# US 12,178,804 B2 · Salts of cycloserine compounds and applications thereof

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- Number: US 12,178,804 B2
- Document ID: US12178804B2
- Status: Granted
- Kind: B2
- Application number: 17/275,794
- Filed: 2019-09-12
- Published: 2022-02-17
- Granted: 2024-12-31
- Earliest claimed: 2018-09-13
- Assignees: SyneuRx International (Taiwan) Corp.
- Applicants: SyneuRx International (Taiwan) Corp.
- Inventors: Guochuan Emil Tsai; Ching-Cheng Wang; Tsai-Miao Shih
- Web page: https://patentgrep.com/patent/US12178804B2

## CPC

- A61K 31/42: Oxazoles
- A23L 33/10: using additives (addition of substantially indigestible substances A23L33/21)
- A23L 33/135: Bacteria or derivatives thereof, e.g. probiotics
- A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 31/06: for tuberculosis
- C07D 261/04: having one double bond between ring members or between a ring member and a non-ring member
- A23V 2002/00: Food compositions, function of food ingredients or processes for food or foodstuffs
- A23V 2200/322: having an effect on the health of the nervous system or on mental function
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A23L: FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF (preservation thereof A23B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A23V: INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION

## Abstract

Provided herein is salts of formula [A][B], wherein [A] is a cation form of a cycloserine compound and [B] is an anion 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 decreased 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 a subject in need a composition comprising salts of formula [A][B] described herein.

## Claims

### Claim 1

A method for treating a neuropsychiatric disorder or a bacterial infectious disease, the method comprising administering an effective amount of a salt of formula [A] [B] to a subject in need thereof, wherein [A] is a cation form of a cycloserine compound; and [B] is an anion form of a compound of formula (I):
in which
X is —NH2 or —OH;
each of L1 and L2, independently, is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene, or one of L1 and L2 is N, O, or S, and the other one is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene, as valency permits;
is either a single or double bond; and
wherein the ratio of [A] and [B] in the salt ranges from 10:1 to 1:10.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject has, is suspected of having, or is at risk for the neuropsychiatric disorder or the bacterial infectious disease.

### Claim 3 (depends on 2)

The method of claim 2, wherein the subject has, is suspected of having, or is at risk for the neuropsychiatric disorder, which is selected from the group consisting of schizophrenia, psychotic disorder, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, senile dementia, mild cognitive impairment, benign forgetfulness, closed head injury, autistic spectrum disorder, Asperger's disorder, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive compulsive disorder, tic disorder, childhood learning disorder, premenstrual syndrome, depression, major depressive disorder, anhedonia, suicidal ideation and/or behavior, bipolar disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorder, addiction disorder, personality disorder, Parkinson's disorder, Huntington's disorder, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette's syndrome, nocturnal enuresis, non-epileptic seizure, blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain, hyperalgesia, allodynia, diabetic polyneuropathy, and chronic pain syndrome.

### Claim 4 (depends on 2)

The method of claim 2, wherein the subject has, is suspected of having, or is at risk for the neuropsychiatric disorder, which is selected from the group consisting of ataxia symptoms, spinocerebellar degeneration, autism, pervasive developmental disorder-not otherwise specified (PDD-NOS), anorexia nervosa, phobia, agoraphobia, and claustrophobia.

### Claim 5 (depends on 2)

The method of claim 2, wherein the subject has, is suspected of having, or is at risk for the bacterial infectious disease, which is tuberculosis.

### Claim 6 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 7 (depends on 6)

The method of claim 6, wherein the salt is administered to the human at a frequency of four times a day to one time every three months.

### Claim 8 (depends on 6)

The method of claim 6, wherein the method further comprises administering to the human one or more additional pharmaceutical agents for treating the neuropsychiatric disorder.

### Claim 9 (depends on 8)

The method of claim 8, wherein the one or more additional pharmaceutical agents is selected from the group consisting of an antipsychotic, an antidepressant, a mood stabilizer, an anxiolytic, a psychostimulant or an agent for treating cognitive impairment or dementia.

### Claim 10 (depends on 9)

The method of claim 9, wherein:
(a) the antipsychotic is butyrophenone, phenothiazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, thioxanthene, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, aripiprazole, dopamine partial agonists, lamotrigine, cannabidiol, LY2140023, droperidol, pimozide, butaperazine, carphenazine, remoxipride, piperacetazine, sulpiride, acamprosate, or tetrabenazine;
(b) the antidepressant or mood stabilizer is a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a selective serotonin reuptake inhibitor (SSRI), a noradrenergic and specific serotonergic antidepressant (NASSA), a norepinephrine (noradrenaline) reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor, a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI), or a serotonin-norepinephrine reuptake inhibitor (SNRI);
(c) the anxiolytic is hydroxyzine hydrochloride, diphenhydramine, an azaspirone, a benzodiazepine, or a beta blocker;
(d) the psychostimulant is amphetamine, modafinil, desoxyn, methamphetamine, cocaine, arecoline, dexmethylphenidate, dextroamphetamine, methylphenidate, lisdexamfetamine dimesylate, atomoxetine clonidine hydrochloride, guanfacine hydrochloride, arecoline, or pemoline; and
(e) the agent for treating cognitive impairment or dementia is tacrine, rivastigmine, donepezil, physostigmine, nicotine, arecoline, huperzine alpha, selegiline, riluzole, memantine, vitamin C, vitamin E, carotenoids, or Ginkgo biloba.

### Claim 11 (depends on 8)

The method of claim 8, wherein the one or more additional pharmaceutical agents is selected from the group consisting of 5-hydroxytryptophan (5-HTP), idebenone, amantadine, physostigmine, L-carnitine or derivatives, trimethoprim/sulfamethoxazole, vigabatrin, phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone, Q10, vitamin E and N-Acetyl-Leucine.

### Claim 12 (depends on 1)

The method of claim 1, wherein the method further comprises administering to the human one or more additional pharmaceutical agents for treating and/or reducing the risk for tuberculosis.

### Claim 13 (depends on 12)

The method of claim 12, wherein the additional pharmaceutical agent is isoniazid, rifampin, ethambutol, pyrazinamide, rifabutin, rifapentine, capreomycin, kanamycin, amikacin, streptomycin, fluoroquinolone antibiotics, prothionamide, para-aminosalicylic acid, ethionamide, terizadone, clofazimine, clarithromycin, linezolid, amoxicillin-clavulanate, thiacetazone, bedaquiline, delamanid, or a carbapenmem antibiotic.

### Claim 14 (depends on 1)

The method of claim 1, wherein the human has undergone or is undergoing another treatment of the neuropsychiatric disorder.

### Claim 15 (depends on 9)

The method of claim 9, wherein the antidepressant or mood stabilizer is fluoxetine, paroxetine, escitalopram, citalopram, sertraline, fluvoxamine, venlafaxine, milnacipran, duloxetine, mirtazapine, mianserin, reboxetine, bupropion, amitriptyline, nortriptyline, protriptyline, desipramine, trimipramine, amoxapine, bupropion, clomipramine, desipramine, doxepin, isocarboxazid, tranylcypromine, trazodone, nefazodone, phenelzine, lamatrogine, lithium, topiramate, gabapentin, carbamazepine, oxcarbazepine, valproate, maprotiline, brofaromine, gepirone, moclobemide, isoniazid, or iproniazid.