US 20170181989A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0181989 A1 Tsai (43) Pub. Date: Jun. 29, 2017 (54) SORBC AND BENZOIC ACID AND Publication Classification DERVATIVES THEREOF ENHANCE THE (51) Int. Cl. ACTIVITY OF A NEUROPHARMACEUTICAL A63L/92 (2006.01) (71) Applicant: Los Angeles Biomedical Research A 6LX 3/553 (2006.01) Institute at Harbor-UCLA Medical (52) U.S. Cl. Center, Torrance, CA (US) CPC ........ A61K 31/192 (2013.01); A61 K3I/5513 (2013.01) (72) Inventor: Guochuan Emil Tsai, Pasadena, CA (US) (57) ABSTRACT Methods and compositions are provided for treating neu (73) Assignee: Los Angeles Biomedical Research ropsychiatric disorders such as Schizophrenia, depression, Institute at Harbor-UCLA Medical attention deficit disorder, mild cognitive impairment, Center, Torrance, CA (US) dementia, and bipolar disorder. The methods entail admin istering to a patient diagnosed as having a neuropsychiatric disorder (e.g., Schizophrenia, depression, attention deficit (21) Appl. No.: 15/409,655 disorder, mild cognitive impairment, dementia bipolar dis order, etc.) or as at risk for a neuropsychiatric disorder a (22) Filed: Jan. 19, 2017 benzoic acid, benzoic acid salt, and/or benzoic acid deriva tive, and/or a Sorbic acid, Sorbic acid salt, and/or Sorbic acid Related U.S. Application Data derivative, in combination with a neuropharmacological agent (e.g., an antipsychotic, an antidepressant, medications (62) Division of application No. 14/552,298, filed on Nov. for attention deficit and hyperactivity disorder, cognitive 24, 2014, which is a division of application No. impairment, or dementia, etc.) where the benzoic acid, 12/689,957, filed on Jan. 19, 2010, now Pat. No. benzoic acid salt, or benzoic acid derivative, and/or a Sorbic 9,649,304. acid, Sorbic acid salt, and/or Sorbic acid derivative, is in an (60) Provisional application No. 61/145,931, filed on Jan. amount Sufficient to increase the efficacy of the neurophar 20, 2009. macological agent. Patent Application Publication Jun. 29, 2017 Sheet 1 of 3 US 2017/O181989 A1 8. Bezoate NG Citatio r 8 : t 3. 8. 3. Bassie easte rea tre+ Anthetaire Fig. 1 Patent Application Publication Jun. 29, 2017 Sheet 2 of 3 US 2017/O181989 A1 6O.O PP of Treatments vehicle + amphetamine benzoate + amphetamine NMG + amphetamine combination + amphetamine 5 O. O t 40.0 Š PP 487Hz Fig. 2 Patent Application Publication Jun. 29, 2017 Sheet 3 of 3 US 2017/O181989 A1 PANSS-Total Quality of Life Placebo Placebo Placebo US 2017/O181989 A1 Jun. 29, 2017 SORBIC AND BENZOIC ACID AND SUMMARY OF THE INVENTION DERVATIVES THEREOF ENHANCE THE ACTIVITY OF A NEUROPHARMACEUTICAL 0007. In certain embodiments this invention pertains to “combination’ pharmaceutical compositions comprising a CROSS-REFERENCE TO RELATED benzoic acid, benzoic acid salt, benzoic acid ester or other APPLICATIONS benzoic acid derivative, and/or a Sorbic acid, Sorbic acid salt, sorbic acid ester, or other sorbic acid derivative and a 0001. This application claims benefit of and priority to neuropharmaceutical (e.g., an antipsychotic drug (e.g., ris U.S. Ser. No. 61/145,931, filed on Jan. 20, 2009, which is peridone, olanzapine, etc.), and antidepressant (e.g., Sertra incorporated herein by reference in its entirety for all pur line, fluoxetine hydrochloride, etc.), a psychotropic medica poses. tion for attention deficit and hyperactivity disorder (e.g., STATEMENT AS TO RIGHTS TO INVENTIONS Ritalin, Dexedrine, Atomoxetine, etc.), a psychotropic medi MADE UNDER FEDERALLY SPONSORED cation for dementia (e.g., Aricept, memantine), and the like). RESEARCH AND DEVELOPMENT Typically, the benzoic acid, benzoic acid salt, benzoic acid ester or other benzoic acid derivative, and/or a sorbic acid, 0002. Not Applicable sorbic acid salt, sorbic acid ester, or other sorbic acid derivative is present in an amount Sufficient to increase the FIELD OF THE INVENTION efficacy of the neuropharmaceutical. In certain embodiments 0003. This is invention pertains the field of neuropsy the benzoic acid is provided as a benzoic acid salt (e.g. chiatry. In particular treatment methods are provided for Sodium benzoate, potassium benzoate, calcium benzoate, neuropsychiatric disorders. etc.). In certain embodiments the benzoic acid, benzoic acid salt, or derivative thereof is selected from the group con BACKGROUND OF THE INVENTION sisting of benzoic acid, Sodium benzoate, potassium benzo ate, calcium benzoate, 2-aminobenzoate, 3-aminobenzoate, 0004 Schizophrenia, Alzheimer's Disease, autism, and 4-aminobenzoate. In certain embodiments the Sorbic depression, benign forgetfulness, childhood learning disor acid is provided as a Sorbic acid salt (e.g., sodium Sorbate, ders, close head injury, and attention deficit disorder (ADD), potassium Sorbate, calcium Sorbate, etc.). In certain embodi dementia, mild cognitive impairment, ataxia, Spinocerebel ments the Sorbic acid, Sorbic acid salt, Sorbic acid ester, lar degeneration, Parkinson's disease, obsessive compulsive and/or sorbic acid derivative is selected from the group disorder (OCD), substance abuse, and substance dependence consisting of Sorbic acid, Sodium Sorbate, potassium Sorbate, are examples of neuropsychiatric disorders. Autism, for calcium Sorbate, Sorbohydroxamic acid, a Sorbic aldehyde, a example, is a developmental mental disorder characterized Sorbic acid-thiol adduct, 8-quinolinylsorbate, and m-ni by autistic behavior, social failure, and language delay. trosorbanilide. Alzheimer's Disease is a form of dementia that typically involves progressive mental deterioration, manifested by 0008. In certain embodiments the ratio of benzoic acid, memory loss, confusion, and disorientation. Alzheimer's benzoic acid salt, or benzoic acid derivative and/or sorbic Disease typically is treated by acetylcholine esterase inhibi acid, Sorbic acid salt, or Sorbic acid derivative to neurop tors such as tacrine hydrochloride or donepezil. Attention harmaceutical is stoichiometrically greater than 2:1, greater Deficit Disorder is a disorder that is most prevalent in than 3:1, greater than 4:1 greater than 5:1, greater than 6:1, children and is associated with increased motor activity and greater than 7:1, greater than 8:1, greater than 9:1, or greater a decreased attention span. Attention Deficit Disorder com than 10:1 or 20:1. monly is treated by administration of psychoStimulants or 0009. In certain embodiments the neuropharmaceutical is other medications such as Ritalin, Dexedrin, or atomoxetin. selected from the group consisting of an antidepressant, an Depression is a clinical syndrome that includes a persistent antipsychotic, a psychoStimulant, a mood stablizer, an anxi sad mood or loss of interest in activities, which persists for olytic, an ADHD therapeutic, and an Alzheimer's disease at least two weeks in the absence of treatment. Conventional therapeutic. In certain embodiments the neuropharmaceuti therapeutics include serotonin uptake inhibitors (e.g., PRO cal is an antipsychotic drug (e.g., butyrophenone, phenothi ZAC(R), monoamine oxidase inhibitors, and tricyclic anti azine, fluphenazine, perphenazine, prochlorperazine, thior depressants. idazine, trifluoperazine, mesoridazine, promazine, 0005. The term schizophrenia represents a group of neu triflupromazine, levomepromazine, promethazine, thioxan ropsychiatric disorders characterized by dysfunctions of the thene, chlorprothixene, flupenthixol, thiothixene, Zuclopen thinking process. Such as delusions, hallucinations, and thixol, clozapine, olanzapine, risperidone, quetiapine, Zip extensive withdrawal of the patients interests from other rasidone, amisulpride, asenapine, paliperidone, aripiprazole, people. Approximately one percent of the worldwide popu a dopamine partial agonist, lamotrigine, memantine, tetra lation is afflicted with schizophrenia, and this disorder is benazine, cannabidiol, and/or LY2140023). In certain accompanied by high morbidity and mortality rates. embodiments the neuropharmaceutical is an antidepressant 0006 Conventional antipsychotic drugs, which act on the drug (e.g., a monoamine oxidase inhibitor (MAOI), a tricy dopamine D, receptor, can be used to treat the positive clic antidepressant (TCA), a tetracyclic antidepressant symptoms of Schizophrenia, Such as delusion and halluci (TeCA), a selective serotonin reuptake inhibitor (SSRI), and nation. In general, conventional antipsychotic drugs and the a serotonin-norepinephrine reuptake inhibitor (SNRT). In new atypical antipsychotic drugs, which act on the dop certain embodiments the the neuropharmaceutical is an amine D, and 5HT2 serotonin receptor, are limited in their ADHD medication (e.g., Ritalin, Dexedrine, Atomoxetine, ability to treat cognitive deficits and negative symptoms and the like). In certain embodiments the neuropharmaceu Such as affect blunting (i.e., lack of facial expressions), tical is a medication for improving cognition and/or inhib anergia, and Social withdrawal. iting neurodegeneration (e.g., Aricept. memantine, etc.). US 2017/O181989 A1 Jun. 29, 2017 0010 Also provided are methods for mitigating one or LY2140023). In certain embodiments the, the neuropsychi more symptoms of a neuropsychiatric disorder (e.g., Schizo atric disorder is depression, and the neuropharmaceutical is phrenia, depression, attention deficit disorder, mild cogni an antidepressant drug (e.g., a monoamine oxidase inhibitor tive impairment, dementia, attention deficit hyperactivity (MAOI), a tricyclic antidepressant (TCA), a tetracyclic disorder (ADHD),