodiments of the composition, the pharmaceutically acceptable excipients include 50mg to 500mg of filler, 10mg to 100mg of binder, 10mg to 200mg of disintegrant, 5mg to 100mg of lubricant. In some embodiments of the composition, the amount of bulking agent is 50mg to 500mg, 200mg to 450mg, 250mg to 400mg, 300mg to 380mg, or 330mg to 350 mg. In some embodiments of the composition, the amount of binder is 10mg to 100mg, 20mg to 90mg, 25mg to 80mg, 30mg to 70mg, 35mg to 60mg, or 40mg to 50 mg. In some embodiments of the composition, the amount of disintegrant is 10mg to 200mg, 15mg to 180mg, 20mg to 160mg, 25mg to 140mg, 30mg to 120mg, 40mg to 100mg, or 60mg to 80 mg. In some embodiments of the composition, the amount of lubricant is 5mg to 100mg, 7.5mg to 90mg, 10mg to 80mg, 20mg to 70mg, 30mg to 60mg, or 40mg to 50 mg.

In some embodiments of the composition, the pharmaceutically acceptable excipients are microcrystalline cellulose pH 102, hydroxypropyl cellulose, croscarmellose sodium, and magnesium stearate.

In some embodiments, a pharmaceutical composition for topical administration disclosed herein is spread on an impermeable support to obtain a patch. In particular, impermeable supports are supports for matrix systems (e.g., matrix dispersion systems and adhesive drug-in-drug), reservoir patch systems, or micro-reservoir systems.

In some embodiments, the at least one pharmaceutically acceptable excipient and/or carrier included in the pharmaceutical composition for oral administration is a capsule. All commercially available capsules may be applied to the pharmaceutical compositions of the present invention, including hard and soft gelatin capsules, HPMC capsules, and the like. Commercially available capsule ingredients are also included in the capsule formulations of the present invention, including, but not limited to, Hydroxypropylmethylcellulose (HPMC), gelatin, methyl paraben (i.e., methyl-4-hydroxybenzoate), propyl paraben (i.e., methyl propyl-4-hydroxybenzoate), sodium lauryl sulfate, brilliant blue FCF, neoglobulin, titanium dioxide, sunset yellow FCF, tartrazine, water, or combinations thereof.

In some embodiments, the capsule formulation of the present invention further comprises an enteric coating on the surface of the capsule. For the capsule formulations of the present invention, all commercially available enteric coatings may be applied on the capsule surface. Preferably, the enteric coating is comprised of a material selected from the group consisting of copolymers of methacrylic acid and ethyl acrylate; more preferably, the copolymer of methacrylic acid and ethyl acrylate isMAE 30DP (BASF) with a ratio of methacrylic acid to ethyl acrylate of 1:1 and a solids content of 30%.

For coating purposes, the enteric coating material is dissolved in an organic solvent. Preferably, the organic solvent is propylene glycol.

Although the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, such compositions are generally suitable for administration to various animals. In order to render the compositions suitable for administration to various animals, modifications of pharmaceutical compositions suitable for administration to humans are well known, and such modifications can be designed and/or performed by ordinary skilled veterinary pharmacologists using ordinary experimentation.

For ease of administration and consistent dosage, the compositions described herein are typically formulated in unit dosage forms. However, it will be understood that the total daily amount of the compositions described herein will be determined by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors, including the severity of the disease and disorder being treated; the activity of the particular active ingredient employed; the particular composition employed; the age, weight, general health, sex, and diet of the subject; time of administration, route of administration, and rate of excretion of the particular active ingredient employed; the duration of the treatment; drugs used in combination or concomitantly with the particular active ingredient employed; and similar factors well known in the medical arts.

Kits (e.g., pharmaceutical packs) are also contemplated by the present disclosure. The provided kits can include the pharmaceutical compositions and containers described herein (e.g., vials, ampoules, bottles, syringe and/or dispenser packages or other suitable containers).

In certain embodiments, the kits described herein comprise a container comprising a composition described herein. In certain embodiments, the kits described herein are used to treat and/or reduce the risk of a neuropsychiatric disorder and/or a bacterial infectious disease (e.g., tuberculosis) in a subject in need thereof.

In certain embodiments, the kits described herein further comprise instructions for using the compositions described herein contained in the kit. The kits described herein may also contain information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information contained in the kit is prescription information. In certain embodiments, kits and instructions provide methods of treating and/or reducing the risk of neuropsychiatric disorders and/or bacterial infectious diseases (e.g., tuberculosis). The kits described herein may comprise one or more additional agents described herein as a separate composition.

Method of treatment

Another aspect of the present invention provides a method comprising administering to a subject an effective amount of a salt of formula [ a ] [ B ] described herein or a composition thereof described herein.

In some embodiments, the neuropsychiatric disorder is selected from the group consisting of: schizophrenia, psychotic disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive disorders, benign amnesia, ataxia symptoms, spinocerebellar degeneration, closed brain injury, autism spectrum disorder, autism, Asperger's disorder, unspecified pervasive developmental disorder (PDD-NOS), Fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive compulsive disorder, tic disorders, childhood learning disorders, premenstrual syndrome, depression, major depression, anorgasmia, suicidal ideation and/or behavior, bipolar disorders, anxiety disorders, panic disorders, anorexia nervosa, phobia, agoraphobia, claustrophobia, post-traumatic stress disorders, chronic mild and unpredictable stress, eating disorders, anxiety disorders, panic disorders, anorexia nervosa, panic disorders, and stress disorders, Addictive disorders, personality disorders, parkinson's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, tourette's syndrome, nocturia, non-seizures, blepharospasm, duchenne's muscular dystrophy, stroke, chronic pain, neuropathic pain including hyperalgesia and allodynia, diabetic polyneuropathy and chronic pain syndrome.

Any of the salts of formula [ a ] [ B ] disclosed herein or compositions thereof described herein can be used to treat and/or prevent neuropsychiatric disorders. In certain embodiments, the neuropsychiatric disorder is schizophrenia. In certain embodiments, the neuropsychiatric condition is a psychotic disorder. In certain embodiments, the neuropsychiatric disorder is alzheimer's disease. In certain embodiments, the neuropsychiatric disorder is frontotemporal dementia. In certain embodiments, the neuropsychiatric disorder is vascular dementia. In certain embodiments, the neuropsychiatric disorder is dementia with lewy bodies. In certain embodiments, the neuropsychiatric disorder is senile dementia. In certain embodiments, the neuropsychiatric disorder is mild cognitive impairment. In certain embodiments, the neuropsychiatric disorder is benign amnesia. In certain embodiments, the neuropsychiatric disorder is a symptom of ataxia. In certain embodiments, the neuropsychiatric disorder is spinocerebellar degeneration. In certain embodiments, the neuropsychiatric disorder is closed brain injury. In certain embodiments, the neuropsychiatric disorder is an autism spectrum disorder including autism, asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS). In certain embodiments, the neuropsychiatric disorder is fragile X syndrome. In certain embodiments, the neuropsychiatric disorder is attention deficit hyperactivity disorder. In certain embodiments, the neuropsychiatric disorder is attention deficit disorder. In certain embodiments, the neuropsychiatric disorder is obsessive-compulsive disorder. In certain embodiments, the neuropsychiatric disorder is a tic disorder. In certain embodiments, the neuropsychiatric disorder is a childhood learning disorder. In certain embodiments, the neuropsychiatric disorder is premenstrual syndrome. In certain embodiments, the neuropsychiatric disorder is depression including dysthymia and bereaved depression. In certain embodiments, the neuropsychiatric disorder is major depressive disorder. In certain embodiments, the neuropsychiatric disorder is anhedonia. In certain embodiments, the neuropsychiatric disorder is suicidal ideation and/or behavior. In certain embodiments, the neuropsychiatric disorder is a bipolar disorder comprising type I and type II bipolar disorders. In certain embodiments, the neuropsychiatric disorder is an anxiety disorder comprising a panic disorder and a phobic disorder. In certain embodiments, the neuropsychiatric disorder is a panic disorder. In certain embodiments, the neuropsychiatric disorder is anorexia nervosa. In certain embodiments, the neuropsychiatric disorder is phobia. In certain embodiments, the neuropsychiatric disorder is agoraphobia. In certain embodiments, the neuropsychiatric disorder is claustrophobia. In certain embodiments, the neuropsychiatric disorder is a post-traumatic stress disorder. In certain embodiments, the neuropsychiatric disorder is chronic mild and unpredictable stress. In certain embodiments, the neuropsychiatric disorder is an eating disorder comprising binge eating disorder and anorexia disorder. In certain embodiments, the neuropsychiatric disorder is an addictive disorder comprising substance dependence or substance abuse. In certain embodiments, the neuropsychiatric disorder is a personality disorder. In certain embodiments, the neuropsychiatric disorder is parkinson's disease. In certain embodiments, the neuropsychiatric disorder is huntington's disease. In certain embodiments, the neuropsychiatric disorder is multiple sclerosis. In certain embodiments, the neuropsychiatric disorder is amyotrophic lateral sclerosis. In certain embodiments, the neuropsychiatric disorder is tourette's syndrome. In certain embodiments, the neuropsychiatric disorder is nocturia. In certain embodiments, the neuropsychiatric disorder is a non-epileptic seizure. In certain embodiments, the neuropsychiatric disorder is blepharospasm. In certain embodiments, the neuropsychiatric disorder is duchenne muscular dystrophy. In certain embodiments, the neuropsychiatric disorder is stroke. In certain embodiments, the neuropsychiatric disorder is chronic pain. In certain embodiments, the neuropsychiatric condition is neuropathic pain comprising hyperalgesia and allodynia. In certain embodiments, the neuropsychiatric disorder is diabetic polyneuropathy. In certain embodiments, the neuropsychiatric disorder is chronic pain syndrome.

In certain embodiments, the methods described herein further comprise administering to the subject an additional agent. In certain embodiments, the methods described herein further comprise contacting the biological sample with an additional agent. In certain embodiments, the methods described herein further comprise contacting the tissue with an additional agent. In certain embodiments, the methods described herein further comprise contacting the cell with an additional agent. In certain embodiments, the compositions described herein are compositions for use with one or more additional agents for treating a neuropsychiatric disorder. In certain embodiments, the compositions described herein and one or more additional agents are administered to a subject simultaneously or sequentially.

Any of the salts of formula [ a ] [ B ] disclosed herein or compositions thereof provided herein can be administered by any route, including enterally (e.g., orally), parenterally, intravenously, intramuscularly, intraarterially, intramedullary, intrathecally, subcutaneously, intraventricularly, transdermally, intradermally, subcutaneously, intradermally, rectally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, cream, and/or drops). In particular, contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via the blood and/or lymph supply, and/or direct administration to the afflicted site. The most appropriate route of administration will generally depend on various factors, including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

The exact amount of the salt of formula [ A ] [ B ] described herein required to achieve an effective amount will vary from subject to subject, depending on, for example, the species, age, and general condition of the subject, the severity of the side effects or disorder, the identity of the particular salt of formula [ A ] [ B ] described herein, the mode of administration, and the like. An effective amount may be contained in a single dose (e.g., a single oral dose) or in multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses comprise different or substantially the same amount of a salt of formula [ a ] [ B ] described herein. In certain embodiments, when multiple doses are administered to a subject or to a biological sample, tissue, or cells, the frequency of administering multiple doses to a subject or applying multiple doses to tissue or cells is three doses per day, two doses per day, one dose every other day, one dose every three days, one dose every week, one dose every other week, one dose every month, or one dose every other month. In certain embodiments, the frequency of administering multiple doses to a subject or multiple doses to tissue or cells is once a day dose. In certain embodiments, the frequency of administering multiple doses to a subject or multiple doses to tissue or cells is twice daily. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and the last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifespan of the subject, biological sample, tissue, or cell. In certain embodiments, the duration between the first dose and the last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and the last dose of the multiple doses is the lifespan of the subject, biological sample, tissue, or cell. In certain embodiments, a dose described herein (e.g., any dose of a single dose or multiple doses) independently comprises between 1mg and 3mg, between 3mg and 10mg, between 10mg and 30mg, between 30mg and 100mg, between 100mg and 300mg, between 300mg and 1,000mg, or between 1g and 10g, inclusive, of a salt of formula [ a ] [ B ] described herein. In certain embodiments, the doses described herein independently comprise between 100mg and 1500mg, inclusive, of a salt of formula [ a ] [ B ] described herein. In certain embodiments, the doses described herein independently comprise between 300mg and 1000mg, inclusive, of the salt of formula [ a ] [ B ] described herein.

Dosage ranges as described herein provide guidance for administering the provided pharmaceutical compositions to adults. The amount to be administered, for example, to a child or adolescent can be determined by a medical practitioner or skilled person in the art and can be less than or the same as the amount administered to an adult.

Any of the salts of formula [ a ] [ B ] disclosed herein or compositions thereof as described herein may be administered in combination with one or more additional agents (e.g., therapeutically and/or prophylactically active agents) useful for treating and/or reducing the risk of neuropsychiatric disorders and/or bacterial infectious diseases (e.g., tuberculosis). Any of the salts of formula [ a ] [ B ] or compositions thereof disclosed herein may be administered in combination with an additional agent that improves its activity (e.g., treats and/or reduces the activity (e.g., efficacy and/or efficacy) in a neuropsychiatric disorder and/or the risk of a bacterial infectious disease (e.g., tuberculosis) in a subject in need thereof, improves bioavailability, increases safety, reduces drug resistance, reduces and/or modifies metabolism, inhibits excretion, and/or modifies distribution in a subject, biological sample, tissue, or cell There is no synergistic effect in the pharmaceutical composition of the additional agent, other than two.

Any of the salts of formula [ a ] [ B ] or compositions thereof disclosed herein may be administered concurrently with, before or after one or more additional agents that may be used, for example, as a combination therapy to treat and/or reduce the risk of a neuropsychiatric disorder and/or a bacterial infectious disease (e.g., tuberculosis) in a subject. The medicament comprises a therapeutically active agent. The medicament further comprises a prophylactically active agent. Medicaments include small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the U.S. food and Drug Administration, as provided in the united states Code of Federal Regulations (CFR)) for human or veterinary use), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, antibodies, small molecules linked to proteins, such as antibodies, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional agent is an agent for treating and/or reducing the risk of a neuropsychiatric disorder and/or a bacterial infectious disease (e.g., tuberculosis) in a subject. In certain embodiments, the additional agent is an agent approved by a regulatory agency (e.g., the U.S. FDA) for use in treating and/or reducing the risk of a neuropsychiatric disorder and/or a bacterial infectious disease (e.g., tuberculosis) in a subject. Each additional agent may be administered at a dose and/or on a schedule determined for the agent. The additional agents may also be administered separately, together with each other and/or with any of the salts of formula [ a ] [ B ] disclosed herein or compositions thereof described herein, in a single dose or in different doses. The particular combination to be employed in a regimen will take into account the compatibility of the salt of formula [ a ] [ B ] described herein with one or more additional agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is desirable to utilize one or more additional agents in combination at levels not exceeding those at which they are used alone. In some embodiments, the level of combined utilization will be lower than the level used alone.

In certain embodiments, the additional agent is selected from an agent or a combination thereof for treating and/or reducing the risk of a neuropsychiatric disorder and/or a bacterial infectious disease (e.g., tuberculosis). In certain embodiments, any of the salts of formula [ a ] [ B ] disclosed herein or pharmaceutical compositions thereof described herein may be administered in combination with a therapy for treating and/or reducing the risk of a neuropsychiatric disorder and/or a bacterial infectious disease (e.g., tuberculosis).

In certain embodiments, the additional agent is an agent selected from the group consisting of: antipsychotics, antidepressants, psychostimulants, mood stabilizers, anxiolytics, agents for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), or for the treatment of Alzheimer's Disease (AD). In certain embodiments, the additional agents include, but are not limited to, antipsychotics, antidepressants, mood stabilizers, anxiolytics, psychostimulants, and agents for treating tuberculosis.

Exemplary antipsychotic agents include, but are not limited to, butyrophenone (e.g., haloperidol (haloperidol) (HALDOL)^TM) Phenothiazine (phenothiazine) (e.g., chlorpromazine (THORAZINE) (thorazene)^TM) Fluphenazine (PROLIXIN)^TM) Perphenazine (TRILAFON)^TM) Prochlorperazine (COMPAZINE)^TM) Thioridazine (melaril)^TM) Trifluoperazine (stellazine), and a pharmaceutical composition containing the same^TM) Methoridazine, promazine, triflupromazine (VESPROIN)^TM) Levopromethazine (novomepromazine) (NOZINAN)^TM) Promethazine (PHENERGAN)^TM) Thioxanthene (e.g. chlorprothixene), chlorothioxene (flupentixol) (DEPIXOL)^TM、FLUANXOL^TM) Thiothixene (NANANANE)^TM) Zuclopenthixol (Clotrichal) (Clopixol)^TM、ACUPHASE^TM) Clozapine (clozapine)^TM) Olanzapine (olanzapine) (ZYPREXA)^TM) Risperidone (RISPERDAL)^TM、RISPERDAL CONSTA^TM) Quetiapine (quetiapine) (SEROQUEL)^TM) Ziprasidone (GEODON) (ziprasidone)^TM) Amisulpride (SOLIAN)^TM) Asenapine (asenapine), paliperidone (paliperidone)Aripiprazole (Alipiprazole) (ABILIFY)^TM) Dopamine partial agonists (BIFEPRUNOX)^TM、NORCLOZAPINE^TM(ACP-104)), lamotrigine (lamotrigine) (LAMICTAL)^TM) Cannabidiol (cannabidiol), LY2140023, haloperidol (d)roperidol), pimozide (pimozide), butapiperazine (butaperazine), carphenazine (carphenazine), remoxipride (remoxipride), piperazines (piperacetazine), sulpiride (sulpiride), acamprosate (acamprosate), tetrabenazine (tetroazine) (NITOMAN)^TM、XENAZINE^TM) And the like.

Alternatively, the second therapeutic agent may be an antidepressant and/or a mood stabilizer. In certain embodiments, the antidepressant includes a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a Selective Serotonin Reuptake Inhibitor (SSRI), a Noradrenergic and A Specific Serotonergic Antidepressant (NASSA), a noradrenaline (noradrenaline) reuptake inhibitor, a noradrenaline-dopamine reuptake inhibitor, a serotonin-noradrenaline-dopamine reuptake inhibitor (SNDRI), a serotonin-noradrenaline reuptake inhibitor (SNRI), a mood stabilizer, and/or a monoamine oxidase inhibitor (MAOI). Exemplary SSRIs include fluoxetine (proazac)^TM) Paroxetine (PAXIL), Paroxetine (PAXIL)^TM、SEROXAT^TM) Escitalopram (LEXAPRO)^TM、ESIPRAM^TM) Citalopram (citalopram) (CELEXA)^TM) Sertraline (sertraline) (ZOLOFT)^TM) Fluvoxamine (LUVOX)^TM)). An exemplary SNRI includes venlafaxine (EFFEXOR)^TM) Milnacipran (milnacipram) and duloxetine (cycloxetine) (CYMBALTA)^TM). Additional antidepressants include noradrenergic and specific serotonergic antidepressants (NASSA) (e.g., mirtazapine (AVANZA)^TM、ZISPIN^TM、REMERON^TM) Or mianserin, Noradrenaline Reuptake Inhibitors (NRI) (e.g., reboxetine (EDRONAX)^TM) Norepinephrine-dopamine reuptake inhibitors (e.g., bupropion (bupropion) (WELLBUTIN)^TM、ZYBAN^TM) Amitriptyline (amitriptyline), nortriptyline (nortriptyline), protriptyline (protriptyline), desipramine (desipramine), imipramine (imipramine), trimipramine (trimipramine), and combinations thereof,Amoxapine (amoxapine), bupropion SR, clomipramine (clomipramine), doxepin (doxepin), isocarboxazid (isocarboxazid), venlafaxine XR, tranylcypromine (tranylcypromine), trazodone (nefazodone), phenelzine (phenyelzine), lamotrigine (lamatrogine), lithium, topiramate (topiramate), gabapentin (gabapentin), carbamazepine (carbamazepin), oxcarbazepine (oxacarbazepine), valproic acid (valrate), maprotiline (maprotiline), mirtazapine, bromofamine (brofirine), gepirone (morphepine), moclobemide (moclobemide), isoniazid (isoniazid), nicotinopyramide (isoniazid) and the like.

In some embodiments, the anxiolytic comprises antalol (Atarax), benazedrine (Benadryl), azaspirone (azaspirones), benzodiazepines such as lorazepam (lorazepam), cyprosulfan (prazepam), fluxapam (fluazepam), clonazepam (klonazepam), chlordiazepam (chlordiazepam), halazepam (halazepam), diazepam (temazepam), oxazepam (oxazepam), dipotassium chlordiazepam (chlorizepam), diazepam (diazepam), alprazolam (alprazolam), beta-blockers such as propranolol (propranolol), atenolol (atenolol), and others as will be understood by those skilled in the art.

In some embodiments, the second therapeutic agent may be an agent for treating ADD and/or ADHD. Suitable ADHD drugs include, but are not limited to, amphetamine, modafinil, methamphetamine (desoxyyn), methamphetamine, cocaine, arecoline, dexmethylphenidate (dexmethylphenidate) (dexmethylphenidate hydrochloride (focalin), dexmethylphenidate hydrochloride (XR), dexamphetamine (dexamphetamine), dexamphetamine depot, dexamphetamine ER, dexamphetamine sulfate (dexrostat)), methylphenidate (focused on (conberta), ritalin (daytrana), methylphenidate (metadate) CD, methylphenidate ER, methylphenidate (methalin), methylphenidate ER, ritalin (ritalin), ritalin-LA, ritalin-SR), lisdexamphetamine (dexamphetamine), dexamphetamine (doxylamine), dexamphetamine (doxylamine) (Strophane (doxylamine)), des (doxylamine), dexamphetamine (doxylamine (dox, Clonidine hydrochloride (clonidine (Catapres)), guanfacine hydrochloride (Tenex), arecoline and pimoline.

Further, in some embodiments, the second therapeutic agent may be an agent for treating a cognitive disorder and/or a condition characterized by neurodegeneration (e.g., alzheimer's disease or parkinson's disease). Such therapeutic agents include, but are not limited to, tacrine (tacrine), rivastigmine (rivastigmine), donepezil (Aricept)^TM) Physostigmine, nicotine, arecoline, huperzine A, selegiline, rilutek^TM(riluzole), memantine (AXURA)^TM、AKATINOL^TM、NAMENDA^TM、EBIXA^TM、ABIXA^TM) Vitamin c, vitamin e, carotenoid or ginkgo biloba, and the like.

In certain embodiments, the additional agent is an agent selected from the group consisting of: isoniazid (isoniazid), rifampin (rifamectin), ethambutol (ethambutol), pyrazinamide (pyrazinamide), rifabutin (rifabutin), rifapentine (rifapentine), capreomycin (capreomycin), kanamycin (kanamycin), amikacin (amikacin), streptomycin (streptomycin), fluoroquinolone antibiotics (fluoroquinolone antibiotics) (e.g., levofloxacin (leflufloxacin), moxifloxacin (moxifloxacin), ofloxacin (ofloxacin), gatifloxacin (gatifloxacin), prothioconazole (prothiocanamine), aminosalicylic acid (para-aminosalicylic acid), ethionamide (ethionamide), terzidine (terizamide), chloramphenimine (clarithrone), carbapenem (tiamulin), carbapenem (antibiotic (carbapenem), carbapenem (carbapenem), penicillin (carbapenem), penicillium (carbapenem), carbapenem (antibiotic (e), and antibiotic (e.g. antibiotic (carbapenem), antibiotic (e), antibiotic (e.g., antibiotic (carbapenem), antibiotic (e), antibiotic (carbapenem), antibiotic (e), antibiotic (antibiotic), antibiotic (e), antibiotic (antibiotic), antibiotic (antibiotic), antibiotic (antibiotic, Meropenem (meropenem) and doripenem (doripenem)).

In certain embodiments, the additional agent may be one or more of the following: 5-hydroxytryptophan (5-HTP), idebenone (idebenone), amantadine (amantadine), physostigmine (physostigmine), L-carnitine or derivative, trimethoprim/sulfamethoxazole (trimethoprim/sulfamethoxazole), vigabatrin (vigabarin), phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone or coenzyme Q10 and vitamin E.

In certain embodiments, the additional agent is N-acetyl-leucine.

Without further elaboration, it is believed that one skilled in the art can, based on the description above, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference for the purposes or subjects mentioned herein.

Examples of the invention

Example 1: preparation of D-cycloserine succinate (4:1) form

D-cycloserine (250mg) and succinic acid (145mg) were added to 2mL of deionized water, and stirred at 800rpm at room temperature. The solution was added dropwise to 50mL of isopropanol and stirred at 800rpm for 10 minutes at room temperature. The mixture was filtered and dried in vacuo to obtain the D-cycloserine succinate (4:1) salt form (yield 315.4mg, 79.8%). As described herein, by¹H nuclear magnetic resonance (¹H-NMR), X-ray powder diffraction (XRPD) and thermal analysis (including TGA and DSC analysis) analysis of the salt thus obtained.

¹H-NMR：¹H-NMR analysis was carried out on Bruker Fourier 400 (Bruker) in a deuterated solvent such as dimethyl sulfoxide or deuterium oxide at 25 ℃.

XRPD: the X-ray powder diffractogram was obtained on D8 ADVANCE (Bruker AXS Gmbh, Germany). The sample was scanned in steps of 0.02 ° in continuous mode of 4-45 ° (2 θ) with Cu ka radiation on a rotating stage at 40kV and 40 mA. The incident beam path was equipped with 0.2mm divergence slits and 0.02mm air diffuser screen. The diffracted beam was equipped with a Ni-filter. Detection was done with a Lynxeye detector (bruker AXS).

Thermogravimetric analysis (TGA): TGA data was measured by TGA Q50 (thermal Analyzer Co., TA Instruments) using a platinum crucible at a heating rate of 10 deg.C/min between 35 deg.C and 400 deg.C.

Differential Scanning Calorimetry (DSC): the melting point of the salt form was determined using the Differential Scanning Calorimeter (DSC) method. DSC data was measured and collected by DSC 25 (thermal analyzer) using a T-zero aluminum low mass pan at a heating rate of 10 ℃/minute between 40 ℃ and 300 ℃.

Preparation of D-cycloserine, succinic acid and salts obtained by the method described in example 1¹The results of H-NMR, XRPD and thermal analysis are shown in FIGS. 1 to 12.

Example 2: preparation of D-cycloserine L-tartaric acid (1:1) salt form

D-cycloserine (1000mg) and L-tartaric acid (1470mg) were added to 10mL and 2mL of deionized water, respectively, and stirred at 800rpm, respectively, at room temperature. When they dissolved, the L-tartaric acid solution was added to the D-cycloserine solution. The resulting solution was added dropwise to 200mL of isopropanol and stirred at 800rpm for 10 minutes at room temperature. The mixture was filtered and dried in vacuo to obtain D-cycloserine L-tartaric acid (1:1) as a salt (yield 2047.9mg, 82.91%).

Preparation of L-tartaric acid and salts obtained by the method described in example 2 above¹The results of H-NMR, XRPD and thermal analysis are shown in FIGS. 13 to 20.

Example 3: preparation of D-cycloserine maleic acid (1:1) salt form

D-cycloserine (1000mg) and maleic acid (1136.8mg) were added to 8mL of deionized water, and stirred at 800rpm at room temperature. The solution was added dropwise to 200mL of ethanol containing 70% diethyl ether and stirred at 800rpm for 10 minutes at room temperature. The mixture was filtered and dried in vacuo to obtain the D-cycloserine maleic acid (1:1) salt form (yield 1563.7mg, 73.18%).

Process for the preparation of maleic acid and salts obtained by the process described in example 3 above¹The results of H-NMR, XRPD and thermal analysis are shown in FIGS. 21 to 28.

Example 4: preparation of D-cycloserine D-tartaric acid (2:1) salt form

D-cycloserine (1000mg) and D-tartaric acid (1470mg) were added to 10mL and 3mL of deionized water, respectively, and stirred at 800rpm, respectively, at room temperature. When they dissolved, the D-tartaric acid solution was added to the D-cycloserine solution and stirred for 10 minutes. The resulting solution was added dropwise to 200mL of isopropanol and stirred at 800rpm for 10 minutes at room temperature. The mixture was filtered and dried in vacuo to obtain the D-cycloserine D-tartaric acid (2:1) salt form (yield 2047.9mg, 82.91%).

Of D-tartaric acid and salts obtained by the method described in example 4 above¹The results of H-NMR, XRPD and thermal analysis are shown in FIGS. 29 to 36.

Example 5: d-cycloserine and D-cycloserine salts in a closed system at 40 ℃/75% Relative Humidity (RH) for stress studies

200mg of D-cycloserine, L-tartaric acid, maleic acid, D-tartaric acid, D-cycloserine L-tartaric acid (1:1) salt form and D-cycloserine maleic acid (1:1) salt form and D-cycloserine D-tartaric acid (2:1) salt form from Stelley Sassen Co., Ltd and Maxwell pharmaceutical Co., Ltd were placed separately in a colourless glass bottle and kept in a closed system (i.e. with the bottle lid closed) at 40 ℃/75% RH for the respective stress study.

Initially, the appearance results indicated that D-cycloserine, L-tartaric acid, maleic acid, D-tartaric acid, D-cycloserine L-tartaric acid (1:1) salt form and D-cycloserine maleic acid (1:1) salt form and D-cycloserine D-tartaric acid (2:1) salt form from Maxleyde pharmaceuticals, Inc. remained as fine white powders, whereas the remaining D-cycloserine from Stylece Sassen, Inc. was a pale yellow powder. However, after one month of stress study, both D-cycloserines from sterlesie shasen limited and mamule pharmaceutical limited disintegrated and became dark yellow.

After 60 days of stress study, the D-cycloserine, L-tartaric acid and D-cycloserine L-tartaric acid (1:1) salt forms from strolley shasen ltd and milrody pharmaceuticals ltd and fresh D-cycloserine (t ═ 0 days) from milrody pharmaceuticals ltd and strolley shasen ltd were analyzed by High Performance Liquid Chromatography (HPLC) as shown in fig. 37. After 60 days of stress studies, only the D-cycloserine L-tartaric acid (1:1) salt form was stable.

After 30 days of stress study, D-cycloserine, maleic acid, and D-cycloserine maleic acid (1:1) salt form from the company of sterley shasen, inc and the company of malowry, inc, and fresh D-cycloserine (t ═ 0 days) from the company of malowry, inc and the company of sterley shasen, inc were also analyzed by HPLC, as shown in fig. 38. After 30 days of stress studies, only the D-cycloserine maleic acid (1:1) salt form was stable.

D-cycloserine, D-tartaric acid, D-cycloserine D-tartaric acid (2:1) salt form from scantlie sason limited and mulude pharmaceuticals limited and fresh D-cycloserine (t 0 days) from multlie pharmaceuticals limited and sletlie sason limited were also analyzed by HPLC as shown in fig. 39. Only the D-tartaric acid, D-cycloserine D-tartaric acid (2:1) salt form is stable.

Example 6: hygroscopicity test at room temperature/95% RH of D-cycloserine and D-cycloserine salt forms for stress stability studies by means of an open system

200mg of D-cycloserine, L-tartaric acid, maleic acid, D-tartaric acid, D-cycloserine L-tartaric acid (1:1) salt form, D-cycloserine maleic acid (1:1) salt form and D-cycloserine D-tartaric acid (2:1) salt form from Stelley Sassen Co., Ltd and Maxwell pharmaceutical Co., Ltd were each placed in a colorless glass bottle and kept in an open system (i.e., with the bottle open) at room temperature/95% RH for stress studies. The compound with the vial was weighed daily. The results indicated that D-cycloserine from sterlesie shasen ltd and mamule pharmaceuticals ltd absorbed 59.2% and 62.5% water on day 60, respectively (as shown in figure 40); the D-cycloserine absorbed 41.9% and 41.3% of water on day 30, respectively (as shown in FIG. 41); and the D-cycloserine absorbed 42.7% and 43.3% of water on day 30, respectively (as shown in fig. 42). The L-tartaric acid and D-cycloserine L-tartrate forms absorbed 244.6 and 18.9% of the water on day 60, respectively (as shown in FIG. 40). The maleic acid and D-cycloserine maleate forms absorbed 100.4 and 1.3% of water on day 30, respectively (as shown in FIG. 41). The D-tartaric acid and D-cycloserine D-tartrate forms absorbed 177.0 and 1.3% of water on day 30, respectively (as shown in FIG. 42). This indicates that the D-cycloserine L-tartaric acid (1:1) salt form, the D-cycloserine maleic acid (1:1) salt form and the D-cycloserine D-tartaric acid (2:1) salt form are much less hygroscopic than D-cycloserine and carboxylic acid alone.

Equivalents and ranges

In the claims, articles such as "a" and "an" may be used in reference to one or more of the following unless indicated to the contrary or otherwise apparent from the context. Claims or descriptions that include an "or" between one or more members of a group are deemed to be satisfactory if one, more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention encompasses embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The invention encompasses embodiments in which more than one or all of the group members are present in, used in, or otherwise relevant to a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented in a list format, such as a Markush group (Markush group) format, each subgroup of the elements is also disclosed, and any one or more of the elements may be removed from the group. It should be understood that, in general, where the invention or aspects of the invention are referred to as including particular elements and/or features, certain embodiments or aspects of the invention are formed from, or consist essentially of, such elements and/or features, etc. For the sake of simplicity, those embodiments are not specifically set forth herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and allow for the inclusion of additional elements or steps. Where a range is given, the endpoints are inclusive. Furthermore, unless otherwise indicated or otherwise made apparent from the context and understanding of one of ordinary skill in the art, values expressed as ranges can assume that any particular value or sub-range within the range recited in different embodiments of the invention is one tenth of the unit of the lower limit of the range (unless otherwise clearly indicated in the context).

This application is related to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and the present specification, the present specification controls. In addition, any particular embodiment of the invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to those of ordinary skill in the art, they may be excluded even if such exclusion is not explicitly set forth herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the presence of prior art.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the embodiments of the invention described herein is not intended to be limited by the above description, but rather is as set forth in the following claims. It will be understood by those of ordinary skill in the art that various changes and modifications may be made to the description without departing from the spirit or scope of the present invention as defined by the following claims.