Composition comprising (a) a dual agent acting as a 5-ht2a receptor antagonist and cyp2d6 inhibitor and (b) an NMDA receptor antagonist for use in the treatment of diseases involving glucose

Description

TECHNICAL FIELD

[0001] This disclosure relates to novel compositions and methods targeting CYP2D6 enzyme, NMDA and 5-HT2A receptors for use in the treatments of behavioral and psychological symptoms of dementia, and methods of making such compositions, therapeutic formulations and kits thereof.BACKGROUND

[0002] Brain disorders, including developmental, psychiatric and neurodegenerative diseases, and cancers, represent an enormous disease burden, regarding human suffering and economic cost.

[0003] Diseases affecting the brain and central nervous system represent one of the largest global healthcare challenges and greatest medical needs due to the devastating personal and economic consequences for patients, caregivers and society. An estimated 55 million people worldwide suffer from neurodegenerative diseases with no currently approved disease-modifying therapies available. As modern therapeutic interventions increase life expectancy, the number of patients suffering from these diseases is expected to double every 20 years. Costs for treating these diseases are currently estimated at $818 billion and expected to grow to more than $1 trillion by 2030.

[0004] Alzheimer's disease (AD) accounts for over half of all diagnosed cases of dementia, a degenerative condition that impairs memory, thinking, and independent functioning. AD is currently estimated to afflict between 3 million and 5 million people in the United States and 35 million people worldwide. Without effective treatments to prevent or slow the course of Alzheimer's and related dementias, the number of people living with AD is projected to double by 2035 and triple by 2060 as the world population ages.

[0005] Regardless of the many potential etiologies of cerebrovascular disease, the term Vascular Dementia (VaD) is now established to describe the end stage of vascular cognitive impairment (VCI). Because of historical uncertainty around the diagnostic classification, epidemiologic data are variable. However, age-adjusted rates for Alzheimer disease and VaD are 19.2 and 14.6, respectively, per 1000 person-years, showing that VaD is the second leading cause for dementia in the affluent countries (Gorelik et al., Vascular Contributions to Cognitive Impairment and Dementia. Stroke 42: 2672-2713 (2011)). In many cases, there is overlap or co-morbidity with AD as large post-mortem series have shown repeatedly ("mixed dementia"). As the onset of VaD may be insidious as in AD, diagnostic specificity in a given subject remains a challenge, while the medical need for treatment is no less than in AD.

[0006] Dementia with Lewy Bodies (DLB) has been confirmed in the recent years as a major form of dementia. Its clinical features distinguish DLB from AD and VaD. In particular, there are cognitive, neuropsychiatric, motor, and other symptoms occurring. Therapy is non-specific, and acetylcholine esterase inhibitors (AChEIs) used in AD may worsen the condition, and in particular trigger or worsen delusions and hallucinations. The use of antipsychotics for the acute management of substantial behavioral disturbance, delusions, or visual hallucinations comes with attendant mortality risks in patients with dementia, and particularly in the case of DLB they should be avoided whenever possible, given the increased risk of a serious sensitivity reaction (McKeith et al., Diagnosis and management of dementia with Lewy bodies. Neurology 89: 88-100 (2017)).

[0007] Fronto-Temporal Lobar Degeneration (FTLD) is a clinically and pathologically heterogenous basket of dementias, which show behavioral, cognitive, motor, speech, and other impairments (Rabinovici, Miller, Frontotemporal Lobar Degeneration: Epidemiology, Pathophysiology, Diagnosis and Management. CNS Drugs 24: 375-398 (2010)). The most frequent form is behavioral variant fronto-temporal dementia (bvFTD) characterized by prominent symptoms of the BPSD spectrum. Treatment is non-specific and always off-label as no specific pharmacotherapy exists. In particular in bvFTD, there is a high medical need for a non-neuroleptic therapy addressing specifically the behavioral impairments.

[0008] WO 2014 / 138669 A1 describes pharmaceutical compositions comprising an NMDA antagonist (e.g. dextromethorphan), a CYP2D6 inhibitor (e.g. in the form of a quinidine salt); and an opioid agonist (e.g. morphine, oxycodone, or hydromorphone). The respective compositions are use for pain treatment and the treatment of pain related disorders or to produce analgesia WO 2014 / 011590 A1 describes a composition for treating depression or psychosis in a human, wherein the composition comprises a selective 5-HT2A receptor antagonist / inverse agonist and a NMDAR receptor antagonist. Dextromethorphane is mentioned as a possible NMDA receptor antagonist. Cho et al in Drug metab. Dispos., 2013, 42(1) pp33-39 describes that sarpogretalte and its metabolite M1 potently and selectively inhibit CYP2D6-mediated dextromethorphane O-demethylation in a competitive manner.SUMMARY OF THE INVENTION

[0009] An embodiment of the invention is a pharmaceutical composition composition for use a specified in claim 1 and hereinbelow

[0010] In the pharmaceutical composition, the dual acting agent capable of inhibiting CYP 2D6 and acting as a 5-HT2A receptor antagonist can be present as such, as deuterated derivative thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or a combination thereof. Likewise, the NMDA receptor antagonist can compound 149 (dextromethorpahne), deuterated derivatives thereof, fluorinated derivatives thereof, pharmaceutically acceptable salts, N-oxides thereof, or a combination thereof.

[0011] In an embodiment, the composition is apharmaceutical composition, wherein the NMDA receptor antagonist is dextromethorphan, and the composition is administered once or twice a day, wherein the daily dose of dextromethorphan is about 0.1 mg to about 1000 mg, resulting in an AUC 0-12 of dextromethorphan that is greater than the AUC 0-12 of the NMDA receptor antagonist dextromethorphan that would be achieved by administering the same amount of the NMDA receptor antagonist dextromethorphan without the dual agent.

[0012] Another embodiment is a pharmaceutical composition wherein the composition further comprises wherein the composition further comprises a polymer, an emulsifier, a binder, a disintegrating agent, and / or a lubricant, and use comprises administering the composition to the subject once or twice a day for at least 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, 31 consecutive days, 32 consecutive days, 33 consecutive days, 34 consecutive days, 35 consecutive days, 36 consecutive days, 37 consecutive days, 38 consecutive days, 39 consecutive days, 40 consecutive days, 41 consecutive days, 42 consecutive days, 43 consecutive days, 44 consecutive days, 45 consecutive days, 46 consecutive days, 47 consecutive days, 48 consecutive days, 49 consecutive days, 50 consecutive days, 51 consecutive days, 52 consecutive days, 53 consecutive days, 54 consecutive days, 55 consecutive days, 56 consecutive days, 57 consecutive days, 58 consecutive days, 59 consecutive days, 60 consecutive days, 70 consecutive days, 80 consecutive days, 90 consecutive days, 100 consecutive days, 110 consecutive days, 120 consecutive days, 130 consecutive days, 140 consecutive days, 150 consecutive days, 160 consecutive days, 170 consecutive days, 180 consecutive days, 190 consecutive days, or 200 consecutive days.

[0013] Another embodiment is a pharmaceutical composition wherein the AUC 0-12 of the dual agent, is at least about 10 ng / hr / mL, about 100 ng / hr / mL, 200 ng / hr / mL, about 300 ng / hr / mL, or about 400 ng / hr / mL.

[0014] Another embodiment is a pharmaceutical composition is in the form of an oral dosage form comprising tablets, capsules, liquids, or solutions and for use in anadministration that is cutaneous, oral, nasal, anal, rectal, vaginal, sublingual, buccal, sublabial, muscular, intramuscular, intravenous, peritoneal, epidural, intracerebral, intracerebral or topical, intraarticular, intracardiac, intracavernous, intradermal, intralesional, intramuscular, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, or transmucosal.

[0015] In an embodiment, pharmaceutical composition is a composition for use for administering a therapeutically effective amount of the composition targeting CYP2D6 enzyme, and NMDA and 5-HT2A receptors, wherein the disease or disorder is neuropsychiatric, neurodegenerative, or brain injury, comprising behavioral and psychological symptoms of dementia (BPSD); and producing a symptomatic relief and / or disease modification..BRIEF DESCRIPTION OF FIGURES

[0016] Figure 1: Dixon plots to determine Ki values for CYP2D6 of a compound of formula I or SARPO (A), M-1 (B), and quinidine (C). The concentrations of dextromethorphan were determined 2.5 (filled circles), 5 (open circles), and 10 (triangles) mM, respectively. V represents formation rate of dextrorphan (pmol / min / mg protein). Data are the mean values of triplicate determinations. The solid lines of a compound of formula I or SARPO, M-1, and quinidine fit well to all competitive inhibition types (Cho et al., Effect of the potent CYP2D6 inhibitor sarpogrelate, on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers. Xenobiotica, 45(3):256-63 (2015 March). Figure 2: Mean Neuropsychiatric Inventory Agitation / Aggression Domain Scores by Stage and Visit for Patients Included in the Sequential Parallel Comparison Design and 10-Week Analyses. A, Stage 1 (weeks 1-5); B, stage 2 (weeks 6-10) for placebo nonresponders rerandomized after stage 1; C, 10-week results (the 10-week secondary analysis includes only patients who continued the same treatment assignment throughout study participation; ie, were randomized to receive only dextromethorphan-quinidine or only placebo [excludes patients who were re-randomized from placebo to dextromethorphan-quinidine in stage 2], thus simulating a parallel-group design). Analysis-of-covariance models with treatment as fixed effect and baseline as covariate were used to compare mean change from baseline between groups at each time point. Baseline for stage 2 is the patients' scores at the start of stage 2. Least squares mean treatment differences are as follows: for stage 1, week 1, -0.8 (95%CI, -1.5 to -0.03; P = .04), week 3, -1.0 (95%CI, -1.8 to -0.2; P = .01), and week 5, -1.5 (95%CI, -2.3 to -0.7; P < .001); for stage 2, week 6, 0.7 (95%CI, -0.4 to 1.9; P = .19), week 8, -0.1 (95%CI, -1.3 to 1.2; P = .93), and week 10, -1.6 (95%CI, -2.9 to -0.3; P = .02); for 10-week analysis, week 1, -0.9 (95%CI, -1.8 to -0.04; P = .047), week 3, -1.3 (95%CI, -2.2 to -0.3; P = .01), week 5, -1.8 (95%CI, -2.7 to -0.9; P < .001), week 6, -0.9 (95%CI, -2.0 to 0.1; P = .06), week 8, -1.3 (95%CI, -2.4 to -0.3; P = .01), and week 10, -1.8 (95%CI, -2.8 to -0.7; P = .003). a Observed cases (Cummings et al., Effect of dextromethorphan quinidine on agitation in patients with Alzheimer Disease dementia: a randomized clinical trial. JAMA 314(12):1242-1254 (2015)). Figure 3: Treatment effects on psychosis severity reduction in the 6-week study period in the full analysis set. The full analysis set includes all patients who received ≥1 dose and had a SAPS assessment at baseline and at least one afterward. Data points show least squares means (standard error). (A) SAPS-PD improvement. (B) Change in CGI-severity score. (C) CGI-improvement scores. SAPS=scale for assessment of positive symptoms. CGI=clinical global impression (Cummings et al., Pimavanserin for patients with Parkinson's disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet, 383(9916):533-40 (2014 February 8)). Figure 4: Contribution of specific causes to the combined burden of neurologic disorders and cerebrovascular disease (percent of total disability-adjusted life-years) (Global Burden of Disease Study 2010 (GBD 2010) Results by Cause 1990-2010, Global Health Data Exchange (GHDx)). Figure 5: Chiralpak IA-1 (4.6x250 mm) Iz. 10% IPA + Hex +0.05%AE; F=1 mL / min; T=25 °C. Figure 5 shows separation of M1 enantiomers using Chiralpak. Figure 6: Chromatogram of (-) sarpogrelate obtained by chromatography with a column of XBridge ®< C18 3.5µm, 2.1x50 mm mobile phase, gradient elution from 10% MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA, rate: 0.5 ml / min. Detection: UV 254 nm. Figure 7: Effects of (-) and (+) enantiomers of M1 as well as M-100,907 on MK-801-induced hyperactivity in rats. Data are presented as mean (±SEM) average activity over a 60-min test session. N=5-9 per group. Figure 8: Effects of sarpogrelate on motor activity in rats after olfactory bulbectomy (OBX) or sham surgery (SHAM). Data are presented as mean (±SEM) average activity over a 5-min test session. N=12 per group. Figure 9: Plasma level curves of sarpogrelate and M1 in male Wistar rats after single intravenous administrations of sarpogrelate hydrochloride (2 mg / kg). Data are presented as mean (±SD) concentration (ng / ml). N=4. Figure 10: Plasma level curves of dextromethorphan in male Wistar rats that received dextromethorphan (50 mg / kg, per os) immediately followed by intravenous bolus injection of sarpogrelate (1, 3 or 10 mg / kg; racemate or one of the enantiomers) or vehicle via vascular access port at t = 0 h. Data are presented as mean (±SD) concentration (ng / ml). N=2-3. Figure 11: Effects of a combination of dextromethorphan with sarpogrelate racemate (upper panel), (-) sarpogrelate (middle panel) or (+) sarpogrelate on PCP-induced hyperactivity in rats. Figure 12: Effects of dextromethorphan and sarpogrelate racemate on blood glucose level. Data are presented as area under the curve (mean±SEM) for blood glucose level over the period of time 30-180 min after oral glucose (2 g / kg) challenge. N=8 per group. ABBREVIATIONS AND DEFINITION OF TERMS

[0017] The term "antagonist" is an agent that reduces the effect of an agonist by preventing it from binding to receptors. A neutral antagonist has no activity in the absence of an agonist but can block the activity of either.

[0018] The term "inverse agonist" is an agent that binds to the same receptor as an agonist but typically have the opposite effect on the target cell and inhibit the spontaneous receptor agonist-independent activity. The main pharmacological effect of inverse agonists is receptor antagonism.

[0019] Both antagonists and inverse agonists reduce the activity of a receptor. In the present context, antagonist and inverse agonist are used interchangeably, and both terms are represented by "antagonist."

[0020] The term "dual agent" in the present specification is defined as an agent that acts as an inhibitor or antagonist against two different target receptors or enzymes. In the present context, dual agents having activity against 5-HT2A receptor and CYP2D6 are represented by sarpogrelate (Compound 50), its enantiomers (Compound 51 and Compound 52), and its metabolites.

[0021] The term SGL represents Sarpogrelate racemate or pharmaceutically acceptable salts thereof.

[0022] The term SGL-E1 represents (R) sarpogrelate or pharmaceutically acceptable salts thereof.

[0023] The term SGL-E2 represents (S) sarpogrelate or pharmaceutically acceptable salts thereof.

[0024] The term M1 represents Sarpogrelate racemate metabolite 1 or pharmaceutically acceptable salts thereof.

[0025] The term M1-E1 represents (R) sarpogrelate metabolite 1 or pharmaceutically acceptable salts thereof.

[0026] The term M1-E2 represents (S) sarpogrelate metabolite 1 or pharmaceutically acceptable salts thereof.

[0027] The term DEX represents one or more compounds selected from the group consisting ofdextromethorphan, dextromethorphan (DEX-H 3 ), enantiomers thereof, pharmaceutically acceptable salts, N-oxides thereof, or a combination thereof.

[0028] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids when the pharmaceutically active compound of the present invention is basic, or salts prepared from pharmaceutically acceptable non-toxic bases when the pharmaceutically active compound of the present invention is acidic. Pharmaceutically acceptable organic and inorganic acid salts include, salts formed with acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethane-sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, etc. Salts may be prepared from pharmaceutically acceptable non-toxic bases. Pharmaceutically acceptable non-toxic basic salts include, salts derived from all stable forms of inorganic bases include aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, etc., and salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, tertiary amines, and substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins such as arginine, betaine, caffeine, choline, N,N dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methyl-glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc.

[0029] The term SARPO represents one or more compounds selected from the group consisting of: or pharmaceutically acceptable salts, N-oxides thereof, or a combination thereof.

[0030] The term SARPODEX ™< represents a combination of DEX and SARPO, as defined above.

[0031] The term SARPODEXTER ™< represents an ester of SGL and DO.

[0032] The term SARPODEXAMIDE ™< represents an amide of SGL and MEM.DETAILED DESCRIPTION OF THE INVENTION

[0033] An embodiment of the invention is a pharmaceutical composition for use in the symptomatic and disease-modifying treatment wherein the disease or disorder is as defined in claim 1. In the following, for simplicity, the pharmaceutical composition will be described as comprisingSARPO and DEX with the definitions of these terms as noted above.

[0034] An embodiment of the invention is a composition comprising SARPO and DEX-H 3 , DEX-D 3 , DO, or DO-D 3 .

[0035] An embodiment of the invention is a composition comprising SARPO and dextromethorphan.

[0036] An embodiment of the invention is a composition comprising: M1, M1-E1, M1-E2, SGL, SGL-E1, or SGL-E2; and DEX-H3, DEX-D3, DO, or DO-D3.

[0037] In the above embodiment of the invention, SARPO is M1, M1-E1, M1-E2, SGL, SGL-E1, or SGL-E2.

[0038] An embodiment of the invention is a composition comprising SARPO, wherein the compound is sarpogrelate, and dextromethorphan; or enantiomers thereof, pharmaceutically acceptable salts, N-oxides thereof, or a combination thereof.

[0039] An embodiment of the invention is a composition comprising SARPO, wherein the compound is sarpogrelate, and dextromethorphan, wherein sarpogrelate and dextromethorphan form diastereomeric mixture.

[0040] An embodiment of the invention is a composition comprising SARPO, wherein the compound is sarpogrelate, and dextromethorphan, wherein sarpogrelate and dextromethorphan form a salt, wherein the salt is a diastereomeric mixture.

[0041] An embodiment of the invention is a composition comprising SARPO, wherein the compound is sarpogrelate, and dextromethorphan, wherein sarpogrelate and dextromethorphan form a salt, wherein the salt is a pure diastereomer; or pharmaceutically acceptable salts, N-oxides thereof, or a combination thereof.

[0042] An embodiment of the invention is a composition comprising SARPO, wherein the compound is sarpogrelate metabolite M1, and dextromethorphan; or enantiomers thereof, pharmaceutically acceptable salts, N-oxides thereof, or a combination thereof.

[0043] DEX is an agonist of the σ2 receptor, an N-methyl-D-aspartate (NMDA) antagonist, and an α3β4 nicotinic receptor antagonist. Uptake of norepinephrine and serotonin are also inhibited. Several neuropsychiatric diseases and syndromes such as Alzheimer's disease and behavioral and psychological symptoms of dementia involve dis-regulation of glutamatergic, cholinergic, serotoninergic and norepinephrinergic neurotransmitter systems.

[0044] In another embodiment, the pharmaceutical composition comprises SARPODEX ™< .METHODS OF USE

[0045] Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, represent a heterogeneous group of non-cognitive symptoms and behaviors occurring in subjects with dementia. BPSD constitute a major component of the dementia syndrome irrespective of its subtype. They are as clinically relevant as cognitive symptoms as they strongly correlate with the degree of functional and cognitive impairment. BPSD include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite changes. It is estimated that BPSD affect up to 90% of all dementia subjects over the course of their illness, and is independently associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization, misuse of medication, and increased health care costs. Although these symptoms can be present individually it is more common that various psychopathological features co-occur simultaneously in the same patient. Thus, categorization of BPSD in clusters taking into account their natural course, prognosis, and treatment response may be useful in the clinical practice.

[0046] Nonpharmacological interventions are recommended as first-line therapy, but many patients fail to respond, and pharmacotherapy is often needed. Currently marketed dementia therapies leave much room for improvement when it comes to treat BPSD but also other non-cognitive areas of concern. In the continued absence of a disease-modifying therapy, this is of increasing importance, as symptoms like hostility, aggression, wandering, sexually inappropriate behavior or incontinence pose major problems for caregivers and families, and often are a predictor for (costly) nursing home placement. It is common practice to prescribe ("typical or atypical") neuroleptics to facilitate nursing and caregiving. In all dementias, lowering the seizure threshold is another infrequent but highly unwanted potential adverse effect of neuroleptics. Links between a chronic diabetic metabolic situation and the risk and emergence of AD pathophysiology have been substantiated (Goldwaser et al., Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link between Diabetes Mellitus and Alzheimer's Disease. J Alzheimers Dis 54(2):445-56 (2016 Aug 1)).

[0047] In several large post-mortem series, more than a third of all subjects clinically diagnosed with typical AD showed evidence of cerebrovascular disease (Grandal Leiros et al., Prevalence and concordance between the clinical and the post-mortem diagnosis of dementia in a psychogeriatric clinic, Neurologia S0213-4853(16)30070-6 (2016). From a clinical perspective, it is therefore desirable to address the cognitive impairment by optimizing a latent diabetic metabolic situation or the fairly frequent Type 2 diabetes in the elderly subjects, because glycemic control impacts the severity of cognitive impairment (Zilliox et al., Diabetes and Cognitive Impairment. Curr Diab Rep 16 (9):87 (2016)). Due to the specific anti-diabetic actions of sarpogrelate, an embodiment of the invention is a method of treatment of cognitive symptoms and disease progression in AD, behavioral and psychological symptoms of AD, and cognitive and non-cognitive impairment of mainly vascular origin (multi-infarct dementia, vascular dementia, vascular cognitive impairment) comprising administering a composition comprising one or more agents of the invention to a patient in need thereof.

[0048] The global cost of mental health conditions alone was estimated at US$ 2.5 trillion in 2010, with a projected increase to over US $6 trillion in 2030. In Europe, the cost of all brain disorders was estimated at €798 billion in 2010. In America, neurological illnesses and mental disorders cost the US more than $760 billion a year (Global Burden of Neurological and Mental Disorders, 10 November 2014; World Health Organization: Neurological Disorders: Public Health Challenges. (2006) Institute for Health Metrics and Evaluation; World Health Organization: The global burden of disease: 2004 update (2004); World Economic Forum. The Global Economic Burden of Non-communicable Diseases (2011); Olesen et al., The economic cost of brain disorders in Europe. European Journal of Neurology. 19: 155-162 (2012); Brain Facts: A Primer on the Brain and Nervous System. Society for Neuroscience (2012); The Numbers Count: Mental Disorders in America. National Institute of Mental Health (2010)). Glioblastoma multiforme is the most common malignant primary brain tumor in adults, with an estimated incidence of 4.43 per 100,000 person-years in the United States and a median age at presentation of 64 years. Symptoms often include headaches; nausea and vomiting; and progressive memory, personality, or neurologic deficits. The treatment remains a challenge, and despite the approval of multiple new therapies in the past decade, survival has not improved. The total expenditures in this patient population were estimated at $6364 per month (GBD 2010 Results by Cause 1990-2010; The Global Burden of Disease: Generating Evidence, Guiding Policy, 2013 Institute for Health Metrics and Evaluation).

[0049] Dextromethorphan binds with high affinity to sites associated with sigma ligands and low affinity to the phencyclidine (PCP) channel of the N-methyl-D-aspartate (NMDA) receptor, forming pentametric or tetrametric complexes of the NR1 subunit and one or more of four NR2 subunits (NR2A-2D). After oral administration, dextromethorphan is quickly absorbed in the gastrointestinal tract with peak serum levels reached within 2-2.5 h. Dextromethorphan is absorbed from the bloodstream and crosses the blood-brain into the cerebral spinal fluid by approximately 33-80 % (Hollander et al., High-dose dextromethorphan in amyotrophic lateral sclerosis: phase I safety and pharmacokinetic studies. Ann Neurol 36(6):920-4 (1994)). The activity of dextromethorphan lasts for approximately 5-6 hours with a plasma half-live of 2-4 hours (Pender, et al., Toxicity with dextromethorphan-containing preparations: a literature review and report of two additional cases. Pediatr Emerg Care 7(3):163-5 (1991)). Accordingly, an embodiment of the invention is a pharmaceutical composition as described above for use in the treatment of a patient in need thereof, wherein the use involves administering a composition comprising one or more agents of the invention having high affinity to sites associated with sigma ligands and low affinity to the phencyclidine (PCP) channel of the N-methyl-D-aspartate (NMDA) receptor for the treatment of behavioral and psychological symptoms of dementia, wherein the patient has behavioral and psychological symptoms of dementia, and wherein the agent is DEX.

[0050] Cytochrome P450 in the 2D6 isoenzyme family inactivates dextromethorphan. Dextromethorphan is eliminated renally unchanged or as a demethylated metabolite. Approximately 5-10 % of people of white European ethnicity lack CYP2D6, which is necessary to demethylate dextromethorphan to dextrorphan. This can lead to acute toxic levels of dextromethorphan when 'megadoses' (5-10 times the recommended doses) are given (Motassim et al., Direct determination of dextromethorphan and its three metabolites in urine by high-performance liquid chromatography using a precolumn switching system for sample clean-up, J Chromatogr 422:340-5 (1987)). Dextrorphan, the main metabolite, is pharmacologically active with a half-life of approximately 3.5 to 6 h and is a potent NMDA antagonist (Church et al., Dextromethorphan and phencyclidine receptor ligands: differential effects on K(+)- and NMDA-evoked increases in cytosolic free Ca2+ concentration. Neurosci Lett 124(2):232-4 (1991)). Dextromethorphan is rapidly metabolized by the liver and is O-demethylated to produce its active metabolite dextrorphan, and then further N-demethylated and partially conjugated with glucuronic acid and sulfate ions (Woodworth et al., The polymorphic metabolism of dextromethorphan. J Clin Pharmacol 27(2):139-43 (1987)). Dextromethorphan is an NR1 / NR2A-containing NMDA receptor-preferred antagonist (Avenet et al., Antagonist properties of eliprodil and other NMDA receptor antagonists at rat NR1A / NR2A and NR1A / NR2B receptors expressed in Xenopus oocytes. Neurosci Lett 223(2):133-6 (1997)), while its active metabolite dextrorphan is not and binds with low affinity to sites associated with sigma ligands and high affinity to the PCP-site (Taylor et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan / quinidine (Nuedexta®) clinical use. Pharmacol Ther. 164:170-82 (2016 August)). Accordingly, an embodiment of the invention is a pharmaceutical composition as described above for use in the treatment of a patient in need thereof, wherein the use involves administering a composition comprising one or more agents of the invention having high affinity to sites associated with sigma ligands and low affinity to the phencyclidine (PCP) channel of the N-methyl-D-aspartate (NMDA) receptor for the treatment of behavioral and psychological symptoms of dementia, wherein the patient has behavioral and psychological symptoms of dementia, and wherein the composition comprises DEX effective in the treatment of behavioral and psychological symptoms of dementia, and an inhibitor of CYP2D6 to prevent rapid metabolism of DEX.

[0051] Another embodiment is a pharmaceutical composition as described above for use in treating behavioral and psychological symptoms of dementia in a patient in need thereof, wherein the use involves the step of administering a pharmaceutical composition comprising DEX and a dual acting agent capable of inhibiting CYP 2D6 and acting as a 5-HT2A receptor antagonist.

[0052] The inventive composition can be used to treat of a patient in need thereof by administering the pharmaceutical composition comprising DEX and the dual acting agent capable of inhibiting CYP 2D6 and acting as a 5-HT2A receptor antagonist.

[0053] Dextrorphan (DO) is a substance most notable for its psychoactive effects that likely arise from blockade of NMDA receptors. DO has a substantially higher affinity for NMDA receptors compared to that of DEX. Adverse psychoactive effects of DEX have been associated with its metabolism to DO (Taylor, et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan / quinidine (Nuedexta®) clinical use. Pharmacol Ther. 164:170-82 (2016 August)). Accordingly, a method of reducing adverse effects of DEX comprises co-administration of a CYP2D6 inhibitor. A nother method of reducing adverse effects of DEX comprises co-administration of 5-HT2A receptor antagonist or inverse agonist..

[0054] Psychological symptoms of dementia involve disregulation of glutamatergic, cholinergic, serotoninergic and norepinephrinergic neurotransmitter systems. Therefore, an embodiment is a method of treating behavioral and psychological symptoms of dementia. Another embodiment is the treatment with a compound of formula I or SARPO, DEX, or SARPODEX ™< to improve EEG abnormalities, behavior, cognition, and reduce seizures, as well as improve breathing abnormalities, motor capabilities, bone density, and GI dysfunction. Another embodiment is the treatment with one or more agents of the invention, a compound of formula I or SARPO, DEX, or SARPODEX ™< in the treatment of other diseases and conditions, including involuntary emotional expression disorder (IEED) or pseudobulbar affect (PBA), neurodegenerative diseases, neuropathic pain, and brain injuries.

[0055] Dextromethorphan is metabolized into active metabolites in the liver starting with O- and N-demethylation to form primary metabolites DO and 3-methoxy-morphinan are further N- and O-demethylated, respectively, to 3-hydroxy-morphinan. A major metabolic catalyst is the cytochrome P450 enzyme 2D6 (CYP2D6), which is responsible for the O-demethylation reactions of dextromethorphan and 3-methoxymorphinan. N-demethylation of dextromethorphan and DO are catalyzed by enzymes in the related CYP3A family. Conjugates of DO and 3-hydroxymorphinan can be detected in human plasma and urine within hours of its ingestion. DO is a substance most notable for its psychoactive effects. Therefore, another embodiment is a pharmaceutical composition as described above for use in treating a patient in need thereof comprising administering dextromethorphan, DO, 3-hydroxymorphinan, or 3-methoxy-morphinan, or a combination thereof.

[0056] SGL (sarpogrelate) is a 5-HT2A receptor inverse agonist. SGL inhibits responses to 5-HT mediated by 5-HT2A receptors such as platelet aggregation, vasoconstriction and vascular smooth muscle proliferation. SGL was shown to have the same affinity as ritanserin for 5-HT2A receptors (Nishio et al., Binding affinity of sarpogrelate to 5-HT2A receptor ligand recognition sites in rat renal cortical and mesangial cells in culture. Gen Pharmacol 33: 51-57 (1999 March-April)). The blockade of 5-HT2A receptors can inhibit thrombus formation suppresses platelet aggregation and inhibits vascular smooth muscle cell proliferation (Pertz et al., In-vitro pharmacology of sarpogrelate and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery. J Pharm Pharmacol. 47(4):310-6 (1995 April)). Accordingly, an embodiment is a pharmaceutical composition as described above for use in treatment of a patient in need thereof comprising administering a composition comprising SARPO.

[0057] Both SGL and its metabolite M-1 are CYP2D6 inhibitors (Cho DY, Bae SH, Lee JK, Kim YW, Kim BT, Bae SK. Selective inhibition of cytochrome P450 2D6 by Sarpogrelate and its active metabolite, M-1, in human liver microsomes. Drug Metab Dispos. 2014 Jan;42(1):33-9). Sarpogrelate potently and selectively inhibited CYP2D6-mediated dextromethorphan O-demethylation with an IC50 (Ki) value of 3.05 µM (1.24 µM), in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its inhibitory effect with an IC50 (Ki) value of 0.201 µM (0.120 µM) was more potent than that of sarpogrelate, and was similarly potent as quinidine (Ki, 0.129 µM), a well-known typical CYP2D6 inhibitor. In addition, sarpogrelate and M-1 strongly inhibited both CYP2D6-catalyzed bufuralol 1'-hydroxylation and metoprolol α-hydroxylation activities. However, sarpogrelate and M-1 showed no apparent inhibition of the other following eight CYPs: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4 / 5.

[0058] In vitro: The main metabolite (R,S)-M-1 blocked 5-HT at 5-HT2A receptors. Reportedly, the stereochemical configuration of M1 did not play a key role at binding to the 5-HT2A receptor (Pertz et al., In-vitro pharmacology of sarpogrelate and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery. J Pharm Pharmacol. 47(4):310-6 (1995 April)).

[0059] In vivo: PAD patients were divided into two groups. One group treated with 100 mg a compound of formula I or SARPO, per os 3 times one day for 12 weeks (n = 10), while the other group who remained on conventional therapy as control group (n = 11). Forearm blood flow (FBF) and leg blood flow (LBF) responses to reactive hyperemia (RH) and sublingual administration of nitroglycerin (NTG) were measured by strain-gauge plethysmography. After twelve weeks of its administration, FBF and LBF responses during RH exhibited significant increases from 13.2 6 1.7 to 18.1 6 2.2 mL / min every 100 mL tissue (P 0.01) and from 8.2 6 0.9 to 14.2 6 2.1 mL / min every 100 mL tissue (P 0.05), respectively. Augmentation of FBF and LBF induced by a compound of formula I or SARPO, responses to RH was maintained at 24 weeks. The control group had no change observed in at each follow-up time point. The changes in FBF and LBF after sublingual NTG were similar during follow-up periods in the two groups. These findings suggest that long-term oral administration of a compound of formula I or SARPO, improves vascular function in patients with PAD (Miyazaki et al., Sarpogrelate hydrochloride, a selective 5-HT2A antagonist, improves vascular function in patients with peripheral arterial disease. J Cardiovasc Pharmacol. 49(4):221-7 (2007 April)).

[0060] Another embodiment is a composition comprising (6)-1-{2-[2-(3-methoxyphenil) ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1)), a 5-HT2A receptor inverse agonist and CYP2D6 inhibitor.

[0061] Another embodiment is a composition comprising one or more enantiomers of SGL, M1, or a combination thereof.

[0062] The genetically polymorphic cytochrome CYP2D6 has been implicated in the metabolism of many antipsychotic agents, including thioridazine, perphenazine, chlorpromazine, fluphenazine, haloperidol, zuclopenthixol, risperidone, and sertindole (Michalets, Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 18(1):84-112 (1998)). This enzyme is also important in the metabolism of other drugs that are commonly prescribed to patients with psychiatric disorders, e.g., tricyclic antidepressants (nortriptyline, desipramine, amitriptyline, imipramine, and clomipramine) and selective serotonin reuptake inhibitors, including fluoxetine and paroxetine (Taylor, Cytochromes and psychotropic drug interactions. Br J Psychiatry 168(5):529-32 (1996); Sproule et al., Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clin Pharmacokinet 33(6): 454-71 (1997)). Drugs that inhibit these enzymes would be expected to cause increases in the plasma concentration of co-administered antipsychotic drugs (Michalets, Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 18(1):84-112 (1998)). These increases may, in turn, lead to the development or aggravation of antipsychotics-induced side effects including cardiac toxicity, anticholinergic side effects, or orthostatic hypotension (Ereshefsky, Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry 57 (Suppl 11):12-25 (1996)).

[0063] A number of antipsychotic drugs inhibit CYP2D6-catalyzed DEX O-demethylation compared with other CYP isoform catalyzed reactions. Among the antipsychotic drugs tested, thioridazine and perphenazine were the most potent inhibitors and decreased the DO formation rate to 26.5 and 19.7% of control activity at 10 microM, and 11.4 and 10.7% of control activity at 25 microM, respectively. The inhibitory potency of these drugs on DEX O-demethylation was comparable to the inhibitory effect of 10 to 25 microM quinidine. The estimated mean IC50 values for thioridazine and perphenazine were 2.7 ± 0.5 and 1.5_±0.3 micro M, respectively. The IC50 of quinidine, a potent CYP2D6 inhibitor, was estimated to be 0.52 ± 0.2 microM under these conditions. The estimated IC50s of chlorpromazine, fluphenazine, and haloperidol were 9.7, 16.3, and 14.4 microM, respectively. Cisthiothixene, clozapine, and risperidone exhibited weaker inhibition than the other drugs tested, with mean IC 50 s estimated to be 136.6, 92.2, and 39.1 microM, respectively (Shin et al., Effect Of Antipsychotic Drugs on Human Liver Cytochrome P-450 (CYP) Isoforms in Vitro: Preferential Inhibition of CYP2D6, Drug Metab Dispos 27 (9): 1078-84 (1999)).

[0064] A combination of a 5HT2A receptor antagonist and a CYP2D6 inhibitor provides a therapeutic advantage of the simultaneous 5HT2A receptor antagonism and 2D6 inhibition. A combination of a 5HT2A receptor inverse agonist and a CYP2D6 inhibitor provides a therapeutic advantage of the simultaneous 5HT2A receptor inverse agonism and 2D6 inhibition. A compound of formula I or SARPO provides a unique therapeutic advantage by combining both CYP2D6 inhibition and 5HT2A receptor inverse agonism to improve the magnitude of the therapeutic response to DEX. Thus, such agents avoid potential health risks associated with the concomitant use of an anti-arrhythmic drug quinidine with DEX. Accordingly, an embodiment is a composition comprising SARPODEX ™< .

[0065] Another embodiment is a pharmaceutical composition as described above for use in treating a neurological disorder comprising administering SARPO, and DEX to a subject in need thereof, wherein SARPO and DEX are administered at least once a day for at least eight days.

[0066] Another embodiment is a pharmaceutical composition as described above for use in treating a neurological disorder comprising administering about 5 mg / day to about 600 mg / day, about 5 mg / day to about 300 mg / day, about 5 mg / day to about 400 mg / day, about 5 mg / day to about 500 mg / day, about 5 mg / day to about 600 mg / day, about 5 mg / day to about 1,000 mg / day, about 50 mg / day to about 1000 mg / day, about 100 mg / day to about 1000 mg / day, about 150 mg / day to about 1000 mg / day, about 150 mg / day to about 5000 mg / day, about 150 mg / day to about 300 mg / day, or about 150 mg / day to about 100 mg / day, or an amount as required of a compound of formula I or SARPO, and about 0.1 mg / day to about 1 mg / day, about 0.5 mg / day to about 15 mg / day, about 15 mg / day to about 60 mg / day, about 15 mg / day to about 120 mg / day, about 0.1 mg / day to about 200 mg / day, or an amount as required of DEX to a subject in need thereof.

[0067] Another embodiment is a pharmaceutical composition as described above for use in increasing DEX plasma levels in a subject in need of treatment with DEX, wherein the subject is an extensive metabolizer of DEX, comprising co-administering SARPO with DEX to the subject.

[0068] Another embodiment is a pharmaceutical composition as described above for use in inhibiting the metabolism of DEX, comprising administering SARPO to a subject, wherein the subject is an extensive metabolizer of DEX, and wherein DEX is present in the body of the subject at the same time as SARPO.

[0069] Another embodiment is a pharmaceutical composition as described above for use in increasing DEX plasma levels comprising co-administering SARPO and DEX to a subject in need of treatment with DEX, wherein SARPO is administered on the first day of at least two days of co-administration of SARPO with DEX, wherein an increase in the DEX plasma level occurs on the first day that SARPO and DEX are co-administered, as compared to the same amount of DEX administered without SARPO.

[0070] Another embodiment is a pharmaceutical composition as described above for use in increasing DEX plasma levels comprising co-administering SARPO and DEX, for at least five consecutive days, to a subject in need of treatment with DEX, wherein, on the fifth day, the DEX plasma level is higher than the DEX plasma level that would have been achieved by administering the same amount of DEX administered without SARPO for five consecutive days.

[0071] Another embodiment is a pharmaceutical composition as described above for use in increasing DEX plasma levels comprising co-administering SARPO and DEX, for at least six consecutive days, to a subject in need of treatment with DEX, wherein, on the sixth day, the DEX plasma level is higher than the DEX plasma level that would have been achieved by administering the same amount of DEX administered without SARPO for six consecutive days.

[0072] Another embodiment is a pharmaceutical composition as described above for use in reducing a trough effect of DEX comprising, co-administering SARPO with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering SARPO with DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without SARPO.

[0073] Another embodiment is a pharmaceutical composition as described above for use in reducing a trough effect of DEX comprising, co-administering SARPO with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering SARPO, with DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without SARPO.

[0074] Another embodiment is a pharmaceutical composition as described above for use in reducing a trough effect of DEX comprising, co-administering SARPO with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering SARPO with DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without SARPO.

[0075] Another embodiment is a method of symptomatic and disease-modifying treatment wherein the disease or disorder is Alzheimer's disease (AD), aggression in AD, apathy in AD, sexually inappropriate behavior in AD, Vascular Dementia (VaD), and behavioral and psychological symptoms of dementia (BPSD) of AD, wherein the behavioral and psychological symptoms of dementia comprise hallucinations, dysphoria, euphoria, disinhibition, irritability / lability, aberrant motor activity, night-time behavioral disturbances, appetite and eating abnormalities, comprising administering SARPO and DEX to a subject in need thereof, wherein SARPO and DEX are administered at least once a day for at least 8 days.

[0076] Another embodiment is a pharmaceutical composition as described above for use as described above which is provided as an oral sustained release delivery system for DEX, comprising a composition comprising SARPO, DEX, or SARPODEX ™< , and a water soluble vehicle. The oral sustained release delivery system is a drug-resin complex to prepare different drug-resin complexes to be combined in the suspension, or where one or more drugs are provided as drug-resin complexes and one or more drugs are dissolved in the liquid carrier. Another embodiment is a pharmaceutical composition for use as described above which is provided as a sustained release oral suspension comprising ion exchange resin particles coated with SARPO and suspended in a liquid carrier comprising DEX. Another embodiment is a pharmaceutical composition for use as described above which is provided as a sustained release oral suspension comprising ion exchange resin particles coated with DEX and suspended in a liquid carrier comprising SARPO (Savjani et al., Drug Solubility: Importance and Enhancement Techniques, International Scholarly Research Network ISRN Pharmaceutics Volume 2012, Article ID 195727, 10 pages; US 2,780,355 A; US 4,999,189 A; US 5,128,142 A).

[0077] Another embodiment is a pharmaceutical composition for use as described above which is provided as a controlled release formulation comprising an adsorbate of a mixture of 1 part by weight of a pharmaceutically useful active ingredient comprising SARPO and / or DEX, or SARPODEX ™< and from 0.1 to 100 parts by weight of an inactive substance adsorbed on a cross-linked polymer in a ratio of 1 part by weight of the mixture to 0.5-200 parts by weight of cross-linked polymer, said inactive substance being selected to modify the dissolution of the active drug from the cross-linked polymer in vivo, with the proviso that the active ingredient is not a dihydropyridine when the inactive substance is polyvinylpyrrolidone with an average molecular weight in the range 15,000 to 50,000 and the cross-linked polymer is cross-linked polyvinylpyrrolidone. In another embodiment, the polymer to active drug ratio is about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1. Examples of swelling agents that may be used in the present invention include cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose sodium, sodium starch glycolate, and the like. The swelling agent may be present in an amount from about 5% to about 50%, preferably from about 10% to about 30%, and more preferably from about 10% to about 20%, by weight of the total weight of the composition. The pharmaceutical composition further contains a viscolyzing agent such as xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, etc. Additionally, the pharmaceutical composition may contain a gel forming polymer such as a water soluble salt of a polyuronic acids such as mannuoronic acid, guluronic acid, alginic acid, etc., wherein the salt is formed with a metal such as sodium or potassium, or an ammonium salt thereof in an amount from about 0.1% to about 20% by weight of the total weight of the composition. In addition, the pharmaceutical composition may also contain a hydrophilic water soluble polymer such as hydroxypropyl methylcellulose, hydroxypropylcellulose, polyacrylic acid, or cross-linked polyacrylic acid (US 5,128,142 A; US 6261601 B1; US 4,777,033; US 5,651,985).

[0078] Another embodiment is a pharmaceutical composition, dosage form, or medicament for use as defined in claim 1, which comprises a therapeutically effective amount of DEX, a therapeutically effective amount of SARPO, and a pharmaceutically acceptable excipient.

[0079] In one embodiment, the treatment is with a dosage regimen comprising administration of DEX to a subject in need thereof 6 times a day (every 4 hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours) (OTC Monograph [21CFR341.74]).

[0080] Many neuropsychiatric symptoms manifest very early in neurodegenerative disease stages, and are even considered prodromal indicators or indicators for disease progression (Kazui et al., Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016); Peters et al., Neuropsychiatric Symptoms as Predictors of Progression to Severe Alzheimer's Dementia and Death: The Cache County Dementia Progression Study. Am J Psychiatry 172: 460-465 (2015)).

[0081] Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, in neurodegenerative diseases and disease states including AD have a multifactorial origin (McClam et al., Interventions for neuropsychiatric symptoms in neurocognitive impairment due to Alzheimer's disease: a review of the literature. Harv Rev Psychiatry 23: 377-393 (2015)). Therefore, a strategy aimed at simultaneously targeting multiple etiologies of a disease (hence, multiple drug targets) constitutes the best approach in the development of treatment strategies for a range of diseases including AD (Nikolic et al., Drug design for CNS diseases: polypharmacological profiling of compounds using cheminformatic, 3D-QSAR and virtual screening methodologies. Front Neurosci 10: 265 (2016)).

[0082] Individual BPSD symptoms may appear as mutually exclusive but can nevertheless share the underlying mechanisms. This shared mechanism similarity can occur at the neurochemical and / or neuroanatomical levels and serves as a basis for developing targeted, but not mechanism-specific therapies addressing more than one BPSD symptom. Shared mechanisms are illustrated by similar neurochemical organizations of the projections from cortical areas to basal ganglia to thalamus and back to the cortex. For example, the dorsolateral prefrontal cortex projects to the dorsolateral caudate, which in turn targets lateral dorsomedial parts of internal globus pallidus that sends projections to the principal part of the ventral anterior or mediodorsal thalamus, which returns projections to the cortex. In contrast, the orbitofrontal cortex projects to the ventromedial caudate that projects to medial dorsomedial parts of internal globus pallidus that sends projections to the magnocellular part of ventral anterior or mediodorsal thalamus, which returns projections to the cortex. Thus, different parts of cortex may be responsible for different functions but there are common principles according to which cortical networks operate (Aouizerate et al., Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol 72(3):195-221 (2004)). Therefore, impairments in different circuits underlie the emergence of different BPSD symptoms. Heterogeneity of the clinical presentations of neurodegenerative disorders is determined by the predominant location of the pathology (i.e. by affected networks). For example, the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex are more affected in apathetic patients, and the medial orbital frontal cortex in disinhibited patients with bvFTLD (Massimo et al., Dement Geriatr Cogn Disord 27:96-104 (2009)).

[0083] For 5-HT2A receptors that are targeted by SARPO, it is well established that serotonin via 5-HT2A receptors increases glutamatergic spontaneous excitatory postsynaptic currents in apical dendrites of layer V pyramidal cells of prefrontal cortex (Aghajanian et al., Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825:161-71 (1999)). Such excessive asynchronous transmission may be functionally expressed in a variety of forms dependent on which part of the cerebral cortex is affected - from auditory or visual hallucinations to disinhibition and apathy - but in most cases, will be sensitive to manipulations involving 5-HT2A receptors that are present across various cortical areas (van Dyck et al., PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F] altanserin. J Nucl Med 41(2):234-41 (2000)).

[0084] For glutamatergic signaling that is targeted by dextromethorphan, it is well established that it mediates thalamocortical signaling, causing the activation of corresponding areas of the cortex (Kharazia et al., Glutamate in thalamic fibers terminating in layer IV of primary sensory cortex. J Neurosci 14(10):6021-6032 (1994); Sherman SM. Thalamus plays a central role in ongoing cortical functioning. Nat Neurosci 19(4):533-41 (2016)).

[0085] Diseases like Alzheimer's disease are characterized by systematic, progressive, probably trans-synaptic spread of neurodegeneration. That does not only mean more cell loss in a certain area of the brain but also spreading of the pathology to other brain areas. As different brain areas have different functional roles, this explains why more advanced stages of the disease are accompanied by a wider spectrum of symptoms (Kazui et al., Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016)).

[0086] Behavioral and psychological symptoms of dementia, also known as neuropsychiatric symptoms, are commonly studied in the clinic using research tools such as the Neuropsychiatric Inventory (NPI; Cummings, The Neuropsychiatric Inventory: Assessing psychopathology in dementia patients. Neurology 48:S10-S16 (1997)). The NPI scale recognizes 12 sub-domains of behavioral functioning: delusions, hallucinations, agitation / aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability / lability, aberrant motor activity, night-time behavioral disturbances, and appetite and eating abnormalities.

[0087] Patients rarely display each and every of these NPI symptoms at once as there are NPI items like euphoria that are rare, even at a clinical dementia rating (CDR) score of 3. Conversely, clinical experience indicates that there is rarely a patient showing just one specific item, and none of the rest. Instead, BPSD symptoms occur in various combinations or clusters. For example, a frequent AD cluster could e.g. be aggression, agitation, wandering, repetitiveness, while a frequent Vascular Dementia cluster could e.g. be confusion and restlessness, but the frequency and severity of NPI items is subject to change, e.g. from day to day, but especially during disease progression (Kazui et al., Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016); Johnson et al., Neuropsychiatric profiles in dementia. Alzheimer Dis Assoc Disord 25(4): 326-332 (2011)). As a given patient may present such a cluster of several symptoms of clinical relevance at once, there is a high medical need in treatments that can target various clusters of symptoms or the entire range of BPSD symptoms, irrespective of any currently prevailing pathophysiological hypothesis on the disease.

[0088] The prevalence of delusions is rather low in general population, in people with normal cognitive aging (0.4-2.4%) but is increased in subjects with mild cognitive impairment (MCI; 3.1-3.4%) and markedly increased in dementia (18.0-31.0%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)). Prevalence of hallucinations is also low in the general population, in people with normal cognitive aging (0.4-0.6%) but is increased in subjects with MCI (0.6-1.3%) and dementia (10.5-16.0%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).

[0089] Both delusions and hallucinations are part or symptoms of psychosis in various neurological and psychiatric diseases and disease states. Neuroleptics have traditionally been used off-label to treat such symptoms faute-de-mieux in dementia; however, with very few exceptions both "typical" and "atypical" neuroleptics increase the incidence of CV adverse events and showed a markedly increased death rate when used off-label in dementia. Hence, the FDA issued a "black box" warning against their off-label use outside schizophrenia that leaves little therapeutic options to treat such BPSD symptoms in dementia. On this background, a completely different class, namely 5-HT2A receptor antagonists and inverse agonists demonstrated an antipsychotic-like efficacy profile in preclinical studies (Weiner et al., 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 299(1):268-76 (2001)). Several 5-HT2A receptor antagonists and inverse agonists have been in development for neuropsychiatric indications and there were reports of beneficial antipsychotic effects obtained with compounds such as eplivanserin (Meltzer et al., Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161: 975-84 (2004) entirety). 5-HT2A receptor inverse agonist pimavanserin significantly reduced psychotic symptoms, which includes hallucinations and delusions, in patients with moderate to severe Parkinson's disease (Cummings et al., Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383: 533-40 (2014)) and has been FDA approved specifically for the treatment of these symptoms in PDD. In patients with Alzheimer's disease dementia, HTR2A T102C polymorphism is a significant risk factor for psychosis with an allelic OR of 2.191 for C allele that increased to 5.143 for the homozygous CC genotype (Ramanathan et al., Serotonergic system genes in psychosis of Alzheimer dementia: meta-analysis. Am J Geriatr Psychiatry 17(10):839-46 (2009)).

[0090] Dextromethorphan is described to have NMDA receptor channel blocking properties and NMDA receptor channel blockers such as phencyclidine or ketamine are known to possess psychotomimetic rather than antipsychotic properties. There are reports of psychosis induced by dextromethorphan in humans (Miller, Dextromethorphan psychosis, dependence and physical withdrawal. Addict Biol 10(4):325-7 (2005)). These psychoactive properties of dextromethorphan may be a function of its metabolic degradation resulting in production of dextrorphan (Zawertailo et al., Effect of metabolic blockade on the psychoactive effects of dextromethorphan. Hum Psychopharmacol 25(1):71-9 (2010)). Psychoactive effects of dextromethorphan observed in some subjects do not exclude a possibility that dextromethorphan also has antipsychotic properties under certain circumstances. Indeed, dextromethorphan, but not its metabolite dextrorphan, was reported to attenuate phencyclidine-induced motor behaviors in rats (Székely et al., Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan. Pharmacol Biochem Behav 40(2):381-6 (1991); incorporated by reference in its entirety). Meta-analysis of the randomized controlled studies of another NMDA receptor channel blocker, memantine, in patients with Alzheimer's disease indicated that memantine induces significant improvement in delusions (Kishi et al., The effects of memantine on behavioral disturbances in patients with Alzheimer's disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).

[0091] Agitation and aggression are grouped together as one item on the NPI scale. Prevalence of agitation and aggression is low in general population, in people with normal cognitive aging (2.8-2.9%) but is increased in subjects with MCI (9.1-11.3%) and dementia (30.3-40%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)). So this NPI item is one the most prevalent and at the same time difficult to treat clinical BPSD symptom.

[0092] Preclinical studies indicate that blockade of 5-HT2A receptors reduces aggression in laboratory rodents (Sakaue et al., Modulation by 5-hT2A receptors of aggressive behavior in isolated mice. Jpn J Pharmacol 89(1):89-92 (2002)). Human genetics data indicate that scores on three out of four subscales of the Buss-Perry Aggression Questionnaire (Hostility, Anger and Physical Aggression) show significant association with HTR2A rs7322347 T allele (Banlaki et al., Polymorphism in the serotonin receptor 2a (HTR2A) gene as possible predisposal factor for aggressive traits. PLoS One 10(2):e0117792 (2015)). In a case-control study in Chinese subjects with AD, aggression in AD was significantly associated with 5-HT2A receptor polymorphism such as T102C (Lam et al., 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19(6):523-6 (2004)).

[0093] Various NMDA receptor channel blockers have been shown to attenuate aggressive behaviors in mice and these effects may be difficult to separate from sedative action (Belozertseva, Effects of NMDA receptor channel blockade on aggression in isolated male mice. Aggr Behav 25:381-396 (1999)). In patients with probable Alzheimer disease and clinically significant agitation, dextromethorphan-quinidine combination reduced Agitation / Aggression scores of the NPI (Cummings et al., Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA 314(12):1242-54 (2015)); this combination treatment has been approved for the treatment of agitation). A meta-analysis of randomized controlled studies of another nonselective NMDA receptor channel blocker, memantine, in patients with Alzheimer's disease indicated that also memantine induces significant improvement in agitation / aggression (Kishi et al., The effects of memantine on behavioral disturbances in patients with Alzheimer's disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).

[0094] The prevalence of dysphoria / depression is moderate in general population, in people with normal cognitive aging (7.2-11.4%) but is increased in subjects with MCI (20.1-27.0%) and it is one of the most prevalent problems in dementia (32.3-42%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).

[0095] Preclinical studies using brain stimulation reward indicated that 5-HT2A receptor antagonism may counteract dysphoria induced by conventional neuroleptics such as haloperidol (Benaliouad et al., Blockade of 5-HT2a receptors reduces haloperidol-induced attenuation of reward. Neuropsychopharmacology 32(3):551-61 (2007)). 5-HT2A receptor antagonists exert antidepressant-like effects in preclinical models sensitive to clinically used antidepressant drugs (Marek et al., The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30: 2205-2215 (2005); Patel et al., The highly selective 5-hydroxytryptamine (5-HT)2A receptor antagonist, EMD 281014, significantly increases swimming and decreases immobility in male congenital learned helpless rats in the forced swim test. Synapse 52: 73-75 (2004)).

[0096] NMDA receptor channel blockers such as dextromethorphan have been shown to possess antidepressant-like properties in preclinical models (Sakhaee et al., The role of NMDA receptor and nitric oxide / cyclic guanosine monophosphate pathway in the antidepressant-like effect of dextromethorphan in mice forced swimming test and tail suspension test. Biomed Pharmacother 85:627-634 (2017)). Of the NMDA receptor channel blockers, ketamine, is proven to have rapid and robust antidepressant activity in patients with treatment-resistant major depressive disorder (Singh et al., A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. Am J Psychiatry 173(8):816-26 (2016)). Dextromethorphan given in combination with quinidine also exerts antidepressant action in humans (Murrough et al., Dextromethorphan / quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial. J Affect Disord 218:277-283 (2017)). Dextromethorphan is not a selective NMDA receptor channel blocker and is more potent at serotonin and norephinephrine transporters as well as sigma-1 receptors that may contribute to therapeutic effects of dextromethorphan (Stahl, Mechanism of action of dextromethorphan / quinidine: comparison with ketamine. CNS Spectrums 18: 225-227 (2013)). While monoamine transporters are targeted by most currently used antidepressants, sigma-1 receptors have also been found to contribute to antidepressant-like effects of dextromethorphan in laboratory animals (Nguyen et al., Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One 9(2):e89985 (2014)).

[0097] The prevalence of apathy is low in general population, in people with normal cognitive aging (3.2-4.8%) but is increased in subjects with MCI (14.7-18.5%) and dementia (35.9-49%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)). In a case-control study in Chinese subjects with AD, apathy in AD was significantly associated with 5-HT2A receptor polymorphism such as T102C (Lam et al., 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19(6):523-6 (2004)). Apathy is a symptom frequently seen in patients with schizophrenia and belongs to the group of negative symptoms. 5-HT2A receptor antagonists reduce the severity of negative symptoms in patients with schizophrenia (Davidson et al., Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia. Am J Psychiatry DOI: 10.1176 / appi.ajp.2017.17010122 (2017); Meltzer et al., Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161(6):975-84 (2004)).

[0098] NMDA receptor channel blockers such as memantine are reported to reduce apathy in certain patients with neurodegenerative diseases (Links et al., A case of apathy due to frontotemporal dementia responsive to memantine. Neurocase 19(3):256-61 (2013)) or with the negative symptoms in schizophrenia (Paraschakis, Tackling negative symptoms of schizophrenia with memantine. Case Rep Psychiatry 2014:384783 (2014)).

[0099] The prevalence of anxiety is low in general population, in people with normal cognitive aging (5.0-5.8%) but is increased in subjects with MCI (9.9-14.1%) and dementia (21.5-39%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).

[0100] 5-HT2A receptor antagonists exert anxiolytic in various preclinical models, particularly models of conditioned fear (Adamec et al., Prophylactic and therapeutic effects of acute systemic injections of EMD 281014, a selective serotonin 2A receptor antagonist on anxiety induced by predator stress in rats. Eur J Pharmacol 504(1-2):79-96 (2004); Millan, The neurobiology and control of anxious states. Progr Neurobiol 70: 83-244 (2003)). In humans, 5-HT2A receptor blockade attenuates emotional processing in the orbitofrontal cortex involved in the evaluation of socially relevant stimuli (Hornboll et al., Acute serotonin 2A receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala. J Psychopharmacol 27(10):903-14 (2013)). 5-HT2 receptor antagonist serazepine (CGS-15040A) has shown efficacy in clinical trials in patients with generalized anxiety disorder (Katz et al., Serotonergic (5-HT2) mediation of anxiety-therapeutic effects of serazepine in generalized anxiety disorder. Biol Psychiatry 34: 41-44 (1993)).

[0101] Like other members of the NMDA receptor antagonist class (Chojnacka-Wójcik et al., Glutamate receptor ligands as anxiolytics. Curr Opin Investig Drugs 2(8):1112-9 (2001)), dextromethorphan was observed to induce anxiolytic-like effects in laboratory animals within a certain dose range (Dere et al., NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL / 6 mice. Behav Pharmacol 14(3):245-9 (2003)). Preclinical anxiolytic effects of dextromethorphan may be related not only to the inhibition of NMDA receptor function but also to interaction with the sigma-1 receptors (Kamei et al., (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated sigma 1 sites. Eur J Pharmacol 299(1-3):21-8 (1996)). In patients with AD, treatment with another nonselective NMDA receptor channel blocker, memantine, significantly decreases in the scores of NPI subscale for anxiety (Ishikawa et al., The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease. Acta Neuropsychiatr 28(3):157-64 (2016)).

[0102] The prevalence of euphoria / elation is very low in general population, and in people with normal cognitive aging (0.3-0.4%) but is increased in subjects with MCI (0.6-1.3%) and dementia (3.1-7%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)). Human PET studies have established a positive correlation of the psychostimulant drug-induced-induced changes in euphoria analog scale scores with decreases in [11C]raclopride receptor binding potential (BP) in the caudate nucleus and putamen consistent with an increase in endogenous dopamine (Drevets, Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry 49(2):81-96 (2001)). A nonselective 5-HT2A receptor agonist psilocybin significantly reduced [11C]raclopride BP in the ventral striatum that correlated with depersonalization associated with euphoria (Vollenweider et al., 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man -- a PET study with [11 C]raclopride. Neuropsychopharmacology 20(5):424-33 (1999)). Preclinical data have indicated that the majority of prefrontal cortical pyramidal neurons that project to the dorsal raphe nuclei and ventral tegmental area express 5-HT2A receptors (Vazquez-Borsetti et al., Pyramidal neurons in rat prefrontal cortex projecting to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors. Cereb Cortex 19:1678-86 (2009)). Consequently, blockade of prefrontal 5-HT2A receptors may modulate pyramidal neurons projecting to the midbrain and thereby inhibit the dopaminergic system in the midbrain (Erbdrup et al., Serotonin 2A receptor antagonists for treatment of schizophrenia. Expert Opin Investig Drugs 20(9):1211-1223 (2011)). Dopaminergic midbrain system is also under control of cholinergic projections such as those originating in habenula and activity of these projections are modulated by α3β4-containing nicotinic acetylcholine receptors (McCallum et al., α3β4 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo. Neuropharmacology 63(3):434-40 (2012)). Antagonism at α3β4-containing nicotinic acetylcholine receptors is associated with various effects ascribed to reduced dopamine tone (Maisonneuve et al., Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacol Biochem Behav 75(3):607-18 (2003)). α3β4-containing nicotinic acetylcholine receptors are one of the main targets of dextromethorphan (Taylor et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan / quinidine (Nuedexta®) clinical use. Pharmacol Ther 164:170-82 (2016)).

[0103] The prevalence of disinhibition is low in general population, in people with normal cognitive aging (0.9-1.6%) but is increased in subjects with MCI (3.1-4.7%) and dementia (12.7-17%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).

[0104] Alterations in the balance of functional activity within the 5-HT system underlie impulse control and preclinical studies suggest that the 5-HT2A receptor regulates impulsive behavior, including both inherent and induced behavioral disinhibition (Anastasio et al., Serotonin (5-hydroxytryptamine) 5-HT(2A) receptor: association with inherent and cocaine-evoked behavioral disinhibition in rats. Behav Pharmacol 22(3):248-61 (2011)).

[0105] In humans, there are significant associations found between high levels of behavioral impulsivity and certain 5-HT2A polymorphisms such as the C / C genotype of rs6313 (Jakubczyk A et al. The CC genotype in HTR2A T102C polymorphism is associated with behavioral impulsivity in alcohol-dependent patients. J Psychiatr Res 46(1):44-9 (2012) entirety). Humans with the A / A genotype of the HTR2A 1438A / G polymorphism have higher scores of maladaptive impulsivity (Tomson et al., Effect of a human serotonin 5-HT2A receptor gene polymorphism on impulsivity: Dependence on cholesterol levels. J Affect Disord 206:23-30 (2016)). From a neuroanatomical perspective, neocortex is known to be rich in 5-HT2A receptors and behavioral disinhibition in neurodegenerative diseases such as behavioral variant frontotemporal dementia is correlated with the cortical thickness of the right parahippocampal gyrus, right orbitofrontal cortex and right insula (Santillo et al., Grey and White Matter Clinico-Anatomical Correlates of Disinhibition in Neurodegenerative Disease. PLoS One 11(10):e0164122 (2016)).

[0106] Combination of dextromethorphan and quinidine has positive therapeutic effects in patients with pseudobulbar affect (PBA) (Pioro, Review of Dextromethorphan 20 mg / Quinidine 10 mg (NUEDEXTA®) for Pseudobulbar Affect. Neurol Ther 3(1):15-28 (2014)). PBA may occur in association with a variety of neurological diseases such as amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer's disease, stroke, and brain tumors. PBA is a disinhibition syndrome, in which pathways involving serotonin and glutamate are disrupted (Ahmed et al., Pseudobulbar affect: prevalence and management. Ther Clin Risk Manag 9:483-9 (2013)). Meta-analysis of the randomized controlled studies of another nonselective NMDA receptor channel blocker, memantine, in patients with Alzheimer's disease indicated that memantine induces significant improvement in disinhibition (Kishi et al., The effects of memantine on behavioral disturbances in patients with Alzheimer's disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).

[0107] The prevalence of irritability / lability is low in general population, in people with normal cognitive aging (4.6-7.6%) but is increased in subjects with MCI (14.7-19.4%) and dementia (27-36%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).

[0108] Animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-HT2A receptor in the prefrontal cortical (PFC) feedback regulatory projection onto the amygdala. As this receptor is highly expressed in the prefrontal cortex areas, it affects inhibitory control of emotion-based and emotion-controlled actions, such as various impulse-related behaviors (Aznar et al., Regulating prefrontal cortex activation: an emerging role for the 5-HT2A serotonin receptor in the modulation of emotion-based actions? Mol Neurobiol 48(3):841-53 (2013)).

[0109] Combination of dextromethorphan and quinidine has positive therapeutic effects in patients with pseudobulbar affect that is characterized by emotional lability, uncontrolled crying or laughing which may be disproportionate or inappropriate to the social context (Pioro, Review of Dextromethorphan 20 mg / Quinidine 10 mg (NUEDEXTA®) for Pseudobulbar Affect. Neurol Ther 3(1):15-28 (2014)). In patients with AD, treatment with another nonselective NMDA receptor channel blocker, memantine, significantly decreases the scores of NPI item for irritability / lability (Ishikawa et al., The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease. Acta Neuropsychiatr 28(3):157-64 (2016)). Meta-analysis of the randomized controlled studies of memantine in patients with Alzheimer's disease indicated that memantine was superior to control in irritability / lability (Kishi et al., The effects of memantine on behavioral disturbances in patients with Alzheimer's disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).

[0110] The prevalence of aberrant motor activity is low in general population, in people with normal cognitive aging (0.4-0.6%) but is increased in subjects with MCI (1.3-3.8%) and dementia (16-32%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).

[0111] Aberrant motor behavior in AD is found to be significantly associated with 5-HT2A receptor polymorphism such as T102C (Lam et al., 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19(6):523-6 (2004); Pritchard et al., Role of 5HT 2A and 5HT 2C polymorphisms in behavioural and psychological symptoms of Alzheimer's disease. Neurobiol Aging 29(3):341-7 (2008)).

[0112] Aberrant motor behavior in various neurological disease state such as Parkinson's disease are due to abnormal plasticity processes in basal ganglia that may be expressed as behavioral sensitization that is sensitive to glutamate / NMDA receptor blockade (Chase et al., Striatal glutamatergic mechanisms and extrapyramidal movement disorders. Neurotox Res 5(1-2):139-46 (2003)) and antagonism at α3β4-containing receptors (Maisonneuve et al., Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacol Biochem Behav 75(3):607-18 (2003)), two of the receptor targets of dextromethorphan (Taylor et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan / quinidine (Nuedexta®) clinical use. Pharmacol Ther 164:170-82 (2016)).

[0113] The prevalence of night-time behavioral disturbances is moderate in general population, in people with normal cognitive aging (10.9%) but is increased in subjects with MCI (13.8-18.3%) and dementia (27.4-39%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).

[0114] 5-HT2A receptors play a major role in regulation of sleep (Vanover et al., Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nat Sci Sleep 2:139-50 (2010)). In a clinical trial assessing safety and efficacy of 5-HT2A receptor inverse agonist pimavanserin in patients with moderate to severe Parkinson's disease, participants reported improvements on night-time sleep and daytime wakefulness for pimavanserin compared with placebo (Cummings et al., Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383: 533-40 (2014)). Another 5-HT2A receptor inverse agonist, eplivanserin, has demonstrated clinical efficacy in patients with insomnia (European Medicines Agency. Withdrawal Assessment Report for Sliwens (Eplivanserin), March 18, 2010, London. EMA / CHMP / 90435 / 2010).

[0115] Meta-analysis of the randomized controlled studies of another nonselective NMDA receptor channel blocker, memantine, in patients with Alzheimer's disease indicated that memantine induces significant improvement in nighttime disturbance / diurnal rhythm disturbances (Kishi et al., The effects of memantine on behavioral disturbances in patients with Alzheimer's disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017) entirety). In patients with AD, memantine was effective in reducing fragmented sleep and polysomnography revealed longer total sleep, increases in sleep efficiency and time spent in stage II, and decreases in nocturnal awakening, the periodic limb movement index, and time spent in stage I (Ishikawa et al., The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease. Acta Neuropsychiatr 28(3):157-64 (2016)).

[0116] The prevalence of appetite and eating abnormalities is low in general population, in people with normal cognitive aging (5.3%) but is increased in subjects with MCI (10.4-10.7%) and dementia (19.6-34%) (Geda et al., The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos et al., Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).

[0117] Serotonin plays a major role in emergence and maintenance of various types of eating disorders (Steiger, Eating disorders and the serotonin connection: state, trait and developmental effects. J Psychiatry Neurosci 29(1):20-9 (2004)). The gene encoding 5-HT2A receptor (HTR2A) has been implicated as a functional candidate in many neuropsychiatric phenotypes including eating disorders (Norton et al., HTR2A: association and expression studies in neuropsychiatric genetics. Ann Med 37(2):121-9 (2005)). Eating behavior and appetite are also modulated by one of the receptor targets of dextromethorphan, serotonin transporter, that is affected in patients with eating disorders (Spies et al., The serotonin transporter in psychiatric disorders: insights from PET imaging. Lancet Psychiatry 2(8):743-55 (2015)).

[0118] A dosage form or a composition may be a blend or mixture of DEX and a compound that inhibits the metabolism of DEX, such as SARPO, either alone or within a vehicle. For example, DEX and SARPO, may be dispersed within each other or dispersed together within a vehicle. A dispersion may include a mixture of solid materials wherein small individual particles are substantially one compound, but the small particles are dispersed within one another, such as might occur if two powders of two different drugs are blended with a solid vehicle material, and the blending is done in the solid form. In some embodiments, DEX and SARPO, may be substantially uniformly dispersed within a composition or dosage form. Alternatively, DEX and SARPO, may be in separate domains or phases in a composition or dosage form. For example, one drug may be in a coating, and another drug may be in a core within the coating. For example, one drug may be formulated for sustained release and another drug may be formulated for immediate release.

[0119] Some embodiments include the formulation as a tablet that SARPO, in a form that provides sustained release and DEX in a form that provides immediate release or vice versa. While there are many ways that sustained release of SARPO, may be achieved, in some embodiments, SARPO, is combined with hydroxypropyl methylcellulose. For example, particles of SARPO, hydrochloride could be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL ™< ) to form an admixture of blended powders. This could then be combined with immediate release DEX in a single tablet.

[0120] DEX and / or a 5-HT2A receptor antagonist or inverse agonist such as SARPO may be combined with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice (Troy, ed., Remington: The Science and Practice of Pharmacy, 21st Edition, 2005). The relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.

[0121] Therapeutic compounds may be administered by any means that may result in the contact of the active agent(s) with the desired site or site(s) of action in the body of a patient. The compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. For example, they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.

[0122] Therapeutic compounds may be administered to a subject in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally. Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial, including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol and rectal systemic.

[0123] The ratio of DEX to SARPO, may vary. In some embodiments, the weight ratio of DEX to a compound of formula I or SARPO, may be about 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, or between, any of these values. A ratio of 0.1 indicates that the weight of DEX is 1 / 10 that of SARPO. A ratio of 10 indicates that the weight of DEX is 10 times that of SARPO.

[0124] The amount of DEX in a therapeutic composition may vary. For example, some liquid compositions may comprise about 0.0001% (w / v) to about 50% (w / v), about 0.01% (w / v) to about 20% (w / v), about 0.01% to about 10% (w / v), about 0.001% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 0.5% (w / v), about 1% (w / v) to about 3% (w / v), about 3% (w / v) to about 5% (w / v), about 5% (w / v) to about 7% (w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v), or about 40% (w / v) to about 50% (w / v) of DEX.

[0125] Some liquid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of DEX, or any amount of DEX in a range bounded by, or between, any of these values.

[0126] Some solid compositions may comprise at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to about 90% (w / w) of DEX.

[0127] Some solid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of DEX, or any amount of DEX in a range bounded by, or between, any of these values.

[0128] The amount of SARPO, in a therapeutic composition may vary. If increasing the plasma level of DEX is desired, SARPO, should be administered in an amount that increases the plasma level of DEX. For example SARPO may be administered in an amount that results in a plasma concentration of DEX in the subject, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times, the plasma concentration of the same amount of DEX administered without SARPO.

[0129] In some embodiments, SARPO, is for use in administeration to a subject in an amount that results in a 12 hour area under the curve from the time of dosing (AUC 0-12 ), or average plasma concentration in the subject for the 12 hours following dosing (C avg ) of DEX, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of DEX administered without SARPO.

[0130] In some embodiments, SARPO, is for use in administion to a subject in an amount that results in a maximum plasma concentration (C max ) of DEX in the subject, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, or at least about 40 times the plasma concentration of the same amount of DEX administered without SARPO.

[0131] For co-administration of SARPO, an increase in the DEX plasma level can occur on the first day that SARPO, is administered, as compared to the same amount of DEX administered without SARPO. For example, the DEX plasma level on the first day that SARPO, is administered may be at least about 1.5 times, at least about at least 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times the level that would be achieved by administering the same amount of DEX without SARPO.

[0132] Therapeutic compounds may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0133] Tablets, troches, pills, capsules and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coating, for instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially nontoxic in the amounts employed.

[0134] Compositions or dosage forms may be a liquid, or may comprise a solid phase dispersed in a liquid.

[0135] Therapeutic compounds may be formulated for parenteral or intraperitoneal administration. Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. A dispersion can also have an oil dispersed within, or dispersed in, glycerol, liquid polyethylene glycols, and mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS

[0136] The present invention is based on the finding that the stability of a drug-resin complex improves significantly when the resin is treated with an inorganic alkaline material prior to use. The stability of the drug-resin complex may further be improved by impregnating the drug-resin complex prior to final formulation. The drug-resin complex may further be coated with a diffusion barrier to obtain a desirable drug dissolution profile.

[0137] In one aspect, the present invention provides a pharmaceutical composition for use according to claim 1 with an improved stability that comprises a drug-resin complex, wherein the resin used therein has been treated with an inorganic alkaline material and wherein the drug-resin complex has been impregnated with an alkalizing agent and optionally a solvating agent.

[0138] In another aspect, the present invention provides a pharmaceutical composition for use according to claim 1 with an improved stability that comprises a drug-resin complex, wherein the resin used therein has been treated with an inorganic alkaline material and wherein the drug-resin complex has been impregnated with L-methionine, an antioxidant agent, or a combination thereof. The drug stability may further be improved by adding phosphoric acid and by avoiding use of propylene glycol in the formulation.

[0139] In yet another aspect, the present invention provides a pharmaceutical composition for use according to claim 1 with an improved stability that comprises a drug-resin complex, wherein the resin used therein has been treated with an inorganic alkaline material and wherein the drug-resin complex has been coated with a diffusion barrier to modify the drug dissolution profile.

[0140] Disclosed is further a method of preparing a pharmaceutical composition with improved drug stability. The method comprises the steps of: (1) treating a resin with an inorganic alkaline material; (2) combining a drug and the treated resin to form a drug-resin complex; (3) impregnating or coating the drug-resin complex with suitable reagents to either improve the stability or modify the dissolution profile of the drug; and (4) formulating the complex from the previous step to form a pharmaceutical composition.

[0141] Any non-toxic resin may be suitable for use as long as a drug can be sufficiently bound or adsorbed into the resin. A resin is ion exchange resin. Ion-exchange resins suitable for use in the present invention are water-insoluble and comprise pharmacologically inert organic and / or inorganic matrix containing functional groups that are ionic or capable of being ionized under the appropriate conditions of pH. The organic matrix may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene), or partially synthetic (e.g. modified cellulose and dextrans). The inorganic matrix comprises silica gel modified by the addition of ionic groups. Covalently bound ionic resins may also be used. The covalently bound ionic groups may be strongly acidic (e.g., sulfonic acid, phosphoric acid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g., primary amine), weakly basic (e.g. quaternary ammonium), or a combination of acidic and basic groups (Borodkin, Book chapter: Ion-exchange resin delivery system, in "Polymers for Controlled Drug Delivery", Tarcha, P J, Ed., CRC Press, Boca Raton, 1990).

[0142] An ion exchange resin known to be useful is divinylbenzene sulfonic acid cationic exchange resin, in either sodium salt or potassium salt form. In one embodiment, Purolite C 100 E MR / 4395 is used which has a particle size less than 150 micron. Other commercially available equivalent resins that can be used are Amberlite IRP-69 and Dow XYS-40010.00. Both are sulfonated polymers composed of polystyrene cross-linked with about 8% of divinylbenzene, with an ion-exchange capacity of about 4.5 to 5.5 meq / g of dry resin (H +< form). Their essential difference is in physical form. Amberlite IRP-69 consists of irregularly shaped particles with a size range of about 5 microns to about 149 microns produced by milling the parent large size spheres of Amberlite IRP-120. The Dow XYS-40010.00 product consists of spherical particles with a size range of 45 microns to 150 microns.

[0143] The drugs that in particular are benefited from the present invention are those prone to degradation after complexation, for example, due to oxidation or hydrolysis. In some embodiments, the drug is selected from a group consisting of dextromethorphan, codeine, morphine, hydrocodone, pseudoephedrine, phenylpropanolamine and the salts thereof. In an embodiment, the drug is dextromethorphan.

[0144] The resin, before being complexed with the drug, is treated with an inorganic alkaline material in water. It is observed that a drug-resin complex which is made of the treated resin exhibits significantly improved stability compared to a drug-resin complex using an untreated resin.

[0145] The treatment can be conducted by soaking with stirring, the resin in an aqueous solution of an inorganic alkaline material for an extended time. An elevated temperature may be used to increase the effectiveness of the treatment. The concentration of the inorganic alkaline material may vary. In one embodiment, the inorganic alkaline material is 2N sodium hydroxide. The time required for the treatment also vary, depending on the amount of resins to be pretreated, the temperature, the time, the type of the inorganic alkaline material and its concentration.

[0146] The treatment can also be conducted in a chromatographic column by repeatedly running an aqueous solution of an inorganic alkaline material through the chromatographic column containing the resin to be treated.

[0147] The alkalizing material are pharmaceutically acceptable inorganic salts of alkaline metals and alkaline earth metals such as lithium salts, potassium salts, sodium salts in form of oxide, carbonate, bicarbonate, and the like. An alkalizing agent for the resin is sodium hydroxide.

[0148] All water used is distilled or purified water, free of minerals, ions, and ion exchange components may be used for the invention. In an embodiment, deionized (DI) water is used.

[0149] After the alkaline pretreatment, the treated resin is collected by filtration, optionally, the resin is washed with water numerous times. The resin is then dried at about 50 degrees C. until the water content is less than 8%, as measured by the well-known Karl-Fischer method. The dried, treated resin can then be reacted with a drug to form a drug-resin complex using standard techniques.

[0150] In one embodiment, a drug-resin complex is formed by adding an aqueous solution of a drug to a container containing the treated resin and stirring for sufficient time. The resulting drug-resin complex suspension is filtered, and optionally is washed with water numerous times, to yield the drug-resin complex. The drug-resin complex is then dried until the water content was below 8%, as measured by the Karl-Fischer method.

[0151] The amounts of drug and resin necessary to form an effective drug-resin complex vary greatly. Among the factors to be considered in determining the ratio of drug to resin are the particular drug itself, the resin, the reaction conditions, and the final dosage form. The resin has a high loading capacity for the drug in question. A small loading capacity may make the resulting dosage form overly bulky or expensive to produce. The actual loading of the drug on the resin particles can range from about 1% to 90%by weight but 5% to 30% by weight of the resin.

[0152] The stability of the drug-resin complex is also improved by impregnating the drug-resin complex with an alkalizing agent.

[0153] The alkalizing agent is present in an amount of about 5% to about 30% by weight of the resin. In one embodiment, the alkalizing agent is about 10% by weight of the resin.

[0154] Additionally, the drug-resin complex may be treated with a solvating agent to aid the impregnation of the alkalizing agent. This step can be performed simultaneously with or before the impregnation of magnesium oxide. Solvating agents include polyol, such as polyethylene glycol, glycerol, propylene glycol, polyethylene glycol (PEG), or PEG 3350. The solvating agent may be in an amount of about 5% to about 35% or about 15% by weight of the resin.

[0155] It has been observed that the alkalized drug-resin complex, i.e., the complex which has been impregnated with PEG and MgO, exhibits significantly improved stability, compared to the drug-resin complex without such impregnation.

[0156] The drug-resin complex made from a resin pre-treated with an inorganic alkaline material can further be impregnated with L-methionine. For better result, a solvating agent is added in this step. It is observed that the impregnation with L-methionine and a solvating agent improves the drug stability of the pharmaceutical composition. In one embodiment, the impregnation is conducted by adding a few drops of water to moisten the mixture of L-methionine, PEG and the alkalized drug-resin complex, thoroughly mixing the ingredients, and then drying. For better result, the L-methionine and PEG are grounded to fine powders prior to use. The L-methionine may be in an amount of about 5% to about 30%, or about 10% by weight of the resin. The PEG amount used is about 5% to about 35%, or about 15% by weight of the resin.

[0157] The drug-resin complex can be formulated into any pharmaceutical dosage forms for oral, topical, rectal, vaginal, nasal, or ophthalmic administration. Dosage forms include syrups and suspensions. Commonly known ingredients and procedures to formulate a drug-resin pharmaceutical composition are within the purview of a person skilled in the art. Various methods (US4,221,778, US4,762,709, US4,788,055, US4,959,219, US4,996,047, US5,071,646, and US5,186,930) can be used to formulate the composition.

[0158] The stability of drug-resin pharmaceutical suspensions is tested. Of the commonly known ingredients used in formulating a suspension, propylene glycol is found to destabilize the suspension, and phosphoric acid is found to stabilize the suspension.

[0159] Conventional coating procedures (US 4,221,778 A) can be used to coat the particles. In one embodiment, the coating is carried out in a fluid bed coating apparatus equipped with a Wurster Column. Samples are collected at three intervals in order to assess the coating weight gain influenced release. Following coating, the complex is well mixed with colloidal silicon dioxide at 1%, followed by curing in a forced draft oven for 48 hours at 40 °C.

[0160] The coated drug-resin complex is formulated into a desirable pharmaceutical dosage form. The pharmaceutical composition prepared in accordance with the present invention is able to maintain a sustained release profile that is comparable to a brand name product.

[0161] In one embodiment, the oral formulations and the tablet formulations are enteric coating layered formulations that comprise a separating layer to separate the acidic enteric coating material from omeprazole being an acid susceptible substance. HPC or other suitable polymers disclosed herein may be used in a layer that separates the core material from the enteric coating layer in the described formulations.SYNTHETIC METHODS

[0162] SGL hydrochloride (CAS NO.: 135159-51-2), with its systematic name of Butanedioic acid, mono(2-(dimethylamino)-1-((2-(2-(3-methoxyphenyl) ethyl) phenoxy) methyl) ethyl) ester, hydrochloride, could be produced through many synthetic methods (Chen et al., A practical synthesis of sarpogrelate hydrochloride and in vitro platelet aggregation inhibitory activities of its analogues, Chinese Chemical Letters, Volume 21, Issue 3, March 2010, Pages 287-28; J Med Chem 33(6) (1990); CN103242179 A; WO2015008973).

[0163] The reaction of 2-hydroxy-3'-methoxybibenzyl with epichlorohydrin by means of a base in a suitable solvent gives 2-(2,3-epoxypropoxy)-3'-methoxybibenzyl, which by reaction with dimethylamine in refluxing in a suitable solvent yields 2-[3-(dimethylamino)-2-hydroxypropoxy]-3'-methoxybibenzyl. Finally, this compound is treated with succinic anhydride while refluxing in a suitable solvent with an acid.

[0164] As shown in the scheme below, the reaction of 2-hydroxy-3'-methoxybibenzyl with epichlorohydrin by means of a base NaH in DMF gives 2-(2,3-epoxypropoxy)-3'-methoxybibenzyl, which by reaction with dimethylamine in refluxing THF yields 2-[3-(dimethylamino)-2-hydroxypropoxy]-3'-methoxybibenzyl. Finally, this compound is treated with succinic anhydride in refluxing THF and with HCl in acetone (J Med Chem 33(6) (1990)).

[0165] SGL hydrochloride was synthesized from salicylicaldehyde via benzyl protection, reduction, chlorination, Arbuzov reaction, Wittig-Horner reaction, catalytic hydrogenation to give 2-2-(3-methoxyphenyl)ethyl phenol, which was subjected to react with epichlorohydrin, amination, esterification and salt formation.

[0166] SGL hydrochloride drug substance used in the preparation SGL hydrochloride tablets achieve acceptable purity, single hetero content meets the corresponding requirements. SGL hydrochloride recrystallized from a suitable solvent system to obtain pure SGL salt. The solvent system comprises at one or more solvents such as acetone, acetonitrile, propionitrile, 1,4-dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, sulfolane, dimethyl sulfoxide, etc., or a mixture of more than two kinds thereof with methanol, ethanol, acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be used as the recrystallization solvent SGL hydrochloride; or C 2-10 alkanes, C 3-10 ketones, C 2-10 carboxylic acid esters, C 1-10 halogenated alkanes, aromatic hydrocarbons or aromatic derivative at room temperature to the reflux temperature, water as a recrystallization solvent or an organic solvent, an aqueous 5% or more (US 4,485,258 A; CN 101,239,920 A).

[0167] Enantiomerically pure form of SGL can be produced using chiral ligands to induce formation of a single enantiomer of choice as shown below:

[0168] Chiral organic compounds play an important role in pharmaceuticals, agrochemicals and other materials which possess useful biological activity. Enzymes and other natural binding sites recognize substrates with particular chirality to generate a variety of biological functions. These enzymes or receptor sites are specific in their action, because the enantiomers may exhibit different properties due to the chirality. Hence for biologically active compounds, it is possible that only one of the enantiomer is active and the other is devoid of activity, both enantiomers are active but they have different potencies or both the enantiomers have similar or equal activities. Therefore, the production of enantiomerically pure molecules of drugs is of interest and the methodology has three basic strategies, 1) resolution (2), use of chiral building blocks and (3) asymmetric synthesis. Asymmetric synthesis provides by far the most efficient use of one chiral material to prepare another.

[0169] The preparation of enantiomerically pure molecules of biological interest can be effectively achieved by asymmetric synthesis. This method involves the creation of one or more chiral centers from prochiral starting materials under the influence of chiral substrates. The preparation of enantiomerically pure compounds involves use of chiral auxiliaries, chiral reagents or chiral catalysts, or a combination thereof.

[0170] In another embodiment, the compounds of the disclosure can be prepared from (2R)-3-(dimethylamino)-1,2-propanediol and (2S)-3-(dimethylamino)-1,2-propanediol (Scheme VIII).

[0171] Various versatile and convenient chiral carboxylic acid ligands are available in the literature such as mandelic acid, 2-metylmandelic acid, 2-chloromandelic acid, 3-chloromandelic acid, 4-methoxymandelic acid, O-acetylmandelic acid, α-methoxyphenylacetic acid, malic acid, tartaric acid, etc. The chiral ligands can be prepared from readily available building blocks (Moloney et al., Chiral carboxylic acid ligands derived from camphoric acid, Tetrahedron: Asymmetry, Volume 7, Issue 9, September 1996, Pages 2551-2562; US7230135 B2; Product: (S)-2-Amino-1,2,3,4-tetrahydro-6-methoxy-naphthalene, Chiral Quest Corp; Ager (Ed), CHAPTER I CHIRAL HYDROXY COMPOUNDS AS LIGANDS IN ASYMMETRIC SYNTHESIS, Handbook of Chiral Chemicals, Second Edition; Hu et al., Adventure in Asymmetric Hydrogenation: Synthesis of Chiral Phosphorus Ligands and Asymmetric Hydrogenation of Heteroaromatics, Top Organomet Chem 36:313-354 (2011); Ishihara et al., An extremely simple, convenient, and selective method for acetylating primary alcohols in the presence of secondary alcohols, J. Org. Chem., 58 (15), pp 3791-3793 (1993); Edwards et al., The stereoselective replacement of hydroxyl groups by chlorine, using the mesyl chloride-N,N-dimethylformamide reagent, Carbohydrate Research, Volume 35, Issue 1, Pages 111-129 (July 1974)).

[0172] Enantiomerically pure sarpogrelate can be prepared starting from dimethylamino-propanediol by forming a phenol ether at the primary position on the selectively esterified diol with succinic acid. The sequence of the reactions can be varied by changing order. Enantiomerically pure sarpogrelate can be prepared starting from dimethylamino-propanediol by forming a phenol ether at the primary position selectively and then esterification at the secondary hydroxyl with succinic acid (Scheme X). CHIRAL SEPARATION

[0173] Chiral agents that can be used in the enantiomeric separation and diastereomeric separation of the compounds of the invention include the following:

[0174] Formation of the diastereomeric compounds and salts is carried out in a suitable reaction medium. Suitable reaction media include water, methanol, ethanol, 1-propanol, 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetic acid, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene and xylenes, and / or mixtures thereof.SARPODEXTER ™< AND SARPODEXAMIDE ™<

[0175] Linkers that can be used in the synthesis of SARPODEXAMIDE ™< derivatives in the above scheme include linkers described in the literature (Simplicio et al., Prodrugs for Amines, Molecules 13, 519-547 (2008); Mahato et al., Prodrugs for Improving Tumor Targetability and Efficiency, Adv Drug Deliv Rev. 63(8): 659-670 (2011 Jul 18); Jornada et al., The Prodrug Approach: A Successful Tool for Improving Drug Solubility, Molecules 21, 42 (2016); Jain et al., Mutual prodrugs containing bio-cleavable and drug releasable disulfide linkers, Bioorganic Chemistry 49C:40-48 (July 2013); US20130053301, WO2011089216A1; WO2006136586 A2; US7932294; US 20060046967 A1; US8357723; US8349901; US8354455; US9550734; US20160220694; US20160002167; US20150328323; US9090563; US20140058063; US20130158271; US8288557; US20110274695; WO1998043961) using known amidation and acylation techniques (Synthesis of amides, Organic Chemistry Portal, Making Amides from Acid Anhydrides, Making Amides from Carboxylic Acids, Making Amides from Acyl Chlorides, Making Amides from Nitriles - all available at Chemistry LibreTexts web site; MAKING AMIDES, available at Chemguide.co.uk; WO1998043961).

[0176] Esterification: Esters are derived from carboxylic acids. A carboxylic acid contains the -COOH group, and in an ester the hydrogen in this group is replaced by a hydrocarbon group R' such as an alkyl, cycloalkyl, an aryl, and a hetero-aryl group. Esters are produced when carboxylic acids are heated with alcohols in the presence of an acid catalyst. The catalyst is an acid, usually concentrated sulfuric acid. Dry hydrogen chloride gas can be used in some cases. TsOH (tosic acid) is also often used.

[0177] The esterification reaction is both slow and reversible. The equation for the reaction between an acid RCOOH and an alcohol R'OH (where R and R' can be the same or different) is:

[0178] The alcohol is generally used as solvent so is present in large excess (ESTERIFICATION available at websites: Chem Portal, organic chemistry org;, master organic chemistry, vigo schools, and science jrank org; WO1998043961).PREPARATION OF SARPODEXTER ™<

[0179] In another embodiment of preparation of the compositions of the application, the diastereomerically pure SARPODEXTER can be obtained by reacting the racemic sarpogrelate with optically pure dextrorphan under mild esterification conditions to obtain a mixture of diastereomeric esters, compounds 165-166, which can be separated by crystallization and chromatographic techniques mentioned above and the techniques described in this specification to obtain diastereomerically pure SARPODEXTERs 165 and 166. PREPARATION OF SARPODEXAMIDE ™< DERIVATIVES

[0180] Sarpodexamide tm< derivatives can be obtained by reacting dextromethorphan either as a single isomer or a mixture thereof with 2,2,2-trichloroethyl chloroformate in refluxing toluene thus obtaining the N-demethylated compound.

[0181] The trichloroethoxycarbonyl above can be converted to N-desmethyl dextromethorphan by heating to reflux in presence of powdered zinc in glacial acetic acid.

[0182] The N-desmethyl dextromethorphan obtained as described above or purchased (CAS Number: 125-71-3) can be treated with trifluoromethansulfonic anhydride and pyridine at room temperature (Liebigs Ann. Chem. 1986, 336, and WO1998043961).OPTICALLY PURE SARPODEXAMIDE

[0183]

[0184] As shown in Scheme XIII, amides (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl 4-((4bS,8aS,9S)-3-methoxy-6,7,8,8a,9,10-hexahydro -5H-9,4b-(epiminoethano) phenanthren-11-yl)-4-oxobutanoate (Compound 167) and (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl 4-((4bS,8aS,9S)-3-methoxy-6,7,8,8a,9,10-hexahydro -5H-9,4b-(epiminoethano)phenanthren-11-yl)-4-oxobutanoate (compound 168) can be obtained from sarpogrelate by amidation with N-desmethyl dextromethorphan using HBTU in combination with Hünig's base in 1-2 h. Reagents such as uronium salt (1-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino morpholino carbenium hexafluorophosphate (COMU), ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino) acetate (o-NosylOXY), EDCI and NaHCO 3 , B(OCH 2 CF 3 ) 3 , trimethylaluminium, Lanthanum trifluoromethanesulfonate, ZrOCl 2 • 8 H 2 O, methanesulfonyl chloride and N-methylimidazole, N,N'-carbonyldiimidazole (CDI), etc. can be used.OPTICALLY PURE SARPODEX ™< SALT

[0185]

[0186] Compound 50 and dextromethorphan form a diastereomeric salt mixture of dextromethorphan (S)-4-((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)-4-oxobutanoate (S-SARPODEX ™< ) salt and dextromethorphan (R)-4-((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)-4-oxobutanoate (R-SARPODEX ™< ) salt in chloroform or other suitable solvents such as dichloromethane, DMF, etc., which can be separated by crystallization and recrystallization in suitable solvents such DMF and / or chromatographic techniques referred to and described in this specification.

[0187] A possible process for separating the diastereomers of a compound is by using an ionic liquid to increase separation efficiency. When the diastereomers are separated, for example, by a process such as liquid-liquid extraction, one or more ionic liquids may be used as the extractant.

[0188] This separation process may be performed on a compound containing a mixture of at least one pair of diastereomers, and the diastereomers may be separated by contacting the mixture with at least one ionic liquid in which one of the diastereomers is soluble to a greater extent than the other diastereomer, and separating the lower-solubility diastereomer from the mixture. The disclosure herein thus include processes for the separation of diastereomers, the use of such processes, and the products obtained and obtainable by such processes.

[0189] This separation process may be performed on a compound such as a diastereomeric mixture of SARPODEX ™< salt wherein, the diastereomers are separated by contacting the mixture with at least one ionic liquid in which one of the diastereomers is soluble to a greater extent than the other diastereomer, and separating the lower-solubility diastereomer from the mixture.

[0190] Further provided is a process for separating the erythro or threo diastereomers of SARPODEX ™< from a mixture comprising both diastereomers by liquid-liquid extraction using at least one ionic liquid as an extractive solvent.

[0191] Further disclosed is a process for performing an industrial operation selected from the group consisting of a calibration operation, a cleaning operation, a rinsing operation, a drying operation, a particulate removal operation, a solvent operation, a dispersion operation, a heat transfer operation, and an insulating operation, comprising contacting a mixture comprising a pair of diastereomers of SARPODEX ™< with at least one ionic liquid in which one of the diastereomers is soluble to a greater extent than the other diastereomer, separating the lower-solubility diastereomer from the mixture, and employing the separated diastereomer in the operation.

[0192] Further disclosed is a process for separating one diastereomer from another diastereomer in a pair of diastereomers in a compound. In such a process, an ionic liquid is used to facilitate the separation, and the diastereomers may be separated by contacting the mixture with at least one ionic liquid in which one of the diastereomers is soluble to a greater extent than the other diastereomer, and separating the lower-solubility diastereomer from the mixture.

[0193] The term "ionic liquid" is defined as an organic salt that is fluid at or below about 100 °C.

[0194] "Liquid-liquid extraction" is a process for separating components in solution by their distribution between two immiscible liquid phases. Liquid-liquid extraction involves the transfer of mass from one liquid phase into a second immiscible liquid phase, and is carried out using an extractant or solvent.

[0195] Components in a liquid mixture can be separated by a process such as liquid-liquid extraction using a single equilibrium (or theoretical) stage, or using multiple stages. An equilibrium, or theoretical, stage is a device that allows intimate mixing of a feed with an immiscible liquid such that concentrations approach equilibrium, followed by physical separation of the two immiscible liquid phases. A single stage device can be a separatory funnel, or an agitated vessel, which allows for intimate mixing of the feed with the immiscible extractant. Following intimate mixing, one or both of the liquid phases can be recovered, for example, by decantation.

[0196] Multiple stage devices for liquid separation can be crosscurrent or countercurrent devices. In a multiple stage device, the feed enters a first equilibrium stage and is contacted with an extractant. The two liquid phases are mixed, with droplets of one phase suspended in the second phase, and then the two phases are separated, and SARPODEX ™< from the first stage is contacted with additional extractant, and the separation process is repeated. The process of (1) contacting SARPODEX ™< with extractant, (2) allowing for equilibrium concentrations to be approached, and (3) separating the liquid phases is repeated until the desired purity of the component of interest is achieved. The number of equilibrium stages will depend on the desired purity, as well as the solubility of the components in the extractant and the flow rates of the feed and extractant.

[0197] In a crosscurrent system (or device), the feed is initially contacted with extractant in a first equilibrium stage. SARPODEX ™< from this stage then cascades down through one or more additional stages. At each stage, SARPODEX ™< is contacted with fresh extractant, and further purification of the desired component in SARPODEX ™< is achieved. An example of a crosscurrent system is shown in FIG, where the threo isomer of SARPODEX ™< is purified using the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF 4 ] as the extractant.

[0198] In a countercurrent system or device, the extractant enters at the stage farthest from the feed, and the two phases are passed through and across each other, coming from the two different (e.g. opposite) directions. FIG depicts the countercurrent separation of the threo and erythro isomers of SARPODEX ™< from a feed thereof.

[0199] Equipment used for liquid-liquid extraction can be classified as "stagewise" or "continuous (differential) contact" equipment. Stagewise equipment is also referred to as "mixer-settlers". Mixing the liquids occurs by contacting the feed with the extractant, and the resultant dispersion is settled as the two phases separate. Mixing can occur with the use of baffles or impellers, and the separation process may be carried out in batch fashion or with continuous flow. Settlers can be simple gravity settlers, such as decanters, or can be cyclones or centrifuges, which enhance the rate of settling.

[0200] Continuous contact equipment is typically arranged for multistage countercurrent contact of the immiscible liquids, without repeated separation of the liquids from each other between stages. Instead, the liquids remain in continuous contact throughout their passage through the equipment. Countercurrent flow is maintained by the difference in densities of the liquids and either the force of gravity (vertical towers) or centrifugal force (centrifugal extractors). Gravity-operated extractors can be classified as spray towers, packed towers or perforated-plate (sieve-plate) towers. Gravity-operated towers also include towers with rotating stirrers and pulsed towers as is known in the art.

[0201] When the diastereomers of a compound such as SARPODEX ™< , and in particular the threo and erythro isomers of 2,3-dihydrodecafluoropentane, are separated by a process such as liquid-liquid extraction, any of the equipment described above can be used to perform the separation. In one preferred embodiment, the separation is carried out using a vertical tower with perforated plates. After separation of the phase containing the lower-solubility diastereomer from the phase containing the extractant and the higher-solubility diastereomer, the higher solubility diastereomer may be separated from the extractant by a process such as distillation.

[0202] The transfer of mass from one liquid phase into a separate immiscible phase by liquid-liquid extraction, and equipment for use therein (Robbins and Cusack, "Liquid-Liquid Extraction Operations and Equipment" in Perry's Chemical Engineers' Handbook, 7.sup.th Ed., (McGraw-Hill, 1997, Section 15)). Known liquid-liquid extraction processes that operate on principles that are the same as or similar to those applicable to the separations described herein include the recovery of acetic acid from water using ethyl ether or ethyl acetate as the extractant (Brown, Chem. Engr. Prog. (1963) 59:65), and the recovery of phenolics from water with methyl isobutyl ketone as the extractant (Scheibel, "Liquid-Liquid Extraction," Perry and Weissburg (eds), Separation and Purification, 3rd Ed. (1978) Chapter 3, John Wiley & Sons, Inc., Hoboken, NJ)).

[0203] The dielectrical constant of the solvent (if solvent is used at the resolutions) changes the formation, composition and enantiomer recognition of the crystals (Sakai et al., Tetrahedron: Asymmetry, 14, 3716 (2003)). The composition of crystalline diastereoisomers is also influenced by the pH of the reaction mixture (Fogassy et al., J. Chem. Res., S 11, 346 (1981); Fogassy et al., J. Chem. Soc. Perkin Trans. 2. (1988)). The purity (de) of the diastereoisomer can be improved using a mixture of structurally related resolving agents. It is often referred as "Dutch resolution" in the literature (Kellogg et al., Synthesis, 1626 (2003)). If the diastereoisomeric salt cannot be separated by fractionated precipitation, it is feasible to get its crystalline solvate by fractionated precipitation from a solvate forming solution (Schindler et al., Chirality, 19, 239 (2007)). When the solvent, unsuitable for separation of the diastereoisomers, contains structurally partly similar compounds to the solvate forming solution (US 214,720 A, Chem. Abs. 124, 117097 (1995); US 2,133,894 A; Chem. Abs. 139, 90595 (2001)), the separation of enantiomers became feasiable by fractionated precipitation of the diastereoisomeric salt (Pálovics et al., Separation of the Mixtures of Chiral Compounds by Crystallization, Advances in Crystallization Processes, pp 1-37 (2012)).

[0204] At the crystallization of melts of racemate forming enantiomeric mixtures the eutectic composition usually determinates the composition of the crystallized mixture and the oily residue. That eutectic composition can be known from the binary melting point phase diagram. When the initial isomeric composition (ee0) is higher than the eutectic composition, the pure optical isomer can be crystallized.

[0205] An ionic liquid, or a mixture of two or more thereof, may be used in a process hereof to separate the diastereomers of a compound. Ionic liquids are, quite simply, liquids that are comprised entirely of ions. When, for example, the diastereomers of SARPODEX ™< are separated by a process such as liquid-liquid extraction, the extractant used may be an ionic liquid or a mixture of two or more ionic liquids. Ionic liquids are organic compounds that are liquid at room temperature (approximately 25 °C). They differ from most salts in that they have very low melting points, and they generally tend to be liquid over a wide temperature range. They also generally tend to not be soluble in non-polar hydrocarbons; to be immiscible with water (depending on the anion); and to be highly ionizing (but have a low dielectric strength). Ionic liquids have essentially no vapor pressure, most are air and water stable, and they can either be neutral, acidic or basic.

[0206] A cation or anion of an ionic liquid useful herein can in principle be any cation or anion such that the cation and anion together form an organic salt that is liquid at or below about 100 °C. The properties of an ionic liquid can, however, be tailored by varying the identity of the cation and / or anion. For example, the acidity of an ionic liquid can be adjusted by varying the molar equivalents and type and combinations of Lewis acids used.

[0207] Many ionic liquids are formed by reacting a nitrogen-containing heterocyclic ring, preferably a heteroaromatic ring, with an alkylating agent (for example, an alkyl halide) to form a quaternary ammonium salt, and performing ion exchange or other suitable reactions with various Lewis acids or their conjugate bases to form the ionic liquid. Examples of suitable heteroaromatic rings include substituted pyridines, imidazole, substituted imidazole, pyrrole and substituted pyrroles. These rings can be alkylated with virtually any straight, branched or cyclic C 1-20 alkyl group, but preferably, the alkyl groups are C 1-16 groups, since groups larger than this may produce low melting solids rather than ionic liquids. Various triarylphosphines, thioethers and cyclic and non-cyclic quaternary ammonium salts may also been used for this purpose. Counter ions that may be used include chloroaluminate, tetrachloroaluminate (III), bromoaluminate, gallium chloride, tetrafluoroborate, tetrachloroborate, hexafluorophosphate, nitrate, trifluoromethane sulfonate, methylsulfonate, p-toluenesulfonate, hexafluoroantimonate, hexafluoroarsenate, tetrachloroaluminate, tetrabromoaluminate, perchlorate, hydroxide anion, copper dichloride anion, iron trichloride anion, zinc trichloride anion, as well as various lanthanum, potassium, lithium, nickel, cobalt, manganese, and other metal-containing anions.

[0208] Ionic liquids may also be synthesized by salt metathesis, by an acid-base neutralization reaction or by quaternizing a selected nitrogen-containing compound; or they may be obtained commercially from several companies such as Merck (Darmstadt, Germany) or BASF (Mount Olive, NJ).

[0209] In one embodiment, a library of ionic liquids may be prepared, for example, by preparing various alkyl derivatives of a particular cation (such as the quaternary ammonium cation), and varying the associated anions (US 20090131728 A1). In another embodiment, the diastereomers of the invention can be separated efficiently by cation exchange with mixed-mode sorbent in the solid phase extraction (SPE) procedure.

[0210] In one embodiment, diastereomers can be separated by extractive distillation, wherein an auxiliary which changes the partial pressure of the various diastereomers to be separated to a different degree allowing easier separation of the diastereomers by distillation in a good yield. Separation can be accomplished using fractionating columns, and preferably under reduced pressure of about 10 -3< bar to about 1 bar (US 4874473 A, US 20070225505 A1).

[0211] In one embodiment, reversed (RP-HPLC) and normal phase chromatographic (NP-HPLC) separations can be used to separate the diastereomers of the invention Columns that can be used in the separation of enantiomers can be Primesep C, NUCLEOSIL, cellulose based chiral HPLC columns, SHISEIDO Chiral CD-Ph, etc. (Fekete et al., Comparative Study Separation of Diastereomers by HPLC, Chromatographia, 57, No. ¾ (2003 February), US 7119211 B2).PHARMACEUTICAL FORMULATIONS

[0212] The compositions of this invention can be prepared . SARPO or SARPODEX ™< is added to, and dissolved in, a suitable solvent. The solution, thus obtained, is added to the complex magnesium aluminum silicate to form a paste-like mass. While the foregoing steps are carried out at about room temperature, elevated temperatures can be employed if desired. Subsequently, sodium chloride and sodium saccharin are added to, and uniformly distributed throughout, the paste. Edible coloring and :flavoring materials can be incorporated into the system at any stage of the ipreparative method. In another embodiment, soluble ingredients are added to the SARPO or SARPODEX ™< solution, which is prepared in the first step. The paste which is thus obtained can be incorporated readily into a conventional hard candy-forming mass, which mass, in turn, can be worked up, by conventional procedures, into attractive, pleasant-tasting lozenges each containing therapeutically effective quantities of SARPO or SARPODEX ™< uniformly distributed throughout.

[0213] Variations in the preparative methods presented here are within the scope of the present invention. For example, in producing the compositions of the invention, one can mix SARPO or SARPODEX ™< , and the complex magnesium aluminum silicate and subsequently add a suitable solvent thereto to form a paste therewith. Sodium chloride and sodium saccharin can be added to the dextromethorphan-complex magnesium aluminum silicate mixture prior to forming the mixture into a paste. In the alternative, sodium chloride and sodium saccharin can be added to the paste. Furthermore, suitable flavoring agents and coloring agents can be added either to the dry mixture or to the paste. In carrying out this invention, any medicinally acceptable organic solvent which is suitable for pharmaceutical use and in which SARPO or SARPODEX ™< is soluble can be employed. Thus, for example, organic solvents, such as propylene glycol, glycerine, 1,3-butylene glycol, benzyl alcohol, etc., can be used. In an embodiment of compositions of the invention, benzyl alcohol is employed as the solvent for the SAPRODEX ™< .

[0214] Edible coloring agents and edible flavoring agents can be used in preparing the present compositions. Flavoring agents which are suitable for use include, for example, licorice, ginger, natural fruit extracts, etc. As the coloring agent one can use any color which is suitable for use in foods and drugs. The quantity of coloring and the quantity of flavoring agents used in formulating the composition of this invention is variable.

[0215] In an embodiment, the formulation contains about 0.3 g to about 1.5 g, about 1.0 g, of thickener; about 1 g to about 10 g, about 2.5 g, of 1,2-propylen glycol as a dissolving agent; about 0.12 g to about 0.19 g, or 0.15 g, of at least one paraben preservative such as methyl paraben; about 0.05 g to about 0.2 g, or about 0.1 g, of sorbic acid; about 30 g to about 60 g, or 40 g of a sugar alcohol solution; about 0.05 to about 0.2 g, or 0.1 g of an artificial sweetener; SARPO or SARPODEX ™< -resin complex in an amount to yield a desired strength of about 2.10 g (the amount of a 1:6 complex needed to deliver equivalent to 60 mg of SARPO or SARPODEX ™< in a 20 ml adult 12 hour dose); and sufficient water to bring the volume up to 100 ml.

[0216] In another embodiment, suitable thickeners include: tragacanth; bentonite; acacia and lower alkyl ethers of cellulose (including the hydroxy and carboxy derivatives of the cellulose ethers). Exemplary paraben preservatives are C1-C4 alkyl parabens namely methyl, ethyl, propyl, and butyl parabens. In one embodiment, both methyl and propyl paraben are present in the formulation in a ratio of methyl paraben to propyl paraben of from about 2.5:1 to about 7.5:1. In another embodiment the methyl and propyl paraben ratio is 4:1.

[0217] In one embodiment, the artificial sweetener is a form of saccharin or aspartame. In one embodiment, saccharin is sacharin sodium. In other embodiments, equivalent sweetening amounts of other known sweetening agents such as the sugar alcohol sorbitol may be substituted therefor.

[0218] In another embodiment, the formulation comprises an amount of resinate sufficient to deliver, when administered at one dose every 12 hours, therapeutically effective amount of SARPO and / or DEX, or SARPODEX ™< over a period of approximately 12 hours to a patient in need of such administration.

[0219] In an embodiment, the formulation comprises an adult dose of 20 ml contains approximately 420 mg of resinate, to deliver equivalent to 60 mg of SARPOor SARPODEX ™< when the drug to resin ratio is 1:6 and 2.10 g of resinate are present per 100 ml of formulation. The dosage can be altered analogously to that known for the administration of dextromethorphan which has not been complexed with resin, i.e. the typical 15 mg-30 mg / dose of dextromethorphan hydrobromide 1 to 4 times daily, becomes S-20 ml once to twice daily.SYNTHESIS OF COMPOUNDS AND COMPOSITIONS OF THE INVENTION

[0220] All reactions were performed under an argon atmosphere with dry solvents, unless otherwise stated. Dry chloroform (CH 3 Cl), methylene chloride (CH 2 Cl 2 ), tetrahydrofuran (THF), ethyl acetate, DMF, DMSO, methanol, ethanol, and acetonitrile (CH 3 CN) were purchased or prepared. All commercially available reagents were purchased and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates (Merck TLC Silica Gel 60 F254) using UV light, PMA (an ethanolic solution of phosphomolybdic acid) or ANIS (an ethanolic solution of para-anisaldehyde) as visualizing agent. Purification of products was conducted by column chromatography through silica gel 60 (0.060-0.200 mm). NMR spectra were obtained on Bruker AVANCE III 500 MHz (Bruker Corporation, Billerica, MA, USA) using residual undeuterated solvent or TMS (tetramethylsilane) as an internal reference. High-resolution mass spectra (HR-MS) were recorded on a JEOL JMS-700 (JEOL, Tokyo, Japan) using EI (electron impact).EXAMPLE 1

[0221] Dextromethorphan has been synthesized from a benzylisoquinoline (with a planar structure) by Grewe's cyclization to give the corresponding morphinan, wherein the 1,2,3,4,5,6,7,8-octahydro-1-(4-methoxybenzyl)isoquinoline is converted into the N-formyl derivative, cyclized to the N- formyl normorphinan, and the formyl group reduced to an N-methyl group, to give 3-methoxy-17-methylmorphinan. Dextromethorphan is freely soluble in ethanol 96% and essentially insoluble in water. Dextromethorphan can be monohydrated hydrobromide salt or bound to an ion exchange resin based on polystyrene sulfonic acid. Dextrometorphan's specific rotation in water is + 27.6° (20°C, Sodium D-line).EXAMPLE 2

[0222] Equimolar sarpogrelate (429.506 g / mol) and dextromethorphan (271.40 g / mol) were mixed in a suitable solvent, agitated and let crystallize. The compound of Formula I or sarpogrelate acid anion and dextromethorphan positive cation would form hydrogen bond to form a complex and crystallize.EXAMPLE 3

[0223] To a solution of 54.28 g of dextromethorphan in one liter of chloroform is added a solution of 85.9 g of sarpogrelate in chloroform at 70° C. The salt is precipitated from the hot solution by the addition of ethyl acetate. After cooling the salt is collected, washed with ethyl acetate and dried to yield d-3-methoxy-N-methylmorphinan 4-[1-dimethylamino-3-[2-[2-(3-methoxyphenyl) ethyl]phenoxy]propan-2-yl] oxy-4-oxobutanoate salt (or SARPODEX ™< ). SARPO or SARPODEX ™< is recrystallized from aqueous dimethylformamide (DMF) to yield of 135 g of the compound of formula I or SARPODEX ™< diastereomeric mixture.EXAMPLE 4

[0224] IngredientsAmountSARPO or SARPODEX ™< 15 gGlyceryl tristearate15 gCarbon tetrachloride100 ml

[0225] Glyceryl tristearate is dissolved in the warm carbon tetrachloride at 55-60 °C. SARPO or SARPODEX ™< is then added and suspended in the solution. The suspension is then spray dried using an inlet temperature of 90° C and an outlet temperature of 40° C. The resulting coated SARPO or SARPODEX ™< having an average particle size of from about 10 to about 200 microns is then suspended in the following aqueous vehicle. Tragacanth , USP10.00 gMethylparaben , USP1.20 gPropylparaben , USP0.20 gSaccharin sodium, USP0.30 gSucaryl sodium, USP3.00 gSorbic acid250.00 mLMethyl cellulose, 15 cps1.00 gImitation black currant2.00 mLDistilled water1000.00 mL

[0226] The parabens, saccharin sodium, sucaryl sodium and sorbic acid are dissolved in a portion of the distilled water which has been heated to 85° C. The tragacanth is then added to this solution and dispersed uniformly. The dispersion is again heated, cooled and the sorbitol solution, a solution of the methyl cellulose in water and the imitation black currant are then added with mixing to form the vehicle. The coated SARPO or SARPODEX ™< is then added to the above vehicle and mixed until the particles are thoroughly wetted and uniformly dispersed.

[0227] The controlled drug-release composition of the present invention is characterized by comprising 100 parts by weight of an organic polymeric material which is soluble in an organic solvent and insoluble in water; 5 to 60 parts by weight of a lipid-soluble, low molecular weight release auxiliary agent; and 1 to 70 parts by weight of a drug.

[0228] In one embodiment, the polymeric material is biodegradable or biocompatible, or both, for example, biodegradable aliphatic polyester, or an aliphatic poly(carbonate), poly(lactic acid), lactic acid-glycolic acid copolymer, poly(caprolactone), poly(hydroxybutyric acid) and the like.

[0229] In one embodiment, the release auxiliary agent is a carboxylic acid ester, a monoester or diester of glycerin. In another embodiment, the release auxiliary agent is an ester of an organic acid selected from succinic acid, citric acid, tartaric acid, malic acid or the like, or monoacetate ester or diacetate ester of glycerin.

[0230] In one embodiment, the composition may further comprise a cell adhesion material or an endothelialization promoting agent on a surface of a medical device.

[0231] In one embodiment, in invention is a drug-releasable medical device characterized by containing the compositions of the present disclosure. The drug-releasable medical device forms a layer of the composition on the surface, and contacts with a living body, or is incorporated or indwelled in a living body. The device includes a stent, a catheter, a clip, an organ replacement medical device, a capsule sensor or an artificial organ. The stent in one embodiment is used for treating coronary artery stenosis and gradually releasing the composition from the surface. The release rate is 1 / 10 3< mu g / mm 2< / h to 1 mu g / mm 2< / h on 21 days after indwelling the stent. In addition, the stent of the present invention is characterized in that the drug to be gradually released is carried in a polymeric material coated on the surface of a metal forming the stent or in a porous stent substrate.

[0232] The polymeric material coated on the surface of the stent is amorphous. The polymeric material coated on the surface of the stent is an amorphous biodegradable polymeric material. The polymeric material is a poly(lactic acid) or a lactic acid-glycolic acid copolymer, which is biodegradable. The polymeric material further comprises a release auxiliary agent that promotes the release of a drug to be carried. The auxiliary agent that promotes the release of a drug is a tartrate ester or a malate ester, or a monoester or diester of glycerin. The surface of the metal forming the stent may be a porous body and the above-mentioned drug to be gradually released may be carried in the porous body. In one embodiment, the porous body has a pore size of 0.01 nm to 300 nm in diameter.EXAMPLE 12 OPTICALLY PURE SARPOGRELATE (+)-1-(DIMETHYLAMINO)-3-(2-(3-METHOXYPHENETHYL)PHENOXY)PROPAN-2-OL HYDROCHLORIDE

[0233] 1< HNMR, 400 MHz 1H-NMR (CDCl3, ppm) 11.84-11.52 (br s, 1H) 7.22-7.12 (m, 3H) 6.96-6.90 (m, 1H) 6.83 (d, J=8.1 Hz, 1H) 6.76-7.71 (m, 2H) 6.70-6.67 (m, 1H) 5.56-5.17 (br s, 1H) 4.62-4.45 (m, 1H) 4.14 (dd, J=9.2, 4.0 Hz, 1H) 3.89 (dd, J=9.2, 8.1 Hz, 1H) 3.77 (s, 3H) 2.31-3.12 (m, 2H) 2.97-2.76 (m, 10H); ESI-MS, m / z)330 [M+H] +< ; NMR purity (%) 96; HPLC purity (%) 99; HPLC conditions - Column: XBridge ®< C18 3.5µm, 2.1x50 mm; Mobile phase: gradient elution from 10% MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA; Flow rate: 0.5 ml / min; Detection: UV 254 nm; Sample concentration: 0.5 mg / ml; Molecular formula:C 20 H 28 ClNO 3 ; Molecular weight:365.9041; Melting point (°C):124-125; Optical rotation, [α] D :+22.2 (c 0.39, MeOH).(-)-1-(DIMETHYLAMINO)-3-(2-(3-METHOXYPHENETHYL)PHENOXY)PROPAN-2-OL HYDROCHLORIDE

[0234] 1< HNMR, 400 MHz 1H-NMR (CDCl 3 , ppm) 12.06-11.86 (br s, 1H) 7.23-7.13 (m, 3H) 6.97-6.91 (m, 1H) 6.83 (d, J=8.1 Hz, 1H) 6.76-7.71 (m, 2H) 6.70-6.67 (m, 1H) 5.42-5.08 (br s, 1H) 4.60-4.48 (m, 1H) 4.16-4.10 (m, 1H) 3.91-3.83 (m, 1H) 3.77 (s, 3H) 2.26-3.14 (m, 2H) 2.95-2.76 (m, 10H); ESI-MS, m / z 330 [M +< H] -< ; NMR purity (%) 97; HPLC purity (%) 99; HPLC conditions Column: XBridge ®< C18 3.5µm, 2.1x50 mm; Mobile phase: gradient elution from 10% MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA; Flow rate: 0.5 ml / min; Detection: UV 254 nm; Sample concentration: 0.5 mg / ml. Molecular formula: C 20 H 28 ClNO 3 ; Molecular weight: 365.9041; Melting point (°C):124-125; Optical rotation, [α] D :-20.4 (c 0.53, MeOH). SARPOGRELATE ENANTIOMERS

[0235] Succinic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure M1 (0.50 mmol, 1.0 equiv.) in CH 2 Cl 2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH 2 Cl 2 (50 mL) and sat. aq. NaHCO 3 (30 mL). The organic layer is separated, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The crude residue is purified by column chromatography (silica gel, hexanes:EtOAc) to yield racemic or optically pure sarpogrelate, respectively depending upon the M1 to yield compounds 50-52. Racemic sarpogrelate can be purified by crystallization and / or chiral chromatography to obtain optically pure.

[0236] Enantiomers of compounds described here can be separated using chromatographic techniques. The preparative separation of enantiomers by chromatography on chiral stationary phases (CSPs) has been recognized as being a useful alternative to the more conventional approaches such as enantioselective synthesis and enzymatically catalyzed transformations (Francotte, Enantioselective chromatography as a powerful alternative for the preparation of drug enantiomers, Journal of Chromatography A, Volume 906, Issues 1-2, Pages 379-397 (12 January 2001); Rajendran, et al., Simulated moving bed chromatography for the separation of enantiomers, Journal of Chromatography A, Volume 1216, Issue 4, Pages 709-738 (23 January 2009); Maier et al., Separation of enantiomers: needs, challenges, perspectives, Journal of Chromatography A, Volume 906, Issues 1-2, Pages 3-33 (12 January 2001); Miller et al., Chromatographic resolution of the enantiomers of a pharmaceutical intermediate from the milligram to the kilogram scale, Journal of Chromatography A, Volume 849, Issue 2, Pages 309-317 (23 July 1999); Andersson et al., Preparative chiral chromatographic resolution of enantiomers in drug discovery, Journal of Biochemical and Biophysical Methods, Volume 54, Issues 1-3, Pages 11-23 (31 December 2002); Pirkle et al., Chapter 6 Separation of Enantiomers by Liquid Chromatographic Methods, Asymmetric Synthesis, pp 87-124, in Volume 1: Analytical Methods covers the major analytical methods used to determine enantiomeric ratios, by Morrison (ed), Elsevier, (December 2, 2012)). Racemates of the invention can be resolved from an analytical to a preparative scale by this technique.

[0237] Simulated moving-bed chromatography can be used for the separation of the enantiomers of the compounds of the invention, feasible at all production scales, from laboratory to pilot to production plant (Juza et al., Simulated moving-bed chromatography and its application to chirotechnology, Trends in Biotechnology, Volume 18, Issue 3, Pages 108-118 (1 March 2000)).SEPARATION OF ENANTIOMERS OF SARPOGRELATE HYDROCHLORIDE ((-)-4-(1-(DIMETHYLAMINO)-3-(2-(3-ETHOXYPHENETHYL)PHENOXY)PROPAN-2-YLOXY)-4-OXOBUTANOIC ACID HYDROCHLORIDE)

[0238] Sarpogrelate hydrochloride was separated with the XBridge ®< C18 3.5µm, 2.1x50 mm column, using a mobile phase: gradient elution from 10% MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA, with a flow rate of 0.5 ml / min, at UV 254 nm, to yield 5.30 mg of enantiomer (99% HPLC purity). NMR: 400 MHz 1H-NMR (C0300, ppm) 7.20-7.14 (m, 2H) 7.11 (dd, J=7.4, 1.6 Hz, 1H) 6.94-6.87 (m, 2H) 6.79-6.71 (m, 3H) 5.70-5.62 (m, 1 H) 4.18 (dd, J=10.6, 4.1 Hz, 1 H) 4.15 (dd, J=10.6, 4.7 Hz, 1H) 3.75 (S, 3H) 3.70 (dd, J=13.8, 10.1Hz, 1H) 3.54 (dd, J=13.8, 2.3 Hz, 1H) 2.98 (s, 6H) 2.96-2.77 (m, 4H) 2.76-2.53 (m, 4H). ESI-MS, m / z): 429 [M+H]+. Melting point (°C): 155-156. Optical rotation, [α] D : -20.0 (c 0.33, MeOH).(+)-4-((1-(DIMETHYLAMINO)-3-(2-(3-METHOXYPHENETHYL)PHENOXY) PROPAN -2-YL) OXY)-4-OXOBUTANOIC ACID HYDROCHLORIDE

[0239] Molecular formula:C 24 H 32 ClNO 6 ; Molecular weight:465.9787; Melting point (°C):154-155; Optical rotation, [α] D : +20.8 (c 0.53, MeOH) ; 1HNMR, 400 MHz 1H-NMR (CD3OD, ppm) 7.20-7.14 (m, 2H) 7.11 (dd, J=7.4, 1.6 Hz, 1H) 6.93-6.87 (m, 2H) 6.78-6.71 (m, 3H) 5.70-5.62 (m, 1H) 4.18 (dd, J=10.6, 4.1 Hz, 1H) 4.15 (dd, J=10.6, 4.7 Hz, 1H) 3.75 (s, 3H) 3.70 (dd, J=13.8, 10.1 Hz, 1H) 3.54 (dd, J=13.8, 2.3 Hz, 1H) 2.98 (s, 6H) 2.96-2.77 (m, 4H) 2.76-2.54 (m, 4H); ESI-MS, m / z, 430 [M+H]+; NMR purity (%)96; HPLC purity (%) 99; HPLC conditionsColumn: XBridge ®< C18 3.5µm, 2.1x50 mm; Mobile phase: gradient elution from 10% MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA; Flow rate: 0.5 ml / min; Detection: UV 254 nm; Sample concentration: 0.5 mg / ml.(-)-4-((1-(DIMETHYLAMINO)-3-(2-(3-METHOXYPHENETHYL)PHENOXY) PROPAN-2-YL)OXY)-4-OXOBUTANOIC ACID HYDROCHLORIDE

[0240] Molecular formula:C 24 H 32 ClNO 6 ; Molecular weight:465.9787; Melting point (°C): 155-156; Optical rotation, [α] D :-18.1 (c 0.30, MeOH); NMR, 400 MHz 1H-NMR (CD3OD, ppm) 7.20-7.14 (m, 2H) 7.11 (dd, J=7.4, 1.6 Hz, 1H) 6.93-6.87 (m, 2H) 6.78-6.71 (m, 3H) 5.70-5.62 (m, 1H) 4.18 (dd, J=10.6, 4.1 Hz, 1H) 4.15 (dd, J=10.6, 4.7 Hz, 1H) 3.75 (s, 3H) 3.70 (dd, J=13.8, 10.1 Hz, 1H) 3.54 (dd, J=13.8, 2.3 Hz, 1H) 2.98 (s, 6H) 2.96-2.77 (m, 4H) 2.76-2.54 (m, 4H); ESI-MS, m / z, 430 [M+H]+; NMR purity (%)96; HPLC purity (%)99; HPLC conditions Column: XBridge ®< C18 3.5µm, 2.1x50 mm; Mobile phase: gradient elution from 10% MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA; Flow rate: 0.5 ml / min; Detection: UV 254 nm; Sample concentration: 0.5 mg / mlEXAMPLE 38

[0241]

[0242] 1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-2-hydroxy benzoate (compound 165) colorless oil; R f = 0.23 (silica gel, hexanes:EtOAc 2:1); 1< H-NMR (500 MHz, CDCl 3 ): δ = 10.69 (s, 1H), 7.83 (dd, J 1 = 1.7 Hz, J 2 = 8.0 Hz, 1H), 7.44-7.41 (m, 1H), 7.20-7.16 (m, 2H), 7.11 (dd, J 1 = 1.6 Hz, J 2 = 7.4 Hz, 1H), 6.96 (dd, J 1 = 0.9 Hz, J 2 = 8.4 Hz, 1H), 6.91-6.88 (m, 2H), 6.81-6.77 (m, 1H), 6.76-6.72 (m, 3H), 5.70-5.66 (m, 1H), 4.30-4.29 (m, 2H), 3.76 (s, 3H), 2.91-2.82 (m, 6H), 2.40 (s, 6H) ppm; 13< C-NMR (125 MHz, CDCl 3 ): δ = 169.6, 161.8, 159.7, 156.3, 144.0, 136.0, 130.5, 130.4, 130.1, 129.4, 127.4, 121.2, 120.9, 119.4, 117.8, 114.3, 112.5, 111.3, 111.2, 71.2, 67.6, 59.4, 55.2, 46.1, 36.5, 32.8 ppm; HRMS (EI): calcd for C 27 H 31 NO 5 [M +< ]: 449.2202, found 449.2200.EXAMPLE 39

[0243]

[0244] 2-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propyl2-acetoxybenzoate (Compound 166): colorless oil; R f = 0.20 (silica gel, hexanes:EtOAc 1:1); 1< H-NMR (500 MHz, CDCl 3 ): δ = 7.98 (dd, J 1 = 1.6 Hz, J 2 = 7.8 Hz, 1H), 7.55 (ddd, J 1 = 1.7 Hz, J 2 = 7.8 Hz, J 3 = 7.8 Hz, 1H), 7.28 (ddd, J 1 = 1.1 Hz, J 2 = 7.7 Hz, J 3 = 7.7 Hz, 1H), 7.21-7.17 (m, 2H), 7.13 (dd, J 1 = 1.5 Hz, J 2 = 7.4 Hz, 1H), 7.11 (dd, J 1 = 1.0 Hz, J 2 = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.81 (d, J = 7.7 Hz, 1H), 6.75-6.73 (m, 2H), 4.62-4.53 (m, 2H), 4.20-4.12 (m, 2H), 3.77 (s, 3H), 3.29-3.24 (m, 1H), 2.95-2.85 (m, 4H), 2.51 (s, 6H), 2.31 (s, 3H) ppm; 13< C-NMR (125 MHz, CDCl 3 ): δ = 169.9, 164.3, 159.7, 156.5, 150.9, 144.0, 134.1, 131.7, 130.4, 130.3, 129.4, 127.4, 126.1, 124.0, 123.2, 121.0, 120.9, 114.2, 111.4, 111.1, 65.7, 62.8, 62.0, 55.2, 42.6, 36.6, 32.6, 21.1 ppm; HRMS (EI): calcd for C 29 H 33 NO 6 [M +< ]: 491.2308, found 491.2309.EXAMPLE 40 GENERAL METHOD FOR DEUTERATION OF H-COMPOUND TO FORM D-COMPOUND

[0245] The H-compound (a compound of the invention, about 1.25 mmol) is dissolved in 3 mL of 100 mM pH=7 deuterated phosphate-buffered saline (D-PBS) diluted with 9.00 mL D 2 O to a final concentration of 25 mM. 100 mM D-PBS pH=7 (pH paper) buffer is prepared by dissolving 259.5 mg of K 3 PQ 4 in D 2 O (12.00 mL) and adding 264 µL 20% DCl in D 2 O. The reaction mixture is shaken at room temperature for 11 days while monitoring for completion of hydrogen / deuterium (HID) exchange by LC / MS.

[0246] A small scale workup is performed to prepare the hydrochloride salt of the deuterated compound. Thus a 1.2 mL aliquot of the reaction mixture (10% of total volume) is diluted with 5 mL saturated NaHCO 3 and extracted with EtOAc (3 x 5mL). The organic layer is dried over Na2S04 and filtered. Evaporation of the solvent gave 20 mg of a colorless oil which is converted to the HCl salt by addition of a few drops of 4M HCl in dioxane. The salt is triturated with ether and the solvents were evaporated to give deuterated compound HCl salt. A 9.6 mL aliquot (80% of total volume) is diluted with 40 mL saturated NaHCO 3 and extracted once with EtOAc (200 mL). The organic layer is quickly dried over Na 2 SO 4 . Evaporation of the solvent gives the compound which is stored in a freezer.EXAMPLE 41 PREPARATION OF CRUDE SARPOGRELATE HYDROCHLORIDE

[0247] 1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-2-propanol hydrochloride A 250 ml 13.7 g and water 25 ml were taken in a single-neck flask and stirred to dissolve. The solution is treated with 20% aqueous sodium hydroxide to a pH about 9 to about 14, and was extracted with 30 ml of toluene, and the organic layer was concentrated at 50 °C under reduced pressure to give a brown oil, which was dissolved in 30 mL of tetrahydrofuran. Then, butyryl anhydride 4.5 g was added and heated to reflux with stirring for about 1 to about 4 hours, and concentrated to dryness under reduced pressure at 40 °C. Ethyl acetate (25 mL) is added to dissolve the residue and saturated hydrogen chloride in ethyl acetate solution is added dropwise to adjust PH 1 or lower while stirring for about 50-60 min to obtain sarpogrelate hydrochloride crude wet product, and dried under reduced pressure (-0.08~-0.1MPa) at 45 to 55 °C to yield crude sarpogrelate hydrochloride 14.7 g, yield 86%, HPLC purity 98.6 %.EXAMPLE 42 PURIFICATION OF THE CRUDE HYDROCHLORIDE SARPOGRELATE

[0248] The crude sarpogrelate hydrochloride 5g was dissolved in butanone (20 mL), heated while stirring until dissolved, refluxed for 20~30 min, cooled to 25-35 °C, continued stirring 40~60 min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 °C and dried under reduced pressure to 24 h, to give sarpogrelate hydrochloride 4.6g, yield 92%, HPLC purity of 99.9%.EXAMPLE 43 PURIFICATION OF THE CRUDE HYDROCHLORIDE SARPOGRELATE

[0249] The crude sarpogrelate hydrochloride 5g in butanone 30ml was heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 °C, incubated with stirring 40~60 min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24 h, to give 4.55 sarpogrelate hydrochloride, yield 91 %, HPLC purity 99.7%.EXAMPLE 44 PURIFICATION OF THE CRUDE HYDROCHLORIDE SARPOGRELATE

[0250] The crude sarpogrelate hydrochloride 5 g in butanone 40ml is heated with stirring until dissolved and refluxed 20~30 min, cooling to 25~35 °C, incubated with stirring 40~60 min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white solid, 55~65 °C and dried under reduced pressure to 24 h, to give sarpogrelate hydrochloride 4.5 g, yield 90%, HPLC purity 99.8 %.EXAMPLE 45 PURIFICATION OF THE CRUDE HYDROCHLORIDE SARPOGRELATE

[0251] The crude product was sarpogrelate hydrochloride 5 g, join butanone 20 ml, heated with stirring until dissolved and refluxed 20~30 min, cooled slowly with stirring to room temperature, at -10 °C stand for crystallization, filtration, The filter cake was rinsed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55~65 °C and dried under reduced pressure to 24 h, to give the hydrochloride sarpogrelate 4.62 g, yield 92.4%, HPLC purity 99.2%, largest single matter content of 0.09%.EXAMPLE 46 1,3,4,9,10,10A-HEXAHYDRO-6-METHOXY-2H-10,4A-(IMINOETHANO) PHENANTRENE-11-CARBOXYLIC ACID 2,2,2-TRICHLOROETHYL ESTER

[0252] Dextromethorphan hydrobromide monohydrate (5.56 g, 15 mmoles) was dissolved in 60 ml of chloroform and a solution of 1.2 g sodium hydroxide in 60 mL of water. After stirring for 1 hour the organic layer was separated, dried (sodium sulfate), and evaporated in vacuum. The obtained oil was refluxed in 50 ml of toluene with 2.4 ml of 2,2,2-trichloroethyl chloroformate for 4 hours. The reaction was checked by TLC (Kieselgel 60, chloroform-methanol = 95:5, Rf = 0.7). After completion of the reaction the solvent was evaporated in vacuum. The residual oil was purified on a Kieselgel 60 (0.063-0.200) column (eluent: chloroform-methanol = 95:5), giving 6.0 g oil (13.86 mmoles, yield: 92.42 %). 1H-NMR (300 MHz, CDCl3, 30°C): δ 0.94-1.12 (m, 1H, CH); 1.16-1.72 (m, 9H, CH); 2.26-2.37 (m, 1H, CH); 2.54-2.76 (m, 2H, CH); 3.06 (dd, 1H, J=17.7 and 6.0 Hz, CH); 3.72 (s, 3H, OCH3); 3.79-3.92 (m, 1H, CH), 4.32 (dd, 1H, J=4.6 and 4.4 Hz, CH); amide rotamers: [4.65 and 4.71 (d, 1H, J=12.3 Hz, CH2) and 4.66 and 4.79 (d, 1H, J=12.0 Hz, CH2)]; 6.66 (dd, 1H, J=8.4 and 3.0 Hz, Ar); 6.77 (d, 1H, J=3.0 Hz, Ar); amide rotamers: [6.95 and 6.96 (d, 1H, J=8.4 Hz, Ar)]; GC-MS: 98.0 %; MS: EI m / e 431 (M+, 6.7%), 213 (100.0%).EXAMPLE 47 3-METHOXYMORPHINAN TETRAACETATOZINCATE

[0253] The above prepared trichloroethyl ester derivative 7 (6.0 g, 13.86 mmoles) was dissolved in 57.5 ml of acetic acid and 5.89 ml of distilled water, to which 2.9 g of powered zinc was added. After 50 minutes stirring the completeness of the reaction was checked by TLC. Further 2.9 g of zinc was added to the reaction mixture. After 1 hour stirring the reaction mixture was filtered. The obtained white powder was washed three times with ether. Yield: 10.7 g crude product; mp 161-164 °C; 1H-NMR (300 MHz, CDCl3, 30°C): δ 0.80-1.00 (m, 1H, CH); 1.08-1.42 (m, 5H, CH); 1.43-1.53 (m, 1H, CH); 1.54-1.76 (m, 2H, CH); 1.82 (s, 6H, CH3COO-), 1.80-1.89 (m, 1H, CH); 2.32-2.48 (m,2H, CH); 2.74-3.07 (m, 3H, CH); 3.39-3.46 (m, br, 1H, CH); 3.72 (s, 3H, OCH3); 3.00-5.00 (s, vbr, 3H, NH+ and H2O), 6.75-6.82 (m, 2H, Ar); 7.07 (d, 1H, J=8.4 Hz, Ar); FABMS: C+1 = 258.EXAMPLE 48 N-DESMETHYL-DEXTROMETHORPHAN

[0254] The above prepared 10.7 g of 3-methoxymorphinan tetraacetatozincate 8 was partitioned between 300 ml of chloroform and 100 ml of 1N sodium hydroxide solution in water. The organic layer was separated, dried (sodium sulfate), evaporated in vacuum to yield: 3.1 g (12.04 mmoles, yield: 86.9%); GC-MS: 99.45%; 1H-NMR (300 MHz, CDCl3, 30°C): δ 1.00-1.12 (m, 1H, CH); 1.24-1.45 (m, 5H, CH); 1.46-1.69 (m, 3H, CH); 1.70-1.80 (m, 1H, CH); 2.14 (s, br, 1H, NH); 2.26-2.35 (m,1H, CH); 2.55-2.76 (m, 3H, CH); 3.02-3.16 (m, 3H, CH); 3.79 (s, 3H, OCH3); 6.70 (dd, 1H, J=8.4 and 2.7 Hz, Ar); 6.81 (d, 1H, J=2.7 Hz, Ar); 7.03 (d, 1H, J=8.4 Hz, Ar); MS EI m / e 257 (M+, 100.0%), 228 (M-29), 214 (M-43), 212 (M-45), 171 (M-(2x43)).EXAMPLE 49 N-CD3-DEXTROMETHORPHAN

[0255] To the solution of the above prepared N-desmethyl-dextromethorphan 4 (3.1 g, 12.04 mmoles) in 265 ml of tetrahydrofuran 10.1 g of sodium hydride (60 % dispersion in mineral oil) was added. After 20 minutes stirring 1 ml (2.329 g= 16.067 mmoles) of iodomethane-d3 was dropped into the reaction mixture. The reaction was controlled by TLC. After 1 hour stirring at rt. the reaction mixture was poured into 180 ml of distilled water, which was extracted three times with 100 ml of diethyl ether. The organic layer was separated, dried (sodium sulfate), and evaporated in vacuum. The residue was crystallized in n-hexane. (Yield: 1.7 g, 6.195 mmoles, 51.5 %; mp 98-103 oC). 1H-NMR (300 MHz, DMSO, 30°C): δ 0.93-1.07 (m, 1H, CH); 1.11-1.40 (m, 5H, CH); 1.42-1.52 (m, 1H, CH); 1.53-1.66 (m, 2H, CH); 1.66-1.75 (m, 1H, CH); 1.93 (ddd,1H, J=12.3, 12.2 and 3.3 Hz, CH); 2.25-2.38 (m, 2H, CH); 2.48 (dd, 1H, J=17.7 and 5.7 Hz, CH); 2.68 (dd, 1H, J=5.7 and 3.3 Hz, CH); 2.90 (d, 1H, J=17.7 Hz, CH); 3.70 (s, 3H, OCH3); 6.65 (dd, 1H, J=8.4 and 2.7 Hz, Ar); 6.72 (d, 1H, J=2.7 Hz, Ar); 7.00 (d, 1H, J=8.4 Hz, Ar); 8.85 (s, br, 1H, -OH); FAB-MS m / z 275 (M1H+); MS EI m / z 274 (M1+,100.0%), 271 (M2+, ~2-3%).EXAMPLE 50 N-CD3-DEXTROMETHORPHAN (5) HYDROCHLORIDE SALT

[0256] N-CD3-dextromethorphan 5 (1.7 g) was dissolved in ethyl acetate-methanol mixture and was acidified with HCl in ethyl acetate to pH = 2, n-hexane was added to the solution. The obtained crystals were filtered. Yield: 1.1 g (3.54 mmoles, 57.1%); mp 121-123 oC. 1 H-NMR (see Figure 4) (300 MHz, DMSO, 30°C): sum of protonated epimers: δ 0.87-1.03 (m, 1H, CH); 1.04-1.67 (m, 7H, CH); 1.88-2.05 (m, 1H, CH); 2.12-2.27 (m, 1H, CH); 2.33-2.49 (m, 2H, CH); 2.90-3.19 (m, 3H, CH); 3.50-3.56 (m, 1H, CH); 3.73 (s, 3H, OCH3); 6.79-6.85 (m, 2H, Ar); 7.09-7.16 (m, 1H, Ar); 11.18 and 11.22 (s, 1H, NH+); MS FAB m / z 275 (M1H+,100.0%), 272 (M2H+, 2%); GC-MS: 98.8%; HPLC: 99.4% (220 nm); isotopic enrichment 97 atom % D.EXAMPLE 51 N-CD3-DEXTRORPHAN (6) HYDROCHLORIDE SALT

[0257] N-CD3-dextromethorphan 5 (1.25 g, 4.555 mmoles) was heated in 50 ml of hydrobromic acid (48%) at 110 oC for two hours. After cooling 125 ml of chloroform and 40 ml of ammonium hydroxide solution (25%) were added dropwise to the reaction mixture (pH = 9). The organic layer was separated, dried (sodium sulfate), and evaporated in vacuum. The residue was dissolved in ethanol - ethyl acetate mixture. Acidifying the solution with HCl in ethyl acetate to pH = 2, the obtained HCl salt was crystallized. Yield: 1.0 g (3.369 mmoles, 74.0 %); mp 122-127 °C; 1< H-NMR (300 MHz, DMSO, 30°C): sum of protonated epimers: δ 0.88-1.13 (m, 1H, CH); 1.10-1.67 (m, 7H, CH); 1.82-1.95 (m, 1H, CH); 2.09-2.19 (m, 1H, CH); 2.28-2.37 (m, 1H, CH); 2.40-2.49 (m, 1H, CH); 2.84-3.19 (m, 3H, CH); 3.50-3.56 (m, 1H, CH); 6.64 (dd, 1H, J=8.4 and 2.4 Hz, Ar); 6.71 (d, 1H, J=2.4 Hz, Ar); 7.00 (d, 1H, J=8.4 Hz, Ar); 9.22 (s, br, 1H, -OH); 10.69 and 10.71 (s, 1H, NH+); MS: EI m / e 260 (M1+,100.0%), 257 (M2+, ~2-3%); GC-MS: 97.3 %; HPLC: 99.5 % (220 nm); isotopic enrichment 97 atom % D.BIOLOGICAL STUDIES EXAMPLE 54 DEX METABOLISM AND CENTRAL EFFECTS OF 5HT2A RECEPTOR BLOCKADE

[0258] Antipsychotic drugs attenuate locomotor hyperactivity induced by psychostimulant and psychotomimetic drugs in laboratory rodents. While hyperactivity induced by dopaminergic agents such as d-amphetamine is reversed by both typical and atypical antipsychotics that are currently in the clinic use, 5HT2A receptor antagonists are more effective against hyperactivity induced by NMDA receptor antagonists such as phencyclidine-like channel blockers (Carlsson et al., The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice, J. Neural. Transm. 106(2):123-9 (1999)). Pimavanserin (ACP-103) is an example of a 5HT2A receptor antagonist that was administered in mice in combination with 0.3 mg / kg MK-801 (i.p.) 15 min before the test session (Vanover et al., Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N- (1-methylpiperidin-4-yl) -N'- (4-(2- methylpropyloxy) phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine (2A) receptor inverse agonist, J Pharmacol Exp Ther. 317(2):910-8 (2006 May)). Motor activity data were collected during a 15-min session in a lit room. Mice had no prior exposure to the motor cages. Immediately before placing the mice in the locomotor chambers, effects on myorelaxation / ataxia were determined by placing each of the mouse's forepaws in contact with a horizontal wire while holding the mouse by the base of the tail. Mice were required to bring at least one hindpaw in contact with the wire within 10 s to be scored as a "pass" and failure to do so was considered ataxic. Each dose or dose combination was tested in a separate group of mice. ACP-103 significantly attenuated MK-801-induced hyperactivity in mice at doses of 0.1 and 0.3 mg / kg s.c. [F(7,63)=6.010; p<0.0001], consistent with an antipsychotic-like effect.

[0259] When given in combination with quinidine in patients with neurological diseases (Schoedel et al., Evaluating the safety and efficacy of dextromethorphan / quinidine in the treatment of pseudobulbar affect. Neuropsychiatric Disease and Treatment 2014:10 1161-1174), dextromethorphan is used at the dose of 10 mg that may be administered twice a day. Currently known clinical dose of Sarpogrelate is 100 mg that is typically given three times a day (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, 13:7, 865-874). Thus, current clinical dose of Sarpogrelate significantly exceeds that of dextromethorphan. Given that the molecular weight of sarpogrelate is about 429 and molecular weight of dextromethorphan is about 271, combined use of dextromethorphan and sarpogrelate at the current clinical doses does not result in a molar ratio of 1:1. However, such molar ratio of 1:1 is a pre-requisite for preparing and using sarpogrelate salts of dextromethorphan. As the current clinical use of sarpogrelate is for peripheral (non-CNS) indications (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, 13:7, 865-874), use of sarpogrelate for CNS indications may require lower doses and therefore enable co-administration with dextromethorphan as sarpogrelate salt of dextromethorphan or as a mixture in a molar ratio of 1:1. In laboratory animals, sarpogrelate is typically given at doses of 25 mg / kg and above to induce peripheral effects (Ma et al., Effective treatment with combination of peripheral 5-hydroxytryptamine synthetic inhibitor and 5-hydroxytryptamine 2 receptor antagonist on glucocorticoid-induced whole-body insulin resistance with hyperglycemia. J Diabetes Investig 7(6):833-844 (2016)). An example of higher CNS activity of sarpogrelate is provided by an example where sarpogrelate is given to Sprague-Dawley rats at the doses of 0.3, 1 and 3 mg / kg 30 min prior to a centrally acting 5-HT2A agonist DOI (3 mg / kg; (1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)hydrochloride) and frequency of DOI-induced head shakes is reduced by co-administration of SARPO or SGL.

[0260] SARPO, SGL as well as both enantiomers of its primary metabolite M1 are 5HT2A receptor antagonists (Pertz et al., In-vitro pharmacology of a compound of formula I or SARPO, and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery, J Pharm Pharmacol. 47(4):310-6 (1995 April)). To confirm the ability of M1 S- and R-enantiomers to reach 5HT2A receptors in the CNS, rats are pretreated with 0.1 mg / kg of MK801 and attenuation of MK801-stimulated locomotor hyperactivity is monitored across a range of doses of SARPO, SGL and M1 enantiomers during 120-min test session conducted using conventional motor activity monitors.

[0261] DEX acts at a number of receptors and one of its targets is the NMDA receptor (Taylor et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan / quinidine (Nuedexta®) clinical use. Pharmacol Ther. 164:170-82 (2016 August)). However, DEX is a less potent NMDA receptor antagonist than its metabolite, DO. Accordingly, DEX is less likely to induce phencyclidine-like motor activity than DO. The behavioral effects of DEX, DO and phencyclidine (PCP) were compared in rats. DO (15-120 mg / kg) was similar to PCP (1.25-20 mg / kg) in inducing dose-dependent locomotor hyperactivity, stereotypy and ataxia. DEX (15-120 mg / kg) induced moderate hyperactivity only at the higher doses about 45 min after treatment. DEX and DO modified the locomotor facilitation induced by 10 mg / kg PCP in opposite directions. Pretreatment with DO facilitated, whereas DEX dose-dependently inhibited PCP-elicited hyperactivity (Székely et al., Induction of phencyclidine-like behavior in rats by DO but not DEX, Pharmacol Biochem Behav, 40(2):381-6 (1991 October)).EXAMPLE 55

[0262] SARPO, SGL as well as both enantiomers of its primary metabolite M1 are CYP2D6 inhibitors. DEX is a commonly used substrate in in vitro metabolism studies to reveal 2D6 inhibitory activity of biologically active substances and drugs. In a dedicated set of studies, SARPO, SGL and M1 enantiomers are administered prior to DEX and rats' locomotor activity is monitored for 120 min in order to demonstrate that a compound of formula I or SARPO, and M1 enantiomers prevent emergence of hyperactivity in DEX -treated subjects. These studies are paralleled by measurements plasma DEX levels. The combination of pharmacokinetic (plasma DEX concentration) and pharmacodynamic (MK-801- and DEX -induced hyperactivity) studies are used to identify the M1 enantiomer and the dose level(s) producing the most optimal ratio of anti-hyperactivity and DEX metabolism-suppressing effects.EXAMPLE 57 BLOOD GLUCOSE AND INSULIN SENSITIVITY

[0263] In contrast to the sulfonylurea drugs, which result in significantly higher basal insulin secretion compared to vehicle treatment, DO and DEX did not significantly alter basal insulin secretion from mouse or human islets or in vivo (Marquard et al., Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 21(4):363-72 (2015)). More specifically, application of DEX via drinking water (4 mg / ml) overnight changed neither basal plasma insulin nor fasting blood glucose concentrations in mice, but led to significantly higher glucose-induced plasma insulin concentrations and glucose tolerance than were seen in non-DEX-treated controls (glucose administered intraperitoneally at 1.5 mg / kg body weight).

[0264] Marguard et al. (2015) suggested that effects of DEX are mediated via NMDA receptor channel blocker and specifically pointed at the rapid metabolism of DEX into DO, a potent inhibitor of the NMDA receptors. To prove NMDA receptor involvement, Marguard et al. demonstrated that glucose-stimulated insulin secretion and glucose tolerance are not observed in mice genetically engineered to lack NMDA receptor function.

[0265] To test whether DEX could lead to higher serum insulin concentrations and lower blood glucose concentrations in people with type 2 diabetes mellitus (T2DM), a Phase 2a, Double-blinded, placebo-controlled, randomized, crossover, single-dose proof-of-concept study was performed (Marquard et al., Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 21(4):363-72 (2015)). Twenty males with T2DM on metformin monotherapy (age 59 (46-66) years (mean (range)); mean body mass index (BMI) 29.2 (25.2-34.1) kg m-2; glycated hemoglobin (HbAlc) 6.9 (6.5-7.4)%) were recruited. Each received a single oral dose of 60 mg DEX, 270 mg DEX, 100 mg amantadine or placebo, followed by an oral glucose tolerance test (OGTT) 1 h after drug intake on four treatment days, separated by a washout period of 7-14 days. Consistent with the results in mice, DEX led to neither higher fasting serum insulin concentrations nor lower fasting blood glucose concentrations compared to placebo and did not provoke any severe hypoglycemic events up to a dose of 270 mg. In contrast, following oral glucose intake, both 60 and 270 mg DEX dosages resulted in significantly (P < 0.05) higher maximal serum insulin concentrations compared to those seen with placebo.

[0266] In addition, the primary endpoint was reached for 270 mg DEX; that is, the area under the curve of blood glucose concentrations within the first 2 h of the OGTT (glucose AUC1-3 h) was significantly (P < 0.05) smaller in individuals who received 270 mg doses of DEX than in the same individuals receiving placebo on a different treatment day.

[0267] Blood glucose level is also under control of peripheral 5HT2A receptors (Yamada et al., Hyperglycemia induced by the 5-HT receptor agonist, 5-methoxytryptamine, in rats: involvement of the peripheral 5-HT2A receptor. Eur J Pharmacol.323(2-3):235-40 (1997)). More specifically, administration of non-selective 5HT receptor agonist such as 5-methoxytryptamine induced hyperglycemia that is prevented by pretreatment with 5-HT2A receptor antagonist ketanserin as well as peripherally acting 5-HT2 receptor antagonist, xylamidine. These results suggested that 5-methoxytryptamine-induced hyperglycemia is mediated by the peripheral 5-HT2A receptors.

[0268] Second-generation antipsychotics with dual dopamine and serotonin receptor antagonism have been associated with an increased risk for impaired glucose tolerance and diabetes mellitus. Though this has been largely attributed to weight gain, there is also a direct, receptor-mediated effect of antipsychotics on glucose tolerance. Certain 5HT2A receptor antagonists such as ketanserin impair insulin sensitivity (Gilles et al., Antagonism of the serotonin (5-HT)-2 receptor and insulin sensitivity: implications for atypical antipsychotics. Psychosom Med. 67(5):748-51 (2005))). In the study by Gilles et al., ten healthy male volunteers were included in a double-blind, placebo-controlled crossover study of a single dose of 40 mg of the 5-HT2 antagonist ketanserin versus placebo. Insulin sensitivity was measured by means of the euglycemic-hyperinsulinemic clamp technique. Subjects were treated with the alpha-1 adrenergic antagonist phenoxybenzamine in both parts of the study to control for ketanserin's effects at the level of this receptor. Compared with the placebo condition, subjects showed a significantly decreased insulin sensitivity after ketanserin (placebo: 9.4 + / - 3.6 mg / kg / min; ketanserin: 7.7 + / - 2.1 mg / kg / min; p = .047).

[0269] Thus, combining DEX and 5-HT2A receptor antagonist may lead to synergistic effects on blood glucose and insulin sensitivity that may be undesired in case of a long-term treatment as it may have unwanted metabolic side-effects qualitatively similar to those observed in patients treated with antipsychotic drugs. These effects may limit the doses of DEX and 5-HT2A receptor antagonist that can be safely administered as a combination.

[0270] There are two approaches that are part of this invention and that enable therapeutic use of combinations of DEX and 5HT2A receptor antagonists while reducing the risks of peripheral metabolic adverse effects.

[0271] One approach is based on the use of 5HT2A receptor antagonist that inhibits CYP2D6 and thereby reduces the conversion of DEX into DO. Both DEX and DO are NMDA receptor channel blockers, and NMDA receptor inhibition in pancreatic islets was suggested to be responsible for glucose-stimulated insulin secretion, and glucose intolerance enhanced by DEX and DO (Marquard et al., Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 21(4):363-72 (2015)). Since DO is more potent NMDA receptor channel blocker than DEX (Pechnick et al., Comparison of the Effects of DEX, DO, and Levorphanol on the Hypothalamo-Pituitary-Adrenal Axis, The Journal Of Pharmacology and Experimental Therapeutics, 309:515-522 (2004)), inhibition of DEX metabolism via CYP2D6 may reduce the expression of effects of DEX on glucose-stimulated insulin secretion and glucose tolerance and, therefore, risks of metabolic side-effects.

[0272] The second approach is the selection of a 5HT2A receptor antagonist that has the best ratio of central vs. peripheral 5HT2A receptor occupancy. Accordingly, a 5HT2A receptor antagonist is chosen to produce therapeutically relevant central 5HT2A receptor occupancy at the doses that are at lowest risk of producing unwanted metabolic effects such as glucose intolerance.

[0273] SARPO is a 5HT2A receptor antagonist that has 2D6 inhibitory properties. Acute and chronic effects of SARPO, on glucose tolerance and insulin resistance have been examined (Takishita et al., Effect of sarpogrelate hydrochloride, a 5-HT2 blocker, on insulin resistance in Otsuka Long-Evans Tokushima fatty rats (OLETF rats), a type 2 diabetic rat model. J Cardiovasc Pharmacol 43(2):266-70 (2004)). In these studies, Otsuka Long-Evans Tokushima Fatty rats, a model of type 2 diabetes, were randomly assigned to 2 groups; those with 30 mg / kg BW / d SARPO, treatment of 4 weeks (HTB group) and without (control group). The glucose infusion rate was significantly increased in the HTB group compared with the control group. The blood glucose levels after oral glucose tolerance test and levels of plasma insulin and lipids were significantly lower in the HTB group than in the control group. SARPO, was shown to reverse insulin resistance induced by various means including glucocorticoid drug treatment (Ma et al., Effective treatment with a combination of peripheral 5-hydroxytryptamine synthetic inhibitor and 5-hydroxytryptamine-2 receptor antagonist on glucocorticoid-induced whole-body insulin resistance with hyperglycemia. J Diabetes Investig 7: 833-844 (2016)).

[0274] Synergistic effects of SARPO on blood glucose and insulin sensitivity have been shown for several drugs including carbidopa (Ma et al., Effective treatment with a combination of peripheral 5-hydroxytryptamine synthetic inhibitor and 5-hydroxytryptamine-2 receptor antagonist on glucocorticoid-induced whole-body insulin resistance with hyperglycemia. J Diabetes Investig 7: 833-844 (2016)) and pioglitazone (Iizuka et al., Beneficial effects of a compound of sarpogrelate hydrochloride, a 5-HT2A receptor antagonist or inverse agonist, supplemented with pioglitazone on diabetic model mice. Endocr Res. 34(1-2):18-30 (2009)).

[0275] Insulin-sensitizing effects of SARPO, have also been confirmed in humans (Kokubu et al., Persistent insulin-sensitizing effects of sarpogrelate hydrochloride, a serotonin 2A receptor antagonist, in patients with peripheral arterial disease. Circ J 70(11):1451-6 (2006)). Indices of insulin resistance (fasting immunoreactive insulin) were measured before and after 2 weeks of SARPO, administration (300 mg / day) in 24 patients (19 men, 76+ / -9 years) with peripheral arterial disease. Sixteen of the 24 patients were also examined after 3 months of treatment. After 2 weeks of treatment, significant decreases in fasting immunoreactive insulin (p=0.03) were observed. After 3 months of treatment, significant decreases in fasting immunoreactive insulin (16.0+ / -10.3 vs 9.2+ / -2.0 microU / ml, p=0.03) were maintained.

[0276] SARPO, is rapidly metabolized into M1 that also has both 5HT2A receptor antagonist and 2D6 inhibitory properties. Both enantiomers of M1 are biologically active and share the ability to block 5HT2A receptors and 2D6. To establish which of the enantiomers has the most optimal properties for being combined with DEX, effects of these substances alone and in combination with DEX on oral glucose tolerance are assessed (Taniguchi et al., Diabetes, 55, 2371-2378 (2006)). This method is based on the measurement of whole blood glucose and plasma insulin. Test substances are administered to male Sprague-Dawley rats (group size: 8 per group). Animals are tested after an overnight food deprivation and individually housed. Test substance is administered 60 minutes before glucose challenge, i.e. after baseline blood glucose measurement. Animals are challenged with glucose at 2 g / kg as an oral gavage at T0, after blood glucose measurement. Blood glucose is measured from a drop of blood collected from the cut tip of the tail, using a commercially available glucose-meter at 8 time-points: baseline (before treatment), T0 (before glucose) and then 15, 30, 60, 90, 120 and 180 minutes post-glucose challenge.EXAMPLE 58 EFFECTS OF SGL / M1 ALONE ON AD PATHOPHYSIOLOGY

[0277] Links between a chronic diabetic metabolic situation and the risk and emergence of AD pathophysiology have long been suspected and substantiated in the recent years (Goldwasser et al., Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link between Diabetes Mellitus and Alzheimer's Disease. J Alzheimers Dis 54(2):445-56 (2016 Aug 1)). In several large post-mortem series, more than a third of all subjects clinically diagnosed with typical AD showed evidence of cerebrovascular disease and had to be re-classified as mixed dementia (Grandal Leiros et al., Prevalence and concordance between the clinical and the post-mortem diagnosis of dementia in a psychogeriatric clinic, Neurologia S0213-4853(16)30070-6 (2016)). From a clinical perspective, it is desirable to extend AD therapy beyond currently approved drugs and mechanisms, and also address the cognitive impairment by optimizing a latent diabetic metabolic situation or the fairly frequent Type 2 diabetes in the elderly subjects. Indeed, glycaemic control is thought to have an impact o the severity of cognitive impairment (Zilliox et al., Diabetes and Cognitive Impairment. Curr Diab Rep, 16 (9):87 (2016)).

[0278] Due to the specific anti-diabetic actions of SARPO, described above, it is, therefore, conceivable to attempt an added benefit on both, symptoms and disease progression in AD, and in cognitive impairment of mainly vascular origin (multi-infarct dementia, vascular dementia, vascular cognitive impairment, etc.).

[0279] Based on the Japanese regulatory label, the incidence of adverse events with a SGL, therapy in internal medicine is quite low as compared to placebo and the nature of AEs reported not unsettling; therefore, the benefit-risk ratio of added SARPO therapy seems defendable, also in an elderly, multimorbid population.EXAMPLE 59 STEREOSELECTIVE REVERSAL OF PSYCHOSTIMULANT-INDUCED HYPERACTIVITY IN VIVO BY COMPOUND M1

[0280] Motor activity data were collected during a 15-min session in a lit room. Mice had no prior exposure to the motor cages. Immediately before placing the mice in the locomotor chambers, effects on myorelaxation / ataxia were determined by placing each of the mouse's forepaws in contact with a horizontal wire while holding the mouse by the base of the tail. Mice were required to bring at least one hindpaw in contact with the wire within 10 s to be scored as a "pass" and failure to do so was considered ataxic. Each dose or dose combination was tested in a separate group of mice. ACP-103 significantly attenuated MK-801-induced hyperactivity in mice at doses of 0.1 and 0.3 mg / kg s.c. [F(7,63)=6.010; p<0.0001], consistent with an antipsychotic-like effect.

[0281] HEK-293 cells expressing human recombinant 5HT2A receptor were used in the antagonist radioligand binding studies. SGL racemate and both enantiomers were applied at concentrations ranging from 3.0E-11 M to 1.0E-07 M. M1 enantiomers were applied at concentrations ranging from 1.0E-11 M to 3.0E-08 M. The IC50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting. The inhibition constants (Ki) were calculated using the Cheng Prusoff equation. Both sarpogrelate enantiomers were potent inhibitors of [3H]ketanserin binding (Table 1). M1 enantiomers also potently bind to 5HT2A receptors with the Ki values that are approximately one order of magnitude higher than those of sarpogrelate enantiomers (Table 1). There are no meaningful differences between enantiomers in terms of 5-HT2A receptor binding for sarpogrelate or its main metabolite. Table 3 Inhibitory effects of sarpogrelate (racemate and enantiomers) and M-1 enantiomers on 5-HT2A receptor bindingCompoundIC50, nMpKiSarpogrelate racemate9.68.3(+) Sarpogrelate7.58.4(-) Sarpogrelate118.2(+) M11.29.1(-) M11.39.2

[0282] To confirm the ability of M1 enantiomers to induce effects that are relevant to CNS diseases and that are known for 5-HT2A receptor agonists and inverse agonists, separate groups of female Wistar rats (n=6-9), housed 4-5 per cage under standard colony room conditions with free access to food and water, were pretreated intraperitoneally with varying doses of one of the two M1 enantiomers (0, 3 or 10 mg / kg) followed 15 minutes later by 0.1 mg / kg of MK801 or its vehicle and immediately thereafter placed into computer-controlled motor activity recording chambers (25 x 35.5 x 34 cm, L x W x H; transparent Plexiglas walls and a non-transparent plastic floor; enclosed within sound-attenuating ventilated cubicles) for 60 minutes, during which infrared photocell interruptions (5 cm and 14 cm off the floor) were recorded as a measure of motor activity. MK-801 is a phencyclidine-like NMDA receptor channel blocked commonly used in psychopharmacology research on novel therapies including novel antipsychotics. Analysis of variance (ANOVA) has revealed main effects of the M1 dose and the interaction between M1 dose and MK-801 treatment factors for the (-) M1 enantiomer [F(2,39)=6.154; p=0.0048, F(2,39)=4.613; p=0.0159, respectively] and not for the (+) M1 enantiomer [F(2,42)=0.5211; p=0.5977, F(2,42)=0.5229; p=0.5966, respectively]. As shown in Figure 7, both doses of the (-)M1 enantiomer as well as 3 mg / kg of a prototypical 5-HT2A receptor antagonist M-100,907 reduced hyperactivity induced by MK-801 (Dunnett's multiple comparisons test). Thus, despite no significant differences between M1 enantiomers in terms of binding to 5-HT2A receptors, surprisingly, only one of the enantiomers exerts efficacy in a preclinical model of psychomotor activation that is known to be sensitive to 5-HT2A receptor blockade.EXAMPLE 60 SARPOGRELATE-INDUCED REVERSAL OF MOTOR HYPERACTIVITY INDUCED BY OLFACTORY BULBECTOMY IN RATS

[0283] In a dedicated set of studies, adult male Sprague-Dawley rats (Charles River, Germany) were subjected to bilateral olfactory bulbectomy performed under ketamine / xylasine anesthesia. The animals were allowed to recover for 14 days following surgery while being handled daily to eliminate any aggressiveness that would otherwise arise. Sham-operated animals were treated in the same way but the olfactory bulbs were left intact. Drugs administration and locomotor activity testing were performed 4 times for each rat with 72 hours break between consecutive test sessions. Prior to each test session, animals were first treated with dextromethorphan (0, 15, 30 or 60 mg / kg. per os) followed 15 min later by sarpogrelate (1, 3 and 10 mg / kg, intraperitoneal) and another 15 min later were placed into Opto-Varimex cages for locomotor activity recording over 30 min. Hyperactivity in rats after olfactory bulbectomy is observed mostly during the early portion of the test sessions. Figure 8 presents average activity counted over the first 15 min of the test when activity of the bulbectomized animals was significantly higher than that of the sham controls. ANOVA revealed a significant main effects of both surgery and sarpogrelate dose factors [F(1,88)=5.04, p=0.0273; F(3,88)=5.02, p=0.0029, respectively]. Post hoc pairwise comparisons (Sidak's multiple comparisons test) confirmed that significant differences between bulbectomized and sham-operated were observed only in rats that were pretreated prior to the test with vehicle instead of sarpogrelate. Bulbectomized rats pretreated with 3 or 10 mg / kg of sarpogrelate spent less time in ambulations compared with the respective controls that received vehicle instead of sarpogrelate. These anti-hyperactivity effects of sarpogrelate are observed at the doses that do not affect activity of sham-operated rats and therefore do not reflect a generalized non-specific impairment of motor capabilities. Thus, surprisingly, despite being previously referred to as a peripherally restricted 5-HT2A receptor antagonist with only minimal penetration across the blood-brain barrier (Obata H et al. Antinociception in rat by sarpogrelate, a selective 5-HT(2A) receptor antagonist, is peripheral. Eur J Pharmacol 404(1-2):95-102 (2000)), sarpogrelate is observed to exert behaviorally specific anti-hyperactivity effects in rats after olfactory bulbectomy, a model commonly used to study CNS drugs such as antidepressants.EXAMPLE 61 SARPOGRELATE-INDUCED INHIBITION OF DEXTROMETHORPHAN METABOLISM IN VITRO AND IN VIVO

[0284] Dextromethorphan O-demethylase activity was determined in human liver microsomes. Sarpogrelate (1.0E-8 M to 3.0E-5 M) or M-1 (concentration: 3.0E-9 M to 1.0E-5 M) and dextromethorphan were dissolved in acetonitrile and serially diluted with acetonitrile to the required concentrations to give a final organic solvent concentration of 1.0% in the incubation mixture. The incubation mixtures contained pooled human liver microsomes (final concentrations: 0.25 mg / ml), dextromethorphan, and a NADPH-generating system (1.3 mM NADP+, 3.3 mM glucose 6-phosphate, 3.3 mM MgCl2, and 0.4 U / ml glucose-6-phosphate dehydrogenase). After incubation and centrifugation, the supernatant was diluted 100-fold with acetonitrile and then injected into the LC-MS / MS system. All incubations were performed in triplicate, and mean values were used for analysis. The IC50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting. Both sarpogrelate enantiomers inhibited CYP2D6-mediated dextromethorphan O-demethylation (Table 4). Table 4. Inhibitory effects of sarpogrelate (racemate and enantiomers) and M-1 enantiomers on CYP 2D6 activityCompoundIC50, µMSarpogrelate racemate1.2(+) Sarpogrelate0.58(-) Sarpogrelate1.3(+) M10.038(-) M10.096

[0285] While both enantiomers of M1 markedly inhibited 2D6 activity with the IC50 values of 0.038-0.096 µM, sarpogrelate enantiomers were approximately 10-15 times less potent (Table 4). Based on previous in vivo studies, sarpogrelate was classified as a weak 2D6 inhibitor. This classification was based on a less than 2-fold increase in the substrate AUC (i.e. per guidance provided by the US Food and Drug Administration, Draft guidance for industry: drug interaction studies - study design, data analysis, implication for dosing and labeling recommendations. Center for Drug Evaluation and Research, US FDA (2012), http: / / www.fda.gov / downloads / Drugs / GuidanceComplianceRegulatoryInformation / Guidance s / ucm292362.pdf).

[0286] Pharmacokinetic study was performed in male Wistar rats equipped with the jugular vein cannulas. Sarpogrelate hydrochloride was formulated in Pharmasolv: PBS buffer (5:95) mixture and administered at the dose of 2 mg / kg intravenously. Blood samples were collected from the jugular vein using heparin as anticoagulant at the scheduled time-points: 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, and 6 h. An LC-MS / MS bioanalytical method was used for the simultaneous quantification of sarpogrelate and M1 in plasma samples. Following 2 mg / kg intravenous bolus administration the plasma level curves showed small inter-individual variability (Figure 9). Apparent terminal elimination half-life was estimated at 1.21 ± 0.159 h. Formation of M1 metabolite of sarpogrelate was rapid as the highest M1 concentrations were measured at the first sampling time points. In spite of the rapid formation, concentrations of the free M1 metabolite were orders of magnitude lower in the circulation than those of the parent compound (M1 / sarpogrelate ratio of 2.98 ± 0.597 %). Thus, although M1 enantiomers are significantly more potent 2D6 inhibitors than the parent compound, potential impact of M1 is mitigated by low relative exposure to M1 suggested by the ratio of plasma AUC for M1 and sarpogrelate.EXAMPLE 62

[0287] In a separate set of studies, ability of sarpogrelate to inhibit dextromethorphan metabolism in vivo was studied in rats. Adult male Sprague Dawley rats (RjHan:SD) purchased from Janvier Labs (France) were housed in a climate-controlled room under a 12h light / 12h dark cycle with ad libitum access to food and water. Two-three days prior to blood sampling, rats were provided with a catheter in the jugular vein and, thereafter, rats treated once with Carprofen (5 mg / kg) directly after surgery and catheters were rinsed daily with Heparin (500 IE / ml) (20 µl / rat / day). On the day of the experiment, dextromethorphan (50 mg / kg) was administered by oral gavage, immediately followed by intravenous bolus injection of sarpogrelate (1, 3 or 10 mg / kg; racemate or one of the enantiomers) or vehicle via vascular access port at t = 0 h. Blood samples were collected at four time points until 6 hours post dextromethorphan administration. Sample size was 80 µl Li-heparin whole blood / time point, i.e. 40 µl Li-heparin plasma / time point. Whole blood samples were stored on ice until centrifugation (10 min at 3000 g, 4 °C). Plasma was prepared within 45 min after collection, frozen at -20°C and stored at this temperature until processed for LC-MS analysis.

[0288] As shown in Figure 10, in rats treated with sarpogrelate (racemate or enantiomers) plasma levels of dextromethorphan continued to be high even at the later time points while, in vehicle-treated rats, dextromethorphan levels declined towards the 6-h time point.

[0289] Surprisingly, quantification of the AUC for dextromethorphan indicated that, at the highest tested dose of 10 mg / kg, sarpogrelate increased the dextromethorhan AUC 5.3-6.9 fold. Even at the lower dose of 3 mg / kg, dextromethorphan AUC was increased 2.7 (for the (-) enantiomer) to 3.3 fold (for the (+) enantiomer). Table 5. Area under the curve (0-6 h) analysis of dextromethorphan plasma concentration in rats treated with sarpogrelate (racemate and enantiomers)TreatmentSarpogrelate dose (mg / kg)Dextromethorphan AUC (ng*hr / ml)Fold increase (relative to vehicle)Vehicle-605.8-Sarpogrelate racemate12329.53.833356.15.5103211.95.3(+) Sarpogrelate1827.01.432021.53.3104154.36.9(-) Sarpogrelate1921.41.531649.52.7103195.95.3 EXAMPLE 63 INHIBITION OF PHENCYCLIDINE-INDUCED HYPERACTIVITY IN RATS TREATED BY A COMBINATION OF SARPOGRELATE AND DEXTROMETHORPHAN

[0290] The behavioral effects of DEX, DO and phencyclidine (PCP) were compared in rats. DO (15-120 mg / kg) was similar to PCP (1.25-20 mg / kg) in inducing dose-dependent locomotor hyperactivity, stereotypy and ataxia. DEX (15-120 mg / kg) induced moderate hyperactivity only at the higher doses about 45 min after treatment. DEX and DO modified the locomotor facilitation induced by 10 mg / kg PCP in opposite directions.

[0291] In a dedicated set of studies, SARPO racemate and enantiomers were co-administered with DEX to demonstrate the ability of such drug combination(s) to counteract psychomotor activation and hyperactivity. Male Sprague-Dawley rats were administered intraperitoneally sarpogrelate racemate, (-) sarpogrelate, (+) sarpogrelate or vehicle as well as subcutaneous (racemate experiment) or oral (enantiomer experiments) dextromethorphan or vehicle (water) and were placed individually into the Opto-Varimex-4 auto-tracks. Fifteen minutes later rats were removed from the boxes, injected with phencyclidine (PCP; 5 mg / kg, subcutaneous) and returned to the auto-tracks for additional 105 min (i.e. until a total recording time of 120 min). Data analysis focused on the second half of the test (60-120 min). ANOVA has revealed significant interaction between the dose of sarpogrelate and the dose of dextromethorphan (Figure 11, upper panel; F(9,120)=2.38, P=0.015).

[0292] Similar statistically significant interaction with the dose of dextromethorphan was observed for (-) sarpogrelate (Figure 11, middle panel; F(9,141)=3.07, P=0.002) but not for (+) sarpogrelate (Figure 11, lower panel; F(9,120)=1.65, P=0.1). The post-hoc analysis indicated that, in the presence of dextromethorphan, 3 mg / kg of sarpogrelate racemate as well as 1 mg / kg or 3 mg / kg of (-) sarpogrelate inhibited motor hyperactivity in PCP-treated rats (Dunnett's multiple comparisons test). This pattern of the results is surprising given that the (-) enantiomer of sarpogrelate is less potent than the (+) enantiomer in terms of inhibiting dextromethorphan metabolism both in vitro (Table 4) and in vivo (Table 5).

[0293] When given in the absence of dextromethorphan, neither sarpogrelate racemate nor sarpogrelate enantiomers reduced activity in PCP-treated rats. When given in combination with dextromethorphan, inhibitory effects of sarpogrelate were observed irrespective of whether dextromethorphan by itself reduced (subcutaneous administration, experiment with sarpogrelate racemate) or enhanced (oral administration, experiments with sarpogrelate enantiomers) motor activity in PCP-treated rats. Thus, presence of dextromethorphan may be required for sarpogrelate exert inhibitory effects in subjects with psychomotor activation such as rats with hyperactivity after exposure to a psychotomimetic drug PCP. Such pattern of supra-additive interactions between dextromethorphan and sarpogrelate is surprising.EXAMPLE 64 EFFECTS OF A COMBINATION OF DEXTROMETHORPHAN AND SARPOGRELATE ON BLOOD GLUCOSE

[0294] To test whether DEX could lead to higher serum insulin concentrations and lower blood glucose concentrations in people with type 2 diabetes mellitus (T2DM), a Phase 2a, Double-blinded, placebo-controlled, randomized, crossover, single-dose proof-of-concept study was performed (Marquard et al., Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 21(4):363-72 (2015)). Twenty males with T2DM on metformin monotherapy (age 59 (46-66) years (mean (range)); mean body mass index (BMI) 29.2 (25.2-34.1) kg m-2; glycated hemoglobin (HbA1c) 6.9 (6.5-7.4%) were recruited. Each received a single oral dose of 60 mg DEX, 270 mg DEX, 100 mg amantadine or placebo, followed by an oral glucose tolerance test (OGTT) 1 h after drug intake on four treatment days, separated by a washout period of 7-14 days. Consistent with the results in mice, DEX led to neither higher fasting serum insulin concentrations nor lower fasting blood glucose concentrations compared to placebo and did not provoke any severe hypoglycemic events up to a dose of 270 mg. In contrast, following oral glucose intake, both 60 and 270 mg DEX dosages resulted in significantly (P < 0.05) higher maximal serum insulin concentrations compared to those seen with placebo.

[0295] In addition, the primary endpoint was reached for 270 mg DEX; that is, the area under the curve of blood glucose concentrations within the first 2 h of the OGTT (glucose AUC1-3 h) was significantly (P < 0.05) smaller in individuals who received 270 mg doses of DEX than in the same individuals receiving placebo on a different treatment day.

[0296] Indices of insulin resistance (fasting immunoreactive insulin) were measured before and after 2 weeks of SARPO administration (300 mg / day) in 24 patients (19 men, 76+ / -9 years) with peripheral arterial disease. Sixteen of the 24 patients were also examined after 3 months of treatment. After 2 weeks of treatment, significant decreases in fasting immunoreactive insulin (p=0.03) were observed. After 3 months of treatment, significant decreases in fasting immunoreactive insulin (16.0+ / -10.3 vs 9.2+ / -2.0 microU / ml, p=0.03) were maintained.EXAMPLE 65 METHOD OF ASSESSMENT OF BLOOD GLUCOSE LEVELS AND ORAL GLUCOSE TOLERANCE

[0297] Test substances were administered to male Wistar (Han) rats (180-280 g at the beginning of the experiments; Janvier Labs) housed in groups under free access to food and water. After overnight food deprivation, the tip of the tail was cut, each rat was weighed, housed individually and left without stress in a quiet room. Approximately 1 hour later, baseline blood glucose was measured from a drop of blood collected from the tail tip, using a commercially available glucose-meter (OneTouch ®< , Lifescan) and then rats received intraperitoneal injection of sarpogrelate and / or dextromethorphan and 30 min later blood glucose was measured again and rats immediately challenged with glucose at 2 g / kg by oral gavage. Then, blood glucose was measured at 6 time-points until 180 minutes post-glucose challenge. As shown in Figure 12, there was a main effect of drug treatment (F(4,59=12.0, p<0.0001). Post hoc pairwise group comparisons indicated that, when given alone, dextromethorphan has significantly reduced blood glucose level and this effect of dextromethorphan was reversed when it was administered in combination with sarpogrelate racemate or either of the enantiomers.

Claims

1. A pharmaceutical composition for use in the symptomatic and disease-modifying treatment wherein the disease or disorder is diabetes mellitus, , multi-infarct dementia, Alzheimer's disease (AD), aggression in AD, apathy in AD, sexually inappropriate behavior in AD, incontinence in AD, vascular cognitive impairment (VCI), Vascular Dementia (VaD), diabetic and metabolic syndrome, , and behavioral and psychological symptoms of dementia (BPSD), wherein the behavioral and psychological symptoms of dementia comprise hallucinations, dysphoria, euphoria, disinhibition, irritability / lability, aberrant motor activity, night-time behavioral disturbances, appetite and eating abnormalities, comprising a therapeutically effective amount of a dual acting agent capable of inhibiting CYP 2D6 and acting as a 5-HT2A receptor antagonist selected from the group consisting of or deuterated derivatives thereof, pharmaceutically acceptable salts, N-oxides thereof, or a combination thereof; and a therapeutically effective amount of an NMDA receptor antagonist, which is or a deuterated derivatives thereof, fluorinated derivatives thereof, pharmaceutically acceptable salts, N-oxides thereof, or a combination thereof.

2. Pharmaceutical composition for use according to claim 1, wherein the NMDA receptor antagonist is Compound 149, and the composition is administered once or twice a day, wherein the daily dose of compound 149 is about 0.1 mg to about 1000 mg, resulting in an AUCo-12 of Compound 149 that is greater than the AUCo-12 of the NMDA receptor antagonist Compound 149 that would be achieved by administering the same amount of the NMDA receptor antagonist Compound 149 without the dual agent.

3. Pharmaceutical composition for use according to claim 2, wherein the composition further comprises a polymer, an emulsifier, a binder, a disintegrating agent, and / or a lubricant, and use comprises administering the composition to the subject once or twice a day for at least 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, 31 consecutive days, 32 consecutive days, 33 consecutive days, 34 consecutive days, 35 consecutive days, 36 consecutive days, 37 consecutive days, 38 consecutive days, 39 consecutive days, 40 consecutive days, 41 consecutive days, 42 consecutive days, 43 consecutive days, 44 consecutive days, 45 consecutive days, 46 consecutive days, 47 consecutive days, 48 consecutive days, 49 consecutive days, 50 consecutive days, 51 consecutive days, 52 consecutive days, 53 consecutive days, 54 consecutive days, 55 consecutive days, 56 consecutive days, 57 consecutive days, 58 consecutive days, 59 consecutive days, 60 consecutive days, 70 consecutive days, 80 consecutive days, 90 consecutive days, 100 consecutive days, 110 consecutive days, 120 consecutive days, 130 consecutive days, 140 consecutive days, 150 consecutive days, 160 consecutive days, 170 consecutive days, 180 consecutive days, 190 consecutive days, or 200 consecutive days.

4. Pharmaceutical composition for use according to claim 1, wherein the AUCo-12 of the dual agent, is at least about 10 ng / hr / mL, about 100 ng / hr / mL, 200 ng / hr / mL, about 300 ng / hr / mL, or about 400 ng / hr / mL.

5. Pharmaceutical composition for use according to claim 1, in the form of an oral dosage form comprising tablets, capsules, liquids, or solutions and for use in anadministration that is cutaneous, oral, nasal, anal, rectal, vaginal, sublingual, buccal, sublabial, muscular, intramuscular, intravenous, peritoneal, epidural, intracerebral, intracerebral or topical, intraarticular, intracardiac, intracavernous, intradermal, intralesional, intramuscular, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, or transmucosal.

6. Pharmaceutical composition for use according to claim 1, comprising: a) administering a therapeutically effective amount of the composition; b) targeting CYP2D6 enzyme, and NMDA and 5-HT2A receptors; c) wherein the disease or disorder is neuropsychiatric, neurodegenerative, or brain injury, comprising behavioral and psychological symptoms of dementia (BPSD); and d) producing a symptomatic relief and / or disease modification.