RU2760558C9 - Target drug with new compositions, combinations and methods - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to a pharmaceutical composition for the treatment of a neuropsychiatric or neurodegenerative disease or disorder containing the effective amount of a remedy with double activity showing CYP2D6 inhibitor activity and reverse agonist activity of 5-HT_2A/5-HT_2C receptor or antagonist/reverse agonist activity of 5-HT_2A receptor, where the specified remedy with double activity is N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]ethanamine; and NMDA receptor antagonist selected from a group consisting of memantine and dextromethorphan (DEX).

EFFECT: pharmaceutical composition with double activity is developed that can provide higher efficiency, such as greater pain relief than would be achieved with the injection of any component separately.

8 cl, 207 ex, 17 dwg

Description

FIELD OF TECHNOLOGY

[001] This invention relates to Targeted Drag Rescue (TDR)™ and novel compositions, combinations, therapeutic formulations, symptomatic and disease-modifying therapies, therapies, kits thereof, and methods of using the same.

State of the art

[002] Being overweight alters the body by increasing certain hormones and levels of inflammation, which can lead to metabolic disorders, cancer and brain disorders, including developmental disorders, mental and neurodegenerative diseases, which represent a huge burden of disease in terms of human suffering and economic costs, as well as rapidly increasing health care costs. Diseases that affect the brain and central nervous system represent one of the most significant public health problems and require the highest level of medical care due to the devastating personal and economic consequences for patients, caregivers and society. An estimated 55 million people worldwide suffer from neurodegenerative diseases, and there are currently no approved disease-modifying therapies. As modern therapeutic interventions increase life expectancy, the number of patients suffering from these diseases is expected to double every 20 years. Only nine of the most common neurological diseases, such as Alzheimer's disease and other forms of dementia, low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury, and Parkinson's disease, resulted in spending totaling $789 billion. dollars in 2014 are currently estimated at $818 billion and are estimated to be worth more than $1 trillion by 2030. The total cost of treating brain disorders in Europe in 2010 was 798 billion euros, of which direct health care costs accounted for 37%, direct non-medical costs 23%, and indirect costs 40% (Oleson et al., The economic cost of brain disorders in Europe, EJN, 19, 1,155-162 (2012).

[003] In the past two decades, progress in meeting the specific needs of the treatment of dementia has been slow, and all projects to develop treatments for Alzheimer's disease have failed since the approval of memantine by the EMA (2002) and the FDA (2003). Instead of pushing for "treatment" indications, regulators have addressed the continued high demand for medicines by opening up a range of approved medicines for syndromic-labeled therapies. Such labeling for syndromic indications may cover, for example, behavioral and mental symptoms in dementia (BPSD), subsyndromic features such as aggression or apathy in Alzheimer's disease, hallucinations and delusions in dementia in Parkinson's disease (PDD). Accordingly, there is a need to develop such new syndromic labeled therapies for new compositions, combinations, therapeutic formulations, symptomatic and disease-modifying therapies, and therapies utilizing EXCIVA TDR™ technology.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

[004] Various embodiments of the invention relate to Targeted Drug Rescue (TDR) ™ and new compositions, combinations, therapeutic compositions, symptomatic and disease-modifying therapies, therapeutics, kits based on it and methods for obtaining such compositions, combinations , therapeutic formulations, treatments, therapies and kits containing biological agents, chemicals, nutritional supplements, pharmaceuticals, compositions, treatments, therapies, drugs, prophylactic agents, additives and formulations; including allopathic, alternative, ayurvedic, herbal, complex, homeopathic, natural, medicinal, pharmaceutical, non-natural remedies, adjuvants, auxiliaries, decoctions, chemicals, compositions, combinations, mixtures, drugs, elements, extracts, extractions , compositions, kits, mechanisms, medicines, medicines, potions, tinctures, preparations, prophylactic agents, prescriptions, soluble substances, solutions, solvents, substances, systems, teas, therapies, extracts and treatments; biological agents and vaccines; medicines; diagnostic kits, reagents and tests; dietary products, gastronomic and nutritional products, tinctures and additives; medical products and nutraceuticals; as well as related products and services based on them; for the administration, purification, treatment, diagnosis, healing, disinfection, drug impregnation, prevention and treatment of acute or chronic situations, namely: drug addiction, pathological conditions, developmental defects, disabilities, diseases, disorders, dysfunctions, infections, problems, poisoning , pollution and ailments; arising from or associated with relevant accidental, allergic, auditory, anticancer, cardiovascular, cardiopulmonary, chemotherapeutic, cognitive, congenital, dermatological, endocrine, gastrointestinal, genetic, genital, genitourinary, hereditary, hormonal, hepatological, immunological, collateral, intellectual, karmic, lymphatic, metabolic, mental, muscular, musculoskeletal, neurological, oncological, visual, ophthalmic, osteological, osteopathic, mental, psychological, psychopathic, psychosomatic, physical, physiological, respiratory, reproductive, sexual, skeletal, urological, virtual and visual functions, systems and processes.

[005] In various embodiments, the invention is a composition containing a combination of one or more agents, each of which is characterized by a unique therapeutic mechanism of action (TMA), where the agent is an NMDA receptor antagonist, a 5-HT _2A receptor antagonist, an inverse agonist of the receptor 5 -HT _2A , 5-HT _2C receptor antagonist and/or CYP2D6 inhibitor.

[006] One embodiment of the present invention is a composition containing a compound of formula I:

где, R₁ и R₂ независимо представляют собой Н, замещенный или незамещенный C_1-10алкил, замещенный или незамещенный С_5-10арил, замещенный или незамещенный С_3-10циклоалкил-С_5-10арил, замещенный или незамещенный С_4-10бициклоалкил, замещенный или незамещенный С_4-10бициклоалкил-С_5-10арил. замещенный или незамещенный С_4-10бициклоалкил-С_5-10 гетероарил, замещенный или незамещенный С_4-10 трициклоалкил, замещенный или незамещенный С_4-10 трициклоалкил-С_5-10арил, замещенный или незамещенный С_4-10 трициклоалкил-С_5-10гетероарил, или замещенный или незамещенный С_5-10гетероарил, или R₁ и R₂ вместе с атомом азота образуют насыщенный или ненасыщенный гетероцикл, содержащий один или несколько гетероатомов, выбранных из N, О и S;

where, R ₁ and R ₂ are independently H, substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted C _5-10 aryl, substituted or unsubstituted C _3-10 cycloalkyl-C _5-10 aryl, substituted or unsubstituted C _{4 -10} bicycloalkyl, substituted or unsubstituted C _4-10 bicycloalkyl-C _5-10 aryl. substituted or unsubstituted C _4-10 bicycloalkyl-C _5-10 heteroaryl, substituted or unsubstituted C _4-10 tricycloalkyl, substituted or unsubstituted C _4-10 tricycloalkyl-C _5-10 aryl, substituted or unsubstituted C _4-10 tricycloalkyl-C _{5 -10} heteroaryl, or substituted or unsubstituted C _5-10 heteroaryl, or R ₁ and R ₂ together with a nitrogen atom form a saturated or unsaturated heterocycle containing one or more heteroatoms selected from N, O and S;

R ₃ is independently H, substituted or unsubstituted C _1-10 alkyl. substituted or unsubstituted C _5-10 aryl, substituted or unsubstituted C _5-10 heteroaryl, substituted or unsubstituted C _3-10 cycloalkyl-C _5-10 aryl, substituted or unsubstituted C _4-10 bicycloalkyl, substituted or unsubstituted C _4-10 bicycloalkyl -C _5-10 aryl, substituted or unsubstituted C _4-10 bicycloalkyl-C5 uheteroaryl, substituted or unsubstituted C _4-10 bicycloalkyl-C _1-10 alkyl-C _5-10 aryl, substituted or unsubstituted C _4-10 bicycloalkyl-C _1-10 alkyl-C _5-10 heteroaryl. substituted or unsubstituted C _4-10 tricycloalkyl, substituted or unsubstituted C _4-10 tricycloalkyl-C _1-10 -alkyl-C _5-10 aryl, substituted or unsubstituted C _4-10 tricycloalkyl-C _1-10 alkyl-C _5-10 heteroaryl, substituted or unsubstituted C _4-10 tricycloalkyl-C _5-10 aryl, substituted or unsubstituted C _4-10 tricycloalkyl-C _5-10 heteroaryl, or substituted or unsubstituted C _5-10 heteroaryl, or substituted or unsubstituted C _5-10 heteroaryl;

n is an integer from 0 to 5; R ₄ is H, NH-R ₅ , SR ₅ , -OH, OR ₅ , -CO-R ₅ , -O-CO-R ₅ or -CO-OR ₅ , where R ₅ is an acyl radical; or R ₅ and R ₂ form a heterocycle; or its enantiomers, its metabolites, its derivatives, and/or its prodrugs, its pharmaceutically acceptable salts, its N-oxides, or a combination thereof.

[007] Some embodiments include a composition comprising an effective amount of 1) a composition comprising a compound of formula I as defined above, its enantiomers, its metabolites, its derivatives and/or prodrugs thereof, its pharmaceutically acceptable salts, its N-oxides or a combination of them; or 2) compounds of formula II

,

,

where, R ₆ , R ₇ , and R ₈ are independently H, D, C _1-10 alkyl, halo-C _1-10 alkyl, where halogen is F, Cl or Br, R ₉ and R ₁₀ are independently H; C _1-10 alkyl; halo-C _1-10 alkyl, where halo is F, Cl or Br; IS HE; or R ₉ and R ₁₀ together form a five-membered heterocycle, where the heteroatom is O, S or N; its enantiomers, metabolites, derivatives, prodrugs based on it, its salts, diastereomers, pharmaceutically acceptable salts or N-oxides, or combinations thereof; or 3) combinations of 1 and 2; or their combinations.

[008] Some embodiments include a method of treating a disease or disorder in a subject in need thereof, comprising an effective amount of 1) a composition comprising a compound of Formula I as defined above, its enantiomers, its metabolites, its derivatives, and/or prodrugs thereof. , its pharmaceutically acceptable salts, its N-oxides, or a combination thereof; or 2) a compound of formula II as defined above, its enantiomers, metabolites, derivatives, prodrugs thereof, its salts, diastereomers, pharmaceutically acceptable salts or N-oxides, or combinations thereof, or 3) combinations of 1 and 2.

[009] Some embodiments include a method of treating a disease or disorder in a subject in need thereof, comprising an effective amount of a composition comprising dextromethorphan, its enantiomers, metabolites, derivatives or prodrugs thereof, or a combination thereof; their salts and diastereomers, their pharmaceutically acceptable salts, their N-oxides, methods and intermediates for their preparation, compositions based on them and their uses.

[0010] In one embodiment, the method is a method of reducing the number of doses and/or the total daily dose of a compound of formula II that can be administered while improving efficacy and maintaining tolerability and safety; a method of mitigating an adverse event associated with treatment with a compound of formula II, in which the subject is at risk of experiencing an adverse event as a result of treatment with a compound of formula II; a method of reducing blood plasma levels of metabolites of a Formula II compound, a method of treating a neurological disorder, a method of increasing blood plasma levels of a Formula II compound in a subject in need of treatment with a Formula II compound, wherein the subject is a rapid metabolizer of the Formula II compound; a method for inhibiting the metabolism of a compound of formula II; a method for increasing the metabolic lifespan of a compound of formula II; a method for correcting the rapid metabolism of a compound of formula II; a method for improving the antitussive properties of a compound of formula II; way to treat cough. Another embodiment is a method wherein the disease or disorder is a neurological disorder, wherein the composition is administered at least once daily for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or 8 days.

[0011] Some embodiments include a method of treating a neurological disorder comprising administering from about 5 mg/day to about 600 mg/day, from about 5 mg/day to about 300 mg/day, from about 5 mg/day to about 400 mg /day, from about 5 mg/day to about 500 mg/day, from about 5 mg/day to about 600 mg/day, from about 5 mg/day to about 1000 mg/day, from about 50 mg/day to about 1000 mg/day, from about 100 mg/day to about 1000 mg/day, from about 150 mg/day to about 1000 mg/day, from about 150 mg/day to about 5000 mg/day, from about 150 mg/day up to about 300 mg/day or from about 150 mg/day to about 100 mg/day or the required amount of the compound of formula I and from about 0.1 mg/day to about 1 mg/day, from 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 the required number of compounds of formula II to the subject in need of it.

[0012] Another embodiment is a pharmaceutical composition comprising a compound of Formula II and one or more agents selected from the group consisting of a 5-HT2A receptor antagonist/inverse agonist and a CYP2D6 inhibitor. In another embodiment, the agent is an agent having both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor properties. In another embodiment, the agent is a dual potency (DA) agent having both 5-HT2A receptor inverse agonist and CYP2D6 inhibitory properties. In another embodiment, DA is a compound of Formula I.

BRIEF DESCRIPTION OF GRAPHICS

[0013] Figures 1A, 1B and 1C show Dixon plots for determining Ki values for CYP2D6 compounds of formula I, examples of which are sarpogrelat and M-1, and quinidine. Dextromethorphan concentrations were defined as 2.5 (solid circles), 5 (open circles), and 10 (triangles) mM, respectively. V represents the rate of formation of dextrorphan (pmol/minute/mg protein). Data are means of triplicate determinations. The solid lines of a compound of formula I, exemplified by sarpogrelat and M-1, as well as quinidine, correspond well to all competitive inhibition modes (Cho et al., Effect of the potent CYP2D6 inhibitor on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers. Xenobiotica, 45(3):256-63 (March 2015), incorporated by reference in its entirety).

[0014] Figures 2A, 2B, and 2C show the arousal/aggression domain scores from the Neuropsychiatric Assessment Questionnaire, representing stage and visit averages, for patients included in the sequential side-by-side comparison design and 10-week analyses. A, stage 1 (weeks 1-5); B, stage 2 (weeks 6-10) for placebo non-responders re-randomized after stage 1; C, results at 10 weeks (10-week secondary analysis includes only those patients who continued to receive the same type of treatment throughout study participation; i.e. were randomized to receive dextromethorphan-quinidine alone or placebo alone [excluding patients who re-randomized from placebo to dextromethorphan-quinidine in step 2], thus mimicking a parallel group design). Analysis of covariance models with treatment as the fixed effect and baseline as the covariate were used to compare mean change from baseline between groups at each time point. The baseline for stage 2 is the scores in patients at the start of stage 2. The least squares means of differences between treatments are as follows: for stage 1, week 1, -0.8 (95% CI, from -1 .5 to -0.03; P=0.04), week 3, -1.0 (95% CI, -1.8 to -0.2; P=0.01), and week 5, - 1.5 (95% CI, -2.3 to -0.7; P<0.001); for Stage 2, Week 6, 0.7 (95% CI, -0.4 to 1.9; P=0.19), Week 8, -0.1 (95% CI, -1.3 to 1 .2; P=0.93) and week 10, -1.6 (95% CI, -2.9 to -0.3; P=0.02); for 10-week analysis, week 1, -0.9 (95% CI, -1.8 to -0.04; P=0.047), week 3, -1.3 (95% CI, -2, 2 to -0.3; P=0.01), week 5, -1.8 (95% CI, -2.7 to -0.9; P<0.001), week 6, -0.9 ( 95% CI, -2.0 to 0.1; P=0.06), week 8, -1.3 (95% CI, -2.4 to -0.3; P=0.01) and week 10, -1.8 (95% CI, -2.8 to -0.7; P=0.003). 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), incorporated by reference in its entirety).

[0015] Figures 3A, 3B and 3C show the effects of treatment on reducing the severity of psychosis over a 6 week study period in a full sample analysis. Full sample analysis includes all patients who received ≥1 dose and had a SAPS assessment at baseline and at least one thereafter. For data points, the mean values obtained by the least squares method (standard error) are shown. (A) SAPS-PD improvement. (B) Change in CGI severity score. (C) CGI improvement scores. SAPS = positive symptom score. CGI = overall clinical impression (Cummings et al., Pimavanserin for patients with Parkinson's disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet, 383(9916):533-40 (February 8, 2014), fully inclusive via link).

[0016] Figures 4A, 4B and 4C are Lineweaver-Burk plots showing inhibition of CYP2D6 and human liver microsomes (HLM) by compound 847 (cannabidiol, CBD). Recombinant CYP2D6 was incubated with (A) 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) in the presence of CBD (Figure 4A), (B) dextromethorphan in the presence of CBD (figure 4B) and (C) in the absence of CBD (figure 4C), HLM were incubated with dextromethorphan in the presence or absence of CBD. Each point represents the mean of the duplicate determinations.

[0017] Figures 4D, 4E and 4F show the effects of the major phytocannabinoids Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC), CBD and cannabinol (CBN) on AMMS and dextromethorphan-O-demethylase CYP2D6 and HLM activities. Recombinant CYP2D6 was incubated with (D) 0.6 μM AMMS (figure 4D), (E) 0.6 μm dextromethorphan (figure 4E) in the presence of various amounts of Δ ⁹ -THC, CBD and CBN; and (F) HLM was incubated with 4 μM dextromethorphan in the presence of various amounts of Δ ⁹ -THC, CBD and CBN (figure 4F). Each point represents the mean of two determinations (Yamaori et al., Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6, Drug Metabolism and Disposition, Vol. 39, No. 11 (2011), incorporated by reference in its entirety).

[0018] Figure 5 shows the effect of the (-) and (+) enantiomers of M1 as well as M-100907 on MK-801-induced hyperactivity in rats. Data are presented as mean (±SEM) 60-min activity mean. testing session. N=5-9 per group.

[0019] Figure 6 shows the effect of sarpogrelat on locomotor activity in rats after olfactory bulb removal (OLB) or sham surgery (SHAM). Data are presented as mean (±SEM) 5 min activity mean. testing session. N=12 per group.

[0020] Figure 7 shows plasma levels of sarpogrelat and M1 in male Wistar rats following single intravenous injections of sarpogrelat hydrochloride (2 mg/kg). Data are presented as mean (±SD) concentration (ng/mL). N=4.

[0021] Figure 8 shows plasma levels of dextromethorphan in male Wistar rats that received dextromethorphan (50 mg/kg, po) immediately after an intravenous bolus injection of sarpogrelat (1, 3 or 10 mg/kg; racemate or one of enantiomers) or carrier medium through a vascular access port at time t=0 h. Data are presented as mean (±SD) concentration (ng/mL). N=2-3.

[0022] Figures 9A, 9B and 9C show the effects of the combination of dextromethorphan with racemate compound 50 (upper panel), (-)-compound 51 (middle panel), or (+)-compound 52 on PCP-induced hyperactivity in rats.

[0023] Figure 10 shows the effects of dextromethorphan and racemate sarpogrelat on blood glucose levels. Data are presented as area under the curve (mean ± SEM) of blood glucose over a time period of 30-180 minutes. after oral glucose loading (2 g/kg). N=8 per group.

[0024] Figures 11A and 11B show the mean (SEM) concentrations of (a) buspirone and (b) 1-PP after administration of 20 mg of buspirone after 8 days of pretreatment with 60 mg of Compound 829 (solid square; n=16) or placebo (solid circle; n=16) once daily.

[0025] Figures 12A and 12B show mean (SEM) plasma prolactin concentrations (a) after treatment with 60 mg of Compound 829 (solid square; n=16) or placebo (solid circle; n=16) once per day for 7 days and (b) after simultaneous administration of 20 mg of buspirone after 8 days of pre-treatment with 60 mg of compound 829 (solid square; n=16) or placebo (solid circle; n=16) once a day .

[0026] The figure 13 shows the principles of formation of prodrugs for the most common functional groups of the original drug compounds of formulas I and II, represented by R, while the general diagrams represent various embodiments of prodrugs based on compounds of formulas I and II.

[0027] Figures 14A and 14B show the effect of compound 829 on the effects of NMDA receptor channel blockers as a discriminative stimulus. Data are presented as mean (± S.E.M.) percentage of drug response rate as lever stroke (upper panel) and response rate (responses per second; lower panel). N=6.

[0028] Figure 15A shows the effect of compound 829 in combination with memantine and in combination with dextromethorphan in a tail suspension test. Data are presented as mean (± S.E.M.) immobility time. N=8.

[0029] Figure 15B shows the effect of ritanserin in combination with memantine in a tail suspension test. Data are presented as mean (± S.E.M.) immobility time. N=7-8.

[0030] Figure 16A shows the effect of compound 829 and memantine on the implementation of the punishment response in the Heller-Seifter test. Data are presented as mean (± S.E.M.) number of responses per session. N=4.

[0031] Figure 16B shows the effect of compound 829 and memantine on the implementation of the non-punishment response in the Heller-Seifter test. Data are presented as mean (± S.E.M.) number of responses per session. N=4.

[0032] Figure 17 shows the effect of compound 829 in combination with memantine and ritanserin in combination with memantine on isolation-induced aggression. Data are presented as mean (± S.E.M.) delay time to first attack. N=7.

[0033] Figure 18 shows the total concentration of Compound 146 (M1) in plasma and brain tissue. The total concentration in the brain and blood plasma after intraperitoneal administration of a composition of the present invention containing a compound of formula I, an example of which is compound 146. Data are presented as the mean (± SEM) amount of the compound in brain tissue extracts, measured using UPLC/ MS. N=4.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0034] Various embodiments of the invention Targeted Drug Rescue (TDR) ™ provide corresponding new compositions and combinations, therapeutic compositions, symptomatic and disease-modifying therapies, therapies, kits, as well as methods for obtaining such compositions, combinations, therapeutic formulations, treatments, therapies, and kits containing biological agents, chemicals, nutritional supplements, pharmaceuticals, compositions, treatments, therapies, drugs, prophylactic agents, supplements, and formulations, including the disclosures of patent applications US 62/501693 filed 05/04/2017, PCT/US2017/048748 filed 08/25/2017, WO 2018/039642 A1 filed 03/01/2018, TW 106129169 filed 08/28/2017, US 62/634162 filed 02/22/2018, US 62/636171 filed 02/22/2018, US 62/635554 filed 02/27/2018 and US 62/636099 filed 02/27/2018, all of which are incorporated by reference.

[0035] One embodiment of the present invention is a composition containing a compound of formula I:

где R₁ и R₂ независимо представляют собой Н, замещенный или незамещенный C_1-10алкил, замещенный или незамещенный С_5-10арил, замещенный или незамещенный С_3-10циклоалкил-С_5-10арил, замещенный или незамещенный С_4-10бициклоалкил, замещенный или незамещенный С_4-10бициклоалкил-С_5-10арил, замещенный или незамещенный С_4-10бициклоалкил-С_5-10гетероарил или замещенный или незамещенный С_5-10гетероарил, или R₁ и R₂ вместе с атомом азота образуют насыщенный или ненасыщенный гетероцикл, содержащий один или несколько гетероатомов, выбранных из N, О и S;

where R ₁ and R ₂ independently represent H, substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted C _5-10 aryl, substituted or unsubstituted C _3-10 cycloalkyl-C _5-10 aryl, substituted or unsubstituted C _{4- 10} bicycloalkyl, substituted or unsubstituted C _4-10 bicycloalkyl-C _5-10 aryl, substituted or unsubstituted C _4-10 bicycloalkyl-C _5-10 heteroaryl, or substituted or unsubstituted C _5-10 heteroaryl, or R ₁ and R ₂ together with the nitrogen atom forms a saturated or unsaturated heterocycle containing one or more heteroatoms selected from N, O and S;

R ₃ is independently H, substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted C _5-10 aryl, substituted or unsubstituted C _5-10 heteroaryl, substituted or unsubstituted C _3-10 cycloalkyl-C _5-10 aryl, substituted or unsubstituted C _4-10 bicycloalkyl, substituted or unsubstituted C _4-10 bicycloalkyl-C _5-10 aryl, substituted or unsubstituted C _4-10 bicycloalkyl-C _5-10 heteroaryl, or substituted or unsubstituted C _5-10 heteroaryl; n is an integer from 0 to 5; R ₄ is H, NH-R ₅ , SR ₅ , -OH, OR ₅ , -CO-R ₅ , -O-CO-R ₅ or -CO-OR ₅ , where R ₅ is an acyl radical; or R ₅ and R ₂ form a heterocycle; or their enantiomers, their metabolites, their derivatives and/or prodrugs based on them, their pharmaceutically acceptable salts, their N-oxides, or a combination thereof.

[0036] One embodiment is a compound of Formula I wherein the substituted or unsubstituted C _4-10 cycloalkyl is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl radical. In another embodiment, the cycloalkyl contains one or more N, S, or O heteroatoms.

[0037] Another embodiment is a compound of Formula I wherein the substituted or unsubstituted C _3-10 bicycloalkyl is a bicyclobutyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl, or bicyclodecyl radical. In another embodiment, the bicycloalkyl contains one or more N, S, or O heteroatoms.

[0038] Another embodiment is a compound of Formula I wherein aryl is phenyl, naphthyl, anthracenyl, or phenanthrenyl.

[0039] In another embodiment, the compound is a compound of formula I, where R ₅ represents an acyl radical selected from the group consisting of mono-, di- and tricarboxylic acid radicals.

[0040] In another embodiment, the compound is a compound of Formula I, wherein R ₅ is an acyl radical selected from the group consisting of acetate, acetylsalicylate, adipate, N-acylaspartate, aspartate. butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, N-acylglutarate, glutarate, isophthalate, maleate, malonate, methionate, N-acylmethionate oxalate, pelargonate, pimelate, propionate, phthalate, salicylate, sebacate. succinate, terephthalate, tyrosinate, N-acyl tyrosinate, tryptophanate, N-acyl tryptophanate and valerate.

где R₆, R₇ и R₈ независимо представляют собой Н, D, С_1-10алкил, галоген-С_1-10алкил, где галоген представляет собой F, С1 или Br; R₉ и R₁₀ независимо представляют собой Н; С_1-10алкил; галоген-С_1-10алкил, где галоген представляет собой F, О или Br; ОН; или R₉ и R₁₀ вместе образуют пятичленный гетероцикл, где гетероатом представляет собой О, S или N.[0041] Another embodiment is a compound of formula II,

where R ₆ , R ₇ and R ₈ independently represent H, D, C _1-10 alkyl, halo-C _1-10 alkyl, where halogen is F, C1 or Br; R ₉ and R ₁₀ are independently H; C _1-10 alkyl; halo-C _1-10 alkyl, where halo is F, O or Br; IS HE; or R ₉ and R ₁₀ together form a five-membered heterocycle, where the heteroatom is O, S or N.

[0042] Another embodiment is a compound of formula I wherein R5 and R2 form a heterocycle selected from radicals such as morpholine, dihydrooxazine, oxazine, piperazine, dihydropiperazine, and tetrahydropyrazine. Compounds according to this embodiment include, without limitation, the following compounds 10-24:

[0043] Another embodiment is the pure enantiomer of formula I selected from a compound of formula Ia or Ib.

[0044] Another embodiment is a compound of formula I, where R ₁ , R ₂ and R ₃ are methyl, provided that X is not ethyl.

[0045] In another embodiment, the composition containing the compound of formula I is sarpogrelat (SARPO), where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is a succinoyl radical, including the following compounds : SGL, SGL-E1 and SGL-E2.

[0046] In another embodiment, the composition containing the compound of formula I is a metabolite of sarpogrelate M1, where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is OH, including the following compounds: M1 , M1-E1 and M1-E2.

[0047] In another embodiment, the composition containing the compound of formula I is a metabolite of sarpogrelate M1, where R ₁ and R ₂ together with nitrogen form a saturated or unsaturated heterocycle with one or more heteroatoms selected from N, O and S; and R ₃ is methyl, X is ethyl, and R ₄ is OH. In another embodiment, the heterocycle is a five-membered ring. In another embodiment, the heterocycle is a six-membered ring. In another embodiment, the heterocycle is saturated. Another embodiment is an unsaturated heterocycle. In one embodiment, the heterocycle has one heteroatom. In another embodiment, the heterocycle has two heteroatoms

[0048] Another embodiment is a compound of formula I, wherein the heterocycle formed from R ₁ and R ₂ together with nitrogen is selected from the heterocycles below:

[0049] The term "DEX" refers to a compound of formula II such as dextromethorphan, its enantiomers, its metabolites, its derivatives and/or prodrugs thereof, or a combination thereof. Derivatives include, without limitation, deuterated derivatives such as DEX-H3, DEX-D3, DO and DO-D3.

[0050] The term "SARPO" refers to one or more compounds selected from the group consisting of sarpogrelate (SGL), its enantiomers, its metabolite M1, SG1, SG2, SMG1, SMG2, SMG3, its derivative, its prodrug, and their combinations.

[0051] The term SARPODEX™ refers to the combination of DEX and a compound of formula I. One embodiment of the present invention is a composition containing a compound of formula I and dextromethorphan. One embodiment of the present invention is a composition containing a compound of formula I and DEX-H3, DEX-D3, DO or DO-D3. One embodiment of the present invention is a composition containing: M1, M1-E1, M1-E2, SGL, SGL-E1 or SGL-E2; and DEX-H3, DEX-D3, DO or DO-D3.

где R₃ представляет собой бициклическую систему, а остальная часть формулы I представлена R₇, показанным на формуле If.[0052] The term DERADEX™ or DERAPHAN™ refers to the combination of DEX and a compound of formula I, where the compound is a bicyclo[2.2.1]heptanol derivative of formula I:

where R ₃ represents a bicyclic system, and the rest of the formula I is represented by R ₇ shown in the formula If.

где R₆ представляет собой Н, замещенный или незамещенный -C_1-10алкил, замещенный или незамещенный -С_3-10циклоалкил, замещенный или незамещенный -С_5-10арил, замещенный или незамещенный -C_1-10алкил-С_5-10арил, замещенный или незамещенный -С_5-10гетероарил, или замещенный или незамещенный -С_1-10алкил-С_3-10гетероарил;

where R ₆ is H, substituted or unsubstituted -C _1-10 alkyl, substituted or unsubstituted -C _3-10 cycloalkyl, substituted or unsubstituted -C _5-10 aryl, substituted or unsubstituted -C _1-10 alkyl-C _{5- 10} aryl, substituted or unsubstituted -C _5-10 heteroaryl, or substituted or unsubstituted -C _1-10 alkyl-C _3-10 heteroaryl;

-С_1-10алкил-Х-(Y)_n, -С_3-10циклоалкил-Х-(Y)_m, -C_5-10арил-Х-(Y)m или -С_5-10гетероарил-Х-(Y)m; где X представляет собой связь, N, О, S, -С_1-10алкил, -С_3-10циклоалкил, -С_5-10арил, -CO-C_1-10алкил, -СО-С_3-10циклоалкил, -СОС_5-10арил, -СО-С_5-10гетероарил, -CO-NH-С_1-10алкил, -CO-NH-С_3-10циклоалкил, -CO-NH-C_5-10арил или -CO-NH-С_3-10гетероарил; Y представляет собой Н, С_1-10алкил, С_3-10циклоалкил, С_5-10арил, -CO-C_1-10алкил, -СО-С_3-10циклоалкил, -СОС_5-10арил, СО-С_5-10гетероарил, -CO-NH-C_1-10алкил, -CO-NH-С_3-10циклоалкил, -СО-NH-С_5-10арил или -СО-NH-С_5-10гетероарил; и m представляет собой целое число 1 или 2; или их фармацевтически приемлемые соли или N-оксиды; или пролекарства на их основе.R ₇ is

-C _1-10 alkyl-X-(Y) _n , -C _3-10 cycloalkyl-X-(Y) _m , -C _5-10 aryl-X-(Y)m or -C _5-10 heteroaryl-X -(Y)m; where X is a bond, N, O, S, -C _1-10 alkyl, -C _3-10 cycloalkyl, -C _5-10 aryl, -CO-C _1-10 alkyl, -CO-C _3-10 cycloalkyl , -COC _5-10 aryl, -CO-C _5-10 heteroaryl, -CO-NH-C _1-10 alkyl, -CO-NH-C _3-10 cycloalkyl, -CO-NH-C _5-10 aryl or -CO-NH-C _3-10 heteroaryl; Y is H, C _1-10 alkyl, C _3-10 cycloalkyl, C _5-10 aryl, -CO-C _1-10 alkyl, -CO-C _3-10 cycloalkyl, -COS _5-10 aryl, CO- C _5-10 heteroaryl, -CO-NH-C _1-10 alkyl, -CO-NH-C _3-10 cycloalkyl, -CO-NH-C _5-10 aryl, or -CO-NH-C _5-10 heteroaryl; and m is an integer 1 or 2; or their pharmaceutically acceptable salts or N-oxides; or prodrugs based on them.

[0053] The term DERATINE™ refers to the combination of an NMDA receptor antagonist and a compound of formula I as defined above.

[0054] The term SARPOTINE™ is a combination of an NMDA receptor antagonist and a compound of Formula I as defined above.

[0055] One embodiment of the present invention is a composition containing a compound of formula I and DEX-H3, DEX-D3, DO or DO-D3.

[0056] In another embodiment, the compound of formula I or analogs can be obtained using the following carboxylic acids: malic acid HO ₂ C-CH ₂ -CH(OH)-CO ₂ H (compounds 25-29), methionine H ₃ CS- (CH ₂ ) ₂ -CH (NH ₂ ) -CO ₂ H (compounds 30-34), phthalic acid C ₆ H ₄ (CO ₂ H) ₂ (compounds 35-37), malonic acid HO ₂ C-CH ₂ - CO ₂ H (compounds 38-40), tyrosine HO-C ₆ H ₄ -CH ₂ -CH (NH ₂ ) -CO ₂ H (compounds 41-43), tryptophan C ₈ H ₆ N-CH ₂ -CH (NH ₂ )-CO ₂ H (compounds 44-46), maleic acid HO ₂ C-CH=CH-CO ₂ H (compounds 47-49), succinic acid HO ₂ C-(CH ₂ ) ₂ -CO ₂ H (compounds 50-52), glutaric acid HO ₂ C-(CH ₂ ) ₃ -CO ₂ H (compounds 53-55), adipic acid HO ₂ C-(CH ₂ ) ₄ -CO ₂ H (compounds 56-58), pimelic acids HO ₂ C-(CH ₂ ) ₅ -CO ₂ H (compounds 59-61), sebacic acid HO ₂ C-(CH ₂ ) ₆ -CO ₂ H (compounds 62-64), formic acid HCO ₂ H (compounds 65-67), acetic acid CH ₃ CO ₂ H (compounds 68-70), propionic acid CH ₃ CH ₂ CO ₂ H (compounds 71-73), butyric acid CH ₃ (CH ₂ ) ₂ CO ₂ H (compounds 74-76), valeric acid CH ₃ (CH ₂ ) ₃ CO ₂ H (compounds 77-79 ), caproic acid CH ₃ (CH ₂ ) ₄ CO ₂ H (compounds 80-82), enanthic acid CH ₃ (CH ₂ ) ₅ CO ₂ H (compounds 83-85), caprylic acid CH ₃ (CH ₂ ) ₆ CO ₂ H (compounds 86-88), pelargonic acid CH ₃ (CH ₂ ) ₇ CO ₂ H (compounds 89-91), capric acid CH ₃ (CH ₂ ) ₈ CO ₂ H (compounds 92-94), oxalic acid HO -CO-CO ₂ H (compounds 95-97), isophthalic acid C ₆ H ₄ (CO ₂ H) ₂ (compounds 98-100), terephthalic acid C ₆ H ₄ (CO ₂ H) ₂ (compounds 101-103) , salicylic acid HO-C ₆ H ₄ -CO ₂ H (compounds 104-106), acetylsalicylic acid CH ₃ -CO-O-C ₆ H ₄ -CO ₂ H (compounds 107-109).

[0057] One embodiment of the present invention is a compound of formula I, where the compound is sarpomalate, where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is malate; compounds 25-29. One embodiment of the present invention is a compound of formula I wherein the compound is sarpomethionate, where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is methionate; compounds 30-34. One embodiment of the present invention is a compound of formula I wherein the compound is sarpophthalate, where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is phthalate; compounds 35-37. One embodiment of the present invention is a compound of formula I wherein the compound is sarpomalonate, where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is malonate; compounds 38-40. One embodiment of the present invention is a compound of formula I, wherein the compound is sarpothyrosinate, where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is tyrosinate; compounds 41-43. One embodiment of the present invention is a compound of formula I, wherein the compound is sarpotryptophanate, where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is tryptophanate; compounds 44-46. In one embodiment, the composition is a combination of DEX and at least one compound selected from compounds 10-46: SGL, SGL-E1, SGL-E2, M1, M1-E1, M1-E2. One embodiment of the present invention is a composition comprising a compound of Formula I, wherein the compound is sarpogrelat, and dextromethorphan.

[0058] One embodiment of the present invention is a composition containing a compound of formula I, where the compound is sarpogrelate, and dextromethorphan, where sarpogrelate and dextromethorphan form a diastereomeric mixture.

[0059] One embodiment of the present invention is a composition containing a compound of formula I, where the compound is sarpogrelate, and dextromethorphan, where sarpogrelate and dextromethorphan form a salt, where the salt is a diastereomeric mixture. One embodiment of the present invention is a composition containing a compound of formula I, where the compound is sarpogrelate, and dextromethorphan, where sarpogrelate and dextromethorphan form a salt, where the salt is a pure diastereomer. One embodiment of the present invention is a composition comprising a compound of Formula I, wherein the compound is a sarpogrelate M1 metabolite, and dextromethorphan. One embodiment of the present invention is a composition comprising dextromethorphan and a compound of formula I wherein the compound is sarpomalate forming a salt containing a mixture of diastereomers or a pure diastereomer thereof. One embodiment of the present invention is a composition comprising a compound of formula I wherein the compound is sarpomethionate and dextromethorphan forming a salt containing a mixture of diastereomers or a pure diastereomer thereof. One embodiment of the present invention is a composition containing a compound of formula I wherein the compound is sarpophthalate and dextromethorphan forming a salt containing a mixture of diastereomers or a pure diastereomer. One embodiment of the present invention is a composition comprising a compound of formula I wherein the compound is sarpomalonate and dextromethorphan forming a salt containing a mixture of diastereomers or a pure diastereomer thereof. One embodiment of the present invention is a composition comprising a compound of formula I wherein the compound is sarpothyrosinate and dextromethorphan forming a salt containing a mixture of diastereomers or a pure diastereomer thereof. One embodiment of the present invention is a composition comprising a compound of formula I wherein the compound is sarpotryptophanate and dextromethorphan forming a salt containing a mixture of diastereomers or a pure diastereomer thereof.

[0060] One embodiment of the present invention is a composition containing a compound of formula I, where the compound is SGL, and dextromethorphan-HCl, forming a salt containing a mixture of diastereomers or its pure diastereomer. One embodiment of the present invention is a composition comprising a compound of formula I wherein the compound is SGL and dextromethorphan-HBr forming a salt containing a mixture of diastereomers or a pure diastereomer thereof. One embodiment of the present invention is a composition containing a compound selected from the group consisting of SGL, its enantiomers, its metabolite M1, SG1, SG2, SMG1, SMG2, SMG3, its derivative, a prodrug based on it, and combinations thereof. One embodiment of the present invention is a composition comprising a compound selected from the group consisting of SGL, its enantiomers, its metabolite M1, SG1, SG2, SMG1, SMG2, SMG3, its derivative, a prodrug thereof, and a combination thereof, and dextromethorphan .

[0061] Another embodiment is a compound of Formula 1 wherein Ra and R2 form a five or six membered heterocyclic moiety, compounds 110-145 being illustrative compounds. One embodiment of the present invention is a composition comprising a compound selected from the group consisting of SGL, its enantiomers, its metabolite M1, SG1, SG2, SMG1, SMG2, SMG3, its derivative, a prodrug thereof, and a combination thereof, and dextromethorphan .

[0062] In another embodiment, examples of a compound of formula I wherein the heterocycle is formed from R ₁ and R ₂ together with nitrogen are compounds of formulas Ic-Is containing saturated (shown below) and unsaturated heterocycles:

[0063] In another embodiment, this compound is a compound of formulas Ic - Is, where the 5-membered heterocycle is unsaturated.

[0064] In another embodiment, the composition comprises DEX and a compound of formula I and/or prehexilin, flecainide, quinidine, (R)-propafenone, (S)-propafenone. isoniazid, (R) fluoxetine, (S) fluoxetine, nefazodone, paroxetine, ketoconazole. chloroquine, oxamniquine, primaquine, quinine, acebutolol, betaxolol, bufuralol, oxprenolol, pindolol, propranolol, budipine, simvastatin, fluvastatin, lovastatin, pravastatin, perazine, aimalicin, corynanthine, lobelia or their derivatives.

[0065] In another embodiment, the composition contains a compound of formula I. where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is OH, represented by the following compounds: M1, M1-E1 and M1- E2.

[0066] In another embodiment, the composition contains a compound of formula I, where R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is a succinoyl radical represented by the following compounds: SGL, SGL-E1 and SGL -E2.

[0067] In one embodiment, the composition contains a compound of formula I, where R ₅ represents -O(CO)-CH ₂ -CH ₂ -(CO)OY, where alkyl, cycloalkyl, aryl, heteroaryl, -alkenylaryl, -aralkyl, alkyl-ONO ₂ , cycloalkyl-ONO ₂ , aryl-ONO ₂ , heteroaryl-ONO ₂ , -alkenylaryl-ONO ₂ and -aralkyl-ONO ₂ are selected by way of example and without limitation from the following compounds: 1-(dimethylamino)-3- (2-(3-Methoxyphenethyl)phenoxy)propan-2-ylmethylsuccinate, 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl ((nitrooxy)methyl)succinate, 1-( dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl(2-(nitrooxy)ethyl)succinate, 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan- 2-yl(3-(nitrooxy)propyl)succinate, 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl(4-(nitrooxy)butyl)succinate, 4-(( 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)-4-oxobutanoic nitric anhydride, etc.

[0068] In one embodiment, the composition contains DEX-H ₃ , DEX-D ₃ , DO, DO-D ₃ , levomethorphan, morphine, codeine, thebaine, benzocaine, ketamine, methadone, memantine (3,5-dimethyladamantane-1- amine), amantadine, dextropropoxyphene-((2R)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl-propionate), ketobemidone-(1-(4-(3-hydroxyphenyl)-1 -methylpiperidin-4-yl)propan-1-one), tropane alkaloids such as cocaine, atropine, scopolamine, etc.

[0069] In another embodiment, the composition contains a combination of a compound of formula I and a compound of formula II containing DEX-H ₃ , DEX-D ₃ , DO, DO-D ₃ , levomethorphan, morphine, codeine, thebaine, or benzocaine; and/or ketamine, methadone. memantine, amantadine, dextropropoxyphene, ketobemidone, cocaine, atropine, or scopolamine.

[0070] In another embodiment, the composition comprises a combination of a compound of formula I and ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone, cocaine, atropine, or scopolamine, where the compound of formula I is racemic compound 50 (sarpogrelate), racemic compound 146 (M1 ) or compound 829 (deramciclane). In another embodiment, the composition contains memantine. In another embodiment, the composition contains sarpogrelat and memantine. In another embodiment, the composition contains enantiomerically pure S-compound 51 (S-sarpogrelate) and R-compound 52 (R-sarpogrelate) and memantine. In another embodiment, the composition contains enantiomerically pure S-compound 147 (S-M1), R-compound 148 (R-M1) and memantine. In another embodiment, the composition contains enantiomerically pure deramciclane and memantine.

[0071] In another embodiment, the compound of the present invention is a compound of formula I, where R ₁ , R ₂ and R ₃ are independently substituted with one, two or three halogens, where halogen is F, Cl or Br. Examples of fluoro derivatives of formula I:

[0072] In another embodiment, the compound of formula I or analogs can be obtained using the following carboxylic acids: difluorosuccinic acid HO ₂ C-CF ₂ -CH ₂ -CO ₂ H (201-206), trifluorosuccinic acid HO ₂ C-CF ₂ -CHF-CO ₂ H (207-212), tetrafluorosuccinic acid HO ₂ C-(CF ₂ ) ₂ -CO ₂ H, difluorosuccinic acid (213-215), HO ₂ C-CHF-CHF-CO ₂ H (216- 219), difluoroglutaric acid HO ₂ C-(CH ₂ ) ₂ -CF ₂ -CO ₂ H (219-221), difluoroglutaric acid HO ₂ C-CF ₂ - (CH ₂ ) ₂ -CO ₂ H (222-225) , difluoroacetic acid HO ₂ C-CF ₂ H (226-228) and trifluoroacetic acid HO ₂ C-CF ₃ (229-).

[0073] In another embodiment, a compound of formula I is a compound of formula Ic or formula Id as defined above, and derivatives thereof, comprising acid addition salts selected from: acetate, acetylsalicylate. adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, glutamate, glutarate, isophthalate, maleate, malonate, methionate, oxalate, pelargonate, pimelate, propionate, phthalate, salicylate, sebacate, succinate. terephthalate, tyrosinate, tryptophanate, valerate, N-acylaspartate, N-acylglutamate, N-acyl tyrosinate, N-acyl trypto fan, N-acyl methionate, citrate, galactonate, glucaric acid (sugar acid), mannonate, mucat, rhamnonate, and tartrate.

[0074] In another embodiment, a compound of formula I is a compound of formula Ic or formula Id as defined above, and derivatives thereof, comprising acid addition salts formed from di- and tricarboxylic acids selected from: adipic acid, aspartic acid, N -acylaspartic acid, citric acid, fumaric acid, galactonic acid, glutaric acid, glutamic acid, N-acylglutamic acid, glucaric acid (sugar acid), malic acid, maleic acid, mannonic acid, mucic acid, oxalic acid, pimelic acid, phthalic acid, isophthalic acid, terephthalic acid, rhamnonic acid, sebacic acid, succinic acid and tartaric acid.

[0075] Another embodiment is a composition comprising a derivative of a compound of formula Ic or formula Id, and a derivative of a compound of formula II, wherein the corresponding derivative of formula Ic, formula Id, and formula II is independently an acid addition salt of hydrogen acetate, hydrogen acetylsalicylate, hydrogen adipate, hydrogen aspartate , gidrogenbutirat, gidrogenkaprat, gidrogenkaproat, gidrogenkaprilat, gidrogenenantat, gidrogenformiat, gidrogenfumarat, gidrogenglutamat, gidrogenglutarat, gidrogenizoftalat, gidrogenmaleat, gidrogenmalonat, gidrogenmetionat, gidrogenoksalat, gidrogenpelargonat, gidrogenpimelat, gidrogenpropionat, gidrogenftalat, gidrogensalitsilat, gidrogensebatsinat, gidrogensuktsinat, gidrogentereftalat, gidrogentirozinat, gidrogentriptofanat, gidrogenvalerat , hydrogen-N-acylaspartate, hydrogen-N-acylglutamate, hydrogen-N-acyltyrosinate, hydrogen-N-acyltryptophanate, hydrogen-N-acylmethionate, hydrogencitrate, hydrogengalactonate, hydroglucaric acid otu (sugar acid), hydrogen mannonate, hydrogen mucat, hydrogen rhamnonate and hydrogen tartrate.

[0076] Another embodiment is a composition comprising an acid addition salt of dextromethorphan and M1 selected from: dextromethorphan dihydrogen adipate and M1, dextromethorphan dihydrogen aspartate and M1, dextromethorphan dihydrogen fumarate and M1, dextromethorphan dihydrogen glutamate and M1, dextromethorphan dihydrogen glutarate and M1, dextromethorphan dihydrogen glutarate and M1, dihydrogen isophthorphan , digidrogenmaleata dextromethorphan M1, digidrogenmalonata dextromethorphan M1, digidrogenoksalata dextromethorphan M1, digidrogenpimelata dextromethorphan M1, digidrogenftalata dextromethorphan M1, digidrogensebatsinata dextromethorphan M1, digidrogensuktsinata dextromethorphan M1, digidrogentereftalata dextromethorphan M1, dihydrogen-N-atsilaspartata dextromethorphan and M1, dextromethorphan dihydrogen-N-acylglutamate and M1, dextromethorphan dihydrogencitrate and M1, dextromethorphan dihydrogengalactonate and M1, dextromethorphan dihydrogenglucarate and M1, dextromethorph dihydrogen saccharate on and M1, dextromethorphan dihydrogen mannonate and M1, dextromethorphan dihydrogen mucate and M1, dextromethorphan dihydrogen rhamnonate and M1, and dextromethorphan dihydrogen tartrate and M1.

[0077] In another embodiment, the compound of formula I is a compound of formula Ic or formula Id as defined above, and their fluorine derivatives. In another embodiment, the compound of formula I is a compound of formula Ic or formula Id, wherein the compound is a fluoro derivative (FD) of formula Ic (FDIc) or formula Id (FDId) selected from Compounds 221-269 and dextromethorphan or a compound of formula II is , as defined above.

[0078] Another embodiment is a composition comprising an acid addition salt of dextromethorphan and FDIc selected from: dextromethorphan dihydrogen adipate and FDIc, dextromethorphan dihydrogen aspartate and FDIc, dextromethorphan dihydrogen fumarate and FDIc, dextromethorphan dihydrogen glutamate and FDIc, dextromethorphan dihydrogen glutamate and FDIc, dihydrogen glutarate dextromethorphan and FDIc , digidrogenmaleata dextromethorphan FDIc, digidrogenmalonata dextromethorphan FDIc, digidrogenoksalata dextromethorphan FDIc, digidrogenpimelata dextromethorphan FDIc, digidrogenftalata dextromethorphan FDIc, digidrogensebatsinata dextromethorphan FDIc, digidrogensuktsinata dextromethorphan FDIc, digidrogentereftalata dextromethorphan FDIc, dihydrogen-N-atsilaspartata dextromethorphan FDIc, dextromethorphan dihydrogen-N-acylglutamate and FDIc, dextromethorphan dihydrogencitrate and FDIc, dextromethorphan dihydrogengalactonate and FDIc, dextromethorphan dihydrogenglucarate and FDIc, dextromethorphan dihydrogen saccharate and FDIc, dextromethorphan dihydrogen mannonate and FDIc, dextromethorphan dihydrogen mucate and FDIc, dextromethorphan dihydrogen rhamnonate and FDIc, and dextromethorphan dihydrogen tartrate and FDIc.

[0079] Another embodiment is a composition comprising an acid addition salt of dextromethorphan and FDId selected from: dextromethorphan dihydrogenadipate and FDId, dextromethorphan dihydrogenaspartate and FDId, dextromethorphan dihydrogenfumarate and FDId, dextromethorphan dihydrogenglutamate and FDId, dextromethorphan dihydrogenglutarate, and FDId FDId, digidrogenmaleata dextromethorphan FDId, digidrogenmalonata dextromethorphan FDId, digidrogenoksalata dextromethorphan FDId, digidrogenpimelata dextromethorphan FDId, digidrogenftalata dextromethorphan FDId, digidrogensebatsinata dextromethorphan FDId, digidrogensuktsinata dextromethorphan FDId, digidrogentereftalata dextromethorphan FDId, dihydrogen-N-atsilaspartata dextromethorphan FDId , dextromethorphan dihydrogen-N-acylglutamate and FDId, dextromethorphan dihydrogencitrate and FDId, dextromethorphan dihydrogengalactonate and FDId, dextromethorphan dihydrogenglucarate and FDId, dextromethorphan dihydrogen saccharate and FDId, dextromethorphan dihydrogen mannonate and FDId, dextromethorphan dihydrogen mucate and FDId, dextromethorphan dihydrogen rhamnonate and FDId, and dextromethorphan dihydrogen tartrate and FDId.

[0080] In another aspect of the present invention, the compound is a derivative of a compound of formula I, including the following compounds:

[0081] In some embodiments, the compound of formula I is a compound of formula Ic or formula Id:

[0082] In some embodiments, a compound of formula Ic or formula Id is M1, where Y is CH ₃ ; R4 is OH. In some embodiments, a compound of formula Ic or formula Id as defined above is a fluorine derivative, wherein R4 is OCF ₃ .

[0083] One embodiment of the present invention is a composition containing a compound having formula I.

где R₃ представляет собой бициклическую систему, а остальная часть формулы I представлена R₇: как показано в формуле If

where R ₃ represents a bicyclic system, and the rest of the formula I is represented by R ₇ : as shown in the formula If

где R₆ представляет собой Н, замещенный или незамещенный -С_1-10алкил, замещенный или незамещенный -С_3-10циклоалкил, замещенный или незамещенный -С_5-10арил, замещенный или незамещенный -С_1-10алкил-С_5-10арил, замещенный или незамещенный -С_5-10гетероарил, или замещенный или незамещенный -С_1-10алкил-С_5-10гетероарил;

where R ₆ is H, substituted or unsubstituted -C _1-10 alkyl, substituted or unsubstituted -C _3-10 cycloalkyl, substituted or unsubstituted -C _5-10 aryl, substituted or unsubstituted -C _1-10 alkyl-C _{5- 10} aryl, substituted or unsubstituted -C _5-10 heteroaryl, or substituted or unsubstituted -C _1-10 alkyl-C _5-10 heteroaryl;

-С_1-10алкил-Х-(Y)_n, -С_3-10циклоалкил-Х-(Y)_m, -С_5-10арил-X-(Y)m или -С_5-10гетероарил-Х-(Y)_m; где X представляет собой связь, N, О, S, -C_1-10алкил, -С_3-10циклоалкил, -С_5-10арил, -CO-C_1-10алкил, -СО-С_3-10циклоалкил, -СОС_5-10арил, -СО-С_5-10гетероарил, -CO-NH-C_1-10алкил, -CO-NH-С_3-10циклоалкил, -CO-NH- С_5-10арил или -СО-NH-С_5-10гетероарил; Y представляет собой Н, С_1-10алкил, С_3-10циклоалкил, С_5-10арил, -СО-С_1-10алкил, -СО- С_3-10циклоалкил, -СОС_5-10арил, СО-С_5-10гетероарил, -CO-NH-С_1-10алкил, -CO-NH-С_3-10циклоалкил, -CO-NH-C_5-10арил или -СО-NH-С_5-10гетероарил; и m представляет собой целое число 1 или 2; или его фармацевтически приемлемые соли или N-оксиды; или пролекарства на его основе.R ₇ is

-C _1-10 alkyl-X-(Y) _n , -C _3-10 cycloalkyl-X-(Y) _m , -C _5-10 aryl-X-(Y)m or -C _5-10 heteroaryl-X -(Y) _m ; where X is a bond, N, O, S, -C _1-10 alkyl, -C _3-10 cycloalkyl, -C _5-10 aryl, -CO-C _1-10 alkyl, -CO-C _3-10 cycloalkyl , -COC _5-10 aryl, -CO-C _5-10 heteroaryl, -CO-NH-C _1-10 alkyl, -CO-NH-C _3-10 cycloalkyl, -CO-NH-C _5-10 aryl or -CO-NH-C _5-10 heteroaryl; Y is H, C _1-10 alkyl, C _3-10 cycloalkyl, C _5-10 aryl, -CO-C _1-10 alkyl, -CO-C _3-10 cycloalkyl, -COS _5-10 aryl, CO- C _5-10 heteroaryl, -CO-NH-C _1-10 alkyl, -CO-NH-C _3-10 cycloalkyl, -CO-NH-C _5-10 aryl, or -CO-NH-C _5-10 heteroaryl; and m is an integer 1 or 2; or its pharmaceutically acceptable salts or N-oxides; or prodrugs based on it.

[0084] In some embodiments, the compound is a compound of formula If, where R ₆ is aryl and R ₇ is substituted or unsubstituted -C _1-10 alkyl-X-(Y) _n . In some embodiments, R ₆ is substituted or unsubstituted C _1-10 alkyl-C _5-10 aryl, and R ₇ is substituted or unsubstituted -C _1-10 alkyl-X-(Y) _n . In some embodiments, R ₆ is phenyl, R ₇ is -C _1-10 alkyl-N-(C _1-10 alkyl) ₂ .

[0085] In one embodiment, the compound of formula I includes, without limitation, the following examples: RS4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-3.3 -difluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-3,3-difluoro-4-oxobutanoic acid; R4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-3,3-difluoro-4-oxobutanoic acid; RS4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-4-oxobutanoic acid; R4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-4-oxobutanoic acid; RS4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3-trifluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3-trifluoro-4-oxobutanoic acid; R4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3-trifluoro-4-oxobutanoic acid; RS4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3,3-trifluoro-4-oxobutanoic acid; 84-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3,3-trifluoro-4-oxobutanoic acid; R4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3,3-trifluoro-4-oxobutanoic acid; RS4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3-difluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3-difluoro-4-oxobutanoic acid; R4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3-difluoro-4-oxobutanoic acid; RS4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3,3-tetrafluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3,3-tetrafluoro-4-oxobutanoic acid; R4-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3,3-tetrafluoro-4-oxobutanoic acid; RS5-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-4,4-difluoro-5-oxopentanoic acid; S5-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-4,4-difluoro-5-oxopentanoic acid; R5-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-4,4-difluoro-5-oxopentanoic acid; RS5-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-4,4-difluoro-5-oxopentanoic acid; S5-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-4,4-difluoro-5-oxopentanoic acid; R5-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-4,4-difluoro-5-oxopentanoic acid; RS5-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-5-oxopentanoic acid; S5-((4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-5-oxopentanoic acid; R5-((4-dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-difluoro-5-oxopentanoic acid; RS4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl-2,2-difluoroacetate; S4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl-2,2-difluoroacetate; R4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl-2,2-difluoroacetate; RS4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl-2,2,2-trifluoroacetate; S4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl-2,2,2-trifluoroacetate; R4-(dimethylamino)-1-(2-(3-methoxyphenethyl)phenoxy)butan-2-yl-2,2,2-trifluoroacetate; RS4-((difluoromethyl)(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; S4-((difluoromethyl)(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-((difluoromethyl)(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; RS4-((fluoromethyl)(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; S4-((fluoromethyl)(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-((fluoromethyl)(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; RS4-(methyl(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; S4-(methyl(trifluoromethyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-(methyl(trifluoromethyl)amino)-l-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; RS4-((difluoromethyl)(methyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; S4-((difluoromethyl)(methyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-((difluoromethyl)(methyl)amino)-l-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; RS4-((fluoromethyl)(methyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; S4-((fluoromethyl)(methyl)amino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-((fluoromethyl)(methyl)amino)-l-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; RS4-(dimethylamino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; S4-(dimethylamino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-(dimethylamino)-1-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; RS 1-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-4-(dimethylamino)butan-2-ol; S1-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-4-(dimethylamino)butan-2-ol; R1-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-4-(dimethylamino)butan-2-ol; RS4-(dimethylamino)-1-(2-(3-(fluoromethoxy)phenethyl)phenoxy)butan-2-ol; S4-(dimethylamino)-1-(2-(3-(fluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-(dimethylamino)-1-(2-(3-(fluoromethoxy)phenethyl)phenoxy)butan-2-ol; RS3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; S3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; R3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; RSN-(difluoromethyl)-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; SN-(difluoromethyl)-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RN-(difluoromethyl)-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-H-(trifluoromethyl)butan-1-amine; RSN-(fluoromethyl)-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; SN-(fluoromethyl)-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RN-(fluoromethyl)-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RSN-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; SN-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RN-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RSN-(difluoromethyl)-N-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; SN-(difluoromethyl)-N-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RN-(difluoromethyl)-N-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RSN-(fluoromethyl)-N-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; SN-(fluoromethyl)-N-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RN-(fluoromethyl)-N-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RSN,N-dimethyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; SN,N-dimethyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RN,N-dimethyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RS4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-N,N-dimethyl-3-(trifluoromethoxy)butan-1-amine; S4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-N,N-dimethyl-3-(trifluoromethoxy)butan-1-amine; R4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-N,N-dimethyl-3-(trifluoromethoxy)butan-1-amine; RS4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-N,N-dimethyl-3-(trifluoromethoxy)butan-1-amine; S4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-N,N-dimethyl-3-(trifluoromethoxy)butan-1-amine; R4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-N,N-dimethyl-3-(trifluoromethoxy)butan-1-amine; RS3-(difluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; S3-(difluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; R3-(difluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; RS3-(difluoromethoxy)-N-(difluoromethyl)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; S3-(difluoromethoxy)-N-(difluoromethyl)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; R(-(difluoromethoxy)-N-(difluoromethyl)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RS3-(difluoromethoxy)-N-(fluoromethyl )-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; S3-(difluoromethoxy)-N-(fluoromethyl)-4-(2-(3-( trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; R3-(difluoromethoxy)-N-(fluoromethyl)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl )butan-1-amine; RS3-(difluoromethoxy)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; S3-(difluoromethoxy)- N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; R ₃ -(difluoromethoxy)-N-methyl-4-(2-(3- (trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethoxy)butan-1-amine RS3-(difluoromethoxy)-N-(difluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy) butan-1-amine; S3-(difluoromethoxy)-N-(difluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; R ₃ -(difluoromethoxy)- N-(difluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)buta n-1-amine; RS3-(difluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; S3-(difluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; R3-(difluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RS3-(difluoromethoxy)-N,N-dimethyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; S3-(difluoromethoxy)-N,N-dimethyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; R3-(difluoromethoxy)-N,N-dimethyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RS3-(difluoromethoxy)-4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-N,N-dimethylbutan-1-amine;

S3-(difluoromethoxy)-4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-N,N-dimethylbutan-1-amine; R3-(difluoromethoxy)-4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-N,N-dimethylbutan-1-amine; RS3-(difluoromethoxy)-4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-N,N-dimethylbutan-1-amine; S3-(difluoromethoxy)-4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-N,N-dimethylbutan-1-amine; R3-(difluoromethoxy)-4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-N,N-dimethylbutan-1-amine; RS3-(fluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; S3-(fluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; R3-(fluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; RSN-(difluoromethyl)-3-(fluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; SN-(difluoromethyl)-3-(fluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RN-(difluoromethyl)-3-(fluoromethoxy)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-n-(trifluoromethyl)butan-1-amine; RS3-(fluoromethoxy)-N-(fluoromethyl)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; S3-(fluoromethoxy)-n-(fluoromethyl)-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-n-(trifluoromethyl)butan-1-amine; R3-(fluoromethoxy)-N-(fluoromethyl)-4-(2-(3-(trifluorometho x i) phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RS3-(fluoromethoxy)-n-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-n-(trifluoromethyl)butan-1-amine; S3-(fluoromethoxy)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; R3-(fluoromethoxy)-n-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-n-(trifluoromethyl)butan-1-amine; RSN-(difluoromethyl)-3-(fluoromethoxy)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; SN-(difluoromethyl)-3-(fluoromethoxy)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RN-(difluoromethyl)-3-(fluoromethoxy)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RS3-(fluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; S3-(fluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; R3-(fluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RS3-(fluoromethoxy)-N,N-dimethyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine;

S3-(fluoromethoxy)-N,N-dimethyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; R3-(fluoromethoxy)-N,N-dimethyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RS4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-(fluoromethoxy)-N,N-dimethylbutan-1-amine; S4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-(fluoromethoxy)-N,N-dimethylbutan-1-amine; R4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-(fluoromethoxy)-N,N-dimethylbutan-1-amine; RS3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; S3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; R3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-bis(trifluoromethyl)butan-1-amine; RSN-(difluoromethyl)-3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; SN-(difluoromethyl)-3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RN-(difluoromethyl)-3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine;

RSN-(fluoromethyl)-3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; SN-(fluoromethyl)-3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RN-(fluoromethyl)-3-methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine;

RS3-methoxy-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; S3-methoxy-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; R3-methoxy-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-(trifluoromethyl)butan-1-amine; RS4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; S4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; R4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; RSN-(fluoromethyl)-3-methoxy-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; SN-(fluoromethyl)-3-methoxy-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RN-(fluoromethyl)-3-methoxy-N-methyl-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)butan-1-amine; RS4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; S4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; R4-(2-(3-(difluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; RS4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; S4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; R4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; RS4-(2-(3(fluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; S4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; R4-(2-(3-(fluoromethoxy)phenethyl)phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine; RS1-(piperidin-1-yl)-3-(m-tolyloxy)propan-2-ol; S1-(piperidin-1-yl)-3-(m-tolyloxy)propan-2-ol; R1-(piperidin-1-yl)-3-(m-tolyloxy)propan-2-ol; RS 1-(4-(3-methoxyphenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; S1-(4-(3-methoxyphenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; R1-(4-(3-methoxyphenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; RS1-(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yl)-3-(m-tolyloxy)propan-2-ol; S1-(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yl)-3-(m-tolyloxy)propan-2-ol; R1-(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yl)-3-(m-tolyloxy)propan-2-ol; RS1-morpholino-3-(m-tolyloxy)propan-2-ol; S1-morpholino-3-(m-tolyloxy)propan-2-ol; R1-morpholino-3-(m-tolyloxy)propan-2-ol; RS3,3'-(phenylazandiyl)bis(1-phenoxypropan-2-ol); S3,3'-(phenylazandiyl)bis(1-phenoxypropan-2-ol); R3,3'-(phenylazandiyl)bis(1-phenoxypropan-2-ol); RS1-(2,2,5,5-tetramethylpyrrolidin-1-yl)-3-(m-tolyloxy)propan-2-ol; S1-(2,2,5,5-tetramethylpyrrolidin-1-yl)-3-(m-tolyloxy)propan-2-ol; R1-(2,2,5,5-tetramethylpyrrolidin-l-yl)-3-(m-tolyloxy)propan-2-ol; RS1-(tert-butylamino)-3-(3,4-dimethylphenoxy)propan-2-ol; S1-(t-butylamino)-3-(3,4-dimethylphenoxy)propan-2-ol; R1-(tert-butylamino)-3-(3,4-dimethylphenoxy)propan-2-ol; RS1-(4-(3-chlorophenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; S1-(4-(3-chlorophenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; R1-(4-(3-chlorophenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; RS1-(dimethylamino)-3-(2-phenoxyphenoxy)propan-2-ol; S1-(dimethylamino)-3-(2-phenoxyphenoxy)propan-2-ol; R1-(dimethylamino)-3-(2-phenoxyphenoxy)propan-2-ol; RS1-(pyrrolidin-1-yl)-3-(m-tolyloxy)propan-2-ol; S1-(pyrrolidin-1-yl)-3-(m-tolyloxy)propan-2-ol; R1-(pyrrolidin-1-yl)-3-(m-tolyloxy)propan-2-ol; RS1-amino-3-(3,5-dimethylphenoxy)propan-2-ol; S 1-amino-3-(3,5-dimethylphenoxy)propan-2-ol; R1-amino-3-(3,5-dimethylphenoxy)propan-2-ol; RS1-(dimethylamino)-3-(2-phenethylphenoxy)propan-2-ol; S1-(dimethylamino)-3-(2-phenethylphenoxy)propan-2-ol; R1-(dimethylamino)-3-(2-phenethylphenoxy)propan-2-ol; RS1-(benzylamino)-3-(3-(trifluoromethyl)phenoxy)propan-2-ol; S1-(benzylamino)-3-(3-(trifluoromethyl)phenoxy)propan-2-ol; R1-(benzylamino)-3-(3-(trifluoromethyl)phenoxy)propan-2-ol; RS1-amino-3-phenoxypropan-2-ol; S1-amino-3-phenoxypropan-2-ol; R1-amino-3-phenoxypropan-2-ol; RS1-((3-chloro-2-methylphenyl)amino)-3-phenoxypropan-2-ol; S1-((3-chloro-2-methylphenyl)amino)-3-phenoxypropan-2-ol; R1-((3-chloro-2-methylphenyl)amino)-3-phenoxypropan-2-ol; RS1-((2-((2,4-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((2,4-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((2,4-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-((3-(aminomethyl)phenyl)(methyl)amino)-3-phenoxypropan-2-ol; S1-((3-(aminomethyl)phenyl)(methyl)amino)-3-phenoxypropan-2-ol; R1-((3-(aminomethyl)phenyl)(methyl)amino)-3-phenoxypropan-2-ol; RS1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-((2-((4-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((4-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((4-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-((3-methoxypropyl)amino)-3-phenoxybutan-2-ol; S1-((3-methoxypropyl)amino)-3-phenoxybutan-2-ol; R1-((3-methoxypropyl)amino)-3-phenoxybutan-2-ol; RS1-(isopropylamino)-3-((2-methyl-1H-indol-4-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((2-methyl-1H-indol-4-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((2-methyl-1H-indol-4-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-((6-methylfuro[3,2-c]pyridin-4-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((6-methylfuro[3,2-c]pyridin-4-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((6-methylfuro[3,2-c]pyridin-4-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-(naphthalene-1-ylmethoxy)propan-2-ol; S1-(isopropyl amino)-3-(naphthalene-1-ylmethoxy)propan-2-ol; R1-(isopropylamino)-3-(naphthalene-1-ylmethoxy)propan-2-ol; RS1-(isopropylamino)-3-((3-(4-methylpipnrazin-1-yl)pyrazin-2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((3-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((3-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)propan-2-ol; RS1-(2-nitro-1H-imidazol-1-yl)-3-phenoxypropan-2-ol; S1-(2-nitro-1H-imidazol-1-yl)-3-phenoxypropan-2-ol; R1-(2-nitro-1H-imidazol-1-yl)-3-phenoxypropan-2-ol; RS1-(6-amino-2-ethoxy-9H-purin-9-yl)-3-phenoxypropan-2-ol; S1-(6-amino-2-ethoxy-9H-purin-9-yl)-3-phenoxypropan-2-ol; R1-(6-amino-2-ethoxy-9H-purin-9-yl)-3-phenoxypropan-2-ol; RS1-(isopropylamino)-3-((2-methylfuro[3,2-c]pyridin-4-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((2-methylfuro[3,2-c]pyridin-4-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((2-methylfuro[3,2-c]pyridin-4-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-(p-tolyloxy)propan-2-ol; S1-(isopropylamino)-3-(p-tolyloxy)propan-2-ol; R1-(isopropylamino)-3-(p-tolyloxy)propan-2-ol; RS1-(isopropylamino)-3-((5-methyl-3-morpholinopyrazin-2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((5-methyl-3-morpholinopyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((5-methyl-3-morpholinopyrazin-2-yl)oxy)propan-2-ol; RS1-(4-(2-chlorophenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; S1-(4-(2-chlorophenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; R1-(4-(2-chlorophenyl)piperazin-1-yl)-3-phenoxypropan-2-ol; RS1-(isopropylamino)-3-((2-methylthieno[3,2-c]pyridin-4-yl)oxy)propan-2-ol; 81-(isopropylamino)-3-((2-methylthieno[3,2-c]pyridin-4-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((2-methylthieno[3,2-c]pyridin-4-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-(pyrimidin-2-yloxy)propan-2-ol; 81-(isopropylamino)-3-(pyrimidin-2-yloxy)propan-2-ol; R1-(isopropylamino)-3-(pyrimidin-2-yloxy)propan-2-ol; RS1-((3,4-dimethoxyphenethyl)amino)-3-phenoxypropan-2-ol; S1-((3,4-dimethoxyphenethyl)amino)-3-phenoxypropan-2-ol; R1-((3,4-dimethoxyphenethyl)amino)-3-phenoxypropan-2-ol; RS1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(isopropylamino)-3-phenoxypropan-2-ol; S1-(isopropylamino)-3-phenoxypropan-2-ol; R1-(isopropylamino)-3-phenoxypropan-2-ol;

RS1-(4-(3-(lH-l,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(3-(1H-1,2,4-triazol-l-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(isopropylamino)-3-(o-tolyloxy)propan-2-ol; S1-(isopropylamino)-3-(o-tolyloxy)propan-2-ol; R1-(isopropylamino)-3-(o-tolyloxy)propan-2-ol; RS2-(isopropylamino)-1-(4-methoxyphenoxy)ethan-1-ol; S2-(isopropylamino)-1-(4-methoxyphenoxy)ethan-1-ol; R2-(isopropylamino)-1-(4-methoxyphenoxy)ethan-1-ol; RS(Z)-l-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-1-yl)phenoxy)propan-2-ol; S(Z)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-1-yl)phenoxy)propan-2-ol; R(Z)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-1-yl)phenoxy)propan-2-ol; RS1-(isopropylamino)-3-(4-(2-(methylthio)ethoxy)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(4-(2-(methylthio)ethoxy)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(4-(2-(methylthio)ethoxy)phenoxy)propan-2-ol; RS(E)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-1-yl)phenoxy)propan-2-ol; S(E)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-1-yl)phenoxy)propan-2-ol; R(E)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-1-yl)phenoxy)propan-2-ol; RS1-(isopropylamino)-3-(mesityloxy)propan-2-ol; S1-(isopropylamino)-3-(mesityloxy)propan-2-ol; R1-(isopropylamino)-3-(mesityloxy)propan-2-ol; RS1-(isopropylamino)-3-(4-((1-(methylthio)propan-2-yl)oxy)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(4-((1-(methylthio)propan-2-yl)oxy)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(4-((1-(methylthio)propan-2-yl)oxy)phenoxy)propan-2-ol; RS1-(isopropylamino)-3-(4-(3-methyl-1H-indol-2-yl)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(4-(3-methyl-1H-indol-2-yl)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(4-(3-methyl-1H-indol-2-yl)phenoxy)propan-2-ol; RS1-(isopropylamino)-3-(2-((5-methylisoxazol-3-yl)methoxy)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(2-((5-methylisoxazol-3-yl)methoxy)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(2-((5-methylisoxazol-3-yl)methoxy)phenoxy)propan-2-ol; RS1-(isopropylamino)-3-(2-((3-methylisoxazol-5-yl)methoxy)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(2-((3-methylisoxazol-5-yl)methoxy)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(2-((3-methylisoxazol-5-yl)methoxy)phenoxy)propan-2-ol; RS1-(4-((2H-l,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-((2H-1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-((2H-1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(isopropylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol; RS1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(isopropylamino)-3-(3-methoxyphenoxy)propan-2-ol; S1-(isopropylamino)-3-(3-methoxyphenoxy)propan-2-ol; R1-(isopropylamino)-3-(3-methoxyphenoxy)propan-2-ol; RS1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(4-(2-(1H-pyrazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(2-(1H-pyrazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(1H-pyrazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol;

RS1-(4-((2H-1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-((2H-1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-((2H-1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RSN-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)propionamide; SN-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)propionamide; RN-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)propionamide; RS1-(isopropylamino)-3-((4-methylnaphthalene-1-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((4-methylnaphthalene-1-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((4-methylnaphthalen-1-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-((2-(methylthio)pyrimidin-4-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((2-(methylthio)pyrimidin-4-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((2-(methylthio)pyrimidin-4-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-(naphthalene-2-yloxy)propan-2-ol; S1-(isopropylamino)-3-(naphthalene-2-yloxy)propan-2-ol; R1-(isopropylamino)-3-(naphthalene-2-yloxy)propan-2-ol; RS1-(isopropylamino)-3-((3-(phenylthio)pyrazin-2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((3-(phenylthio)pyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((3-(phenylthio)pyrazin-2-yl)oxy)propan-2-ol; RS3-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenyl)propanal; S3-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenyl)propanal; R3-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenyl)propanal; RS1-(isopropylamino)-3-phenylpropan-2-ol; S1-(isopropylamino)-3-phenylpropan-2-ol; R1-(isopropylamino)-3-phenylpropan-2-ol; RS1-(isoproylamino)-3-(m-tolyloxy)propan-2-ol; S1-(isopropylamino)-3-(m-tolyloxy)propan-2-ol; R1-(isopropylamino)-3-(m-tolyloxy)propan-2-ol; RS1-(isopropylamino)-3-((6-morpholinopyridazin-3-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((6-morpholinopyridazin-3-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((6-morpholinopyridazin-3-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-(2-methyl-3-nitrophenoxy)propan-2-ol;

S1-(isopropylamino)-3-(2-methyl-3-nitrophenoxy)propan-2-ol; R1-(isopropylamino)-3-(2-methyl-3-nitrophenoxy)propan-2-ol; RS1-(isopropylamino)-4-(p-tolylthio)butan-2-ol; S1-(isopropylamino)-4-(p-tolylthio)butan-2-ol; R1-(isopropylamino)-4-(p-tolylthio)butan-2-ol; RS1-(4-(2-(1H-pyrazol-l-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(2-(1H-pyrazol-1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(2-(lH-pyrazol-l-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-((2-aminopyridin-3-yl)oxy)-3-(isopropylamino)propan-2-ol;

S1-((2-aminopyridin-3-yl)oxy)-3-(isopropylamino)propan-2-ol; R1-((2-aminopyridin-3-yl)oxy)-3-(isopropylamino)propan-2-ol; RS1-(tert-butylamino)-3-(3-methyl-2-nitrophenoxy)propan-2-ol;

S1-(t-butylamino)-3-(3-methyl-2-nitrophenoxy)propan-2-ol; R1-(t-butylamino)-3-(3-methyl-2-nitrophenoxy)propan-2-ol; RS1-(2-cyclohexylphenoxy)-3-(isopropylamino)propan-2-ol;

S1-(2-cyclohexylphenoxy)-3-(isopropylamino)propan-2-ol; R1-(2-cyclohexylphenoxy)-3-(isopropylamino)propan-2-ol; RS1-(4-(1-hydroxy-2-methoxyethyl)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(1-hydroxy-2-methoxyethyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(1-hydroxy-2-methoxyethyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(3-aminophenoxy)-3-(2-methyl-1H-benzo[d]imidazol-1-yl)propan-2-ol; S1-(3-aminophenoxy)-3-(2-methyl-1H-benzo[d]imidazol-1-yl)propan-2-ol; R1-(3-aminophenoxy)-3-(2-methyl-1H-benzo[d]imidazol-1-yl)propan-2-ol; RS1-(4-(2-(cytobutylmethoxy)ethoxy)phenoxy)-3(isopropylamino)propan-2-ol; S1-(4-(2-(cyclobutylmethoxy)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; Rl-(4-(2-(cyclobutylmethoxy)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-((2-((6-chloropyridazin-3-yl)oxy)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((6-chloropyridazin-3-yl)oxy)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((6-chloropyridazin-3-yl)oxy)ethyl)amino)-3-phenoxypropan-2-ol; RS1-(4-(2-(cyclopropylmethoxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-(2-(cyclopropylmethoxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; Rl-(4-(2-(cyclopropylmethoxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS3,3'-(butylazandiyl)bis(l-phenoxypropan-2-ol); S3,3'-(butylazandiyl)bis(1-phenoxypropan-2-ol); R3,3'-(butylazandiyl)bis(l-phenoxypropan-2-ol); RS1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(3,4-dimethylphenoxy)-3-(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yl)propan-2-ol; S1-(3,4-dimethylphenoxy)-3-(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yl)propan-2-ol; R1-(3,4-dimethylphenoxy)-3-(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yl)propan-2-ol; RS3-((2-hydroxy-3-phenoxypropyl)amino)propan-1-ol; S3-((2-hydroxy-3-phenoxypropyl)amino)propan-1-ol; R3-((2-hydroxy-3-phenoxypropyl)amino)propan-l-ol; RS5-(2-hydroxy-3-(isopropylamino)propoxy)chroman-3-yl nitrate; S5-(2-hydroxy-3-(isopropylamino)propoxy)chroman-3-yl nitrate; R5-(2-hydroxy-3-(isopropylamino)propoxy)chroman-3-yl nitrate; RS1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-((3-morpholinopyrazin-2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((3-morpholinopyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((3-morpholinopyrazin-2-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((6-methylpyrazin-2-yl)oxy)propan-2-ol; RSN-(8-(2-hydroxy-3-(isopropylamino)propoxy)-1,2,3,4,4a,7,8,8a-octahydro-1,4-ethanonaphthalen-5-yl)methanesulfonamide; SN-(8-(2-hydroxy-3-(isopropylamino)propoxy)-1,2,3,4,4a, 7,8,8a-octahydro-1,4-ethanonaphthalen-5-yl)methanesulfonamide; RN-(8-(2-hydroxy-3-(isopropylamino)propoxy)-1,2,3,4,4a,7,8,8a-octahydro-1,4-ethanonaphthalen-5-yl)methanesulfonamide; RS1-(isopropylamino)-3-((6-methoxypyridazin-3-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((6-methoxypyridazin-3-yl)oxy)propan-2-ol; R1-(isopropylamino)-3-((6-methoxypyridazin-3-yl)oxy)propan-2-ol; RS1-(isopropylamino)-3-(thiazol-2-yloxy)propan-2-ol; S1-(isopropylamino)-3-(thiazol-2-yloxy)propan-2-ol; R1-(isopropylamino)-3-(thiazol-2-yloxy)propan-2-ol; RS1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; S1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; R1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; RS1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; S1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; R1-(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; RS1-(4-allyl-2-methoxyphenoxy)-3-(isopropylamino)propan-2-ol; S1-(4-allyl-2-methoxyphenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-allyl-2-methoxyphenoxy)-3-(isopropylamino)propan-2-ol; RS1-(isopropylamino)-3-(2,4,5-trimethylphenoxy)propan-2-ol; S1-(isopropylamino)-3-(2,4,5-trimethylphenoxy)propan-2-ol; R1-(isopropylamino)-3-(2,4,5-trimethylphenoxy)propan-2-ol; RS1-(isopropylamino)-3-(2-methoxyphenoxy)propan-2-ol; S1-(isopropylamino)-3-(2-methoxyphenoxy)propan-2-ol; R1-(isopropylamino)-3-(2-methoxyphenoxy)propan-2-ol; RS1-(4-(2-methoxyethyl)phenoxy)-3-((3-phenylpropyl)amino)propan-2-ol; S1-(4-(2-methoxyethyl)phenoxy)-3-((3-phenylpropyl)amino)propan-2-ol; R1-(4-(2-methoxyethyl)phenoxy)-3-((3-phenylpropyl)amino)propan-2-ol; RS1-(2-(methylthio)phenoxy)-3-(2,2,5,5-tetramethylpyrrolidin-1-yl)propan-2-ol; S1-(2-(methylthio)phenoxy)-3-(2,2,5,5-tetramethylpyrrolidin-1-yl)propan-2-ol;

R1-(2-(methylthio)phenoxy)-3-(2,2,5,5-tetramethylpyrrolidin-l-yl)propan-2-ol; RS3,3'-((2-hydroxyethyl)azandiyl)bis(1-phenoxypropan-2-ol);S3,3'-((2-hydroxyethyl)azandiyl)bis(1-phenoxypropan-2-ol);R3,3'-((2-hydroxyethyl)azandiyl)bis(1-phenoxypropan-2-ol);RS1-(2-(methylthio)phenoxy)-3-(2,2,6,6-tetramethylpiperidin-1-yl)propan-2-ol;S1-(2-(methylthio)phenoxy)-3-(2,2,6,6-tetramethylpiperidin-1-yl)propan-2-ol;R1-(2-(methylthio)phenoxy)-3-(2,2,6,6-tetramethylpiperidin-1-yl)propan-2-ol;RS1-(3,6-dihydropyridin-1(2H)-yl)-3-(o-tolyloxy)propan-2-ol;S1-(3,6-dihydropyridin-1(2H)-yl)-3-(o-tolyloxy)propan-2-ol; R ₁ -(3,6-dihydropyridin-1(2H)-yl)-3-(o-tolyloxy)propan-2-ol; RS1-((4-methoxyphenyl)amino)-3-phenoxypropan-2-ol; S1-((4-methoxyphenyl)amino)-3-phenoxypropan-2-ol; R1-((4-methoxyphenyl)amino)-3-phenoxypropan-2-ol; RS1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; S1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; R1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; RS1-(4-(2-methoxyphenyl)piperazin-1-yl)-3-(m-tolyloxy)propan-2-ol; S1-(4-(2-methoxyphenyl)piperazin-1-yl)-3-(m-tolyloxy)propan-2-ol; Rl-(4-(2-methoxyphenyl)piperazin-1-yl)-3-(m-tolyloxy)propan-2-ol; RS1-((2-((2,5-dimethylphenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; S1-((2-((2,5-dimethylphenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; R1-((2-((2,5-dimethylphenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; RS1-(((1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol; S1-(((1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol; Rl-(((1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol; RS1-(tert-butylamino)-3-((3-methyl-1H-indol-4-yl)oxy)propan-2-ol; S1-(t-butylamino)-3-((3-methyl-1H-indol-4-yl)oxy)propan-2-ol; R1-(t-butylamino)-3-((3-methyl-1H-indol-4-yl)oxy)propan-2-ol; RS1-(methylamino)-3-phenoxypropan-2-ol; 81-(methylamino)-3-phenoxypropan-2-ol; R1-(methylamino)-3-phenoxypropan-2-ol; RS1-((2-hydroxyethyl)amino)-3-phenoxypropan-2-ol; 81-((2-hydroxyethyl)amino)-3-phenoxypropan-2-ol; R1-((2-hydroxyethyl)amino)-3-phenoxypropan-2-ol; RS1-((4-methylthiazol-5-yl)oxy)-3-(4-(2-(neopentyloxy)phenyl)piperazin-1-yl)propan-2-ol; S1-((4-methylthiazol-5-yl)oxy)-3-(4-(2-(neopentyloxy)phenyl)piperazin-1-yl)propan-2-ol; Rl-((4-methylthiazol-5-yl)oxy)-3-(4-(2-(neopentyloxy)phenyl)piperazin-l-yl)propan-2-ol; RS1-(4-(2-ethoxyphenyl)piperazin-l-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; S1-(4-(2-ethoxyphenyl)piperazin-1-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; R1-(4-(2-ethoxyphenyl)piperazin-1-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; RS1-phenoxy-3-(quinuclidin-3-ylamino)propan-2-ol; S1-phenoxy-3-(quinuclidin-3-ylamino)propan-2-ol; R1-phenoxy-3-(quinuclidin-3-ylamino)propan-2-ol; RS1-(4-(3-chlorophenyl)piperazin-1-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; S1-(4-(3-chlorophenyl)piperazin-1-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; Rl-(4-(3-chlorophenyl)piperazin-l-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; RS1-(((6,7-dimethoxyisochroman-l-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol; 81-(((6,7-dimethoxyisochroman-1-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol; Rl-(((6,7-dimethoxyisochroman-l-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol; RS1-((2-aminoethyl)amino)-3-phenoxypropan-2-ol; S1-((2-aminoethyl)amino)-3-phenoxypropan-2-ol; R1-((2-aminoethyl)amino)-3-phenoxypropan-2-ol; RS1-(4-(2-(isopentyloxy)phenyl)piperazin-l-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; S1-(4-(2-(isopentyloxy)phenyl)piperazin-1-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; R1-(4-(2-(isopentyloxy)phenyl)piperazin-l-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; RS1-(4-(2-isobutoxyphenyl)piperazin-l-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; S1-(4-(2-isobutoxyphenyl)piperazin-1-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; R1-(4-(2-isobutoxyphenyl)piperazin-l-yl)-3-((4-methylthiazol-5-yl)oxy)propan-2-ol; RS1-((2-((2,6-dimethylphenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((2,6-dimethylphenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((2,6-dimethylphenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-((2-((2-chlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((2-chlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((2-chlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-phenoxy-3-((2-(o-tolylamino)ethyl)amino)propan-2-ol; S1-phenoxy-3-((2-(o-tolylamino)ethyl)amino)propan-2-ol;

R1-phenoxy-3-((2-(o-tolylamino)ethyl)amino)propan-2-ol; RS1-((4-methoxybutyl)amino)-3-phenoxypropan-2-ol; 81-((4-methoxybutyl)amino)-3-phenoxypropan-2-ol; R1-((4-methoxybutyl)amino)-3-phenoxypropan-2-ol; RS 1-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; S1-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol;

R1-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; RS1-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; S1-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; Rl-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol; RS1-((2-((2-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((2-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; Rl-((2-((2-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-((2-((2-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S1-((2-((2-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; Rl-((2-((2-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-(isopropylamino)-3-((l-tosyl-1H-indol-4-yl)oxy)propan-2-ol; 81-(isopropylamino)-3-((1-tosyl-1H-indol-4-yl)oxy)propan-2-ol; Rl-(isopropylamino)-3-((1-tosyl-1H-indol-4-yl)oxy)propan-2-ol.

[0086] Another embodiment is a compound of formula If, where R ₆ and R ₇ are independently substituted with one, two, or three halogens, where halogen is F, Cl, or Br. Examples of halogenated compounds of formula I include, without limitation:

N-methyl-N-(trifluoromethyl)-2-((1,7,7-trimethyl-2-phenylbicyclo[2.2.1]heptan-2-yl)oxy)ethan-1-amine,

N,N-bis(trifluoromethyl)-2-((1,7,7-trimethyl-2-phenylbicyclo[2.2.1]heptan-2-yl)oxy)ethan-1-amine,

2-((1,7-dimethyl-2-phenyl-7-(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)-N,N-bis(trifluoromethyl)ethan-1-amine,

2-((1-methyl-2-phenyl-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)-N,N-bis(trifluoromethyl)ethan-1-amine,

N-methyl-2-((1-methyl-2-phenyl-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)-N-(trifluoromethyl)ethan-1-amine ,

N,N-dimethyl-2-((1-methyl-2-phenyl-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)ethan-1-amine,

2-((1,7-dimethyl-2-phenyl-7-(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)-N,N-dimethylethane-1-amine and

N,N-dimethyl-2-((1,7,7-trimethyl-2-(4-(trifluoromethoxy)phenyl)bicyclo[2.2.1]heptan-2-yl)oxy)ethan-1-amine.

[0087] Another embodiment is a composition containing a compound of formula If below:

2-phenyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-phenyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(p-methoxyphenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo(2,2,1)heptane;

2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-dimethylamino-2'-methylpropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(2-diisopropylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-1'-(4'-benzylpiperazinyl)propoxy-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-diisopropylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(2'-diethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(3'-dimethylaminopropoxy)-2-(4'-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(p-chlorobenzyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 2-(p-chlorobenzyl)-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; 2-(3'-dimethylamino-2'-methyl)-propoxy-2-(p-chlorophenyl)-1,7,7-trimethylbicyclo[2,2,1]heptane;

2-(3'-dimethylaminopropoxy)-2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptane; 2-(2'-dimethylaminoethoxy)-2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptane; 2-(3-diethylaminopropoxy)-2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptane; 2-(2'-diethylaminoethoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2.2.1]heptane; 2-(3'-dimethylaminopropoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2.2.1]heptane; 2-(3'-diethylaminopropoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2.2.1]heptane; 2-benzyl-2-3'-(N-cyclohexyl-N-methyl)aminopropoxy]-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(p-methoxyphenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

(1R,2S,4R)-(-)-2-[(2'-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-trimethylbicyclo[2,2,1 ]heptane;

(1R,2S,4R)-(-)-2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

(1R,2S,4R)-(-)-2-benzyl-2-(2'-methyl-3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

(1RS,2RS,4RS)-2-phenyl-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; (1S,2R,4S)-(+)-2-phenyl-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane; N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]ethanamine (deramciclane); N-methyl-N-(trifluoromethyl)-2-((1,7,7-trimethyl-2-phenylbicyclo [2.2.1]heptan-2-yl)oxy)ethan-1-amine,

N,N-bis(trifluoromethyl)-2-((1,7,7-trimethyl-2-phenylbicyclo[2.2.1]heptan-2-yl)oxy)ethan-1-amine,

2-((1,7-dimethyl-2-phenyl-7-(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)-N,N-bis(trifluoromethyl)ethan-1-amine,

2-((1-methyl-2-phenyl-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)-N,N-bis(trifluoromethyl)ethan-1-amine,

N-methyl-2-((1-methyl-2-phenyl-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)-N-(trifluoromethyl)ethan-1-amine ,

N,N-dimethyl-2-((1-methyl-2-phenyl-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)ethan-1-amine,

2-((1,7-dimethyl-2-phenyl-7-(trifluoromethyl)bicyclo[2.2.1]heptan-2-yl)oxy)-N,N-dimethylethane-1-amine and

N,N-dimethyl-2-((1,7,7-trimethyl-2-(4-(trifluoromethoxy)phenyl)bicyclo[2.2.1]heptan-2-yl)oxy)ethan-1-amine.

[0088] Another embodiment is a composition containing an acid addition salt of a compound of formula If, comprising hydrogen acetate, hydrogen acetylsalicylate, hydrogen adipate, hydrogen aspartate, hydrogen butyrate, hydrogen caprate, hydrogen caproate, hydrogen caprylate, hydrogen enanthate, hydrogen formate, hydrogen fumarate, hydrogen glutarate, hydrogen isophthalate, hydrogen maleate, hydrogen malonate, hydrogen oxalate , hydrogen pelargonate, hydrogen pimelate, hydrogen propionate, hydrogen phthalate, hydrogen salicylate, hydrogen sebacate, hydrogen succinate, hydrogen terephthalate, hydrogen tyrosinate, hydrogen tryptophanate, hydrogen methionate; hydrogen-N-acyl-methionate and hydrogenvalerate.

[0089] Another embodiment is a composition containing an acid addition salt of N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2. 1] heptanyl] oxy] ethanamine (deramciclane) envisaging gidrogenatsetat deramciclane, gidrogenatsetilsalitsilat deramciclane, gidrogenadipat deramciclane, gidrogenaspartat deramciclane, gidrogenbutirat deramciclane, gidrogenkaprat deramciclane, gidrogenkaproat deramciclane, gidrogenkaprilat deramciclane, gidrogenenantat deramciclane, gidrogenformiat deramciclane, gidrogenfumarat deramciclane, gidrogenglutarat deramciclane, gidrogenizoftalat deramciclane , Deramcilan Hydrogen Maleate, Deramcilan Hydrogen Malonate, Deramcilan Hydrogenoxalate, Deramcilan Hydrogenpelargonate, Deramcilan Hydrogen Pimelate, Deramcilan Hydrogen Propionate, Deramcilan Hydrogen Phthalate, Deramcilan Hydrogen Salicylate, Deramcilan Hydrogen Sebacate, Deramcilan Hydrogen Succinate, Deramcilan Hydrogen Terephthalate, Deramcilan Hydrogen Tyrosinate , deramcilan hydrogentryptophanate, deramcilan hydrogenmethionate; deramciclane hydrogen-N-acyl methionate; or deramcilan hydrogen valerate.

[0090] One embodiment of the present invention is a composition comprising dextromethorphan or an acid addition salt thereof and a compound of formula I selected from the group consisting of:

2-phenyl-2-(2-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-phenyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-phenyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(p-methoxyphenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-dimethylamino-2'-methylpropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(2-diisopropylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-1'-(4'-benzylpiperazinyl)propoxy-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-diisopropylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(2'-diethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(3'-dimethylaminopropoxy)-2-(4'-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(p-chlorobenzyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(p-chlorobenzyl)-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(3'-dimethylamino-2'-methyl)-propoxy-2-(p-chlorophenyl)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(3'-dimethylaminopropoxy)-2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(2'-dimethylaminoethoxy)-2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(3-diethylaminopropoxy)-2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(2'-diethylaminoethoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(3'-dimethylaminopropoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(3'-diethylaminopropoxy)-2-(2'-thienyl)-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-benzyl-2-3'-(N-cyclohexyl-N-methyl)aminopropoxy]-1,7,7-trimethylbicyclo[2.2.1]heptane;

2-(p-methoxyphenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

(1R,2S,4R)-(-)-2-[(2'-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-trimethylbicyclo[2,2,1 ]heptane;

(1R,2S,4R)-(-)-2-benzyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

(1R,2S,4R)-(-)-2-benzyl-2-(2'-methyl-3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

(1RS,2RS,4RS)-2-phenyl-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

(1S,2R,4S)-(+)-2-phenyl-2-(2'-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2.2.1]heptane;

N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]ethanamine (deramciclane); or their acid addition salts.

[0091] One embodiment of the present invention is a composition comprising dextromethorphan or an acid addition salt thereof and deramcilan, deramcilan acetate, deramcilan acetyl salicylate, deramcilan adipate, deramcilan butyrate, deramcilan caprate, deramcilan caproate, deramcilan caprylate, deramcilan enanthate, deramcilan formate, fumarate deramciclane glutarate deramciclane, isophthalate deramciclane, maleate deramciclane, malonate deramciclane, oxalate deramciclane, pelargonate deramciclane, pimelate deramciclane, propionate deramciclane phthalate deramciclane, salicylate deramciclane, sebacate deramciclane, succinate deramciclane terephthalate deramciclane, tirozinat deramciclane, triptofanat deramciclane or valerate deramciclane ; or a combination of them.

[0092] In some embodiments, the compound of formula II is a fluorine derivative, such as, without limitation: (4bS,8aS,9S)-11-methyl-3-(trifluoromethoxy)-6,7,8,8a,9,10-hexahydro -5H-9,4b-(epiminoethano)phenanthrene; (4bS,8aS,9S)-3-(trifluoromethoxy)-11-(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene; (4bS,8aS,9S)-3-methoxy-11-(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene.

[0093] In some embodiments, the compound of Formula II is an acid addition salt selected from acetate, acetylsalicylate, adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, glutamate, glutarate, isophthalate, maleate, malonate, methionate, oxalate, pelargonate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, tyrosinate, tryptophanate, valerate, N-acylaspartate, N-acylglutamate, N-acyl tyrosinate, N-acyltryptophanate, N-acylmethionate, citrate, galactonate, glucaric acid (sugar acid), mannonate, mucat, rhamnonate and tartrate.

[0094] In another embodiment, dextromethorphan or a compound of formula II as defined above, and a derivative of a compound of formula I, wherein the derivative is an acid addition salt selected from: acetate, acetylsalicylate, adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, glutamate, glutarate, isophthalate, maleate, malonate, methionate, oxalate, pelargonate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, tyrosinate, tryptophanate, valerate, N-acyl aspartate, N-acylglutamate , N-acyl tyrosinate, N-acyl tryptophanate, N-acyl methionate, citrate, galactonate, glucaric acid (sugar acid), mannonate, mucat, rhamnonate, and tartrate.

[0095] In some embodiments, the compound of formula II is an acid addition salt selected from N-acylaspartate, N-acylglutarate, N-acyl tyrosinate, N-acyl tryptophanate, and N-acyl methionate.

[0096] Examples include addition salts of the base compounds of formula II, represented by dextromethorphan, such as gidrogenatsetat dextromethorphan gidrogenatsetilsalitsilat dextromethorphan gidrogenadipat dextromethorphan gidrogenaspartat dextromethorphan gidrogenbutirat dextromethorphan gidrogenkaprat dextromethorphan gidrogenkaproat dextromethorphan gidrogenkaprilat dextromethorphan gidrogenenantat dextromethorphan gidrogenformiat dextromethorphan gidrogenfumarat dextromethorphan, gidrogenglutarat dextromethorphan, dextromethorphan gidrogenizoftalat, gidrogenmaleat dextromethorphan, dextromethorphan gidrogenmalonat, gidrogenoksalat dextromethorphan, dextromethorphan gidrogenpelargonat, gidrogenpimelat dextromethorphan, dextromethorphan gidrogenpropionat, gidrogenftalat dextromethorphan, dextromethorphan gidrogensalitsilat, gidrogensebatsinat dextromethorphan, dextromethorphan gidrogensuktsinat, gidrogentereftalat dextromethorphan, dextromethorphan gidrogentirozinat, Hydrogen dextromethorphan entriptophanate and dextromethorphan hydrogenvalerate.

[0097] Another embodiment of the present invention is a composition comprising an acid addition salt of a compound of formula I and an acid addition salt of a compound of formula II. Another embodiment of the present invention is a composition containing an acid addition salt of deramcilan and an acid addition salt of dextromethorphan.

[0098] Another embodiment of the present invention is a composition containing an acid addition salt of a halogenated compound of formula I and an acid addition salt of dextromethorphan. Another embodiment is a composition containing a halogenated compound of formula I, which is a trifluoromethyl derivative of M1.

[0099] aspartate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, camphorsulfonate, camsylate, chloride, citrate, decanoate, edetate, lauryl sulfate, estolate, ethanesulfonate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylarsanilate, hexanoate , hexylresorcinol, hydroxynaphthoate, isethionate, iodide, lactate, galactopyranosyl-d-gluconate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucat, napsilate, nitrate, octanoate, oleate, pamoate, 4,4'- methylenebis(3-hydroxy-2-naphthoate), pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, theoclate, 8-chloro-1,3-dimethyl-7h-purine-2,6-dione , tosylate, malate, methionate, phthalate, malonate, tyrosinate, tryptophanate, maleate, fumarate.

[00100] One embodiment of the present invention is an addition salt of a compound of formula I formed with an organic acid such as aspartic acid, benzenesulfonic acid, besylic acid, benzoic acid, bicarboxylic acid, tartaric acid, bromide, camphorsulfonic acid, camsilic acid, chloride, citric acid, decanoic acid, edetate, lauryl sulfonic acid, estolic acid, ethane sulfonic acid, esyl acid, fumaric acid, gluceptic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexanoic acid, hexylresorcinol, hydroxynaphthoic acid, isethionic acid, iodide, lactic acid, galactopyranosyl-d-gluconic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methyl bromide, methyl nitric acid, methyl sulfonic acid, mucic acid, napsilic acid, nitric acid , octanoic acid, oleic acid, pamoic acid, 4,4'-methylenebis (3-hydroxy-2-naphthoic acid, pantothenic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, theoclinic acid, 8-chloro-1,3-dimethyl-7h-purine-2,6-dione, tosylic acid, malic acid, methionic acid, phthalic acid, malonic acid, tyrosine, tryptophan, maleic acid, fumaric acid , succinic acid, glutaric acid, adipic acid, pimelic acid, sebacic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, oxalic acid, isophthalic acid, terephthalic acid, salicylic acid, difluorosuccinic acid, trifluorosuccinic acid, tetrafluorosuccinic acid, difluoroglutaric acid, difluoroacetic acid acid, trifluoroacetic acid and dextromethorphan; or a combination of them.

[00101] In some aspects of the present invention, the compound of formula I is a prodrug according to, where the compound is an ester or addition formed with the following acids: 3-(nitrooxy)propanoic acid (suppliers: AKos (AKOS006377427) and 1717 CheMall (OR235109)), 4-nitrohydroxybutanoic acid (suppliers: AKos (AKOS006378268) and iChemical (EBD3415162)), 3-(nitrohydroxy)butanoic acid (AKos (AKOS006376331, AKOS016035558), MolMall (21929)). Examples include, without limitation, 3-nitrooxy derivatives of compounds 71-73, 4-nitrooxy derivatives of compounds 74-76, and 3-nitrooxy derivatives of compounds 74-76. In some embodiments, the compounds of formula I form addition salts of 3-(nitrooxy)propanoic acid, 3-(nitrooxy)butanoic acid, and 4-(nitrooxy)butanoic acid. In another embodiment, the acid addition salt is formed with 3-(nitrooxy)propanoic acid, 3-(nitrooxy)butanoic acid and 4-(nitrooxy)butanoic acid.

[00102] In another embodiment, pharmaceutically acceptable acid addition salts of compounds of formula I can be formed with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, and nitric acid.

[00103] Other anionic salts of the compounds of formulas I and II include salts formed with the following acid groups:

[00104] Described acid addition salts of formula I are represented by the following formulas:

[00105] Another embodiment is a composition comprising a compound of formula I and at least one compound selected from thioridazine. perphenazine, fluphenazine, zuclopenthixol, risperidone, sertindole, nortriptyline, amitriptyline, imipramine, fluoxetine, paroxetine, aymaline, amiodarone, amitriptyline, aprindine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, doxorubicin, fluphenazine, fluphenazine, lasoprazole, levomepromazine, lopinavir, loratadine, mechitazine, methadone, metoclopramide, mibefradil, moclobemide, nelfinavir, nevirapine, nicardipine, norfluoxetine, perphenazine, pimozide, terfenadine, thioridazine, cimetidine, quinidine, cisapride, rananamine, cocaine, cocaine risperidone, ritonavir, saquinavir, sertraline, terbinafine, ticlopidine, trifluperidol, yohimbine, clomipramine, doxepin, mianserin, imipramine, 2-chlorimipramine, amitriptyline, amoxapine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, tranzotranylproram, isocarcytsia, sertraline, aryloxyindanamine a, benactizine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brazofenzine, moclobemide, rasagiline, nialamide, iproniazid, iprocloside, toloxatone, butriptyline, dosulepine, opipramol and dapoxetine.

[00106] Another embodiment of the present invention is a composition comprising a compound of formula I, a compound of formula II, and at least one compound selected from thioridazine, perphenazine, fluphenazine, zuclopenthixol, risperidone, sertindole, nortriptyline, amitriptyline, imipramine, fluoxetine, paroxetine, aimaline, amiodarone, amitriptyline, aprindine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, doxorubicin, fluphenazine, fluvastatin, haloperidol, imipramine, indinavir, lasoprazole, levomepromazine, lopinavir, loratadine, mechitazine, methokberadimide, methocberadimide, methokberamil, methadone nelfinavir, nevirapine, nicardipine, norfluoxetine, perphenazine, pimozide, terfenadine, thioridazine, cimetidine, quinidine, cisapride, citalopram, clomipramine, clozapine, cocaine, ranitidine, risperidone, ritonavir, saquinavir, sertraline, terbinafine, ticlopidine, mianserin, imipramine, 2 lorimipramina, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, trazodone, citalopram, sertraline ariloksiindanamina, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaksina, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brazofenzine, moclobemide, rasagiline, nialamide, iproniazid, iprocloside, toloxatone, butriptyline, dosulepine, dibenzepine, iprindol, lofepramine, opipramol, and dapoxetine.

[00107] In one embodiment, the composition contains a compound of formula I, where the compound, where R ³ is a conjugate or covalent compound formed either by esterification or by esterification with derivatives of one or more AChI, such as 2-((1-benzylpiperidine -4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (donepezil), (S)-3-(1-(dimethylamino)ethyl)phenylethyl(methyl)carbamate (rivastigmine), dimethyl (2,2,2-trichloro-1-hydroxyethyl)phosphonate (metrifonate), (4aS,6R,8aS)-3-methoxy-11-methyl-4а,5,9,10,11,12 -hexahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepin-6-ol (galanthamine) and 1,2,3,4-tetrahydroacridine-9-amine (tacrine), O,S-dimethylacetylamidothiophosphate , O,O-dimethyl-S-((4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)methyl)phosphorodithioate, 2,2-dimethyl-2,3-dihydrobenzofuran-7 -ylmethylcarbamate, S-(((4-chlorophenyl)thio)methyl)-O,O-diethylphosphorodithioate, 2-chloro-1-(2,4-dichlorophenyl)vinyl diethyl phosphate, O,O-diethyl-0-(3.5 ,6-trichloropyridin-2-yl)phosphorothioate, 0-(3-chloro-4-methyl-2-oxo-2H-chromene -7-yl)-O,O-diethylphosphorothioate, 1-phenylethyl-(E)-3-((dimethoxyphosphoryl)oxy)but-2-enoate, 4-(tert-butyl)-2-chlorophenylmethylmethylphosphoramidate, O,O-diethyl- O-(2-(ethylthio)ethyl)thiophosphate, O,O-diethyl-S-(2-(ethylthio)ethyl)thiophosphate, O,O-diethyl-O-(2-isopropyl-6-methylpyrimidin-4-yl )thiophosphate, 2,2-dichlorovinyldimethylphosphate, (E)-4-(dimethylamino)-4-oxobut-2-en-2-yldimethylphosphate, O,O-dimethyl S-(2-(methylamino)-2-oxoethyl)phosphorodithioate , S,S'-(1,4-dioxane-2,3-diyl)-O,O,O',O'-tetraethyl-bis(phosphorodithioate), O,O-diethyl-S-(2-(ethylthio )ethyl)phosphorodithioate, O-ethyl-O-(4-nitrophenyl)phenylphosphonothioate, O,O,O',O'-tetraethyl-S,S'-methylene-bis(phosphorodithioate), O-ethyl-S,S- dipropylphosphorodithioate, O-(4-(N,N-dimethylsulfamoyl)phenyl)-0,0-dimethylthiophosphate, O-(4-(N,N-dimethylsulfamoyl)phenyl)-O,O-dimethylthiophosphate, ethyl-(3-methyl -4-(methylthio)phenyl)isopropylphosphoramidate, O,O-dimethyl-O-(3-methyl-4-nitrophenyl)thiophosphate, O-ethyl-S-phenylethylphosphonodithioate, isopropyl-2-((ethoxy(isopropylamino)phosphorothioyl)oxy )benzoate, diethyl-2-((dimethoxyfo sphorothioyl)thio)succinate, O,S-dimethylamidothiophosphate, O,S-dimethylamidothiophosphate, S-((5-methoxy-2-oxo-1,3,4-thiadiazol-3(2H)-yl)methyl)-O, O-dimethylphosphorodithioate, methyl 3-((dimethoxyphosphoryl)oxy)but-2-enoate, (E)-dimethyl-(4-(methylamino)-4-oxobut-2-en-2-yl)phosphate, 1.2 -dibromo-2,2-dichloroethyldimethylphosphate, isopropyl-(S)-methylfluorophosphonate, 3,3-dimethylbutan-2-yl-(S)-methylfluorophosphonate, O,O-diethyl-O-(4-nitrophenyl)thiophosphate, S- (2-(ethylsulfinyl)ethyl)-O,O-dimethylthiophosphate, O,O-diethyl-S-((ethylthio)methyl)phosphorodithioate, S-((6-chloro-2-oxobenzo[d]oxazole-3(2Н )-yl)methyl)-O,O-diethylphosphorodithioate, S-((1,3-dioxoisoindolin-2-yl)methyl)-O,O-dimethylphosphorodithioate, (E)-3-chloro-4-(diethylamino)- 4-oxobut-2-en-2-yl-dimethylphosphate, O,O,O',O'-tetramethyl-O,O'-(thiobis(4,1-phenylene))bis(thiophosphate), tetraethyl diphosphate, S- ((tert-butylthio)methyl)-O,O-diethylphosphorodithioate, 2-chloro-1-(2,4,5-trichlorophenyl)vinyldimethylphosphate and dimethyl(2,2,2-trichloro-1-hydroxyethyl)phosphonate or pharmaceutically thereof acceptable derivatives, metabolites, and taxes or salts produced using the principles of prodrug formation described in Figure 13, where parent drug compounds of formulas I and II are represented by R, the general schemes being various embodiments of prodrugs based on compounds of formulas I and II (see eg Rautio et al., The expanding role of prodrugs in contemporary drug design and development, Nature Reviews Drug Discovery, available online at http://dx.doi.org/10.1038/nrd.2018.46 (April 27, 2018 .); Stella, Prodrugs: Some thoughts and current issues. J Pharm. sci. 99, 4755-4765 (2010); Clas et al., Chemistry-enabled drug delivery (prodrugs): recent progress and challenges. drug discov. Today 19, 79-87 (2014); Rautio et al., Prodrugs - Recent approvals and a glimpse of the pipeline. Eur. J Pharm. sci. 109, 146-161 (2017); Rautio et al. Prodrugs: design and clinical applications. Nat. Rev. drug discov. 7, 255-270 (2008); Stella et al., Prodrug strategies to overcome poor water solubility. Adv. drug deliv. Rev.59, 677-694 (2007); Kumpulainen et al. Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol. Eur. J Pharm. sci. 34, 110-117 (2008); Hale et al. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J. Med. Chem. 43, 1234-1241 (2000); Ishikawa et al. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg. Med. Chem. 11, 2427-2437 (2003); Mehellou et al., Aryloxy phosphor ami date triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells. ChemMedChem 4, 1779-1791 (2009); Thornton et al., Nucleoside phosphate and phosphonate prodrug clinical candidates. J. Med. Chem. 59. 10400-10410 (2016); Pradere et al., Synthesis of nucleoside phosphate and phosphonate prodrugs. Chem. Rev.114, 9154-9218 (2014); Starrett et al. Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl) adenine. AntiviralRes. 19, 267-273 (1992); Starrett et al. Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). J. Med. Chem. 37, 1857-1864 (1994); McGuigan et al. Synthesis, anti-human immunodeficiency virus activity and esterase lability of some novel carboxylic ester-modified phosphoramidate derivatives of stavudine (d4T). antivirus. Chem. Chemother. 9, 473-479 (1998); McGuigan et al., Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency. antivirus. Chem. Chemother. 9, 109-115 (1998); Erion et al. Design, synthesis, and characterization of a series of cytochrome P(450) 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver. J. Am. Chem. soc. 126, 5154-5163 (2004); Yuan et al., Evaluation of in vitro models for screening alkaline phosphatase-mediated bioconversion of phosphate ester prodrugs. drugmetab. Dispos. 37, 1443-1447 (2009); Heimbach et al, Absorption rate limit considerations for oral phosphate prodrugs. Pharm. Res. 20, 848-856 (2003); Kadow et al., Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment 6. Preclinical and human pharmacokinetic profiling of BMS-663749, a phosphonooxymethyl prodrug of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl )-l-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxo ethanone (BMS-488043). J. Med. Chem. 55, 2048-2056 (2012); Heimbach et al, Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs. Int. J Pharm. 261, 81-92 (2003); all of which are incorporated herein by reference in their entirety).

[00108] In another embodiment, prodrugs based on compounds of formula I include, without limitation:

[00109] In another embodiment, prodrugs based on a compound of formula I, examples of which are, without limitation, compounds 901-978, represented by formulas P1-P11, PA-1 and PA-2, PF1-PF9, PT1-PT34, where P=phosphate , PA=phosphoramidate, PF=fluorophosphonate, and PT=thiophosphate are also inhibitors of acetylcholinesterase due to the presence of phosphate, phosphoramidate, fluorophosphonate, and phosphothioate moieties that confer such activity (McGleenon et al., Acetylcholinesterase inhibitors in Alzheimer's disease, Br J Clin Pharmacol, 48 , 471-480 (1999) Acetylcholinesterase Inhibitors and Memantme. http://www.fifeadtc.scot.nhs.uk/media/8535/cholinesterase-inhibitors-and-memantine-scp.pdf; incorporated by reference).

APPLICATIONS

) являлись: деменция: 22164 евро; психотические нарушения: 16717 евро; расстройства настроения: 19238 евро; зависимость: 11719 евро; тревожные расстройства: 11687 евро. Помимо психоза, эти пять расстройств относятся к числу расстройств, для лечения которых характерны самые низкие прямые медицинские расходы на одного субъекта (<3000

) (Feinberg et al., The size, burden and cost of disorders of the brain in the UK, J Psychopharmacol. 27(9): 761-770 (сентябрь, 2013 г.); Projections of the Cost of Cancer Care in the United States: 2010-2020, J Natl Cancer Inst. 103(2): 117-128 (19 января, 2011 г.), включенные во всей своей полноте посредством ссылки). Более десяти лет назад было подсчитано, что суммарные затраты на биполярное расстройство (BP), также известное как маниакально-депрессивное заболевание, достигали 45 миллиардов долларов в год. Большая часть этих затрат приходится на непрямые затраты, связанные со снижением функциональных возможностей и потерей работы. Пациенты с BP имеют более высокие показатели использования ресурсов здравоохранения по сравнению с населением в целом и по сравнению с пациентами с другими типами психиатрических состояний. Сопутствующая патология усугубляет тяжелое бремя, которое BP накладывает на общество. Заболевания головного мозга представляют значительное социальное и экономическое бремя в Европе. При ежегодных затратах в 800 миллиардов евро и приблизительно 179 миллионах людей, страдающих от этих заболеваний в 2010 году, заболевания головного мозга представляют собой неоспоримую чрезвычайную ситуацию и серьезную проблему для специалистов в области нейронаук. Общие затраты на психические расстройства в мире в 2010 году оценили в 2,5 триллиона долларов США, а в 2030 году согласно прогнозам они превысят 6 триллионов долларов США. Мультиформная глиобластома является наиболее распространенной злокачественной первичной опухолью головного мозга у взрослых с оценочной частотой возникновения в США, составляющей 4,43 случая на 100000 человеко-лет, и средним возрастом на момент постановки диагноза, составляющим 64 года. Симптомы часто включают головные боли; тошноту и рвоту; а также прогрессирующее ухудшение памяти, личностные или неврологические расстройства. При этом для болезни Альцгеймера и других форм деменции предполагается, что с 2005 по 2030 год рост составит 66%. В Соединенных Штатах Америки депрессия является второй по распространенности причиной инвалидности среди женщин, и лица, не отвечающие на лечение антидепрессантами, являются одними из самых больших потребителей ресурсов здравоохранения. Несмотря на явное снижение качества жизни и снижение продуктивности, связанные с депрессией, зачастую ее редко диагностируют и неадекватно лечат.[00110] The five most costly brain disorders (in millions

) were: dementia: EUR 22,164; psychotic disorders: 16,717 euros; mood disorders: €19,238; dependence: 11,719 euros; anxiety disorders: 11,687 euros. In addition to psychosis, these five disorders are among the disorders with the lowest direct medical costs per subject (<3000

) (Feinberg et al., The size, burden and cost of disorders of the brain in the UK, J Psychopharmacol. 27(9): 761-770 (September 2013); Projections of the Cost of Cancer Care in the United States: 2010-2020, J Natl Cancer Inst. 103(2): 117-128 (January 19, 2011) incorporated by reference in their entirety). Over a decade ago, it was estimated that the total cost of bipolar disorder (BP), also known as manic-depressive illness, was as high as $45 billion a year. Most of these costs are indirect costs associated with reduced functionality and job loss. Patients with BP have higher rates of healthcare resource utilization compared to the general population and compared to patients with other types of psychiatric conditions. The comorbidity exacerbates the heavy burden that BP places on society. Brain diseases represent a significant social and economic burden in Europe. With an annual cost of 800 billion euros and approximately 179 million people suffering from these diseases in 2010, brain diseases represent an undeniable emergency and a major challenge for neuroscientists. The total cost of mental disorders in the world in 2010 was estimated at 2.5 trillion US dollars, and in 2030, according to forecasts, they will exceed 6 trillion US dollars. Glioblastoma multiforme is the most common malignant primary brain tumor in adults, with an estimated incidence in the United States of 4.43 cases per 100,000 person-years and a median age at diagnosis of 64 years. Symptoms often include headaches; nausea and vomiting; as well as progressive memory impairment, personality or neurological disorders. At the same time, for Alzheimer's disease and other forms of dementia, it is assumed that from 2005 to 2030 the increase will be 66%. In the United States of America, depression is the second leading cause of disability among women, and people who do not respond to antidepressant treatment are among the largest consumers of health care resources. Despite the apparent decline in quality of life and productivity associated with depression, it is often underdiagnosed and inadequately treated.

[00111] Drug and alcohol addiction is a serious public health problem. An estimated 26.4 to 36 million people worldwide abuse opioids (UNODC, World Drug Report 2012), with approximately 2.1 million people in the United States of America suffering from substance use disorders associated with prescription opioid analgesics in Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA ) 13-4795 Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013; incorporated by reference in its entirety). The number of unintentional deaths from overdose of prescription painkillers has risen sharply in the United States of America, more than quadrupling since 1999. There is growing evidence that there is a growing body of evidence in the United States of America showing a relationship between increased non-medical abuse of opioid analgesics and heroin abuse (Pradip et al., Associations of Nonmedical Pain Reliever Use and Initiation of Heroin Use in the US , Center for Behavioral Health Statistics and Quality Data Review, SAMHSA (2013); incorporated by reference in its entirety).

[00112] An association has long been assumed and has been confirmed in recent years between metabolic disturbances in chronic diabetes and the risk and occurrence of pathophysiology characteristic of AD (Goldwaser et al., Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link between Diabetes Mellitus and Alzheimer's Disease J Alzheimers Dis (August 1, 2016; incorporated by reference in its entirety). In several large post-mortem studies, more than a third of all subjects clinically diagnosed with typical AD had evidence of cerebrovascular disease and should be categorized as mixed dementia. (Grandal et al., Prevalence and concordance between the clinical and the post-mortem diagnosis of dementia in a psycho geriatric clinic, Neurologia (2016); incorporated by reference in its entirety). Therefore, from a clinical point of view, it is desirable to expand AD therapy beyond currently approved drugs and mechanisms, and also to combat cognitive impairment by optimizing for metabolic disturbance in latent diabetes or the fairly common type 2 diabetes in the elderly. Indeed, the implementation of glycemic control is believed to affect the severity of cognitive impairment (Zilliox et al., Diabetes and Cognitive Impairment. Curr Diab Rep, 16 (9): 87 (2016); incorporated in its entirety by reference). Due to the specific anti-diabetic activity of the compound of formula I described above, in one embodiment, the present invention provides benefits both in terms of symptoms and disease progression in AD, and in cognitive disorders mainly of vascular origin (multi-infarct dementia, vascular dementia, vascular cognitive impairment). violations, etc.).

[00113] In Parkinson's disease, the anticholinergic effects of antipsychotics are highly undesirable because they inevitably lead to deterioration in relation to, in addition, the level of motor activity and symptoms of the autonomic nervous system. In all forms of dementia, lowering of the seizure threshold is another infrequent but highly undesirable possible adverse effect of antipsychotics. Approximately 10 million people worldwide have Parkinson's disease. Parkinson's disease is a synnucleopathy leading to progressive neurodegeneration marked by motor dysfunction and non-motor symptoms, including psychosis. More than 50% of patients with Parkinson's disease develop psychosis at some point. Psychosis affects up to 75% of patients with Parkinson's dementia, and symptoms in this group are more difficult to treat. Such psychosis is expressed primarily in the form of hallucinations and delusions, which can cause severe distress to patients and their caregivers. These episodes pose a significant challenge to treatment and care, increase the likelihood of placement in nursing homes, and are associated with increased mortality. Best treatment guidelines provide early consideration of comorbidities and reduction of dopaminergic therapy. However, these approaches are often insufficient and several other therapy options exist.

[00114] The morbidity and mortality associated with depression is significant and continues to rise. Depression is now the fourth leading cause of disability worldwide, after lower respiratory tract infections, perinatal conditions and HIV/AIDS. Over the course of a lifetime, depression occurs in seventeen percent of people; Worse still, people who already have either an acute or chronic illness are even more likely to develop depression, with depression rates in patients ranging from 30% to 50% depending on the specific medical condition.

[00115] The monoamine hypothesis has been the predominant hypothesis for the onset of depression over the past few decades. According to this hypothesis, depression is associated with a decrease in monoamine function. Consequently, efforts to enhance monoamine transmission by inhibiting the serotonin (5-HT) and norepinephrine (NE) transporters have been a central theme in depression research since the 1960s. Selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) resulting from this line of research are currently the primary treatment options for major depressive disorder (MDD). One recent trend in antidepressant research has been to clarify monoaminergic mechanisms by targeting monoaminergic receptors and accessory transporters (eg, with combination drugs and triple reuptake inhibitors) or by adding atypical antipsychotics when treated with an SSRI or SNRI. In addition, several other hypotheses for the occurrence of depression based on the biological features of the disease and the effectiveness of pharmacological interventions have been put forward in the course of preclinical and clinical studies. The main strategy has been to target glutamate receptors (eg, by intravenous infusions of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist). Other strategies have been based on modulation of cholinergic and gamma-aminobutyric acid (GABA) transmission, neuronal plasticity, stress/hypothalamic-pituitary-adrenal (HPA) axis, the reward system, and neuroinflammation. Thus, there is a need to develop new drugs with complex pharmacological profiles obtained by simultaneously targeting multiple neurotransmitter and neuromodulatory systems.

[00116] BP often occurs in conjunction with other psychiatric disorders, especially anxiety disorders and substance abuse. In addition, BP is associated with various medical conditions that further complicate the treatment of the mental disorder (Am J Manag Care, 11: S85-S90 (2005); incorporated by reference in its entirety).

[00117] BP is a brain disorder that causes atypical changes in mood, energy, activity levels, and ability to perform everyday tasks. BP is characterized by mood disturbance, impulsivity, aggressive behavior, and interpersonal problems. BP is a relapsing and often chronic psychiatric illness associated with functional decline, increased suicide rates, and use of mental health systems. BP is commonly underestimated, and up to 40% of patients with BP are initially misdiagnosed, leading to an increased risk of suicide, mania, and chronic psychosocial distress. With a correct diagnosis, successful treatment is possible for <50% of diagnosed patients, and 10-15% of patients eventually die by suicide (NIMH 2002).

[00118] Although pharmacological treatment guidelines are well known, the treatment of BP remains far from ideal. Most people still experience episodes of illness or significant residual symptoms even when taking medication (NIMH 2002). In addition, functional deficits often persist even during remission (NIMH 2002). Since many patients with BP remain symptomatic even though they are fully compliant with their medication regimens, the need for a deeper understanding of the pathogenesis of this disease from studies of the pharmacological mechanisms of action of drugs in bipolar disorder is becoming increasingly important. The main medical therapy for BP is mood stabilizers, although the pharmacological mechanisms of action are not yet clear. The general neuroprotective effects of mood stabilizers play a role in brain cell dysfunction in BP, and this dysfunction may eventually lead to neuronal loss. Volumetric neuroimaging, which is now increasingly assessing the potential involvement of various brain structures in mood regulation, can be used to test neuroanatomical models of mood disorders. Imaging studies have shown that BP is accompanied by persistent neuronal atrophy. For example, PET images of cerebral blood flow and glucose metabolism rates related to brain activity revealed decreased activity in the subgenual prefrontal cortex during bipolar depression. This decrease in activity was explained, at least in part, by a corresponding decrease in cortical volume, as was magnetic resonance imaging showing mean gray matter volume. BP also has abnormalities in the third ventricle, frontal lobe, cerebellum, and presumably the temporal lobe.

[00119] Brain tumors are formed by abnormal growths and can occur in different parts of the brain. Benign (noncancerous) tumors can grow and press on nearby areas of the brain, but rarely spread to other tissues. Malignant (cancerous) tumors can grow rapidly and spread to other brain tissues. A tumor that grows into or presses on an area of the brain can interfere with the normal functioning of that part of the brain, whether the tumor is benign or malignant, and will subsequently require treatment. The most common type of brain tumor does not arise from the brain tissue itself, but from metastases from extracranial cancers such as lung and breast cancer. Brain tumors include neurofibromatosis type 1 or 2, von Hippel-Lindau disease, tuberous sclerosis, Li-Fraumeni syndrome, Turco syndrome types 1 and 2, Klinefelter's syndrome, and nevoid basal cell carcinoma syndrome. Neuroblastoma is a cancer found in developing nerve cells, usually in children under 10 years of age. Nearly 90% of cases are diagnosed before the age of 5 years. Various factors can influence the type of neuroblastoma a child has and its prognosis.

[00120] Specific treatment for neurological cancer is based on several factors, including the patient's general health and history; the type, location, and size of the tumor; degree of condition and other individual factors. Typically, treatment for patients with cancer of the brain or spinal cord includes surgery, chemotherapy, radiation therapy, and/or steroids to treat and prevent swelling, especially in the brain; anticonvulsant drugs for the treatment and prevention of seizures associated with increased intracranial pressure; shunt placement (to help drain excess fluid in the brain) lumbar puncture/lumbar puncture (to measure pressure in the spinal cord and brain); bone marrow transplant; rehabilitation (recovery of lost motor skills and muscle strength) and/or antibiotics (to treat and prevent infections). Chemotherapy is the use of anticancer drugs for the treatment of cancer. In most cases, chemotherapy affects the ability of the cancer cell to grow or multiply. These medicines can be given by vein or by mouth as a tablet.

[00121] Neuropsychiatric symptoms are a common burden in patients suffering from Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and many other neurodegenerative disorders, including, without limitation, Lewy body dementia (DLB), vascular dementia (VaD), and frontal -temporal lobar degeneration (FTLD) (Kazui H et al. Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016); Van der Schyf CJ. Psychotropic Drug Development Strategies that Target Neuropsychiatric Etiologies in Alzheimer's and Parkinson's Diseases Drug Dev Res. 77: 458-468 (2016)).

[00122] Many neuropsychiatric symptoms appear very early in a neurodegenerative disease and are even considered prodromal indicators or indicators of disease progression. (Kazui H et al. Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016); Peters ME 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)).

[00123] Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, in neurodegenerative diseases and disease states, including without limitation AD, have a multifactorial origin. (McClam TD 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)). Thus, a strategy that aims to simultaneously target multiple disease causes (hence multiple drug targets) is the best approach in developing treatment strategies for a range of diseases, including but not limited to AD (Nikolic K et al. Drug design for CNS diseases: polypharmacological profiling of compounds using cheminformatic, 3D-QSAR and virtual screening methodologies Front Neurosci 10: 265 (2015)).

[00124] Individual BPSD symptoms may appear to be mutually exclusive, but may nonetheless share common mechanisms. This similarity in general mechanisms can be manifested at the neurochemical and/or neuroanatomical levels and provides the basis for the development of targeted, but not mechanism-specific, therapies that target more than one BPSD symptom.

[00125] The general mechanisms are illustrated by the similar neurochemical structures of the neural pathways from cortical regions to the basal ganglia to the thalamus and back to the cerebral cortex. For example, the dorsolateral prefrontal cortex relays signals to the dorsolateral caudate, which in turn targets the lateral dorsomedial portions of the internal globus pallidus, which direct signals to the main portion of the ventral anterior or mediodorsal thalamus, which returns signals to the cortex. In contrast, the orbitofrontal cortex relays signals to the ventromedial caudate nucleus, which relays signals to the medial dorsomedial portions of the internal globus pallidus, which relays signals to the macrocellular portion of the ventral anterior or mediodorsal thalamus, which returns signals to the cortex. Thus, different parts of the cortex may be responsible for different functions, but there are general principles according to which cortical networks function (Aouizerate B et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol 72(3): 195-221 (2004)). Thus, impairments in different circuits underlie the occurrence of various BPSD symptoms. The heterogeneity of the clinical manifestations of neurodegenerative disorders is determined by the dominant location of the pathological focus (ie, affected networks). For example, the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex are more affected in lethargic patients, and the medial orbitofrontal cortex is more affected in disinhibited patients with bvFTLD (eg, Massimo et al. Dement Geriatr Cogn Disord 27:96-104 (2009)) .

[00126] With respect to the 5-HT2A receptors targeted by the compounds of formula I, it is well known that serotonin, via 5-HT2A receptors, enhances glutamatergic spontaneous excitatory postsynaptic currents in the apical dendrites of layer V pyramidal cells of the prefrontal cortex (Aghajanian GK, Marek GJ. 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 can be functionally expressed in various forms depending on which part of the cerebral cortex is affected from auditory or visual hallucinations to disinhibition and apathy, but in most cases it is sensitive to manipulations involving 5-HT _2A receptors, which are present in various areas of the cortex, (van Dyck CH 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)).

[00127] With regard to glutamatergic signaling, which is targeted by dextromethorphan and memantine, it is well known that it mediates thalamocortical signaling by causing activation of the corresponding cortical regions (Kharazia VN, Weinberg RJ. 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)

[00128] Diseases like Alzheimer's disease are characterized by a systematic, progressive, possibly transsynaptic spread of neurodegeneration. This means not only the loss of more cells in a particular part of the brain, but also the spread of pathology to other parts of the brain. Since different parts of the brain perform different functional roles, this explains why the later stages of the disease are accompanied by a wider range 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)).

[00129] Behavioral and psychological symptoms of dementia, also known as neuropsychiatric symptoms, are commonly studied in a clinical setting using research tools such as the Neuropsychiatric Assessment Inventory (NPI; Cummings JL. The Neuropsychiatric Inventory: Assessing psychopathology in dementia patients. Neurology 48 :S10-S16 (1997)). The NPI scale recognizes 12 subdomains of behavioral functioning: delusions, hallucinations, agitation/aggression, dysphoria, restlessness, euphoria, apathy, disinhibition, irritability/lability, impaired motor activity, nighttime behavioral disturbances, and appetite and eating disorders.

[00130] Patients rarely experience all of these NPI symptoms at the same time, as there are NPI elements such as euphoria that are rare even with a CDR score of 3. Conversely, clinical experience shows that it is rare for a patient to show only one particular element and none of the others. Instead, BPSD symptoms occur in various combinations or clusters. For example, a frequent cluster in AD may, for example, represent aggression, agitation, wandering, repetitiveness, while a frequent cluster in vascular dementia may, for example, represent confusion and restlessness, but the frequency and severity of NPI elements may vary. , for example, day by day, but especially during the progression of the disease. (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 DK et al. Neuropsychiatric profiles in dementia. Alzheimer Dis Assoc Disord 25(4 ): 326-332 (2011)). Because such a constellation of several symptoms that are clinically significant can present simultaneously in the patient in question, there is an urgent need in the medical field for treatments that can target different clusters of symptoms or the entire spectrum of BPSD symptoms, regardless of any currently prevalent the time of the pathophysiological hypothesis about the disease.

[00131] The prevalence of delusional states is quite low in the general population, in people with normal cognitive aging (0.4-2.4%), but increases in subjects with mild cognitive impairment (MCI; 3.1-3.4% ) and increases markedly in dementia (18.0-31.0%) (Geda YE et al. The Prevalence of Neuropsychiatry Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008) Lyketsos CG 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 QF et al The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis J Affect Disord 190:264-71 (2016)). The prevalence of hallucinations is also low in the general population, in people with normal cognitive aging (0.4-0.6%), but increases in subjects with MCI (0.6-1.3%) and dementia (10.5-0.6%). 16.0%) (Geda YE 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 CG 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 QF et al The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta- analysis J Affect Disord 190:264-71 (2016)).

[00132] Both delusions and hallucinations are part of or symptoms of psychosis in various neurological and psychiatric diseases and disease states. For lack of a better treatment for dementia, antipsychotics have long been used for non-approved indications to treat such symptoms; however, with rare exceptions, both "typical" and "atypical" antipsychotics increase the incidence of CV adverse events and have shown a substantially increased mortality rate when used in non-approved indications for dementia. Therefore, the FDA has issued a black box warning prohibiting their use for non-approved indications in non-schizophrenia, leaving few therapeutic options for treating such BPSD symptoms in dementia. Against this backdrop, a completely different class, namely 5-HT2A receptor antagonists and inverse agonists, have demonstrated an efficacy profile similar to that of antipsychotics in preclinical studies (Weiner et al. 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 299( l):268-76 (2001)). Several 5-HT _2A receptor antagonists and inverse agonists were under development for use in neuropsychiatric indications, and there were reports of beneficial antipsychotic effects obtained with compounds such as eplivanserin (Meltzer HY et al. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder Am J Psychiatry 161: 975-84 (2004)). The 5-HT2A receptor inverse agonist pimavanserin significantly reduced psychotic symptoms, which included hallucinations and delusions, in patients with moderate to severe Parkinson's disease (Cummings J 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 approved by the FDA specifically for the treatment of these symptoms in PDD. In patients with dementia in Alzheimer's disease, the HTR2A T102C polymorphism is a significant risk factor for the development of psychosis, while the allelic OR was 2.191 in the case of the C allele, which increased to 5.143 in the case of the homozygous CC genotype (Ramanathan S, Glatt SJ. Serotonergic system genes in psychosis of Alzheimer dementia: meta-analysis Am J Geriatr Psychiatry 17(10):839-46 (2009)).

[00133] Dextromethorphan has NMDA receptor channel blocking properties, and NMDA receptor channel blockers such as phencyclidine or ketamine are known to have psychotomimetic rather than antipsychotic properties. There are reports of dextromethorphan-induced psychosis in humans (Miller SC. Dextromethorphan psychosis, dependence and physical withdrawal. Addict Biol 10(4):325-7 (2005)). These psychoactive properties of dextromethorphan may be determined by its metabolic degradation leading to the production of dextrorphan (Zawertailo LA et al. Effect of metabolic blockade on the psychoactive effects of dextromethorphan. Hum Psychopharmacol 25(l):71-9 (2010)). The psychoactive effects of dextromethorphan observed in some subjects do not rule out the possibility that dextromethorphan also has antipsychotic properties under certain circumstances. Indeed, dextromethorphan, but not its metabolite dextrorphan, has been reported to attenuate phencyclidine-induced motor behaviors in rats (Szekely JI et al. :381-6 (1991)). A meta-analysis of randomized controlled trials of another NMDA receptor blocker, memantine, in patients with Alzheimer's disease showed that memantine causes significant improvement in delirium (Kishi T 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)).

[00134] On the NPI scale, arousal and aggression are combined as one item. The prevalence of arousal and aggression is low in the general population, in people with normal cognitive aging (2.8-2.9%), but increases in subjects with MCI (9.1-11.3%) and dementia (30.3 -40%) (Geda YE 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 CG 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 QF et al The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis J Affect Disord 190:264-71 (2016)). Thus, this element of NPI is one of the most common and at the same time is a clinical symptom of BPSD, difficult to treat.

[00135] Preclinical studies show that blockade of 5-HT _2A receptors reduces aggression in laboratory rodents (Sakaue M et al. Modulation by 5-hT2A receptors of aggressive behavior in isolated mice. Jpn J Pharmacol 89(1): 89-92 ( 2002)). Human genetic data indicate that scores on three of the four subscales of the Bass-Perry Aggression Inventory (hostility, anger, and physical aggression) show a significant association with the T allele of HTR2A rs7322347 (Banlaki Z 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 of Chinese subjects with AD, aggression in AD was significantly associated with a 5-HT _2A receptor polymorphism such as T102C (Lam LC et al. 5-HT _2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19(6):523-6 (2004)).

[00136] Various NMDA receptor channel blockades have been shown to reduce aggressive behavior in mice, and these effects are difficult to separate from sedation (Belozertseva IV, Bespalov AY. Effects of NMDA receptor channel blockade on aggression in isolated male mice. Aggr Behav 25: 381-396 (1999)). In patients with suspected Alzheimer's disease and clinically significant agitation, the combination of dextromethorphan-quinidine provided a reduction in NPI arousal/aggression scores (Cummings JL et al. Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA 314 (12): 1242-54 (2015))). A meta-analysis of randomized controlled trials of another non-selective NMDA receptor channel blocker, memantine, in patients with Alzheimer's disease showed that memantine also produced a significant improvement in arousal/aggression (Kishi T 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)).

[00137] The prevalence of dysphoria/depression is moderate in the general population, in people with normal cognitive aging (7.2-11.4%), but increases in subjects with MCI (20.1-27.0%), and this is one of the most common problems in dementia (32.3-42%) (Geda YE 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 CG 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 QF et al The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis J Affect Disord 190:264-71 (2016)).

[00138] Preclinical studies using brain stimulation reward have shown that 5-HT2A receptor antagonism can reverse dysphoria caused by typical neuroleptics such as haloperidol (Benaliouad F et al. Blockade of 5-HT2a receptors reduces haloperidol-induced attenuation of reward Neuropsychopharmacology 32(3): 551-61 (2007)). The selective 5-HT2A receptor antagonist _M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30 : 2205-2215 (2005) Patel JG 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. 52: 73-75 (2004)).

[00139] NMDA receptor channel blockers such as dextromethorphan have been shown to have antidepressant-like properties in preclinical models (Sakhaee E 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 has been shown to have rapid and pronounced antidepressant activity in patients with treatment-resistant major depressive disorder (Singh JB 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 has an antidepressant effect in humans (Murrough JW et al. Dextromethorphan/quinidine pharmacotherapy in patients with resistant treatment 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 effective when combined with serotonin and norepinephrine transporters, as well as sigma-1 receptors, which may contribute to the therapeutic action of dextromethorphan (Stahl SM. Mechanism of action of dextromethorphan/quinidine: comparison with ketamine. CNS Spectrums 18:225-227 (2013)). Although monoamine transporters are the targets of most currently used antidepressants, sigma-1 receptors have also been found to contribute to the antidepressant-like effects of dextromethorphan in laboratory animals (Nguyen L et al. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One 9(2):e89985 (2014)).

[00140] The prevalence of apathy is low in the general population, in people with normal cognitive aging (3.2-4.8%), but increases in subjects with MCI (14.7-18.5%) and dementia (35, 9-49%) (Geda YE 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 CG et al Zhao QF 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 of Chinese subjects with AD, apathy in AD was significantly associated with a 5-HT2A receptor polymorphism such as T102C (Lam LC 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 often observed 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 M 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); ):975-84 (2004)).

[00141] NMDA receptor channel blockers such as memantine have been reported to reduce apathy in some patients with neurodegenerative diseases (Links KA et al. A case of apathy due to frontotemporal dementia responsive to memantine. Neurocase 19(3):256-61 (2013)) or with negative symptoms of schizophrenia (Paraschakis A. Tackling negative symptoms of schizophrenia with memantine. Case Rep Psychiatry 2014:384783 (2014)).

[00142] The prevalence of anxiety is low in the general population, in people with normal cognitive aging (5.0-5.8%), but increases in subjects with MCI (9.9-14.1%) and dementia (21, 5-39%) (Geda YE 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 CG 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 QF et al The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta- analysis J Affect Disord 190:264-71 (2016)).

[00143] 5-HT _2A receptor antagonists exhibit anxiolytic effects in various preclinical models, in particular in models of conditioned fear (Adamec R 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(l-2):79-96 (2004) Millan MJ The neurobiology and control of anxious states Progr Neurobiol 70: 83-244 (2003)). In humans, blockade of 5-HT2A receptors reduces the intensity of processing of emotional information in the orbitofrontal cortex involved in the evaluation of socially significant stimuli (Hornboll B et al. Pharmacological blockade of 5-HT2A receptors reduces orbitofrontal activation during processing of fearful and angry faces in healthy subjects. Neurolmage 47: S39 S41 (2009)). The 5-HT2 receptor antagonist serazepine (CGS-15040A) has shown efficacy in clinical trials in patients with generalized anxiety disorder (Katz RJ et al. Serotonergic (5-HT2) mediation of anxiety-therapeutic effects of serazepine in generalized anxiety disorder. Biol Psychiatry 34 : 41-44 (1993)).

[00144] Like other members of the NMDA receptor antagonist class (Chojnacka-Wcjcik E et al. Glutamate receptor ligands as anxiolytics. Curr Opin Investig Drugs 2(8): 1112-9 (2001)), dextromethorphan has been shown to cause anxiolytic effects in laboratory animals in a certain dose range (Dere E 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)). The preclinical anxiolytic effects of dextromethorphan may be associated not only with inhibition of NMDA receptor function, but also with interaction with sigma-1 receptors (Kamei H et al. (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated sigma 1 sites Eur J Pharmacol 299(l-3):21-8 (1996)). In AD patients, treatment with another non-selective NMDA receptor channel blocker, memantine, significantly lowers NPI subscale scores for anxiety (Ishikawa I 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)).

[00145] The prevalence of euphoria/exaltation is very low in the general population and in people with normal cognitive aging (0.3-0.4%), but increases in subjects with MCI (0.6-1.3%) and dementia ( 3.1-7%) (Geda YE 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 CG et al., Zhao QF et al., The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis J Affect Disord 190:264-71 (2016)).

[00146] Human studies using PET have established a positive correlation of psychostimulant-induced changes in analogue euphoria scores with a decrease in the binding potential (BP) of the [11C] racloprid receptor in the caudate nucleus and putamen in accordance with an increase in endogenous dopamine levels (Drevets WC. Amphetamine -induced dopamine release in human ventral striatum correlates with euphoria Biol Psychiatry 49(2):81-96 (2001)). The non-selective 5-HT2A receptor agonist psilocybin significantly reduced the BP of [11C]raclopride in the ventral striatum, which correlated with euphoria-related depersonalization (Vollenweider FX et al. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man -- a PET study with [11C]raclopride Neuropsychopharmacology 20(5):424-33 (1999)).

[00147] Preclinical data have shown that most pyramidal neurons in the prefrontal cortex, which signal to the dorsal raphe nuclei and ventral tegmental region, express 5-HT2A receptors (Vazquez-Borsetti P. 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)). Therefore, blockade of 5-HT _2A receptors in the prefrontal cortex can modulate pyramidal neurons that transmit signals to the midbrain and thus inhibit the dopaminergic system in the midbrain (Erbdrup BH et al. Serotonin 2A receptor antagonists for treatment of schizophrenia. Expert Opin Investig Drugs 20(9): 1211-1223 (2011)). The midbrain dopaminergic system is also under the control of cholinergic neural pathways, such as those originating in the leash, and the activity of these neural pathways is modulated by α3β4-containing nicotinic acetylcholine receptors (McCallum SE et al. α2β4 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 attributed to a decrease in dopamine tone (Maisonneuve IM, Glick SD. 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 CP et al. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther 164:170-82 (2016)).

[00148] The prevalence of disinhibition is low in the general population, in people with normal cognitive aging (0.9-1.6%), but increases in subjects with MCI (3.1-4.7%) and dementia (12, 7-17%) (Geda YE 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 CG et al Zhao QF et al, The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta -analysis J Affect Disord 190:264-71 (2016)).

[00149] Changes in the balance of functional activity in the 5-HT system underlie the control of impulsivity, and preclinical studies show that the 5-HT2A receptor regulates impulsive behavior, including both innate and induced disinhibition of behavior (Anastasio NC 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)).

[00150] In humans, there are significant associations found between high levels of behavioral impulsivity and certain 5-HT2A polymorphisms, such as the C/C rs6313 genotype (Jakubczyk A et al. The CC genotype in HTR2A T102C polymorphism is associated with behavioral impulsivity in alcohol- dependent patients J Psychiatr Res 46(l):44-9 (2012)). People with the A/A genotype for the 1438A/G HTR2A polymorphism have higher scores for maladaptive impulsivity. (Tomson K 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 point of view, it is known that the neocortex is rich in 5-HT2A receptors and behavioral disinhibition in neurodegenerative diseases, such as the behavioral variant of frontotemporal dementia, correlates with the thickness of the cortex of the right parahippocampal gyrus, the cortex of the right orbitofrontal region, and the right insula. (Santillo AF et al. Gray and White Matter Clinico-Anatomical Correlates of Disinhibition in Neurodegenerative Disease. PLoS One 1 l(10):e0164122 (2016)).

[00151] The combination of dextromethorphan and quinidine has positive therapeutic effects in patients with pseudobulbar affect (PBA) 15-28 (2014)). PVA can occur in association with various neurological diseases such as amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer's disease, stroke, and brain tumors. PVA is a disinhibition syndrome in which metabolic pathways involving serotonin and glutamate are disrupted (Ahmed A, Simmons Z. Pseudobulbar affect: prevalence and management. Ther Clin Risk Manag 9:483-9 (2013)). A meta-analysis of randomized controlled trials of another non-selective NMDA receptor channel blocker, memantine, in patients with Alzheimer's disease showed that memantine produced a significant improvement in disinhibition (Kishi T et al. The effects of memantine on behavioral disturbances in patients with Alzheimer's disease: a metaanalysis Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).

[00152] The prevalence of irritability/lability is low in the general population, in people with normal cognitive aging (4.6-7.6%), but increases in patients with MCI (14.7-19.4%) and dementia ( 27-36%) (Geda YE 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 CG 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 QF et al The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta- analysis J Affect Disord 190:264-71 (2016)).

[00153] Studies using functional magnetic resonance imaging in animals and humans indicate a specific involvement of the 5-HT2A receptor in the regulatory projection of prefrontal cortical feedback (PFC) to the amygdala. Since this receptor is highly expressed in regions of the prefrontal cortex, it has an effect on the control of inhibition of emotion-based and emotion-controlled actions, such as various behaviors associated with impulsivity (Aznar S, Klein AB. Regulating prefrontal cortex activation: an emerging role for the 5-HTrA serotonin receptor in the modulation of emotion-based actions? Mol Neurobiol 48(3):841-53 (2013)).

[00154] The combination of dextromethorphan and quinidine has beneficial therapeutic effects in patients with pseudobulbar affect, which is characterized by emotional lability, uncontrollable crying or laughing that may be disproportionate or inappropriate in a social context. (Pioro EP. Review of Dextromethorphan 20 mg/Quinidine 10 mg (NUEDEXTA®) for Pseudobulbar Affect. Neurol Ther 17;3(1): 15-28 (2014)). In AD patients, treatment with another non-selective NMDA receptor channel blocker, memantine, significantly lowers scores for the irritability/lability NPI element (Ishikawa I 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)). A meta-analysis of randomized controlled trials of memantine in patients with Alzheimer's disease showed that memantine is an excellent means of controlling irritability/lability (Kishi T 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)).

[00155] The prevalence of aberrant motor activity is low in the general population, in people with normal cognitive aging (0.4-0.6%), but increases in subjects with MCI (1.3-3.8%) and dementia ( 16-32%) (Geda YE 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 CG 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 QF et al The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta- analysis J Affect Disord 190:264-71 (2016)).

[00156] Aberrant motor behavior in AD has been found to be significantly associated with 5-HT2A receptor polymorphisms such as T102C (Lam LC et al. 6):523-6 (2004), Pritchard AL et al, Role of 5HT 2A and 5HT 2C polymorphisms in behavioral and psychological symptoms of Alzheimer's disease, Neurobiol Aging 29(3):341-7 (2008)).

[00157] Aberrant motor behavior in various neurological disease states, such as Parkinson's disease, is due to abnormal plasticity processes in the basal ganglia, which can be expressed as behavioral sensitization that is sensitive to blockade of glutamate/NMDA receptors (Chase TN et al. Striatal glutamatergic mechanisms and extrapyramidal movement disorders. a novel treatment. Pharmacol Biochem Behav 75(3):607-18 (2003)), two of the dextromethorphan receptor targets (Taylor CP et al. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther 164 :170-82 (2016)).

[00158] The prevalence of nighttime behavioral disturbances is moderate in the general population, in people with normal cognitive aging (10.9%), but increases in subjects with MCI (13.8-18.3%) and dementia (27, 4-39%) (Geda YE 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 CG et al Zhao QF et al, The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta -analysis J Affect Disord 190:264-71 (2016)).

[00159] 5-HT2A receptors play a major role in the regulation of sleep (Vanover KE, Davis RE. Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nat Sci Sleep 2:139-50 (2010)). In a clinical trial evaluating the safety and efficacy of the 5-HT2A receptor inverse agonist, pimavanserin, in patients with moderate to severe Parkinson's disease, participants reported improved nighttime sleep and daytime wakefulness with pimavanserin compared with placebo (Cummings J 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).

[00160] A meta-analysis of randomized controlled trials of another non-selective NMDA receptor channel blocker, memantine, in patients with Alzheimer's disease showed that memantine causes a significant improvement in nighttime/circadian rhythm disturbances (Kishi T et al. The effects of memantine on behavioral disturbances in patients with Alzheimer's disease: a metaanalysis Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)). In patients with AD, memantine was effective in reducing the incidence of fragmented sleep, and polysomnography showed an increase in total sleep duration, increased sleep efficiency and increased time spent in stage II, as well as a decrease in the likelihood of awakening at night, the index of periodic limb movements and time spent in stage I (Ishikawa I 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)).

[00161] The prevalence of appetite and eating disorders is low in the general population, in people with normal cognitive aging (5.3%), but increases in subjects with MCI (10.4-10.7%) and dementia (19, 6-34%) (Geda YE 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 CG 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 QF et al The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta- analysis J Affect Disord 190:264-71 (2016)).

[00162] Serotonin plays an important role in the onset and maintenance of various types of eating disorders (Steiger H. Eating disorders and the serotonin connection: state, trait and developmental effects. J Psychiatry Neurosci 29(l):20-9 (2004)). The gene encoding the 5-HT2A receptor (HTR2A) has been implicated as a functional candidate in many neuropsychiatric phenotypes, including eating disorders (Norton N, Owen MJ. 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 dextromethorphan's target receptors, the serotonin transporter, which is affected in patients with eating disorders (Spies M et al. The serotonin transporter in psychiatric disorders: insights from PET imaging. Lancet Psychiatry 2(8):743 -55 (2015)).

[00163] Thus, current evidence suggests that the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease, is complex, involving many neuroanatomical substrates, with a neurochemical and neuropharmacological mechanism leading to the following: i) one therapeutic mechanism of action (TMA) can be used to treat more than one clinically diagnosable element of BPSD (eg, symptom or NPI group of symptoms); ii) TMA alone can be used to treat the symptoms of two or more clinically distinct neurodegenerative diseases (eg, AD, PD, DLB, FTLD, etc.) as shown by the emerging efficacy profile of Nuprazid®; iii) coverage of the entire spectrum of BPSD symptoms by a single TMA is unlikely; iv) TMA alone may not provide the maximum possible therapeutic effect even for a single BPSD symptom or cluster of symptoms.

[00164] Thus, in contrast to the limited clinical efficacy seen with pimavanserin therapy, which is an MTA-based therapy (Nuplazid®; Ballard C et al. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study Lancet Neurology (2018) 17: 213-22), combination therapy involving multiple MTAs represented by compounds of formula I and compounds of formula II provides both a broader and more intense efficacy profile.

[00165] One embodiment is a method of treating the behavioral and mental symptoms of dementia in a patient in need thereof, comprising the step of administering a pharmaceutical composition comprising a compound of formula II (DEX) and one or more agents selected from the group consisting of a 5-HT2A receptor antagonist , a 5-HT2A receptor inverse agonist and CYP2D6 inhibitor. In another embodiment, the agent is a dual potency (DA) agent having both 5-HT2A receptor antagonist and CYP2D6 inhibitory properties. In another embodiment, the agent is a DA having both 5-HT2A receptor inverse agonist and CYP2D6 inhibitory properties. In another embodiment, DA is a compound of Formula I.

[00166] DEX is a σ2 receptor agonist, an N-methyl-D-aspartate (NMDA) receptor antagonist, and an a3p4 nicotinic receptor antagonist. The uptake of norepinephrine and serotonin is also inhibited. Some neuropsychiatric diseases and syndromes, such as Alzheimer's disease, and the behavioral and psychological symptoms of dementia, involve dysregulation of the glutamatergic, cholinergic, serotonergic, and norepinephrine neurotransmitter systems. Accordingly, in another embodiment, the composition comprises an NMDA receptor antagonist such as ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone, and dextromethorphan (Jamero et al., The Emerging Role of NMDA Antagonists in Pain Management, US Pharm. 36(5) :HS4-HS8 (2011) Sang, NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials, J Pain Symptom Manage 19 (1 Suppl) S21-5 (2000) incorporated herein by reference in its entirety). In another embodiment, the composition is a combination of a compound of formula I and ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone, or dextromethorphan. The compound of formula I forms a combination as a mixture, complex, conjugate, covalently bonded compound or salt.

[00167] In another embodiment, the pharmaceutical composition contains a compound of formula I and a compound of formula II (examples of which are SARPODEX™, DERADEX™ or DERAPHAN™). Another embodiment is a method of treating a patient in need thereof comprising the step of administering a pharmaceutical composition containing SARPODEX™, DERADEX™ or DERAPHAN™.

[00168] The psychological symptoms of dementia include dysregulation of the glutamatergic, cholinergic, serotonergic, and norepinephrine neurotransmitter systems. Therefore, one embodiment is a method of treating the behavioral and psychological symptoms of dementia. Another embodiment is the treatment of a person in need thereof, comprising administering a composition containing a compound of formula I and a compound of formula II to provide improvement in EEG disorders, behavior, cognition and seizures, and to provide improvement in respiratory disorders, motor abilities, bone density and gastrointestinal dysfunction. Another embodiment is the treatment of a person in need thereof, comprising administering a composition containing DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ to provide improvement in EEG disturbances, behavior, cognition and seizure reduction, and to providing improvement in respiratory disorders, motor abilities, bone density and gastrointestinal dysfunction. Another embodiment is the treatment of a person in need thereof, comprising administering a composition containing DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™, for the treatment of other diseases and conditions, including Involuntary Emotional Expression Disorder (IEED) or Pseudobulbar Affect ( PVA), neurodegenerative diseases, neuropathic pain and brain injury.

[00169] Another embodiment is a composition containing a DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ compound alone or in combination with other drugs such as analgesics (e.g. acetaminophen), antihistamines (e.g. chlorpheniramine ), decongestants (eg pseudoephedrine) and/or expectorants (eg guaifenesin).

[00170] In the liver, dextromethorphan is metabolized to active metabolites, this process begins with O- and N-demethylation to form the primary metabolites DO and 3-methoxymorphinan, which are further N- and O-demethylated to 3-hydroxymorphinan, respectively. The main 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 is catalyzed by enzymes of the related CYP3A family. Conjugates of DO and 3-hydroxymorphinan can be detected in human plasma and urine within a few hours after ingestion. DO is the substance best known for its psychoactive effects. [00171] SGL is a 5-HT2A receptor inverse agonist and CYP2D6 inhibitor. SGL inhibits 5-HT2A receptor mediated responses such as platelet aggregation, vasoconstriction, and proliferation of vascular smooth muscle. SGL (MCI-9042) has been shown to have the same 5-HT2A receptor affinity as ritanserin (Nishio et al., Binding affinity of a compound of formula I or sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes Arch Int Pharmacodyn Ther 331(2): 189-202 (March-April 1996); incorporated by reference in its entirety). Blockade of 5-HT2A receptors can inhibit thrombosis, suppress platelet aggregation, and inhibit proliferation of vascular smooth muscle cells (Pertz et al., In-vitro pharmacology of a compound of Formula I 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 (April 1995), incorporated by reference in its entirety). Accordingly, an embodiment is a method of treating a patient in need thereof comprising administering a composition comprising a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00172] Another embodiment is a method of treatment wherein the patient is suffering from a disease or disorder including peripheral arterial disease, such as Raynaud's disease and intermittent claudication; pulmonary hypertension (Saini et al., 2004; incorporated by reference in its entirety), angina pectoris (Kinugawa et al., 2002; incorporated by reference in its entirety), and/or diabetes mellitus (Pietraszek et al., 1993; Ogawa et al., 1999; incorporated by reference in its entirety). In another embodiment, a method of treating a patient after coronary stenting provides a compound of formula I and is useful in restenosis (Doggrell, sarpogrelate: cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, Volume 13, Issue 7 (2004); incorporated by reference throughout its fullness).

[00173] DO is a substance best known for its psychoactive effects, which likely result from blockade of NMDA receptors. DO has a significantly higher affinity for NMDA receptors than DEX. Adverse psychoactive effects of DEX have been linked to its metabolism prior to DO (Taylor, et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther. 164:170-82 (August, 2016); included by reference in its entirety). Thus, another embodiment is a method of reducing the adverse effects of DEX during treatment of a patient in need thereof, comprising the step of administering a pharmaceutical composition containing DEX and one or more agents selected from the group consisting of a 5-HT2A receptor antagonist/inverse agonist and an inhibitor CYP2D6. In another embodiment, the agent is an agent having both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor properties. In another embodiment, the agent is an agent that has both a 5-HT2A receptor inverse agonist and a CYP2D6 inhibitor. In another embodiment, the agent is a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00174] Another embodiment is a composition containing (6)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1) (Nagatomo et al., 2004; Saini et al., 2004; incorporated by reference in its entirety), a 5-HT2A receptor inverse agonist and a CYP2D6 inhibitor.

[00175] The genetically polymorphic cytochrome CYP2D6 is involved in the metabolism of many antipsychotics, including thioridazine, perphenazine, chlorpromazine, fluphenazine, haloperidol, zuclopenthixol, risperidone, and sertindole (Michalets, 1998). This enzyme is also important in the metabolism of other drugs commonly prescribed to patients with psychiatric disorders, such as tricyclic antidepressants (nortriptyline, desipramine, amitriptyline, imipramine, and clomipramine) and selective serotonin reuptake inhibitors, including fluoxetine and paroxetine (Taylor and Lader, 1996; Sproule et al., 1997; incorporated by reference in their entirety). Drugs that inhibit these enzymes are expected to cause increases in plasma concentrations of co-administered antipsychotic drugs (Goff, 1993; Ereshefsky, 1996; Michalets, 1998; incorporated by reference in its entirety). These increases may, in turn, lead to the development or exacerbation of antipsychotic-induced side effects, including cardiotoxicity, anticholinergic side effects, or orthostatic hypotension (Ereshefsky, 1996; Desta et al., 1999; incorporated by reference in its entirety).

[00176] Many antipsychotic drugs have inhibited CYP2D6 catalyzed O-demethylation of DEX. Among the antipsychotic drugs tested, thioridazine and perphenazine were the most potent inhibitors and reduced the rate of DO formation to 26.5 and 19.7% of control activity at 10 μM and to 11.4 and 10.7% of control activity at 25 μM, respectively. The inhibitory efficacy of these drugs on DEX O-demethylation was compared to that of 10-25 μM quinidine. Estimated mean IC50 values for thioridazine and perphenazine were 2.7±0.5 and 1.5±0.3 µM, respectively. The IC50 value of quinidine, a potent inhibitor of CYP2D6, was estimated to be 0.52±0.2 µM under these conditions. The estimated IC50 values for chlorpromazine, fluphenazine, and haloperidol were 9.7, 16.3, and 14.4 µM, respectively. Cis-thiothixene, clozapine, and risperidone exhibited weaker inhibition than the other drugs tested, with mean IC values estimated to be 136.6, 92.2, and 39.1 µM, respectively (Shin et al., Effect Of Antipsychotic Drugs on Human Liver Cytochrome P-450 (Cyp) Isoforms in Vitro: Preferential Inhibition of CYP2D6, Drug Metabolism And Disposition, Vol. 27, No. 9 (1999); incorporated by reference in its entirety).

[00177] In one embodiment, the pharmaceutical composition of the present invention contains one or more inhibitors of CYP2D6, such as, but not limited to, aimaline, amiodarone, amitriptyline, aprindine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, doxorubicin, fluoxetine, fluphenazine, fluvastatin, fluvoxamine , haloperidol, imipramine, indinavir, lasoprazole, levomepromazine, lopinavir, loratadine, mechitazine, methadone, metoclopramide, mibefradil, moclobemide, nelfinavir, nevirapine, nicardipine, norfluoxetine, paroxetine, perphenazine, pimozide, terfenadine, thioridazine, cimetidine, quinidine, quinidine , clomipramine, clozapine, cocaine, desipramine, ranitidine, risperidone, ritonavir, saquinavir, sertraline, terbinafine, ticlopidine, trifluperidol, venlafaxine, and yohimbine.

[00178] In one embodiment, the present invention is a combination of a 5HT2A receptor antagonist and a CYP2D6 inhibitor providing the therapeutic benefit of both 5HT2A receptor antagonism and 2D6 inhibition. In another embodiment, the present invention is a combination of a 5HT2A receptor inverse agonist and a CYP2D6 inhibitor providing the therapeutic benefit of simultaneous 5HT2A receptor inverse agonism and 2D6 inhibition. A compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ provide a unique therapeutic benefit by combining both CYP2D6 inhibition and 5HT2A receptor inverse agonism to improve the magnitude of the therapeutic response to DEX. Thus, a compound of formula I and formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ avoids the potential health risks associated with concomitant use of the antiarrhythmic drug quinidine with DEX. Accordingly, an embodiment is a composition containing a compound of formula I and formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00179] Some embodiments include a method of reducing the number of doses and/or total daily dose of dextromethorphan, its metabolite, derivative or prodrug (DEX) that can be administered while improving efficacy and ensuring tolerability and safety, comprising oral administration of an effective the amount of a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00180] Some embodiments include a method of reducing a treatment-related adverse event comprising co-administering a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ to a subject in need of treatment with DEX and /or compounds of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™, wherein the subject is at risk of an adverse event as a result of treatment with DEX and/or a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™ , DERADEX™ or DERAPHAN™.

[00181] Some embodiments include a method of reducing plasma levels of DO comprising co-administering a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ to a subject in need of DEX treatment, wherein a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ are administered on the first day and for at least two days of treatment with DEX, with a decrease in plasma DO level occurring on the first day of administration of a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™, compared to the same amount of DEX administered without a compound of formula I.

[00182] Another embodiment is a method of reducing plasma DO levels comprising co-administering a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ for at least eight consecutive days to a subject in need of treatment with DEX, where on the eighth day the plasma DO level is lower than the plasma DO level that would be achieved with the same amount of DEX administered without the Formula I compound for eight consecutive days.

[00183] A 5-HT2A receptor antagonist/inverse agonists such as a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ can be used to improve the therapeutic properties of DEX, for example in the treatment of neurological disorders . A compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ regardless of stereochemistry can be effective in inhibiting or reducing the rate of DEX metabolism in some subjects, which is achieved by co-administering a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00184] Another embodiment is a method of treating a neurological disorder comprising administering to a subject in need thereof a 5-HT2A receptor antagonist/inverse agonist and DEX, wherein the subject is a rapid DEX metabolizer.

[00185] Another embodiment is a method of treating a neurological disorder comprising administering to a subject in need thereof an inverse agonist, a 5-HT2A receptor antagonist and DEX, wherein the subject is a rapid DEX metabolizer.

[00186] Another embodiment is a method of increasing plasma levels of DEX in a subject in need of DEX treatment, wherein the subject is a rapid DEX metaboliser, comprising co-administering a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™ , DERADEX™ or DERAPHAN™ to the subject.

[00187] Another embodiment is a method of inhibiting DEX metabolism comprising administering a compound of formula I, or a compound of formula I and a compound of formula II, or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ to a subject, wherein the subject is a rapid metabolizer DEX, and where DEX is present in the body of the subject simultaneously with the compound of formula I.

[00188] Another embodiment is a method of increasing the metabolic life of DEX, comprising administering a compound of formula I and a compound of formula II, or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ to a subject in need of DEX treatment, wherein the subject is a rapid metabolizer of DEX, and where DEX is present in the body of the subject simultaneously with the compound of formula I.

[00189] Another embodiment is a method of correcting rapid DEX metabolism comprising administering a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ to a subject in need thereof.

[00190] Another embodiment is a method of improving the antitussive properties of DEX comprising administering a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ in combination with administering DEX to a subject in need of cough treatment.

[00191] Another embodiment is a method of treating cough comprising administering a combination of a Formula I compound and a Formula II compound or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ to a subject in need thereof.

[00192] Another embodiment is a method of treating a neurological disorder comprising administering a compound of formula I and a compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ to a subject in need thereof, wherein the compound of formula I and the compound of formula II or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ are administered at least once daily for at least eight days.

[00193] Another embodiment is a method of treating a neurological disorder comprising administering from about 5 mg/day to about 600 mg/day, from about 5 mg/day to about 300 mg/day, from about 5 mg/day to about 400 mg/day, from about 5 mg/day to about 500 mg/day, from about 5 mg/day to about 600 mg/day, from about 5 mg/day to about 1000 mg/day, from about 50 mg/day to about 1000 mg/day, from about 100 mg/day to about 1000 mg/day, from about 150 mg/day to about 1000 mg/day, from about 150 mg/day to about 5000 mg/day, from about 150 mg/day day to about 300 mg/day, or from about 150 mg/day to about 100 mg/day, or the required amount of a compound of formula I and from about 0.1 mg/day to about 1 mg/day, from 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 the required amount of DEX to a subject in need thereof.

[00194] Another embodiment is a method of increasing plasma levels of DEX in a subject in need of DEX treatment, wherein the subject is a rapid DEX metaboliser, comprising co-administering to the subject a compound of Formula I with DEX.

[00195] Another embodiment is a method of inhibiting DEX metabolism, comprising administering a compound of Formula I to a subject, wherein the subject is a rapid DEX metaboliser, and wherein DEX is present in the subject's body concurrently with the compound of Formula I.

[00196] Another embodiment is a method of increasing the metabolic life of DEX, comprising administering a compound of Formula I to a subject in need of treatment with DEX, wherein the subject is a rapid DEX metabolizer and wherein the DEX is present in the subject's body concurrently with the compound of Formula I.

[00197] Another embodiment is a method of increasing plasma levels of DEX comprising co-administering a compound of formula I and DEX to a subject in need of treatment with DEX, wherein the compound of formula I is administered on the first day for at least two days of co-administration a compound of formula I with DEX, wherein the increase in plasma levels of DEX occurs on the first day of co-administration of the compound of formula I and DEX compared to the same amount of DEX administered without the compound of formula I.

[00198] Another embodiment is a method of increasing plasma DEX levels, comprising co-administering a compound of Formula I and DEX for at least five consecutive days to a subject in need of DEX treatment, where on the fifth day the plasma DEX level becomes higher than the level of DEX in blood plasma, which would be achieved with the introduction of the same amount of DEX, administered without the compound of formula I for five consecutive days.

[00199] Another embodiment is a method of increasing plasma DEX levels, comprising co-administering a compound of formula I and DEX for at least six consecutive days to a subject in need of DEX treatment, where on the sixth day the plasma DEX level becomes higher than the level of DEX in blood plasma, which would be achieved with the introduction of the same amount of DEX, administered without the compound of formula I for six consecutive days.

[00200] Another embodiment is a method of reducing the residual effect of DEX, comprising co-administration of a compound of formula I with DEX to a subject in need of treatment with DEX, wherein the plasma level of DEX is achieved 12 hours after co-administration of a compound of formula I with DEX , wherein the DEX level is at least twice the plasma level that would be achieved by administering the same amount of DEX without the Formula I compound.

[00201] Another embodiment is a method of reducing the residual effect of DEX, comprising co-administration of a compound of formula I with DEX to a subject in need of treatment with DEX, wherein the plasma level of DEX is reached 12 hours after co-administration of a compound of formula I with DEX, wherein the DEX level is at least twice the plasma level that would be achieved by administering the same amount of DEX without the Formula I compound.

[00202] Another embodiment is a method of reducing the residual effect of DEX, comprising co-administration of a compound of formula I with DEX to a subject in need of treatment with DEX, wherein the plasma level of DEX is reached 12 hours after co-administration of a compound of formula I with DEX, which is at least twice the plasma level that would be achieved by administering the same amount of DEX without the compound of formula I.

[00203] Another embodiment is a method of reducing the likelihood of an adverse event or other adverse effect, such as addiction, associated with DEX treatment, comprising co-administering a compound of Formula I and DEX to a subject in need of DEX treatment, where the subject is susceptible to the risk of an adverse event as a result of treatment with DEX.

[00204] Another embodiment is a method of reducing the likelihood of an adverse event associated with treatment with a Formula I compound, comprising co-administering DEX and a Formula I compound to a subject in need of treatment with a Formula I compound, wherein the subject is at risk for an adverse event as a result of treatment with a compound of formula I.

[00205] Another embodiment is a method of improving the antitussive properties of DEX, comprising administering a compound of formula I in combination with administering DEX to a subject in need of cough treatment.

[00206] Another embodiment is a method of treating cough comprising administering a combination of a compound of Formula I and DEX to a subject in need thereof.

[00207] Another embodiment is a method of treating a neurological disorder comprising administering a compound of formula I and DEX to a subject in need thereof, wherein the compound of formula I and DEX are administered at least once daily for at least 8 days.

[00208] Another embodiment is a method of treating a neurological disorder comprising administering a composition comprising DEX, a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ to a subject in need thereof, wherein DEX is a compound of formula I , DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ is administered at least once a day for at least 8 days.

[00209] Another embodiment is a method of treating a neurological disorder comprising administering a composition comprising DEX, a Formula I compound, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ to a subject in need thereof, wherein the Formula I compound and DEX administered at least once a day for at least 8 days.

[00210] Another embodiment is a sustained release DEX oral delivery system comprising a composition containing DEX, a compound of Formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ and a carrier.

[00211] Another embodiment is a method of reducing the number of doses of DEX that can be administered without loss of efficacy, comprising orally administering an effective amount of a composition containing DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ to a subject in need of treatment with DEX.

[00212] Another embodiment is a pharmaceutical composition, dosage form, or medical preparation comprising a therapeutically effective amount of DEX, a therapeutically effective amount of a compound of Formula I, and a pharmaceutically acceptable excipient.

[00213] In one aspect, a method for increasing the metabolic life of DEX is provided, comprising administering a 5-HT2A receptor antagonist/inverse agonist to a subject in need of DEX treatment, wherein the 5-HT2A receptor antagonist/inverse agonist is an inhibitor of a CYP2D6 enzyme, and wherein DEX is present in the subject at the same time as the CYP2D6 inhibitor. In another embodiment, the composition contains DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00214] In another aspect, a method is provided for preventing adverse events associated with DEX treatment, comprising co-administration of a 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, to a subject in need of DEX treatment, wherein the subject is at risk of developing an adverse event resulting from treatment with DEX.

[00215] In another aspect, a method is provided for using 5HT2A receptor antagonists, such as a compound of formula I, to improve the therapeutic properties of DEX in the treatment of neurological disorders.

[00216] In another aspect, a method of treating a disorder or disease is provided, comprising administering a composition comprising a 5HT2A receptor antagonist and DEX to a subject in need thereof. In another embodiment, the composition contains DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00217] In another aspect, a method is provided for selecting a 5-HT2A receptor antagonist/inverse agonist for use in combination with DEX for a subject in need thereof.

[00218] In another embodiment, NMDA receptor antagonists reduce the physical aspects of morphine dependence as measured by the naloxone-blocked withdrawal sign (Bristow et al., Competitive and glycine: NMDA receptor antagonists attenuate withdrawal-induced behaviors and increased hippocampal acetylcholine efflux in morphine- dependent rats Neuropharmacology 36: 241-250 (1997) Popik et al., Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine J. Pharmacol Exp. Ther. 280: 854-865 (1997) Popik et al., Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists Neuropharmacology 37: 1033-1042 (1998 ); incorporated by reference in its entirety) and are capable of attenuating not only the physical, but also the affective and motivational components of withdrawal symptoms. mental states, as well as addiction (Cornish et al. A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug & Alcohol Dependency. 67(2): 177-83(2002); incorporated by reference in its entirety). By reducing withdrawal symptoms, such drugs should be of benefit to patients in the emergency detoxification phase of opioid dependence treatment (Cornish et al., A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug & Alcohol Dependence 67(2): 177-83 (2002); incorporated by reference in its entirety).

[00219] Accordingly, an embodiment is a method of treating a subject in need of treatment for disorders or diseases associated with drug dependence and substance abuse, comprising administering DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN ™.

[00220] Chronic exposure to morphine leads to a series of biochemical adaptations of the glutamatergic receptor system in the limbic system sensitizing agents J Neurosci 16: 274-282 (1996; incorporated by reference in its entirety). Excitatory amino acids are involved in mediating many of the neurochemical and behavioral effects that result from chronic drug exposure when abused, some of which can be prevented or reversed with the use of glutamatergic antagonists (Inturrisi, Preclinical evidence for a role of glutamatergic systems in opioid tolerance and dependence Semin Neurosci 9: 110-119 (1997); incorporated by reference in its entirety). Continuous self-administration of addictive drugs, including opioids, leads to overstimulation of dopamine in brain reward centers and increased release of excitatory amino acids, including glutamate, leading to the development of tolerance and dependence, which can be blocked by glutamate antagonists (Herman et al., Clinical medication development for opiate addiction: focus on nonopioids and opioid antagonists for the amelioration of opiate withdrawal symptoms and relapse prevention Semin Neurosci 9: 158-172 (1997; incorporated by reference in its entirety). Accordingly, one embodiment is a method of treating a subject in need of treatment for drug dependence and substance abuse disorders or diseases that result from opioid tolerance and dependence by alleviating opiate withdrawal symptoms and preventing relapse, comprising administering DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00221] DEX provides neuroprotection to dopamine neurons in some inflammation-based animal models of Parkinson's disease (Li et al., Protective effect of dextromethorphan against endotoxic shock in mice. Biochemical Pharmacology. 69(2): 233-40 (2005); Liu et al. al., Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation, Journal of Pharmacology & Experimental Therapeutics, 305(1):212-8 (2003); disease model: role of NADPH oxidase FASEB Journal 18(3): 589-91 (2004) Zhang et al., 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroiveprotect against LPS-induced neurotoxicity FASEB Journal 19 (3): 395-7 (2005); incorporated by reference in their entirety). 1-10 μM DEX protected dopamine neurons from lipopolysaccharide (LPS)-induced decrease in dopamine uptake in primary mixed cultures of rat midbrain neurons and glial cells. In terms of morphology, in cultures treated with LPS, in addition to the reduction in the number of dopamine neurons, the dendrites of the remaining dopamine neurons were significantly less developed than those in the controls. In cultures pre-treated with DEX (10 μM) prior to stimulation with LPS, dopamine neurons were significantly more numerous and dendrites less damaged. A significant degree of neuroprotection was noted in cultures when adding DEX within 60 minutes after adding LPS. Thus, DEX significantly protects monoamine neurons not only during pre-treatment but also during post-treatment (Zhang et al., Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. FASEB Journal, 18(3) : 589-91 (2004); incorporated by reference in its entirety). Animal studies using both LPS and MPTP PD models also show a potent protective effect of DEX (Zhang et al., Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. FASEB Journal, 18( 3): 589-91 (2004); incorporated by reference in its entirety). Accordingly, an embodiment is a method of treating a subject in need of treatment for Parkinson's disease comprising administering DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00222] The neuroprotective effect of DEX is associated with the inhibition of excessive microglial activation by inhibiting the formation of superoxide anion by NADPH oxidase, and this neuroprotective effect of DEX is not associated with its NMDA receptor antagonist property. A correlation has been observed between anti-inflammatory activity and neuroprotection of NMDA receptor antagonists such as MK801, AP5 and memantine, suggesting that dopamine receptor neuroprotection conferred by DEX in neurodegenerative models associated with inflammation is not mediated by the NMDA receptor. This finding is consistent with past reports suggesting that NMDA receptor blockade is associated with the neuroprotective effects of DEX in models of glutamate-induced acute excitotoxicity. Accordingly, an embodiment is a method of treating a subject in need of treatment for a disorder or disease comprising administering DEX and a compound of Formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™, wherein the disorder or disease is an inflammation-associated neurodegenerative disorder.

[00223] The GC-dependent effects of morphine activate the hypothalamic-pituitary-adrenal (HPA) axis. Activation of the HPA axis increases the amount of GC products in the form of highly active immunomodulatory hormones (Freier et al., A mechanism of action for morphine-induced immunosuppression: corticosterone mediates morphine-induced suppression of natural killer cell activity. J Pharmacol Exp Ther 270(3): 1127 -33 (1994), Mellon et al., Role of central opioid receptor subtypes in morphine-induced alterations in peripheral lymphocyte activity, Brain Res 789(1): 56-67 (1998), incorporated by reference in its entirety). Accordingly, an embodiment is a method of treating a subject in need of treatment for a disorder or disease comprising administering DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™, wherein the disorder or disease is an opioid addiction. For heroin addicts experiencing withdrawal, DEX dosages of up to about 500 mg/day have been suggested, including DEX doses of 120, 240, and 480 mg/day. DEX at high doses caused modest increases in heart rate, blood pressure, temperature, and plasma bromide (Cornish et al., A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients Drug & Alcohol Dependence 67(2): 177-83 (2002; incorporated by reference in its entirety). Among the Han Chinese in Taiwan in particular, DEX has been reported to be metabolized by a "dextromethorphan-metabolizing enzyme CYP2D6" significantly different from that of Western populations (Yeh et al., Analysis of pharmacokinetic parameters for assessment of dextromethorphan metabolic phenotypes. J. Biomed Sci 10: 552-564 (2003; incorporated by reference in its entirety).

[00224] Patients with bipolar disorder (BP) exhibit significantly higher levels of interleukin-6, interleukin-8, and TNF-alpha during manic and depressive episodes compared to normal controls (Kim et al., Alexithymia and Stress Response Patterns among Patients with Depressive Disorders in Korea. Psychiatry Investig. 6(1): 13-8 (2009); O'Brien et al., Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. J Affect Disord. 90(2- 3): 263-7 (2006) Brietzke et al., Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder J Affect Disord. in its entirety).

[00225] At autopsy, the frontal cortex of cadavers with BP showed significantly higher levels of IL-1 beta receptor protein and mRNA and neuroinflammatory markers inducible nitric oxide synthase (iNOS) and c-fos (Rao et al., Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients Mot Psychiatry 15(4): 384-92 (2010); incorporated by reference in its entirety). Taken together, an imbalance in the immune system, which subsequently leads to an inflammatory response of neurons, may be associated with the progression of brain atrophy and exacerbation of BP symptoms. Treatment of BP with immune-targeted therapies has demonstrated an antidepressant effect. For example, unmasked acetylsalicylic acid when added to fluoxetine resulted in increased remission rates in individuals with major depression who had not previously responded to fluoxetine monotherapy (Mendlewicz et al., Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open -label study Int Clin Psychopharmacol 21(4): 227-31 (2006); incorporated by reference in its entirety).

[00226] Thus, the use of an anti-inflammatory agent combined with a mood stabilizing agent improves the effect of BP treatment. Mood stabilizers have been shown to activate interconnected intracellular signaling pathways that mediate neurogenesis and synaptic plasticity. It was found that the decrease in brain volume in patients with BP is largely suppressed by long-term treatment with valproate (VPA), which leads to neuroprotective effects, since VPA makes neurons less susceptible to various forms of stroke (Chen et al., Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes Mol Psychiatry 11(12): 1116-1125 (December 2006); incorporated by reference in its entirety) and even stimulates neurogenesis in the adult brain rodent. VPA induces cytoprotective proteins such as Bcl-2, glucose-regulated protein 78 (Grp78), brain-derived neurotrophic factor (BDNF) and heat shock protein 70. In addition, VPA activates neurite outgrowth, while VPA has been reported to be in therapeutic levels inhibits histone deacetylase (HDAC), an enzyme that catalyzes the removal of an acetyl group from histone lysine residues, promoting local biosynthesis of BDNF in neurons. Accordingly, an embodiment is a method of treating a subject in need of treatment of a related disorder or disease comprising administering DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™, wherein the disorder or disease is BP.

[00227] Another embodiment is a method for reducing the adverse effects of DEX in a subject in need, comprising:

a. introduction to the subject of the DEX and

b. administering a compound of formula I to a subject.

[00228] Some embodiments include a method of treating neuropsychiatric disorders, comprising administering a therapeutically effective amount of DEX and a therapeutically effective amount of a compound of formula I to a human in need thereof.

[00229] Some embodiments include a method of improving the therapeutic properties of DEX in the treatment of neuropsychiatric disorders, comprising the co-administration of DEX and a compound of formula I.

[00230] Some embodiments include a method of increasing plasma levels of DEX in a subject that is a rapid DEX metabolizer, comprising co-administering a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I, and DEX to the subject.

[00231] Some embodiments include a method of inhibiting DEX metabolism, comprising administering to a subject a 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, wherein the subject is a rapid DEX metabolizer and wherein DEX is present in the subject at the same time as the antagonist/inverse agonist 5-HT2A receptor.

[00232] Some embodiments include a method for increasing the metabolic life of DEX, including increasing the half-life (T _1/2 ) of DEX. These embodiments may include administering to the subject a 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, wherein the subject is a rapid DEX metaboliser and wherein DEX is present in the subject at the same time as the 5-HT2A receptor antagonist/inverse agonist.

[00233] Some embodiments include a method of correcting rapid DEX metabolism comprising administering a 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, to a subject in need thereof, eg, a subject in need of pain treatment.

[00234] Some embodiments include a method of improving the therapeutic properties of DEX in the treatment of neuropsychiatric disorders, comprising administering a 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, in combination with administering DEX to a subject in need of treatment for a neuropsychiatric disorder.

[00235] Some embodiments include a method of treating neuropsychiatric disorders comprising administering a combination of a 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, and DEX to a subject in need thereof.

[00236] DEX is used as a cough suppressant. According to the FDA's OTC prescribing information for DEX [21CFR341.74], DEX should be administered 6 times a day (every 4 hours), 4 times a day (every 6 hours), or 3 times a day (every 8 ocloc'k).

[00237] DEX is rapidly metabolized in the human liver. Such rapid hepatic metabolism may limit systemic drug exposure in individuals who are rapid metabolizers. Subjects may be: 1) rapid DEX metabolizers those who rapidly metabolize DEX; 2) poor DEX metabolizers - those who metabolize DEX poorly; or 3) intermediate DEX metabolizers - those whose DEX metabolism is somewhere between that of a fast and a weak metabolizer. Fast metabolizers can also be ultra-fast metabolizers. Rapid DEX metabolizers make up a significant portion of the population. DEX can, for example, be metabolized to DO.

[00238] When receiving the same oral dose of DEX, plasma levels of DEX are significantly higher in poor metabolizers or intermediate metabolizers compared to fast DEX metabolizers. Low plasma concentrations of DEX may limit its clinical utility as a single agent for rapid metabolizers and possibly intermediate DEX metabolizers. Some antidepressants, such as the compound of formula I, inhibit the metabolism of DEX and thus are able to improve its therapeutic efficacy. Similarly, antidepressants can provide less frequent DEX, such as once a day instead of twice a day, once a day instead of three times a day, once a day instead of four times a day, twice a day instead of three times per day or twice a day instead of four times a day, without loss of therapeutic efficacy.

[00239] Pain or other neuropsychiatric disorders can be treated by a method comprising administering a therapeutically effective amount of DEX and a therapeutically effective amount of a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I, to a person in need thereof.

[00240] Examples of neuropsychiatric disorders that can be treated or that can be treated with increased efficacy with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist, a compound of formula I, include, without limitation, affective disorders, psychiatric disorders, brain functioning disorders, motor disorders, forms of dementia, traumatic brain injury, chronic traumatic encephalopathy, PTSD, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[00241] Mood disorders that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist, a compound of formula I, include, but are not limited to, depression, major depressive disorder, treatment-resistant depression, and treatment-resistant bipolar depression, forms of BP including cyclothymia , seasonal affective disorder, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH) and attention deficit/hyperactivity disorder (AD/HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, anorexia , obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug dependence or substance abuse, nicotine dependence, psychosexual dysfunction, pseudobulbar affect, and emotional lability. [00242] Depression can be manifested by mood changes, feelings of deep sadness, despair, slower pace of thinking, sleep disturbance, loss of concentration, pessimistic anxiety, agitation, and low self-esteem. Physical symptoms of depression can include insomnia, anorexia, weight loss, decreased tone and libido, apathy, and abnormal hormonal circadian rhythms.

[00243] Psychiatric disorders that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I, include, but are not limited to, anxiety disorders, including, but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder , agoraphobia, obsessive-compulsive disorder and post-traumatic stress disorder (PTSD); mania, manic-depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation and apathy in Alzheimer's disease.

[00244] Apathy or loss of motivation is the most common change in behavior in Alzheimer's disease (AD). This is true across the spectrum of cognitive impairment, from mild cognitive impairment to severe Alzheimer's disease (AD), as well as a range of other neuropsychiatric disorders. Apathy is a form of executive cognitive dysfunction. Patients with apathy suffer from reduced performance of daily activities and specific cognitive deficits and rely on families to provide more care, resulting in increased family stress. Apathy is one of the primary syndromes associated with frontal and subcortical pathology, and apathy in AD appears to have several neuroanatomical correlates that involve components of the frontal subcortical networks. Despite the profound implications of this common syndrome, only a few tools have been developed to measure apathy specifically, and these tools have not been directly compared. The assessment of apathy in AD requires clinicians to distinguish between loss of motivation and loss of performance due to cognitive decline. Although apathy can be misdiagnosed as depression due to overlapping symptoms, modern research has shown that apathy is a separate syndrome. In treatment, differentiating apathy from depression is important because these disorders are treatable with different types of interventions.

[00245] The Apathy Assessment (IA) Inventory, which is a scoring scale for a general assessment of apathy and a separate assessment of emotional dullness, lack of initiative and lack of interest, is a reliable method for assessing several parameters of apathy syndrome in dementia and non-dementia elderly subjects, and the subject's awareness of these symptoms. IA assesses apathy as effectively as the apathy domain on the Neuropsychiatric Inventory (Robert et al., The Apathy Inventory: assessment of apathy and awareness in Alzheimer's disease, Parkinson's disease and mild cognitive impairment, the Journal of Geriatric Psychiatry, Volume 17, Issue 12, pages 1099-1105 (December 2002); Landes et al., Apathy in Alzheimer's Disease, the Journal of American Geriatric Society, Volume 49, Issue 12, pages 1700-1707 (December 2001) Malloy et al., Apathy and Its Treatment in Alzheimer's Disease and Other Dementias, Psychiatric Times, Vol.XXII, Issue 13 (November 01, 2005), incorporated by reference in its entirety). Apathy may be the result of damage to one or more areas of the brain, such as the frontal cortex, thalamus, striatum, and amygdala. In most cases, direct damage to the frontal lobes or subcortical nuclei, which are associated with the frontal lobes, causes apathy. The apathy associated with Alzheimer's disease is very difficult to treat. Antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors, etc., alleviated the course of apathy only to a certain extent.

[00246] Accordingly, an embodiment of the invention is a combination of DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ and one or more antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors, dopaminergic agents. Another embodiment is a combination of DEX and a compound of formula I or DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ and one or more drugs such as donepezil, memantine, amantadine, bupropion, ropinirole, methylphenidate, amphetamine, modafinil , metrifonate, tacrine, galantamine, rivastigmine, nefiracetam, Ginkgo biloba extract, etc. (Ruthirakuhan et al., Pharmacological interventions for apathy in Alzheimer's disease (Protocol), Cochran Database of Systemic Studies, 2016, Issue 5. Art. No.: CD012197, published by John Wiley & Sons, Ltd.; Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease: A Systematic Review Across Modalities, Journal of Geriatric Psychiatry and Neurology, Vol 30, Issue 1, 2017; references incorporated by reference in their entirety).

[00247] Acetylcholinesterase is one of the most significant components of the central cholinergic pathways. It stops the synaptic action of acetylcholine through hydrolysis, which leads to the formation of a fragment of choline, which is necessary for the restoration of the neurotransmitter. The pathogenesis of Alzheimer's disease (AD) is associated with a deficiency of the neurotransmitter acetylcholine in the brain. Acetylcholinesterase inhibitors (AChEIs) are effective because they accelerate acetylcholine-mediated signaling between neurons. This is achieved by increasing the concentration of acetylcholine by reversibly inhibiting its hydrolysis by acetylcholinesterase. (USFDA Reference ID: 3096907; Guidance on Donepezil Hydrochloride completed August 2017, incorporated by reference in its entirety).

[00248] Accordingly, in one embodiment, the composition contains an AChI such as 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one ( donepezil), (S)-3-(1-(dimethylamino)ethyl)phenylethyl(methyl)carbamate (rivastigmine), dimethyl(2,2,2-trichloro-1-hydroxyethyl)phosphonate (metrifonate), dimethyl(2,2 ,2-trichloro-1-hydroxyethyl)phosphonate (metrifonate), (4aS,6R,8aS)-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzo[2, 3]benzofuro[4,3-cd]azepin-6-ol (galanthamine) and 1,2,3,4-tetrahydroacridine-9-amine (tacrine), O,S-dimethylacetylamidothiophosphate, O,O-dimethyl-S- ((4-oxobenzo[a][1,2,3]triazin-3(4H)-yl)methyl)phosphorodithioate, 2,2-dimethyl-2,3-dihydrobenzofuran-7-ylmethylcarbamate, S-(((4 -chlorophenyl)thio)methyl)-O,O-diethylphosphorodithioate, 2-chloro-1-(2,4-dichlorophenyl)vinyldiethylphosphate, O,O-diethyl-O-(3,5,6-trichloropyridin-2-yl) phosphorothioate, O-(3-chloro-4-methyl-2-oxo-2H-chromen-7-yl)-O,O-diethylphosphorothioate, 1-phenylethyl-(E)-3-((dimethoxyphosphoryl)oxy)but- 2-enoate, 4-(tert-butyl)-2-chlorophenyl methyl meth ylf osphor amide at, O,O-d andethyl-O-(2 -(ethylthio)ethyl)thiophosphate, O,O-diethyl-S-(2-(ethylthio)ethyl)thiophosphate, O,O-diethyl-O - (2-isopropyl-6-methylpyrimidin-4-yl) thiophosphate, 2,2-dichlorovinyl dimethyl phosphate, (E) -4- (dimethylamino) -4-oxobut-2-en-2-yl-dimethyl phosphate, O, O- dimethyl S-(2-(methylamino)-2-oxoethyl)phosphorodithioate, S,S'-(1,4-dioxane-2,3-diyl)-O,O,O',O'-tetraethyl-bis(phosphorodithioate ), O,O-diethyl-S-(2-(ethylthio)ethyl)phosphorodithioate, O-ethyl-O-(4-nitrophenyl)phenylphosphonothioate, O,O,O',O'-tetraethyl-S,S'- methylene bis(phosphorodithioate), O-ethyl S,S-dipropylphosphorodithioate, O-(4-(N,N-dimethylsulfamoyl)phenyl)-O,O-dimethylthiophosphate, O-(4-(N,N-dimethylsulfamoyl)phenyl )-O,O-dimethylthiophosphate, ethyl (3-methyl-4-(methylthio)phenyl)isopropylphosphoramidate, O,O-dimethyl-O-(3-methyl-4-nitrophenyl)thiophosphate, O-ethyl-S-phenylethylphosphonodithioate, isopropyl 2-((ethoxy(isopropylamino)phosphorothioyl)oxy)benzoate, diethyl 2-((dimethoxyphosphorothioyl)thio)succinate, O,S-dimethylamidothiophosphate, O,S-dimethylamidothiophosphate, S-((5-methoxy-2- oxo-1,3,4-thiadiazo l-3(2H)-yl)methyl)-O,O-dimethylphosphorodithioate, methyl-3-((dimethoxyphosphoryl)oxy)but-2-enoate, (E)-dimethyl-(4-(methylamino)-4-oxobut -2-en-2-yl)phosphate, 1,2-dibromo-2,2-dichloroethyldimethylphosphate, isopropyl(S)-methylfluorophosphonate, 3,3-dimethylbutan-2-yl(S)-methylfluorophosphonate, O,O-diethyl -O-(4-nitrophenyl)thiophosphate, S-(2-(ethylsulfinyl)ethyl)-O,O-dimethylthiophosphate, O,O-diethyl- S-((ethylthio)methyl)phosphorodithioate, S-((6-chloro -2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-O,O-diethylphosphorodithioate, S-((1,3-dioxoisoindolin-2-yl)methyl)-O,O-dimethylphosphorodithioate, (E )-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yldimethylphosphate, O,O,O',O'-tetramethyl-O,O'-(thiobis(4,1-phenylene) )bis(thiophosphate), tetraethyl diphosphate, S-((tert-butylthio)methyl)-O,O-diethylphosphorodithioate, 2-chloro-1-(2,4,5-trichlorophenyl)vinyldimethylphosphate and dimethyl(2,2,2- trichloro-1-hydroxyethyl)phosphonate or their pharmaceutically acceptable derivatives, metabolites, analogs or salts.

[00249] Substance abuse and drug dependence that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I include, without limitation, drug dependence, cocaine dependence, psychostimulants (e.g., crack, cocaine , AIDS, meth), nicotine, alcohol, opioids, anxiolytics and sleeping pills, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents and volatile nitrites. Nicotine addiction includes nicotine addiction in all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.

[00250] Brain dysfunctions that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I include, without limitation, disorders including forms of mental retardation such as vascular dementia, dementia in Alzheimer's disease , dementia with Lewy bodies, frontotemporal lobar degeneration, memory loss, amnesia/amnestic syndrome, epilepsy, mental disorders, coma, decreased attention, speech disorders, vocal spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome and schizophrenia . Brain dysfunction also includes disorders caused by cerebrovascular disease, including but not limited to stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, and the like, and the symptoms include confusion, dementia, coma, decreased attention, apathy and speech disorders.

[00251] Movement disorders that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I include, without limitation, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral paralysis, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), Tourette's syndrome, and Wilson's disease.

[00252] Forms of dementia that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I include, without limitation, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontal temporal dementia, Creutzfeldt-Jakob disease, normotensive hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and frontotemporal lobar degeneration (FTLD).

[00253] Motor neuron diseases that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I include, without limitation, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS) , progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), forms of spinal motor neuron atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[00254] Neurodegenerative diseases that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I include, but are not limited to, Alzheimer's disease, prion diseases, cerebellar ataxia, spinal cerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration , progressive supranuclear palsy, Wilson's disease, Menkes' disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, olivopontocerebellar atrophy or degeneration , strionigral degeneration, syndrome Guillain-Barre and spastic paraplegia.

[00255] Seizure disorders that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I include, without limitation, epileptic seizures, non-epileptic seizures, epilepsy, febrile seizures; partial seizures, including, without limitation, simple partial seizures, Jacksonian seizures, complex partial seizures, and partial continuous epilepsy; generalized seizures, including, without limitation, generalized tonic-clonic seizures, petit mal seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[00256] Types of headaches that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I include, without limitation, migraine, trigeminal cephalgia, tension headache, and cluster headaches, including Bing-Horton syndrome.

[00257] Other neurological disorders that can be treated with a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I, a derivative, metabolite of any of these compounds, or a prodrug based on any of these compounds include Rett syndrome, autism , tinnitus, disorders of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders due to uncontrolled spasms of the laryngeal muscles, including, without limitation, spastic abduction-type dysphonia, adduction-type spastic dysphonia, muscle tension dysphonia, and voice tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrixate-induced neurotoxicity; urinary incontinence, including, without limitation, stress urinary incontinence, urge and fecal incontinence, and erectile dysfunction.

[00258] The analgesic properties of DEX can be improved by a method comprising coadministration of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I, a metabolite, a derivative of any of these compounds, or a prodrug based on any of these compounds with DEX .

[00259] The analgesic properties of a compound of formula I can be improved by a method comprising co-administration of DEX with a compound of formula I.

[00260] These methods can be used to treat or provide relief from any pain, including, without limitation, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, and the like.

[00261] Examples of musculoskeletal pain include low back pain (i.e., lumbosacral pain), primary dysmenorrhea, and arthritis pain such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoarthritis, axial spondyloarthritis, including ankylosing spondylitis, etc.

[00262] In some embodiments, a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I, is used to treat chronic musculoskeletal pain.

[00263] Examples of neuropathic pain include idiopathic and diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom amputee pain, central pain, and so on. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, multiple sclerosis central pain, HIV-associated neuropathy, and radiotherapy or chemotherapy-associated neuropathy, etc.

[00264] The term "treatment" or "treatment" includes the diagnosis, cure, mitigation, treatment or prevention of a disease in a human or other animals, or any activity that otherwise affects the structure or any function of the body of a human or other animals.

[00265] Any 5-HT2A receptor antagonist/inverse agonist can be used in combination with DEX to improve the therapeutic properties of DEX. DEX and the 5-HT2A receptor antagonist/inverse agonist may be administered as separate compositions or dosage forms, or may be administered as a single composition or dosage form containing both components.

[00266] 5-HT2A receptor antagonists/inverse agonists that can be co-administered with DEX include, but are not limited to, a compound of formula I, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chlorimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine , nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindanamine, benactizine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, telociprane , nialamide, iproniazid, iproclozide, toloxatone, butriptyline, dosulepine, dibenzepine, iprindol, lofepramine, opipramol, norfluoxetine, dapoxetine, etc., or a metabolite of any of these compounds, or a prodrug based on any of these compounds, or a pharmaceutically acceptable salt any of these compounds.

[00267] The combination of a compound of formula I with DEX can provide greater efficacy, such as greater pain relief, than would be achieved by administering either component alone. In fast metabolizers, DEX can be rapidly and extensively metabolized, resulting in low systemic exposure even at high doses. The compound of formula I, in addition to having antidepressant and analgesic properties, is an inhibitor of DEX metabolism. Metabolites of a compound of formula I, which include a compound of formula I, a derivative, a metabolite, are also inhibitors of DEX metabolism. Thus, a compound of formula I, including a form of a compound of formula I that is rapidly converted in the body (e.g., salt, hydrate, solvate, polymorph, etc.), is a prodrug based on the compound of formula I.

[00268] As explained above, this inhibition can increase plasma levels of DEX resulting in additive or synergistic efficacy such as alleviation of neurological disorders including pain, depression, smoking cessation, etc. Thus, while the inhibition of DEX metabolism is only one of the many potential benefits of the combination, co-administration of DEX with a compound of formula I can thus increase the efficacy of a compound of formula I in many conditions. Co-administration of DEX with a compound of formula I can enhance the analgesic properties of a compound of formula I under many conditions. Co-administration of DEX with a compound of formula I may also enhance the antidepressant properties of a compound of formula I in many conditions, including providing a faster onset of action.

[00269] Another potential benefit of co-administration of DEX and a compound of Formula I is that it may be useful in reducing the likelihood of an adverse event such as drowsiness or confusion associated with DEX treatment. This may be useful, for example, for subjects at risk of experiencing an adverse event as a result of treatment with DEX.

[00270] Another potential benefit of co-administration of DEX and a compound of formula I is that it may be useful in reducing the likelihood of an adverse event, such as seizure, associated with treatment with a compound of formula I. This may be useful for, for example, subjects with the risk of an adverse event as a result of treatment with a compound of formula I.

[00271] With regard to DEX, co-administration with a compound of formula I may reduce the likelihood of an adverse event in the central nervous system, gastrointestinal tract, or other type of adverse event associated with any of these compounds. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, insomnia, lightheadedness, tremors, hallucinations, seizures, CNS depression, fear, anxiety, headache, increased irritability or agitation, tinnitus, drowsiness, dizziness, lethargy, drowsiness, confusion, disorientation, exhaustion, incoordination, fatigue, euphoria, nervousness, insomnia, sleep disturbances, seizures, agitation, catatonic-like states, hysteria, hallucinations, delusions, paranoia, headaches and/or migraine and extrapyramidal symptoms such as oculogyric crisis, torticollis, hyperexcitability, increased muscle tone, ataxia, and tongue protrusion.

[00272] Adverse events in the gastrointestinal tract include, without limitation, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, bloating, flatulence, bleeding peptic ulcers, loose stools, constipation, stomach pain, heartburn, gas, loss appetite, a feeling of fullness in the stomach, indigestion, bloating, acidity, dry mouth, gastrointestinal disturbances and stomach pain.

[00273] Co-administration of DEX and a 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds may be administered as a single dosage form, or may be administered as two separate dosage forms. In addition, the two compounds may be administered at the same time, but this is not necessary. The compounds can be administered at different times, provided that they are present in the human body simultaneously for at least part of the time during which coadministration is being treated.

[00274] In some embodiments, co-administration of a combination of a compound of Formula I and DEX results in analgesic properties. For example, the combination may have improved analgesic properties over the compound of formula I alone or over DEX alone, including potentially faster onset of action.

[00275] In some embodiments, the combination may have improved analgesic properties by at least about 0.5%, by at least about 1%, by at least about 10%, by at least about 20%, by at least at least about 30%, by at least about 50%, by at least 100%, up to about 500% or up to 1000%, from about 0.5% to about 1000%, from about 10% to about 20%, from about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about t about 130% to about 140%, from about 140% to about 150%, from about 150% to about 160%, from about 160% to about 170%, from about 170% to about 180%, from about 180% to about 190%, from about 190% to about 200%, or any degree of pain relief in the range between or limited to any of these values, compared with the compound of formula I alone.

[00276] In some embodiments, the combination may have improved analgesic properties by at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least at least about 30%, by at least about 50%, by at least 100%, up to about 500% or up to 1000%, from about 0.5% to about 1000%, from about 10% to about 20%, from about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about t about 130% to about 140%, from about 140% to about 150%, from about 150% to about 160%, from about 160% to about 170%, from about 170% to about 180%, from about 180% to about 190%, from about 190% to about 200%, or any degree of pain relief in the range between or limited by any of these values, compared to DEX alone.

[00277] Unless otherwise indicated, any reference herein to a compound such as DEX, a compound of formula I, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternative solid forms such as polymorphs, solvates, hydrates, etc.; tautomers; deuterium-modified compounds such as deuterium-modified DEX and a compound of formula I; or any chemicals that can rapidly convert to a compound described herein under the conditions under which the compounds are used as described herein. Examples of deuterium-modified DEXs and compounds of formula I include, without limitation, the compounds shown below.

[00278] The dosage form or composition may be a combination or mixture of DEX and a compound that inhibits DEX metabolism, such as a compound of formula I, either alone or in a carrier medium. For example, DEX and a compound of formula I may be dispersed within each other or dispersed together in a carrier medium. The dispersion may include a mixture of solid materials, where the fine individual particles are effectively one compound, but the fine particles are dispersed in each other, which can occur if two powders of two different drugs are mixed with a solid carrier medium material and mixed in solid form. In some embodiments, the implementation of the DEX and the compound of formula I can be substantially uniformly dispersed in the composition or dosage form. Alternatively, DEX and a compound of formula I may be in separate zones or phases in a composition or dosage form. For example, one drug may be in the coating and another drug may be in the coated core. For example, one drug may be formulated for sustained release and another drug may be formulated for immediate release.

[00279] Some embodiments include administering a tablet that contains a compound of formula I in a form that provides sustained release and DEX in a form that provides immediate release, or vice versa. While there are many ways in which a sustained release of a compound of formula I can be achieved, in some embodiments a compound of formula I is combined with hydroxypropyl methylcellulose. For example, particles of the hydrochloride compound of formula I can be mixed with microcrystalline cellulose and hydroxypropyl methylcellulose (eg, METHOCEL™) to form a mixture of mixed powders. This mixture can then be combined with immediate release DEX in one tablet.

[00280] DEX and/or a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I, may be combined with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington's Pharmaceutical Sciences, 2005. The relative ratios of active ingredient and carrier can be determined, for example, by the solubility and chemical nature of the compounds, the chosen route of administration, and standard pharmaceutical practice.

[00281] Therapeutic compounds can be administered by any means that can bring the active agent(s) into contact with the desired site or sites of action in the patient's body. The compounds may be administered by conventional means available for use in combination with pharmaceuticals, either as single therapeutic agents or in combination of therapeutic agents. For example, they can be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.

[00282] Therapeutic compounds can be administered to a subject in various forms adapted to the chosen route of administration, such as orally or parenterally. Parenteral administration at this ratio includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial, including transdermal, ophthalmic, sublingual and buccal; local, including ophthalmic, dermal, ocular, rectal and nasal inhalation through insufflation, aerosol and rectal systemic.

[00283] The ratio of DEX to compound of formula I may vary. In some embodiments, the weight ratio of DEX to the compound of Formula I may be from about 0.1 to about 10, from about 0.1 to about 2, from about 0.2 to about 1, from about 0.1 to about 0.5 , from about 0.1 to about 0.3, from about 0.2 to about 0.4, from about 0.3 to about 0.5, from about 0.5 to about 0.7, from about 0.8 up to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio within or in between any of these values . A ratio of 0.1 indicates that the weight of DEX is 1/10 of the weight of the compound of formula I. A ratio of 10 indicates that the weight of DEX is 10 times that of the compound of formula I.

[00284] The amount of DEX in a therapeutic composition may vary. For example, some liquid compositions may contain from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) to about 20% (w/v), from 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), from about 1% (w/v) to about 3% (w/v), from about 3% (w/v) to about 5% (w/v), from 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) ), from about 15% (w/v) to about 20% (w/v), from about 20% (w/v) to about 30% (w/v), from about 30% (w/v) to about 40% (w/v) or from about 40% (w/v) to about 5 0% (w/v) DEX.

[00285] Some liquid dosage forms may contain from about 10 mg to about 500 mg, from about 30 mg to about 350 mg, about 50 mg to about 200 mg, from about 50 mg to about 70 mg, from 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 PO 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 the range limited by any of these values or nah dressed between them.

[00286] Some solid compositions may contain 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%, from about 10% (w/w) to about 30% (w/w), from about 10% (w/w) /wt) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w) , from about 30% (w/w) to about 40% (w/w), from about 40% (w/w) to about 50% (w/w), from 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) DEX.

[00287] Some solid dosage forms may contain from about 10 mg to about 500 mg, from about 30 mg to about 350 mg, from about 20 mg to about 50 mg, from about 30 mg to about 60 mg, from about 40 mg to about 50 mg, from about 40 mg to about 42 mg, from about 42 mg to about 44 mg, from about 44 mg to about 46 mg, from about 46 mg to about 48 mg, from about 48 mg to about 50 mg, from about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about PO mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, approximately 120 mg, or approximately 180 mg DEX, or any amount of DEX within or in between any of these values And.

[00288] The amount of a compound of formula I in a therapeutic composition may vary. If an increase in plasma DEX levels is required, then the compound of formula I must be administered in an amount that increases the level of DEX in blood plasma. For example, a compound of formula I may be administered in an amount that provides a subject's plasma DEX concentration 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 a compound of Formula I.

[00289] In some embodiments, a compound of formula I may be administered to a subject in an amount that provides area under the curve at 12 hours from the time of dosing (AUC _0-12 ) or mean plasma concentration in the subject 12 hours after dosing (C _avg ) DEX on day 8, which 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, in 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 with the same amount of DEX administered without a compound of formula I.

[00290] In some embodiments, a compound of formula I may be administered to a subject in an amount that provides a maximum plasma concentration (C _max ) of DEX in the subject on Day 8, which 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 at the same amount of DEX administered without a compound of formula I.

[00291] In the case of co-administration of a compound of formula I, there may be an increase in plasma DEX levels on the first day of administration of a compound of formula I, compared with the same amount of DEX administered without a compound of formula I. For example, the level of DEX in blood plasma on the first day administration of a compound of Formula I may be at least about 1.5 times, at least about 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 , which would be achieved with the introduction of the same amount of DEX without the compound of formula I.

[00292] In some embodiments, the AUC value of DEX on the first day of administration of the compound of formula I may be at least two times the AUC value that would be achieved by administering the same amount of DEX without the compound of formula I.

[00293] In some embodiments, the C _max value of DEX on the first day of administration of the compound of formula I may be at least two times the value of C _max that would be achieved by administering the same amount of DEX without the compound of formula I.

[00294] In some embodiments, the residual level of DEX (e.g., plasma level 12 hours after administration) on the first day of administration of a compound of Formula I may be at least two times the residual level that would be achieved with the same amount of DEX without compound of formula I.

[00295] In some embodiments, a compound of formula I is administered on the first day of at least two days of treatment with DEX, wherein the reduction in plasma DO levels occurs on the first day of co-administration of the compound of formula I and DEX compared to the same amount of DEX, administered without a compound of formula I. For example, the plasma DO level on the first day can be reduced by at least 5% compared to the plasma DO level that would be achieved with the same amount of DEX administered without the compound of formula I.

[00296] In some embodiments, a compound of Formula I and DEX are co-administered for at least five consecutive days to a subject in need of DEX treatment, wherein on the fifth day the plasma DEX level is above the plasma DEX level, which would be achieved by administering the same amount of DEX administered without the compound of formula I for five consecutive days. For example, the level of DEX in blood plasma on the fifth day (for example, at 0 hours, 1 hour, 3 hours, 6 hours or 12 hours after administration) may be at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times the level that would be achieved by administering the same amount of DEX without compound formula I for five consecutive days.

[00297] In some embodiments, a compound of formula I and DEX are co-administered for at least six consecutive days to a subject in need of DEX treatment, wherein on the sixth day the plasma DEX level is above the plasma DEX level, which would be achieved by administering the same amount of DEX administered without the compound of formula I for six consecutive days. For example, plasma DEX levels on day six (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5-fold, at least 10-fold, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 75 times, or up to about 500 times the level that would be achieved by administering the same amount of DEX without a compound of formula I for six consecutive days.

[00298] In some embodiments, a compound of formula I and DEX are co-administered for at least seven consecutive days to a subject in need of DEX treatment, where on the seventh day the plasma DEX level is higher than the plasma DEX level that was would be achieved by administering the same amount of DEX administered without the compound of formula I for seven consecutive days. For example, plasma DEX levels on day seven (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5-fold, at least 10-fold, at least 20 times, at least 30 times, at least 50 times, at least 70 times, at least 80 times, at least 90 times, or up to about 500 times the level that would be achieved by administering the same amount of DEX without a compound of formula I for seven consecutive days.

[00299] In some embodiments, a compound of formula I and DEX are co-administered for at least eight consecutive days, with the plasma DEX level reached on the eighth day, e.g., at 0 hours, 1 hour, 3 hours, 6 hours or 12 hours after co-administration of a compound of formula I with DEX, which is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, in at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times the plasma level that would be achieved by administering such the same amount of DEX without compound of formula I for eight consecutive days.

[00300] In some embodiments, a compound of Formula I and DEX are co-administered for at least eight consecutive days to a subject in need of treatment with DEX, wherein on the eighth day the plasma DO level is below the plasma DO level, which would be achieved by administering the same amount of DEX administered without the compound of formula I for eight consecutive days. For example, plasma DO levels on day 8 (eg, 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, by at least 20%, by at least 30%, at least 40%, or at least 50% of the plasma DO level that would be achieved by administering the same amount of DEX without a Formula I compound for eight consecutive days.

[00301] In some embodiments, a compound of formula I may be administered to a subject in an amount that provides an AUC value of _0-12 of the compound of formula I in the subject on day 8, which is at least about 100 ng h/mL, at least about 200 ng h/mL, at least about 500 ng h/mL, at least about 600 ng h/mL, at least about 700 ng h/mL, at least about 800 ng h/mL, at least about 900 ng h/mL, at least about 1000 ng h h/mL, at least about 1200 ng h h/mL, at least 1600 ng h h. /ml or up to about 15,000 ng⋅h/ml.

[00302] In some embodiments, a compound of formula I may be administered to a subject in an amount that provides a C _avg value of the compound of formula I in the subject on day 8, which is at least about 10 ng/mL, at least about 20 ng/mL, at least about 40 ng/ml, at least about 50 ng/ml, at least about 60 ng/ml, at least about 70 ng/ml, at least about 80 ng/ml, at least about 90 ng/ml, at least about 100 ng/ml, at least 120 ng/ml, or up to about 1500 ng/ml.

[00303] Some liquid compositions may contain from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) to about 20% (w/v), from about 0.01% to about 10% (w/v), from about 1% (w/v) to about 3% (w/v), from about 3% (w/v) to about 5% (w/v) /volume), from about 5% (w/v) to about 7% (w/v), from about 5% (w/v) to about 15% (w/v), from about 7% (w/v) ) to about 10% (w/v), from about 10% (w/v) to about 15% (w/v), from about 15% (w/v) to about 20% (w/v), from 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% (weight/volume) of a compound of formula I or any amount of a compound of formula I in the range limited by or in between any of these values.

[00304] Some liquid dosage forms may contain from about 10 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 10 mg to about 50 mg, from about 50 mg to about 100 mg, from about 40 mg to about 90 mg, from about 200 mg to about 300 mg, from about 70 mg to about 95 mg, from about 100 mg to about 200 mg, from about 105 mg to about 200 mg, from about 110 mg to about 140 mg, from about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of a compound of formula I, or any amount of a compound of formula I within or between any of these values.

[00305] Some solid compositions may contain 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%, from about 10% (w/w) to about 30% (w/w), from about 10% (w/w) /wt) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w) , from about 30% (w/w) to about 40% (w/w), from about 40% (w/w) to about 50% (w/w), from 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 a compound of formula I, or any the amount of the compound of formula I in the range limited by any of these values or located between them.

[00306] Some solid dosage forms may contain from about 10 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 10 mg to about 50 mg, from about 50 mg to about 100 mg, from about 40 mg to about 90 mg, from about 200 mg to about 300 mg, from about 70 mg to about 95 mg, from about 100 mg to about 200 mg, from about 105 mg to about 200 mg, from about 110 mg to about 140 mg, from about 50 mg to about 150 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of a compound of formula I, or any amount of a compound of formula I within the limited range any of these values or somewhere in between.

[00307] In some embodiments, a compound of Formula I is administered at a dose that provides a plasma level of a compound of Formula I of about 0.1 µM to about 10 µM, about 0.1 µM to about 5 µM, about 0.2 µM to about 3 µM, 0.1 µM to about 1 µM, about 0.2 µM to about 2 µM, 1 µM to about 10 µM, about 1 µM to about 5 µM, about 2 µM to about 3 µM, or from about 2.8 µM to about 3 µM, from about 1.5 µM to about 2 µM, from about 4.5 µM to about 5 µM, from about 2.5 µM to about 3 µM, about 1.8 µM, about 4.8 µM, about 2.9 µM, about 2.8 µM, or any plasma level within or between any of these values.

[00308] In some embodiments, a compound of formula I may be administered to a subject in an amount that provides an AUC value of _0-12 of the compound of formula I in the subject on day 8, which is at least about 200 hh/mL, at least about 400 ng h/mL, at least about 700 ng h/mL, at least about 1000 ng h h/mL, at least about 3000 ng h h/mL, at least about 7000 ng h h ./ml, at least about 10,000 ng*h/ml, at least about 15,000 ng*h/ml, at least about 20,000 ng*h/ml, at least about 30,000 ng*h/ml , up to about 50,000 ng*h/mL, up to about 150,000 ng*h/mL, or any AUC value within or between any of these values.

[00309] In some embodiments, a compound of formula I is administered to a subject in an amount that provides a C _max value of the compound of formula I in the subject on day 8, which is at least about 20 ng/ml, at least about 60 ng/ml, by at least about 90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up to about 1000 ng/mL , at least about 4000 ng/ml, up to about 10,000 ng/ml, up to about 50,000 ng/ml, or any C _max value in the range limited by or in between any of these values.

[00310] In some embodiments, the compound of formula I is administered to the subject in an amount that provides a C _avg value of the compound of formula I in the subject on day 8, which is at least about 20 ng/ml, at least about 30 ng/ml, by at least about 50 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200 ng /ml, at least about 300 ng/ml, up to about 1000 ng/ml, up to about 5000 ng/ml, up to about 30,000 ng/ml, or any C _avg value in the range limited by or in between any of these values.

[00311] For compositions containing both DEX and a compound of formula I, some liquids may contain from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) /volume) to about 20% (w/v), about 0.01% to about 10% (w/v), about 1% (w/v) to about 3% (w/v), from about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% ( w/v), from about 7% (w/v) to about 10% (w/v), from about 10% (w/v) to about 15% (w/v), from about 15% (w/v). volume) to about 20% (w/v), from about 20% (w/v) to about 30% (w/v), from about 30% (w/v) to about 40% (w/v), about 40% (w/v) to about 50% (w/v) DEX and compounds of formula I in combination, or any amount within the range limited to or between any of these values. Some solid compositions may contain at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w). wt), at least about 70% (w/w), at least about 80%, from about 10% (w/w) to about 30% (w/w), from about 10% (w/w) to about 20% (w/w), from about 20% (w/w) to about 30% (w/w), from about 30% (w/w) to about 50% (w/w), from 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), from about 50% (w/w) to about 60% (w/w), from about 70% (w/w) to about 80% (w/w), from about 80% (w/w). wt) up to about 90% (w/w) of DEX and a compound of formula I in combination and or any number within or between any of these values. In some embodiments, the weight ratio of DEX to a compound of Formula I in a single composition or dosage form may be from about 0.1 to about 2, from about 0.2 to about 1, from about 0.1 to about 0.3, from 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 within or between any of these values.

[00312] A therapeutically effective amount of a therapeutic compound may vary depending on the circumstances. For example, the daily dose of DEX may in some cases range from about 0.1 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 20 mg to about 600 mg, from about 60 mg to about 700 mg, from about 100 mg to about 400 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 20 mg to about 60 mg, about 60 mg to about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140 mg, about 160 mg to about 200 mg, from about 200 mg to about 300 mg, from about 220 mg to about 260 mg, from about 300 mg to about 400 mg, from about 340 mg to about 380 mg, from about 400 mg to about 500 mg, from about 500 mg to about 600 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 360 mg, or any daily dose within the range limited by any of these values, or located between them. DEX can be administered once a day, or twice a day, or every 12 hours, three times a day, four times a day, or six times a day in an amount that is approximately one-half, one-third, one-fourth, or one-sixth, respectively, of daily dose.

[00313] The daily dosage of a compound of Formula I may, in some instances, vary from about 10 mg to about 1000 mg, from about 50 mg to about 600 mg, from about 100 mg to about 2000 mg, from about 50 mg to about 100 mg, from about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 100 mg to about 150 mg, about 150 mg to about 300 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg, about 560 mg to about 640 mg, or about t about 500 mg to about 600 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or any daily dose within or in between any of these values . The compound of formula I can be administered once a day or twice a day, or every 12 hours or three times a day in an amount that is approximately half or one third of the daily dose, respectively.

[00314] In some embodiments, a subject in need thereof is administered 1) about 50 mg/day to about 100 mg/day, about 100 mg/day to about 150 mg/day, about 150 mg/day to about 300 mg/day, about 150 mg/day to about 200 mg/day, about 200 to about 250 mg/day, about 250 to about 300 mg/day of a compound of formula I, or about 300 to about 500 mg/day compounds of formula I; and/or 2) from about 15 mg/day to about 60 mg/day, from about 15 mg/day to about 30 mg/day, from about 30 mg/day to about 45 mg/day, from about 45 mg/day up to about 60 mg/day, from about 60 mg/day to about 100 mg/day, from about 80 mg/day to about 110 mg/day, from about 100 mg/day to about 150 mg/day, or from about 100 mg /day to approximately 300 mg/day DEX.

[00315] In some embodiments, the subject is administered about 150 mg/day of a Formula I compound and about 30 mg/day of DEX, about 150 mg/day of a Formula I compound and about 60 mg/day of DEX, about 150 mg/day of a Formula I compound, and about 90 mg/day DEX, about 150 mg/day of a compound of formula I and about 120 mg/day of DEX, about 200 mg/day of a compound of formula I and about 30 mg/day of DEX, about 200 mg/day of a compound of formula I and about 60 mg/day DEX, approximately 200 mg/day of a compound of formula I and approximately 90 mg/day of DEX, approximately 200 mg/day of a compound of formula I and approximately 120 mg/day of DEX, approximately 300 mg/day of a compound of formula I and approximately 30 mg/day day DEX, approximately 300 mg/day of the compound of formula I and approximately 60 mg/day of DEX, approximately 300 mg/day of the compound of formula I and approximately 90 mg/day of DEX or approximately 300 mg/day day of the compound of formula I and approximately 120 mg/day of DEX.

[00316] In some embodiments, the subject is administered about 100 mg/day of a compound of formula I and about 15 mg/day of DEX for 1, 2, or 3 days, and then about 200 mg/day of a compound of formula I and about 30 mg/day of DEX . In some embodiments, the subject is administered about 100 mg/day of a Formula I compound and about 30 mg/day of DEX for 1, 2, or 3 days, followed by about 200 mg/day of a Formula I compound and about 60 mg/day of DEX.

[00317] In some embodiments, the subject is administered about 75 mg/day of a compound of formula I and about 15 mg/day of DEX for 1, 2, or 3 days, followed by about 150 mg/day of a compound of formula I and about 30 mg/day of DEX . In some embodiments, the subject is administered about 75 mg/day of a compound of formula I and about 30 mg/day of DEX for 1, 2, or 3 days, followed by about 150 mg/day of a compound of formula I and about 60 mg/day of DEX.

[00318] A 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, may be administered for as long as needed to treat a neurological condition such as pain, depression, or cough. In some embodiments, the 5-HT2A receptor antagonist/inverse agonist, such as a compound of Formula I, and DEX are administered at least once daily, such as once daily or twice daily, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days or longer.

[00319] Therapeutic compounds may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into food from the diet. For oral administration for therapeutic purposes, the active compound may be combined with an excipient and used in the form of swallowable tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, cachets and the like.

[00320] Tablets, lozenges, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, gum acacia, corn starch, 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 sweetener such as sucrose, lactose or saccharin; or a flavoring such as peppermint oil, wintergreen oil or cherry flavoring. If the unit dosage form is a capsule, it may contain, in addition to materials of the type mentioned above, a liquid carrier. Various other materials may be present as a coating, for example tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetener, methyl and propyl parabens as preservatives, a coloring agent, and a flavoring agent such as cherry or orange flavor. The material in the dosage form or pharmaceutical composition may be required to be pharmaceutically pure and substantially non-toxic in the amounts used.

[00321] Some compositions or dosage forms may be liquids or may contain a solid phase dispersed in a liquid.

[00322] Therapeutic compounds can be formulated for parenteral or oral administration. Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water appropriately mixed with a surfactant such as hydroxypropyl cellulose. The dispersion may also have the oil dispersed in glycerol or dispersed with glycerol, liquid polyethylene glycols, and mixtures thereof. Under normal conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

[00323] Although dementias such as Alzheimer's disease (AD) are characterized by cognitive impairment, neuropsychiatric symptoms (behavioral and psychological symptoms of dementia, BPSD) are among the leading factors influencing care burden and hospitalization. The frequency of BPSD symptoms increases with disease progression (eg, up to 60% in mild to moderate AD and up to 90% in severe AD).

[00324] Currently available therapeutics for dementia leave much room for improvement when it comes to treating BPSD, but also other non-cognitive problem areas. In the long absence of disease-modifying therapy, this becomes increasingly important as symptoms such as hostility, aggression, wandering, sexually inappropriate behavior or incontinence pose serious problems for caregivers and families, and are a factor for (costly) accommodation in a nursing home.

[00325] Prescribing (“typical or atypical”) antipsychotics to facilitate care and maintenance is global standard practice. However, the FDA has determined that off-label use of antipsychotics poses a serious health risk to subjects with dementia and has added a black box warning to the instructions citing serious cardiovascular adverse events and an increased risk of death. EU approval of risperidone allows short-term use by patients with moderate AD only if they cause harm to themselves or others. In Parkinson's disease, the anticholinergic effects of neuroleptics are highly undesirable, since they inevitably worsen, among other things, motor impairment, as well as disorders in the functioning of the autonomic nervous system. In all dementias, a decrease in seizure threshold is another infrequent but highly undesirable possible side effect of antipsychotics. These concerns about the use of antipsychotic drugs in dementia lead to a decrease in the use of antipsychotics in this category of patients, which leaves the vast majority of patients with mild to moderate AD with BPSD symptoms essentially untreated.

[00326] Accordingly, some embodiments are novel compositions and methods useful in the symptomatic and disease-modifying treatment of neurodegenerative diseases and brain injury, including their sequelae such as organic brain syndrome and chronic traumatic encephalopathies; chronic or intractable pain, ocular signs associated with retinopathy, anxiety disorders, post-traumatic stress disorder, depression, diabetes mellitus and its complications, such as peripheral neuropathies with or without neuropathic pain, Buerger's disease, Raynaud's disease, coronary heart disease, angina pectoris, atherosclerosis, including CNS-like multi-infarct dementia, vascular cognitive impairment, vascular dementia or Binswanger's disease, and nephropathy.

[00327] In a first aspect, a method for increasing the metabolic lifespan of DEX is provided, comprising administering a 5-HT2A receptor antagonist/inverse agonist of Formula I to a subject in need of treatment with DEX, wherein the 5-HT2A receptor antagonist/inverse agonist is an inhibitor of the CYP2D6 enzyme, and where DEX is present in the subject's body at the same time as M1.

[00328] In a second aspect, a method is provided for preventing adverse events associated with DEX treatment, comprising co-administering a Formula I 5-HT2A receptor antagonist/inverse agonist to a subject in need of DEX treatment, wherein the subject is at risk of experiencing an adverse event as a result of treatment with DEX.

[00329] A third aspect provides a method of using formula I 5HT2A receptor antagonists to improve the therapeutic properties of DEX in the treatment of neuropsychiatric disorders.

[00330] In a fourth aspect, a method for treating a neuropsychiatric disorder is provided, comprising administering a 5HT2A receptor antagonist of Formula I and DEX to a subject in need thereof.

[00331] In one embodiment of the first, second, third and fourth aspects, the 5-HT2A receptor antagonist/inverse agonist is an M1-based prodrug, such as a compound of formula I, or pharmaceutically acceptable salts thereof.

[00332] In one embodiment of the first, second, and third aspects, the 5-HT2A receptor antagonist/inverse agonist is the M1 enantiomer, such as (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy) propan-2-ol) or (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-ol) or pharmaceutically acceptable salts thereof.

[00333] In one embodiment of the third and fourth aspects, the neuropsychiatric disorder is Alzheimer's disease.

[00334] In a fifth aspect, a method is provided for selecting a 5-HT2A receptor antagonist/inverse agonist for use in combination with DEX in subjects in need thereof.

[00335] In one embodiment of the fifth aspect, a specific enantiomer of a 5HT2A receptor antagonist with potent inhibitory activity against CYP2D6 has a higher degree of penetration through the blood-brain barrier.

[00336] In one embodiment of the fifth aspect, a particular enantiomer of a 5HT2A receptor antagonist with potent CYP2D6 inhibitory activity has a better ratio of central to peripheral effects when administered in combination with DEX, with central effects assessed by direct or indirect interaction methods with the 5HT2A receptor , while peripheral effects are assessed using methods based on the measurement of blood glucose.

[00337] In one embodiment of the fifth aspect, DEX and the selected 5-HT2A antagonist are administered in a combined dose, wherein the amount of DEX administered is from about 20 mg/day to about 80 mg/day.

[00338] In one embodiment of the fifth aspect, DEX is administered at a combined dose with the selected M1 enantiomer, wherein the amount of M1 enantiomer administered is from about 0.1 mg/day to about 1000 mg/day.

[00339] One embodiment of the present invention is a method for enhancing the therapeutic properties of DEX by administering it with a 5HT2A receptor antagonist that has potent CYP2D6 inhibitory activity and numerous therapeutic benefits of its own.

[00340] Some embodiments include a method of treating a disease or disorder, comprising administering from 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 24 hours, 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 the required amount of a compound of formula I and from 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 any amount of a compound of Formula I within the range limited by any of these values or in between, or the required amount of DEX to the subject in need of it.

[00341] Borodkin, Book chapter: Ion-exchange resin delivery system, in "Polymers for Controlled Drug Delivery", Tarcha, P J, Ed., CRC Press, Boca Raton, 1990; incorporated by reference in its entirety). The composition of the present invention may be formulated into any pharmaceutical dosage form for oral, topical, rectal, vaginal, nasal, or ophthalmic administration and include syrups and suspensions using well-known ingredients, as well as procedures and methods (U.S. Patent Application No. 4,221,778 , 4762709, 4788055, 4959219, 4996047, 5071646 and 5186930; Borodkin, Book chapter: Ion-exchange resin delivery system, in "Polymers for Controlled Drug Delivery", Tarcha, PJ, Ed., CRC Press, Boca Raton, 1990; included by reference in its entirety), which can be used to formulate the compositions of the present invention.

[00342] The present invention may be formulated into any pharmaceutical dosage form for oral, topical, rectal, vaginal, nasal, or ophthalmic administration and include syrups and suspensions, and the ingredients and procedures for formulating the pharmaceutical composition are well known within the skill of the art. fields of technology, including various known methods (applications for US patent No. 4221778, 4762709, 4788055, 4959219, 4996047, 5071646, 4221778 and 5186930; fully incorporated herein by reference), which can be used to formulate the composition of the present invention. In one embodiment, the administration is dermal, oral, nasal, anal, rectal, vaginal, sublingual, buccal, sublabial, muscular, intramuscular, intravenous, peritoneal, epidural, intracerebral, intracerebroventricular, dermal, or topical, intraarticular, intracardiac, intracavernous, intradermal , intralesional, intramuscular, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical. intravitreal, transdermal or transmucosal.

[00343] Oral and tablet formulations include multilayer enteric-coated formulations that contain a separating layer to separate the acidic enteric-coated material and omeprazole. which is acid sensitive. HPC or other suitable polymers disclosed herein can be used in the layer that separates the core material and the enteric coating layer in the formulations described.

SYNTHESIS METHODS

[00344] SGL Hydrochloride (CAS No: 135159-51-2), systematically referred to as complex mono(2-(dimethylamino)-1-((2-(2-(3-methoxyphenyl)ethyl)phenoxy)methyl) hydrochloride ethyl) ester of butanediolic acid can be prepared by 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); CN 103242179 A; WO 2015008973; incorporated by reference in their entirety).

[00345] Reaction of 2-hydroxy-3'-methoxybibenzyl with epichlorohydrin via a base in a suitable solvent gives 2-(2,3-epoxypropoxy)-3'-methoxybibenzyl, which by reaction with dimethylamine at reflux in a suitable solvent gives 2 -[3-(dimethylamino)-2-hydroxypropoxy]-3'-methoxybibenzyl. Finally, this compound is treated with succinic anhydride at reflux in a suitable solvent with an acid.

[00346] As shown in the scheme below, the reaction of 2-hydroxy-3'-methoxybibenzyl with epichlorohydrin via NaH base in DMF gives 2-(2,3-epoxypropoxy)-3'-methoxybibenzyl, which by reaction with dimethylamine at reflux refrigeration in THF gives 2-[3-(dimethylamino)-2-hydroxypropoxy]-3'-methoxybibenzyl. Finally, this compound is treated with succinic anhydride at reflux in THF and with HCl in acetone (J Med Chem 33(6) (1990), incorporated by reference herein).

[00347] SGL hydrochloride was synthesized in approximately 46% overall yield from salicylaldehyde via benzyl protection, reduction, chlorination, Arbuzov reaction, Wittig-Horner reaction, catalytic hydrogenation to give 2-2-(3-methoxyphenyl)ethylphenol, which subjected to reaction with epichlorohydrin, amination, esterification and salt formation reaction.

[00348] In order to achieve an acceptable level of purity of the SGL hydrochloride drug used in the preparation of the required SGL hydrochloride tablets, a single hetero-containing compound must meet the requirements. U.S. Patent Application 4,485,258 discloses a method for synthesizing the first SGL hydrochloride and recrystallizing from acetone to obtain, but experiments show that SGL hydrochloride has poor solubility in acetone and hydrochloric acid, making them unsuitable as a solvent for SGL recrystallization. In CN 101239920 A it is disclosed as acetonitrile, propionitrile, 1,4-dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, sulfolane, dimethyl sulfoxide or a mixture of more than two of them with methanol, ethanol, acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be used in as a solvent for the recrystallization of SGL hydrochloride, while the purity of the product can reach 98%. C _2-10 alkanes, C _3-10 ketones, C _2-10 carboxylic acid esters, C _1-10 halogenated alkanes, aromatic hydrocarbons or aromatic derivatives at room temperature to reflux temperature are characterized by low solubility in hydrochloric acid, so they should not be used as a solvent for SGL or SGL hydrochloride, moreover, if water or 5% or more aqueous organic solvent is used, a high purity product cannot be obtained. The existing literature does not mention the issue of controlling the content of a single impurity.

[00349] An enantiomerically pure form of SGL can be obtained using chiral ligands to initiate the formation of one selected enantiomer, as shown below.

[00350] Chiral organic compounds play an important role in pharmaceuticals, agrochemicals, and other materials that exhibit beneficial biological activity. Enzymes and other natural binding sites recognize substrates of a particular chirality to create a range of biological functions. These enzymes or receptor sites are specific in terms of their action as enantiomers can exhibit different properties due to chirality. Thus, for biologically active compounds, it is possible that only one of the enantiomers is active and the other has no activity, both enantiomers are active but they have different potencies, or both enantiomers have similar or equal activity. Thus, obtaining enantiomerically pure drug molecules is of interest, and the technique has three main strategies 1) separation, (2) the use of chiral moieties, and (3) asymmetric synthesis. Asymmetric synthesis provides a much more efficient use of one chiral material to produce another.

[00351] Obtaining enantiomerically pure molecules of interest from a biological point of view can be effectively achieved by asymmetric synthesis. This method involves the creation of one or more chiral centers from prochiral starting materials under the action of chiral substrates. The preparation of enantiomerically pure compounds involves the use of chiral auxiliaries, chiral reagents, or chiral catalysts, or combinations thereof.

[00352] In another embodiment, the compounds of the present invention can be prepared from (2R)-3-(dimethylamino)-1,2-propanediol and (2S)-3-(dimethylamino)-1,2-propanediol (Scheme VIII).

[00353] Various versatile and suitable chiral carboxylic acid ligands are available in the literature, such as mandelic acid, 2-methylmandelic acid, 2-chloromandelic acid, 3-chloromandelic acid, 4-methoxymandelic acid, O-acetylmandelic acid, α-methoxyphenylacetic acid, malic acid, tartaric acid, etc. Chiral ligands can be made from readily available moieties. (Moloney et al., Chiral carboxylic acid ligands derived from camphoric acid, Tetrahedron: Asymmetry, Volume 7, Issue 9, September 1996, pages 2551-2562; US 7230135 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); , 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); incorporated by reference throughout its fullness).

[00354] The formation of 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™

[00355] Amidation/Acylation (http://www.organic-chemistry.org/synthesis/C1N/amides.shtm; https://chem.libretexts.org/Core/Organic_Chemistry/Amides/Synthesis_of_Amides; http://www .chemguide.co.uk/organicprops/amides/preparation.html; WO 1998043961 incorporated by reference in its entirety).

[00356] Linkers that can be used in the synthesis of SARPODEXAMIDE™ derivatives in the above scheme include, without limitation, linkers (described in 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 (July 18, 2011); 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); U.S. Patent Application No. 20130053301, Patent Application No. WO 2011089216 A1 ; WO 2006136586 A2; US patent applications №№7932294; 20060046967 A1; 8,357,723; 8,349,901; 8,354,455; 9,550,734; 20160220694; 20160002167; 20150328323; 9,090,563; 20140058063; 20130158271; 8,288,557; 20110274695; patent № WO 1998043961, incorporated by reference in its entirety).

[00357] Ester formation. Esters are obtained from carboxylic acids. The carboxylic acid contains a -COOH group and in the ester the hydrogen in this group is replaced by an R' hydrocarbon group such as an alkyl, cycloalkyl, aryl and heteroaryl 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 (tosilic acid) is also often used.

[00358] The esterification reaction is both slow and reversible at the same time. The equation for the reaction between the acid RCOOH and the alcohol R'OH (where R and R' may be the same or different) is:

[00359] Alcohol is usually used as a solvent, so it is present in large excess. (http://www.chemguide.co.uk/organicprops/alcohols/esterification.html; http://www.organic-chemistry.org/namedreactions/fischer-esterification.shtm; http://www.masterorganicchemistry.com /reaction-guide/conversion-of-carboxylic-acids-to-esters-using-acid-and-alcohols-fischer-esterification/; http://vigoschools.org/~mmc3/AP%20Lab/ap%201ab%20documents /Esterfication.pdf; http://science.jrank.org/pages/2573/Esterification.html https://chem.libretexts.org/Core/Organic_Chemistry/Carboxylic_Acids/Reactivity_of_Carboxylic_Acids/Fischer_Esterification; patent application no. WO 1998043961; included by reference in its entirety).

SARPODEXTER™

In another embodiment for the preparation of compositions according to the present application, diastereomerically pure SARPODEXTER can be prepared by reacting racemic sarpogrelate with optically pure dextrorphan (DO-H ₃ , compound 151) under moderate esterification conditions to give a mixture of diastereomeric esters, compounds 165-166, which can be separated by crystallization and chromatographic techniques as above and as described herein to obtain diastereomerically pure SARPODEXTER 165 and 166.

EXAMPLES

Derivatives of SARPODEXAMIDE™

[00360] The compound of formula I or derivatives of Sarpodexamide ^tm can be obtained by reacting dextromethorphan either as a single isomer or a mixture thereof with 2,2,2-trichloroethyl chloroformate at reflux in toluene, thus obtaining an N-demethylated compound.

[00361] The trichloroethoxycarbonyl above can be converted to N-desmethyldextromethorphan by heating to reflux in the presence of powdered zinc in glacial acetic acid.

[00362] N-desmethyldextromethorphan prepared as described above or purchased (CAS number: 125-71-3) can be treated with trifluoromethanesulfonic anhydride and pyridine at room temperature (as described in Liebigs Ann. Chem. 1986, 336 and WO 1998043961 included in its entirety in this document).

OPTICALLY PURE SARPODEXAMIDE

As shown in Scheme XIII, the 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 prepared from sarpogrelat by amidation with N-desmethyldextromethorphan using HBTU in combination with Hunig's base for 1-2 hours. Reagents such as uronic acid can be used. (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate salt (COMU), ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (o-Nosy1OXY), EDCI and NaHCO ₃ , B(OCH ₂ CF ₃ ) ₃ , trimethylaluminum, lanthanum trifluoromethanesulfonate, ZrOCl ₂ ⋅8H ₂ O, methanesulfonyl chloride and N-methylimidazole, N,N'-carbonyldiimidazole (CDI), etc.

OPTICALLY PURE DEX SALTS Formula I, SARPODEX™, DERADEX™ or DERAPHAN™

Compound 50 and compound 149 form a mixture of diastereomeric salts based on the dextromethorphan salt (S)-4-((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)-4- oxobutanoate (S-SARPODEX™) and dextromethorphan salt (R)-4-((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)-4-oxobutanoate (R -SARPODEX™) in chloroform or other suitable solvents such as dichloromethane, DMF, etc., which can be separated by crystallization and recrystallization in suitable solvents such as DMF and/or the chromatographic techniques referred to and described in this description.

[00363] In one embodiment, a method is provided for separating diastereomers of a compound using an ionic liquid to improve separation efficiency. When separating diastereomers, for example by a method such as liquid-liquid extraction, one or more ionic liquids can be used as the extractant.

[00364] In one embodiment, this separation method can be performed on a compound containing a mixture of at least one pair of diastereomers, and the diastereomers can be separated by contacting the mixture with at least one ionic liquid in which one of the diastereomers is soluble in a larger degree than the other diastereomer and separating the lower solubility diastereomer from the mixture. The present invention disclosed herein thus includes methods for separating diastereomers, the use of such methods, and the products obtained and obtainable using such methods.

[00365] In another embodiment, this separation method can be carried out with a compound, such as a diastereomeric mixture of DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ salts, wherein the diastereomers are separated by contacting the mixture with at least one ionic liquid , in which one of the diastereomers is more soluble than the other diastereomer, and isolating the lower solubility diastereomer from the mixture.

[00366] In yet another embodiment, a method is provided for isolating the erythro or threo diastereomers DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ from a mixture containing both diastereomers by liquid-liquid extraction with at least one ionic liquid as an extracting solvent.

[00367] Another embodiment is a method for carrying out an industrial operation selected from the group consisting of a standardizing operation, a cleaning operation, a washing operation, a drying operation, a particle removal operation, a dissolution operation, a dispersion operation, a heat transfer operation, and an isolation operation involving bringing a mixture containing a pair of DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ diastereomers, in contact with at least one ionic liquid in which one of the diastereomers is more soluble than the other diastereomer, isolating a diastereomer with lower solubility from the mixture and using the isolated diastereomer in operation.

[00368] Another embodiment is a method of separating one diastereomer from another diastereomer in a pair of diastereomers in a compound. In such a method, an ionic liquid is used to facilitate separation, and diastereomers can be separated by contacting the mixture with at least one ionic liquid in which one of the diastereomers is more soluble than the other diastereomer and separating the lower solubility diastereomer from the mixture. .

[00369] The term "ionic liquid" is defined as an organic salt that is liquid at or below about 100°C.

[00370] "Liquid-liquid extraction" is a method of separating components in solution by distributing them between two immiscible liquid phases. Liquid-liquid extraction involves the transfer of mass from one liquid phase to a second immiscible liquid phase and is carried out using an extractant or solvent.

[00371] The components in a liquid mixture can be separated in a manner such as liquid-liquid extraction using a single equilibrium (or theoretical) step or multiple steps. The equilibrium or theoretical stage is a device that thoroughly mixes the feedstock with an immiscible liquid so that the concentrations reach equilibrium, followed by physical separation of the two immiscible liquid phases. The one-stage device may be a separating funnel or a shaker vessel that ensures thorough mixing of the feedstock with the immiscible extractant. After thorough mixing, one or both of the liquid phases can be recovered, for example by decanting.

[00372] Multi-stage liquid separation devices can be cross-flow devices or counter-current devices. In a multi-stage device, the raw material enters the first equilibrium stage and contacts with the extractant. The two liquid phases are mixed, with drops of one phase suspended in the second phase, and then the two phases are separated, and DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ from the first stage is brought into contact with additional extractant, and the separation process is repeated. The method of (1) contacting DERATINE™, SARPOTINE™, DERADEX™, DERAPHAN™ or SARPODEX™ with an extractant, (2) ensuring that equilibrium concentrations are reached, and (3) separating liquid phases is repeated until the required 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 consumption of raw materials and extractant.

[00373] In a cross-flow system (or device), the feedstock is initially brought into contact with an extractant in a first equilibrium stage. DEX, formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ from this stage then descends through one or more additional stages. At each stage, the composition is in contact with a fresh extractant and an additional stage of purification of the necessary component in the composition is achieved. An example of a cross-flow system where the threo isomer of the composition is purified using 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquid ([BMIM][BF ₄ ]) as the extractant. In a countercurrent system or device, the extractant enters the stage furthest from the feed inlet and the two phases pass through and across each other, coming from two different (eg opposite) directions.

[00374] Equipment used for liquid-liquid extraction can be classified as either "staged" or "continuous (differential) contact" equipment. Staged equipment is also called "mixer-settlers". Mixing of liquids occurs by contacting the raw material with the extractant, and the resulting dispersion is deposited as the two phases separate. Mixing may be by means of baffles or agitators and the separation process may be carried out in batch or continuous flow. Settling tanks may be simple gravity settling tanks such as decanters, or may be cyclones or centrifuges which increase the settling rate.

[00375] Continuous contact equipment is typically configured for multistage countercurrent contacting of immiscible liquids without reseparating the liquids from each other between stages. Instead, the fluids remain in continuous contact throughout their passage through the equipment. The backflow is maintained by the density difference of the liquids and either by gravity (vertical towers) or centrifugal force (squeeze centrifuges). Gravity extractors can be classified as spray towers, packed towers, or perforated tray (sieve tray) towers. Gravity towers also include rotary agitator towers and pulsed towers, as is known in the art.

[00376] When separating the diastereomers of a composition compound, and in particular the threo and erythro isomers of 2,3-dihydrodecafluoropentane, 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 separating the phase containing the lower solubility diastereomer from the phase containing the extractant and the higher solubility diastereomer, the higher solubility diastereomer can be separated from the extractant by a process such as distillation.

[00377] Mass transfer from a single liquid phase to a separate immiscible phase by liquid-liquid extraction and equipment for use in carrying it out are discussed further in such sources as Robbins and Cusack, "Liquid-Liquid Extraction Operations and Equipment" in Perry's Chemical Engineers' Handbook , 7th ^Ed ., (McGraw-Hill, 1997, Section 15), which is incorporated by reference. Known liquid-liquid extraction processes that operate on principles that are the same or similar to those for the separations described herein include the extraction of acetic acid from water using ethyl ether or ethyl acetate as the extractant (Brown, Chem. Engr. Prog. (1963) 59:65) and the extraction of phenolics from water using methyl isobutyl ketone as an extractant as described by Scheibel in "Liquid-Liquid Extraction" (Perry and ^Weissburg (eds), Separation and Purification, 3rd Ed. (1978) Chapter 3, John Wiley & Sons, Inc., Hoboken, NJ), which is incorporated by reference.

et al., Separation of the Mixtures of Chiral Compounds by Crystallization, Advances in Crystallization Processes, стр. 1-37 (2012), включен посредством ссылки).[00378] The dielectric constant of the solvent (if a solvent is used in the separations) alters the formation, composition, and recognition of the enantiomers of the crystals (Sakai et al., Tetrahedron: Asymmetry, 14, 3716 (2003); incorporated by reference in its entirety). The composition of crystalline diastereoisomers is also affected 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), incorporated by reference in its entirety). The purity of the (de) diastereoisomer can be improved by using a mixture of structurally related resolving agents. This is often referred to in the literature as the "Dutch split" (Kellogg et al., Synthesis, 1626 (2003) incorporated by reference). If the salt of the diastereoisomer cannot be isolated by fractional precipitation, it is possible to obtain its crystalline solvate by fractional precipitation from the solvate-forming solution (Schindler et al., Chirality, 19, 239 (2007), incorporated by reference). When a solvent unsuitable for separating diastereoisomers contains compounds that are partially structurally similar with a solvate-forming solution ), incorporated by reference), separation of the enantiomers was made possible by fractional precipitation of the diastereomeric salt (

et al., Separation of the Mixtures of Chiral Compounds by Crystallization, Advances in Crystallization Processes, pp. 1-37 (2012), incorporated by reference).

[00379] When crystallizing racemate melts to form enantiomeric mixtures, the eutectic composition generally determines the composition of the crystallized mixture and the oily residue. This eutectic composition can be known from the phase diagram of the melting point of the binary system. If the initial isomeric composition (ee0) is higher than the eutectic composition, the pure optical isomer can be crystallized.

[00380] An ionic liquid or a mixture of two or more of them can be used in this process to separate diastereomers of a compound. If, for example, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ diastereomers 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 (about 25°C). They differ from most salts in that they have very low melting points, and they tend to be usually liquid over a wide range of temperatures. They are also generally insoluble in non-polar hydrocarbons; not amenable to mixing with water (depending on the anion); and are highly ionized (but have a low dielectric density). Ionic liquids do not inherently have vapor pressure, most are stable in air and water, and they can be either neutral, acidic, or basic.

[00381] An ionic liquid cation or anion useful herein can in principle be any cation or anion, provided that the cation and anion together form an organic salt that is liquid at or below about 100°C. The properties of the ionic liquid can, however, be adjusted by changing the type of cation and/or anion. For example, the acidity of an ionic liquid can be controlled by changing the mole equivalents and the type and combinations of Lewis acids used.

[00382] Many ionic liquids are formed by reacting a nitrogen-containing heterocyclic ring, preferably a heteroaromatic ring, with an alkylating agent (e.g., an alkyl halide) to form a quaternary ammonium salt and carrying out ion exchange or other suitable reactions with various Lewis acids or their conjugate bases to form an 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 because groups larger than these can form low melting solids rather than ionic liquids. Various triarylphosphines, thioethers, and cyclic and non-cyclic quaternary ammonium salts can also be used for this purpose. Counterions that can be used include chloraluminate, bromoaluminate, gallium chloride, tetrafluoroborate, tetrachloroborate, hexafluorophosphate, nitrate, trifluoromethanesulfonate, methylsulfonate, p-toluenesulfonate, hexafluoroantimonate, hexafluoroarsenate, tetrachloroaluminate, tetrabromoaluminate, perchlorate, hydroxide anion, copper dichloride anion, trichloride anion iron, anion of zinc trichloride, as well as various lanthanum-, potassium-, lithium-, nickel-, cobalt-, manganese- and other metal-containing anions.

[00383] Ionic liquids can also be synthesized by a salt exchange reaction, by an acid neutralization reaction with a base, or by quaternization of a selected nitrogen-containing compound; or they can be obtained commercially from several companies such as Merck (Darmstadt, Germany) or BASF (Mount Olive, NJ).

[00384] Illustrative examples of applicable ionic liquids are described in references such as J. Chem. Tech. Biotechnol. 68:351-356 (1997); Chem. Ind. 68:249-263 (1996); J Phys. Condensed Matter, 5: (supp 34B): B99-B106 (1993); Chemical and Engineering News, March 30, 1998, 32-37; J. Mater. Chem. 8:2627-2636 (1998); Chem. Rev. 99:2071-2084 (1999); and US Patent Application No. 2004/0133058; all of which are incorporated by reference.

[00385] In one embodiment, a library of ionic liquids can be obtained, for example, by obtaining different alkyl derivatives of a particular cation (such as a quaternary ammonium cation) and varying the associated anions (U.S. Patent Application 20090131728 A1, incorporated by reference in its entirety) . In another embodiment, the diastereomers of the present invention can be efficiently separated by cation exchange with a combined sorbent in a solid phase extraction (SPE) procedure.

[00386] In one embodiment, the diastereomers can be separated by extractive distillation, where an adjuvant that changes the partial pressure of the various diastereomers to be separated to varying degrees allows for easier separation of the diastereomers by distillation in good yield. Separation can be carried out using fractionating columns and preferably under reduced pressure from about 10 ^-3 bar to about 1 bar (US 4874473 A, US 20070225505 A1, incorporated by reference in its entirety).

(февраль, 2003 г.), заявка на патент США №7119211 В2, включены посредством ссылки во всей своей полноте).[00387] In one embodiment, reverse phase (RP-HPLC) and normal phase (NP-HPLC) separations can be used to separate the diastereomers of the present invention. Columns that can be used to separate enantiomers can be Primesep C, NUCLEOSIL, cellulose-based chiral HPLC, SHISEIDO Chiral CD-Ph, etc. (Fekete et al., Comparative Study Separation of Diastereomers by HPLC, Chromatographia, 57, No.

(February 2003), US Patent Application No. 7,119,211 B2, incorporated by reference in its entirety).

ADAMANTANYLAMINO-4-OXOBUTANOATE DERIVATIVES

[00388] Using the above protocols for the formation of amides and esters, derivatives of compounds 50-52 can be obtained to obtain amide compounds 1001-1006 and ester compounds 1007-1009:

compound 1001 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-(adamantan-1-ylamino)-4-oxobutanoate;

compound 1002 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-(adamantan-1-ylamino)-4-oxobutanoate;

compound 1003 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-(adamantan-1-ylamino)-4-oxobutanoate;

compound 1004 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-((3,5-dimethyladamantan-1-yl)amino)-4-oxobutanoate ;

compound 1005 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-((3,5-dimethyladamantan-1-yl)amino)-4-oxobutanoate;

compound 1006 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-((3,5-dimethyladamantan-1-yl)amino)-4-oxobutanoate ;

compound 1007 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-(2,2,2-trichloro-1-(dimethoxyphosphoryl)ethyl)succinate;

compound 1008 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-(2,2,2-trichloro-1-(dimethoxyphosphoryl)ethyl)succinate and

compound 1008 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-(2,2,2-trichloro-1-(dimethoxyphosphoryl)ethyl)succinate.

PHARMACEUTICAL COMPOSITIONS

[00389] The compositions of the present invention can be prepared by adding a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ to and dissolving in a suitable solvent. The solution thus obtained is added to the complex magnesium aluminosilicate to form a paste. Although the above steps are carried out at about room temperature, elevated temperatures can be used if necessary. Then sodium chloride and sodium saccharin are added and evenly distributed in the paste. Edible coloring and flavoring materials can be included in the system at any stage of the production process. In another embodiment, the soluble ingredients are added to the solution of the compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™, which is prepared in the first step. The paste thus obtained can be readily incorporated into a traditional caramel-forming mass, which in turn can be processed by conventional procedures into attractive, palatable lozenges, each containing therapeutically effective amounts of a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ evenly distributed in it.

[00390] Variations of the preparation methods presented here are within the scope of the present invention. For example, in preparing the compositions of the present invention, a racemate or an enantiomerically pure compound of Formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ and a complex magnesium aluminosilicate can be mixed and then a suitable solvent added thereto to form a paste therewith. Sodium chloride and sodium saccharin may be added to the dextromethorphan-complex magnesium aluminosilicate mixture prior to making the mixture into a paste. Alternatively, sodium chloride and sodium saccharin can be added to the paste. In addition, suitable flavors and colors can be added to either the dry mix or the paste. In carrying out the present invention, any medically useful organic solvent which is suitable for pharmaceutical use and in which a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ is soluble can be used. Thus, for example, organic solvents such as propylene glycol, glycerol, 1,3-butylene glycol, benzyl alcohol, etc. can be used. In an embodiment of the compositions of the present invention, benzyl alcohol is used as a solvent for SARPODEX™.

[00391] Edible colors and edible flavors can be used in the preparation of the compositions of the present invention. Flavors that are suitable for use include, for example, licorice, ginger, natural fruit extracts, and the like. As the colorant, any colorant suitable for food and drug use can be used. The amount of colorant and the amount of flavor used in formulating the composition of the present invention vary.

[00392] In an embodiment, the composition contains from about 0.3 g to about 1.5 g, about 1.0 g, of a thickener; from about 1 g to about 10 g, about 2.5 g, 1,2-propylene glycol as a solvent; from about 0.12 g to about 0.19 g or 0.15 g of at least one paraben preservative such as methyl paraben; from about 0.05 g to about 0.2 g or about 0.1 g of sorbic acid; from about 30 g to about 60 g or 40 g of sugar alcohol solution; from about 0.05 to about 0.2 g or 0.1 g of artificial sweetener; complex of a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ with resin in an amount to obtain the required strength of approximately 2.10 g (1:6 amount of complex required to deliver the equivalent of 60 mg of a compound of formula I , DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ at a dose of 20 ml for an adult in 12 hours); and enough water to bring the volume up to 100 ml.

[00393] In another embodiment, suitable thickeners include tragacanth; bentonite; gum arabic and cellulose lower alkyl ethers (including hydroxy and carboxy derivatives of 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 from about 2.5:1 to about 7.5:1. In another embodiment, the ratio of methyl and propyl paraben is 4:1.

[00394] In one embodiment, the artificial sweetener is in the form of saccharin or aspartame. In one embodiment, the saccharin is sodium saccharin. In other embodiments, the sweetener may be substituted with equivalent amounts of other known sweeteners, such as the sugar alcohol sorbitol.

[00395] In another embodiment, the composition comprises an amount of resinate sufficient to deliver, when administered in a single dose every 12 hours, an antitussive effective amount of a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ over a period of approximately 12 hours to a patient in need of such an administration.

[00396] In an embodiment, the formulation contains a 20 ml adult dose, while containing approximately 420 mg of resinate to deliver the equivalent of 60 mg of a compound of Formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™, or DERAPHAN™ when the drug ratio resinate agent is 1:6, and 2.10 g of resinate is present for every 100 ml of formulation. The dosage can be varied similarly to that known for the administration of dextromethorphan which has not been complexed with the resin, i.e. the usual 15 mg-30 mg/dose of dextromethorphan hydrobromide 1-4 times daily becomes S-20 ml once or twice daily.

[00397] In another embodiment, the composition contains non-toxic substances that block the NMDA receptor according to the present invention, which are dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™, or derivatives thereof, and Saprodexter™, mixtures thereof and pharmaceutically acceptable salts.

[00398] In another embodiment, the composition contains substances that block the NMDA receptor, including dizocilpine (5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene), ketamine (2 -(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one), magnesium, selfotel ((2S,4R)-4-(phosphonomethyl)piperidine-2-carboxylic acid), aptiganel ((E)-1- (3-ethylphenyl)-1-methyl-2-(naphthalen-1-yl)guanidine), felbamate (2-phenylpropan-1,3-diyldicarbamate), phencyclidine (1-(1-phenylcyclohexyl)piperidine), amantadine (1 -aminoadamantine), memantine (3,5-dimethylaminoadamantone), pyrroloquinoline quinone (PQQ, 4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid) , (R)-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid, (R)-2-amino-5-phosphonopentanoate, (S) and (R) 6-(1H -tetrazol-5-ylmethyl)decahydroisoquinolin-3-carboxylic acid, (S)-a-amino-5-(phosphonomethyl)[1,19-biphenyl]-3-propanoic acid, (S) and (R) (6) -cis-4-(4-phenylbenzoyl)piperazine-2,3-dicarboxylic acid, cis-4-phosphonomethyl-2-piperidinecarboxylic acid acid, 2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid), and cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, mixtures thereof and pharmaceutically acceptable salt. (U.S. Patent Application No. 5891885, Christie et al., Native N-Methyl-D-aspartate Receptors Containing NR2A and NR2B Subunits Have Pharmacologically Distinct Competitive Antagonist Binding Sites, The Journal Of Pharmacology And Experimental Therapeutics, Vol. 292, No. 3 , pp. 1169-74 (2000), incorporated by reference in their entirety).

[00399] In another embodiment, the therapeutic composition contains at least one other pharmacologically active substance, for example, caffeine (a stimulant), an antiemetic drug such as metoclopramide, domperidone, belladonna alkaloids, and phenothiazines such as chlorpromazine, prochlorperazine and promethazine, non-narcotic analgesics, eg acetaminophen, or a nonsteroidal anti-inflammatory drug such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin , phenylbutazone, piroxicam, sulindac, tolmetin, zomepirak and the like.

SYNTHESIS OF THE COMPOUNDS OF THE PRESENT INVENTION

[00400] All reactions were carried out under argon with dry solvents unless otherwise noted. 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 received. 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 (phosphomolybdic acid in ethanol) or ANIS (para-anisaldehyde in ethanol) as imaging agent. The products were purified by column chromatography through silica gel 60 (0.060-0.200 mm). NMR spectra were obtained on a Bruker AVANCE III 500 MHz (Bruker Corporation, Billerica, MA, USA) using residual non-deuterated solvent or TMS (tetramethylsilane) as an internal standard. High resolution mass spectra (HR-MS) were recorded on a JEOL JMS-700 (JEOL, Tokyo, Japan) using EI (electron impact).

[00401] EXAMPLE 1 Dextromethorphan was synthesized from benzylisoquinoline (planar) by Greve cyclization to give the corresponding morphinan, where 1,2,3,4,5,6,7,8-octahydro-1-(4-methoxybenzyl)isoquinoline was converted to an N-formyl derivative cyclized to N-formylnormorphinan and the formyl group was reduced to an N-methyl group to give 3-methoxy-17-methylmorphinan. Dextromethorphan is readily soluble in 96% ethanol and essentially insoluble in water. Dextromethorphan may be the monohydrate hydrobromide salt or linked to a polystyrene sulfonic acid ion exchange resin. The specific rotation of dextromethorphan in water is +27.6° (20°C, sodium D-line).

[00402] EXAMPLE 2 Equimolar sarpogrelate (429.506 g/mol) and dextromethorphan (271.40 g/mol) were mixed in a suitable solvent, shaken, and allowed to crystallize. The compound of formula I and the positive dextromethorphan cation will form a hydrogen bond to form a complex and crystallize.

[00403] EXAMPLE 3 To a solution of 54.28 g of dextromethorphan in one liter of chloroform was added a solution of 85.9 g of sarpogrelat in chloroform at 70°C. Salt was precipitated from the hot solution by adding ethyl acetate. After cooling, the salt was collected, washed with ethyl acetate and dried to give d-3-methoxy-N-methylmorphinan-4-[1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]propan-2-yl ]hydroxy-4-oxobutanoate salt and recrystallized from aqueous dimethylformamide (DMF) to give 135 g of a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™.

[00404] EXAMPLE 4 Ingredients. 15 g of a compound of formula I, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™; 15 g glyceryl tristearate; 100 ml carbon tetrachloride. Receipt. Glyceryl tristearate was dissolved in warm carbon tetrachloride at 55-60°C. The compound of formula I, its derivative, SARPODEX™ or its derivative was then added and suspended in solution. The suspension was then spray dried using an inlet temperature of 90°C and an outlet temperature of 40°C. The resulting compound of Formula I coated with DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ having an average particle size of about 10 to about 200 microns was then suspended in the following aqueous vehicle.

Ingredients. 10.00 g tragacanth, USP; 1.20 g methylparaben, USP; 0.20 g propylparaben, USP; 0.30 g sodium saccharin, USP; 3.00 g sodium sucaryl, USP; 250.00 ml of sorbic acid; 1.00 g methylcellulose, 15 cps; 2.00 ml artificial blackcurrant flavor and 1000.00 ml distilled water.

[00405] Parabens, sodium saccharin, sodium sucaryl and sorbic acid were dissolved in a portion of distilled water, which was heated to 85°C. Tragacanth was then added to this solution and evenly dispersed. The dispersion was heated again, cooled, and the sorbitol solution, the methylcellulose solution in water, and the "blackcurrant" artificial flavor were then added with stirring to form a carrier medium. The compound of formula I coated, DERATINE™, SARPOTINE™, SARPODEX™, DERADEX™ or DERAPHAN™ coated is then added to the above carrier medium and mixed until complete wetting and uniform dispersion of the particles.

[00406] The controlled release drug composition of the present invention was characterized by containing 100 parts by weight of an organic polymeric material that is soluble in an organic solvent and insoluble in water; 5-60 parts by weight of a lipid-soluble low molecular weight release aid and 1-70 parts by weight of a drug.

[00407] In one embodiment, the polymeric material is biodegradable or biocompatible or both, such as biodegradable aliphatic polyester or aliphatic poly(carbonate), poly(lactic acid), lactic acid-glycolic acid, poly(caprolactone), poly(hydroxybutyric acid) and the like.

[00408] In one embodiment, the release aid is a carboxylic acid ester, monoester, or diester of glycerol. In another embodiment, the release aid is an organic acid ester selected from succinic acid, citric acid, tartaric acid, malic acid, or the like, or a monoacetate ester or diacetate ester of glycerol.

[00409] In one embodiment, the composition may also contain a cell adhesion material or agent to promote endothelialization on the surface of the medical device.

[00410] In one embodiment, the present invention is a drug-releasing medical device characterized by the content of the compositions of the present invention. The drug-releasing medical device has a composition layer formed on the surface and is in contact with a living organism, or is embedded in or permanently located in a living organism. The device includes a stent, a catheter, a brace, a medical organ replacement device, a capsule transducer, or an artificial organ. The stent, in one embodiment, is used to treat coronary artery stenosis and gradually release the composition from a surface. The release rate is from 1/10 ³ µg/mm ² /h. up to 1 μg / mm ² / h. 21 days after stent insertion. In addition, the stent of the present invention is characterized in that the drug to be released is in a polymeric material deposited on the surface of the metal forming the stent, or in a porous substrate of the stent.

[00411] The polymeric material deposited on the surface of the stent is amorphous. The polymeric material deposited on the surface of the stent is an amorphous biodegradable polymeric material. The polymeric material is a poly(lactic acid) or copolymer of lactic acid and glycolic acid, which is biodegradable. The polymeric material also contains a release aid that promotes the release of the drug that is applied. The drug release adjuvant is a tartaric ester or malate ester, or a monoester or diester of glycerol. The surface of the metal constituting the stent may be a porous body, and the aforementioned drug to be gradually released may be located in the porous body. In one embodiment, the porous body has a pore diameter ranging from 0.01 nm to 300 nm.

[00412] EXAMPLE 5. OPTICALLY PURE SARPOMALT. Malic acid is a component of many foods that we eat every day. Although it is found as a naturally occurring organic compound in a variety of fruits, many people are starting to take malic acid supplements to improve their overall health as well as treat a variety of ailments. Currently, this acid is most commonly used as a food additive and preservative. It is a weak and relatively harmless acid when used in appropriate amounts. As a dietary supplement, it is generally considered to have health benefits and is present in high amounts in apple juices. However, as with any supplement, do not exceed the recommended amounts for consumption. (http://www.newsmax.com/FastFeatures/Malic-Acid-Benefits-Health-Supplements/2015/03/31/id/635519/, incorporated by reference). Natural organic compounds with an asymmetric carbon usually exist as an optically active material and exhibit physiological activity markedly different from that of the enantiomers.

[00413] Malic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of racemate or enantiomerically pure M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or diastereomerically pure sarpomalate, respectively, depending on the M1 and malic acid used (compounds 25-29). Racemic sarpomalate can be purified by crystallization and/or chiral chromatography to give diastereomerically pure sarpomalate.

[00414] EXAMPLE 6. OPTICALLY PURE SARPOMETIONATE. Methionine (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 h and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or diastereomerically pure sarpomethionate, respectively, depending on the M1 and methionine used (compounds 30-34). Racemic sarpomethionate can be purified by crystallization and/or chiral chromatography to give diastereomeric pure sarpomethionate.

[00415] EXAMPLE 7. OPTICALLY PURE SARPOPHTHALATE. Phthalic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0. 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpophthalate, respectively, depending on the M1 and phthalic acid used, to give compounds 35-37. Racemic sarpophthalate can be purified by crystallization and/or chiral chromatography to give diastereomerically pure sarpomalate.

[00416] EXAMPLE 8. OPTICALLY PURE SARPOMALONATE. Malonic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0. 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpomalonate, respectively, depending on M1 to give compounds 38-40. Racemic sarpomalonate can be purified by crystallization and/or chiral chromatography to give optically pure sarpomalonate.

[00417] EXAMPLE 9. OPTICALLY PURE SARPOTYROSINATE. Tyrosine (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, the mixture was stirred at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ ( 50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpothyrosinate, respectively, depending on M1 to give compounds 41-43. Racemic sarpothyrosinate can be purified by crystallization and/or chiral chromatography to give optically pure sarpothyrosinate.

[00418] EXAMPLE 10. OPTICALLY PURE SARPOTRYPTOPHANATE. Tryptophan (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, the mixture was stirred at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ ( 50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpotryptophanate, respectively, depending on M1 to give compounds 44-46. Racemic sarpotryptophanate can be purified by crystallization and/or chiral chromatography to give optically pure sarpotryptophanate.

[00419] EXAMPLE 11. OPTICALLY PURE SARPOMALEATE. Maleic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0. 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpomaleate, respectively, depending on M1 to give compounds 47-49. Racemic sarpomaleate can be purified by crystallization and/or chiral chromatography to give optically pure sarpomaleate.

[00420] EXAMPLE 12. OPTICALLY PURE SARPOGRELATE. Succinic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0. 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpogrelate, respectively, depending on M1 to give compounds 50-52. Racemic sarpogrelate can be purified by crystallization and/or chiral chromatography to provide optically pure sarpogrelate.

[00421] EXAMPLE 13. OPTICALLY PURE SARPOGLUTARATE. Glutaric acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpoglutarate, respectively, depending on M1 to give compounds 53-55. Racemic sarpoglutarate can be purified by crystallization and/or chiral chromatography to give optically pure sarpoglutarate.

[00422] EXAMPLE 14. OPTICALLY CLEAR SARPOADIPAT. Adipic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpoadipate, respectively, depending on M1 to give compounds 56-58. Racemic sarpoadipate can be purified by crystallization and/or chiral chromatography to give optically pure sarpoadipate.

[00423] EXAMPLE 15. OPTICALLY PURE SARPOPIMELATE. Pimelic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpopimelate, respectively, depending on M1 to give compounds 59-61. Racemic sarpopimelate can be purified by crystallization and/or chiral chromatography to give optically pure sarpopimelate.

[00424] EXAMPLE 16. OPTICALLY PURE SARPOSEBACYNATE. Sebacic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarposebacinate, respectively, depending on M1 to give compounds 62-64. Racemic sarposebacinate can be purified by crystallization and/or chiral chromatography to give optically pure sarposebacinate.

[00425] EXAMPLE 17. OPTICALLY PURE SARPOFORMATE. Formic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpoformate, respectively, depending on M1 to give compounds 65-67. Racemic sarpoformate can be purified by crystallization and/or chiral chromatography to give optically pure sarpoformate.

[00426] EXAMPLE 18. OPTICALLY PURE SARPOACETATE. Acetic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpoacetate, respectively, depending on M1 to give compounds 68-70. Racemic sarpoacetate can be purified by crystallization and/or chiral chromatography to give optically pure sarpoacetate.

[00427] EXAMPLE 19. OPTICALLY PURE SARPOPROPIONATE. Propionic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpopionate, respectively, depending on M1 to give compounds 71-73. Racemic sarpopionate can be purified by crystallization and/or chiral chromatography to give optically pure sarpopionate.

[00428] EXAMPLE 20. OPTICALLY PURE SARPOBUTYRATE. Butyric acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpobutyrate, respectively, depending on M1 to give compounds 74-76. Racemic sarpobutyrate can be purified by crystallization and/or chiral chromatography to give optically pure sarpobutyrate.

[00429] EXAMPLE 21. OPTICALLY PURE SARPOVALERATE. Valeric acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpovalerate, respectively, depending on M1 to give compounds 77-79. Racemic sarpovalerate can be purified by crystallization and/or chiral chromatography to give optically pure sarpovalerate.

[00430] EXAMPLE 22. OPTICALLY PURE SARPOCAPROATE. Caproic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpocaproate, respectively, depending on M1 to give compounds 80-82. Racemic sarpocaproate can be purified by crystallization and/or chiral chromatography to give optically pure sarpocaproate.

[00431] EXAMPLE 23. OPTICALLY PURE SARPOENANTHATE. Enanthic (heptanoic) acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of racemate or enantiomerically pure M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpoenanthate, respectively, depending on M1 to give compounds 62-64. Racemic sarpoenanthate can be purified by crystallization and/or chiral chromatography to give optically pure sarpoenanthate.

[00432] EXAMPLE 24. OPTICALLY PURE SARPOCAPRILATE. Caprylic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpocaprylate, respectively, depending on M1 to give compounds 86-88. Racemic sarpocaprylate can be purified by crystallization and/or chiral chromatography to give optically pure sarpocaprylate.

[00433] EXAMPLE 25. OPTICALLY PURE SARPOPELARGONATE. Pelargonic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpopelargonate, respectively, depending on M1 to give compounds 89-91. Racemic sarpopelargonate can be purified by crystallization and/or chiral chromatography to give optically pure sarpopelargonate.

[00434] EXAMPLE 26. OPTICALLY CLEAR SARPOCAPRATE. Capric acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpocaprate, respectively, depending on M1 to give compounds 92-94. Racemic sarpocaprate can be purified by crystallization and/or chiral chromatography to give optically pure sarpocaprate.

[00435] EXAMPLE 27. OPTICALLY PURE SARPOOXALATE. Oxalic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpooxalate, respectively, depending on M1 to give compounds 95-97. Racemic sarpooxalate can be purified by crystallization and/or chiral chromatography to give optically pure sarpooxalate.

[00436] EXAMPLE 28. OPTICALLY PURE SARPO ISOPHTHALATE. Isophthalic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpoisophthalate, respectively, depending on M1 to give compounds 98-100. Racemic sarpoisophthalate can be purified by crystallization and/or chiral chromatography to give optically pure sarpoisophthalate.

[00437] EXAMPLE 29. OPTICALLY PURE SARPO TEREPHTHALATE. Terephthalic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpoterephthalate, respectively, depending on M1 to give compounds 101-103. Racemic sarpoterephthalate can be purified by crystallization and/or chiral chromatography to give optically pure sarpoterephthalate.

[00438] EXAMPLE 30. OPTICALLY PURE SARPOSALYCYLATE. Salicylic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarposalicylate, respectively, depending on M1 to give compounds 104-106. Racemic sarposalicylate can be purified by crystallization and/or chiral chromatography to give optically pure sarposalicylate.

[00439] EXAMPLE 31. OPTICALLY PURE SARPOACETYLSALICYLATE. Acetylsalicylic acid (0.55 mmol, 1.1 eq.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 eq.) and 4-dimethylaminopyridine at 0°C were added to a stirred solution of the racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25°C, stirred the mixture at 25°C for 18-24 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give racemically or optically pure sarpoacetylsalicylate, respectively, depending on M1 to give compounds 107-109. Racemic sarpoacetylsalicylate can be purified by crystallization and/or chiral chromatography to give optically pure sarpoacetylsalicylate. (Park et al., Aspirination of a-Aminoalcohol (Saprogrelate M1), Molecules 21(9), 1126 (2016); incorporated by reference in its entirety).

[00440] EXAMPLE 32 To a stirred solution of M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml) or CH ₃ CN (5 ml) was added aspirin (0.55 mmol, eq.) and 1,'-carbonyldiimidazole (CDI, 0.60 mmol, 1.2 eq.) at 25°C. The mixture was stirred for 12 hours and diluted with CH ₂ Cl ₂ (40 ml) and sat. aq. NH ₄ Cl (25 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give compound 107. Racemic sarpoacetyl salicylate, which is compound 107, can be purified by crystallization and/or chiral chromatography to give optically pure sarpoacetylsalicylates 108 and 109.

[00441] EXAMPLE 33 To a stirred solution of M1 (0.50 mmol, 1.0 eq.) in THF (5 ml) was added acetylsalicylic acid (0.75 mmol, 1.5 eq.), triphenylphosphine (0.75 mmol , 1.5 eq.) and diisopropyl azodicarboxylate (DIAD, 0.75 mmol, 1.5 eq.) at 0°C. The mixture was stirred at the same temperature for 1 hour, and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (30 ml) and sat. aq. NH ₄ Cl (15 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give compound 107. Racemic sarpoacetyl salicylate, which is compound 107, can be purified by crystallization and/or chiral chromatography to give optically pure sarpoacetylsalicylates 108 and 109.

[00442] EXAMPLE 34 To a stirred solution of acetyl alicylate (1.00 mmol, 2.0 eq.) in CH ₂ Cl ₂ (5 ml) was added oxalyl chloride (2 M and CH ₂ Cl ₂ , 0.60 ml, 1 ,20 mmol, 2.4 eq.) and dimethylformamide (DMF, 8.0 μl, 0.10 mmol, 0.2 eq.) at 0°C. Then the temperature was gradually raised to 25°C. The mixture was stirred at the same temperature for ₁₂ hours. _Pyridine (0.24 ml, 3.0 mmol, 6.0 eq.) and the previously prepared solution of aspirinyl chloride. The mixture was stirred for another 12 hours and diluted with CH ₂ Cl ₂ (50 ml) and sat. aq. NaHCO ₃ (30 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to give compound 107. Racemic sarpochetyl salicylate, which is compound 107, can be purified by crystallization and/or chiral chromatography to give optically pure sarpoacetyl salicylates 108 and 109.

[00443] EXAMPLE 35 To a stirred solution of salicylate ester (241 mg, 0.536 mmol, 1.0 eq.) in pyridine (2 ml) was added Ac ₂ O (76 μl, 0.81 mmol, 1.5 eq.) at 0°C. The temperature was raised to 25°C. The mixture was stirred at the same temperature for 12 hours. The mixture was then concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with H ₂ O (10 ml). The organic layer was separated, dried (Na ₃ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc=1:2) to give compound 107 (239 mg, 90% yield). Racemic sarpoacetyl salicylate compound 107 can be purified by crystallization and/or chiral chromatography to give optically pure sarpo acetyl alicylates 108 and 109.

[00444] EXAMPLE 36.

1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-2-acetoxybenzoate (compound 163): colorless oil; R _f =0.25 (silica gel, hexanes: EtOAc 1:1); ¹ H-NMR (500 MHz, CDCl ₃ ): δ=7.99 (dd, J ₁ =1.6 Hz, J ₂ =7.9 Hz, 1H), 7.53-7.50 (m, 1H ), 7.18 (ddd, J ₁ =1.1 Hz, J ₂ =7.9 Hz, J ₃ =7.9 Hz, 1H), 7.18-7.14 (m, 2H), 7, 10-7.06 (m, 2H), 6.89-6.86 (m, 2H), 6.77 (d, J=7.7 Hz, 1H), 6.72-6.71 (m, 2H), 5.56-5.51 (m, 1H), 4.28-4.22 (m, 2H), 3.75 (s, 3H), 2.92-2.71 (m, 6H) , 2.32 (s, 6H), 2.30 (s, 3H) ppm; ¹³ C-NMR (125 MHz, CDCl ₃ ): δ=169.7, 163.9, 159.7, 156.5, 150.9, 144.1, 134.0, 131.9, 130.5, 130.3, 129.3, 127.4, 126.1, 123.9, 123.4, 121.0, 120.9, 114.2, 111.39, 111.37, 71.2, 67, 6, 59.4, 55.2, 46.4, 36.5, 32.8, 21.1 ppm; HRMS (EI): calculated for C ₂₉ H ₃₃ NO ₆ [M ⁺ ]: 491.2308, obtained 491.2310.

[00445] EXAMPLE 37.

1-(Dimethylamino)-3-(2-(3-ethoxyphenethyl)phenoxy)propan-2-ylacetate (compound 164): colorless oil; R _f =0.19 (silica, hexanes: EtOAc 1:2); ¹ H-NMR (500 MHz, CDCl ₃ ): δ=7.21 (t, 3=7.8 Hz 1H), 7.16 (ddd, J ₁ =1.7 Hz, J ₂ =7.8 Hz J ₃ =7.8 Hz 1H), 7.11 (dd, J ₁ =1.7 Hz, J ₂ =7.4 Hz 1H), 6.87 (ddd, J ₁ =1.0 Hz J ₂ = 7.4 Hz J ₃ \u003d 7.4 Hz, 1H), 6.84 (t, J \u003d 8.9 Hz 2H), 6.78 (t, J \u003d 1.9 Hz, 1H), 6.76- 6.73 (m, 1H), 5.39-5.34 (m, 1H), 4.19-4.09 (m, 2H), 3.80 (s, 3H), 2.91-2, 84 (m, 4H), 2.69-2.61 (m, 2H), 2.30 (s, 6H), 2.05 (s, 3H) ppm; ¹³ C-NMR (125 MHz CDCl ₃ ): δ=170.8, 159.7, 156.5, 144.2, 130.5, 130.3, 129.4, 127.4, 121.0, 120 .9, 114.3, 111.3, 111.2, 70.4, 67.7, 59.7, 55.3, 46.4, 36.6, 33.2, 21.4 ppm; HEMS (EI): calculated for C ₂₂ H ₂₉ NO ₄ [M4 ⁺ ]: 371.2097, obtained 371.2095.

[00446] EXAMPLE 38.

1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-2-hydroxybenzoate (compound 165) colorless oil; R _a = 0.23 (silica gel, texanes: 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 \u003d 0.9 Hz J ₂ \u003d 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): calculated for C ₂₇ H ₃₁ NO ₅ [M ⁺ ]: 449.2202, obtained 449.2200.

[00447] EXAMPLE 39.

2-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propyl-2-acetoxybenzoate (compound 166): colorless oil; R _f =0.20 (silica gel, hexanes: EtOAc 1:1); ¹ H-NMR (500 MHz CDCl ₃ ): ÷=7.98 (dd, J ₁ =1.6 Hz, J2=7.8 Hz 1H), 7.5 5 (ddd, J ₁ =1.7 Hz J ₂ =7.8 Hz, L=7.8 Hz, 1H), 7.28 (ddd, J\=1.1 Hz, J ₁ =7.7 Hz, J3=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 ₁ =8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.81 (A, J=1.1 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; 13C-NMR (125 MHz, CDCl ₃ ): 5=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): calculated for C29H33NO6 [M ⁺ ]: 491.2308, obtained 491.2309.

[00448] EXAMPLE 40. DEUTERATION OF H-COMPOUND TO PRODUCE D-COMPOUND. The H compound (compound of the present invention, approximately 1.25 mmol) was dissolved in 3 ml of 100 mM deuterated phosphate buffered saline (D-PBS) pH 7 diluted with 9.00 ml D ₂ O to a final concentration of 25 mM . 100 mM D-PBS buffer pH 7 (pH indicator paper) was prepared by dissolving 259.5 mg K ₃ PO ₄ in D ₂ O (12.00 ml) and adding 264 μl 20% DCl in D ₂ O. Reaction mixture shaken at room temperature for 11 days while monitoring the completion of the hydrogen/deuterium exchange (HID) by LC/MS.

[00449] Small-scale processing was carried out to obtain the hydrochloride salt of the deuterated compound. Thus, a 1.2 ml aliquot of the reaction mixture (10% of the total volume) was diluted with 5 ml of saturated NaHCO ₃ and was extracted with EtOAc (3×5 ml). The organic layer was dried over Na ₂ SO ₄ and filtered. Evaporation of the solvent gave 20 mg of a colorless oil which was converted to the HCl salt by adding a few drops of 4 M HCl in dioxane. The salt was triturated with ether and the solvents evaporated to give the HCl salt of the deuterated compound. A 9.6 ml aliquot (80% of the total volume) was diluted with 40 ml sat. NaHCO ₃ and extracted once with EtOAc (200 ml). The organic layer was quickly dried over Na ₂ SO ₄ . Evaporation of the solvent gave the compound, which was stored in the refrigerator.

[00450] EXAMPLE 41. PREPARATION OF SARPOGRELATE HYDROCHLORIDE. 250 ml of 13.7 g of 1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-2-propanol hydrochloride and 25 ml of water were introduced into a one-necked flask and stirred until dissolved. The solution was treated with 20% aqueous sodium hydroxide to a pH of about 9 to about 14 and 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 4.5 g of butyryl anhydride 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) was added to dissolve the residue, and saturated hydrogen chloride in the ethyl acetate solution was added dropwise to adjust the pH to 1 or below with stirring for about 50-60 minutes to obtain a crude wet product, sarpogrelate hydrochloride, and dried under reduced pressure (-0.08-0.1 MPa) at 45-55° C. to obtain crude sarpogrelate hydrochloride at 14.7 g, 86% yield, 98.6% HPLC purity.

[00451] EXAMPLE 42. PURIFICATION OF CRUDE SARPOGRELATE HYDROCHLORIDE. The crude sarpogrelate hydrochloride in an amount of 5 g was dissolved in butanone (20 ml), heated with stirring until dissolved, heated under reflux for 20-30 minutes, cooled to 25-35°C, continued stirring for 40-60 minutes, filtered, and the filter cake was washed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55-65° C. and dried under reduced pressure for 24 hours to give 4.6 g of sarpogrelate hydrochloride, 92% yield, 99.9% HPLC purity.

[00452] EXAMPLE 43. PURIFICATION OF CRUDE SARPOGRELATE HYDROCHLORIDE. The crude hydrochloride of sarpogrelate in the amount of 5 g in 30 ml of butanone was heated with stirring until dissolved and heated under reflux for 20-30 minutes, cooled to 25-35°C, incubated with stirring for 40-60 minutes, filtered, and the filter cake was washed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55-65° C. and dried under reduced pressure for 24 hours to give 4.55 g of sarpogrelate hydrochloride, 91% yield, 99.7% HPLC purity.

[00453] EXAMPLE 44. PURIFICATION OF THE CRUDE SARPOGRELATE HYDROCHLORIDE. The crude sarpogrelate hydrochloride in an amount of 5 g in 40 ml of butanone was heated with stirring until dissolved and heated under reflux for 20-30 minutes, cooled to 25-35°C, incubated with stirring for 40-60 minutes, filtered, and the filter cake was washed with a small methyl ethyl ketone to give a white solid, 55~65°C and dried under reduced pressure for 24 hours to give 4.5 g of sarpogrelate hydrochloride, 90% yield, 99.8% HPLC purity.

[00454] EXAMPLE 45. PURIFICATION OF CRUDE SARPOGRELATE HYDROCHLORIDE. The crude product, which is sarpogrelat hydrochloride in an amount of 5 g, was combined with 20 ml of butanone, heated with stirring until dissolution and heated under reflux for 20-30 minutes, slowly cooled with stirring to room temperature, kept at -10°C for crystallization , filtered. The filter cake was washed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55-65° C. and dried under reduced pressure for 24 hours to give 4.62 g of sarpogrelate hydrochloride, 92.4% yield, 99.2% HPLC purity , the highest content of one substance is 0.09%.

[00455] ENANTIOMERS OF SARPOGRELATE. The enantiomers of the compounds described herein can be separated using chromatographic techniques. Preparative separation of enantiomers by chiral stationary phase chromatography (CSP) is considered a viable alternative to most 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 (January 12, 2001); Rajendran, et al., Simulated moving bed chromatography for the separation of enantiomers, Journal of Chromatography A, Volume 1216, Issue 4, pages 709- 738 (January 23, 2009); Maier et al., Separation of enantiomers: needs, challenges, perspectives, Journal of Chromatography A, Volume 906, Issues 12, pages 3-33 (January 12, 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 309-31 7 (July 23, 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 (December 31, 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, Morrison (ed), Elsevier (2 December , 2012); incorporated by reference in their entirety). The racemates of the present invention can be separated at analytical to preparative scales by this technique.

[00456] Motion-bed chromatography can be used to separate the enantiomers of the compounds of the present invention, feasible at all scales of production, from laboratory to pilot plant to industrial plant (Juza et al., Simulated moving-bed chromatography and its application to chirotechnology, Trends in Biotechnology, Volume 18, Issue 3, pages 108-118 (March 1, 2000, incorporated by reference in its entirety).

[00457] EXAMPLE 46 SEPARATION OF ENANTIOMERS OF SARPOGRELATE HYDROCHLORIDE. ((-)-4-((1-(Dimethylamino)-3-(2-(3-ethoxyphenethyl)phenoxy)propan-2-yloxy)-4-oxobutanoic acid hydrochloride). Sarpogrelat hydrochloride was separated using an XBridge® C18 column 3.5 µm, 2.1 x 50 mm using mobile phase: gradient elution from 10% MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA, at a flow rate of 0.5 ml/min, at UV 254 nm to give 5.30 mg enantiomer (99% pure by HPLC) 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, 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) 2.76-2.53 (m, 4H) ESI-MS, mass/charge): 429 [M+H]+. Melting point (°C): 155-156. Rotation of the plane of polarization of light, alpha [D]: -20.0 (c 0.33, MeOH).

[00458] EXAMPLE 47 DEXTROMETHORPHAN MALATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of malic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00459] EXAMPLE 48 DEXTROMETHORPHAN METIONATE. Dissolve dextromethorphan as a free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of methionine or N-acylmethionine (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration, and dried up.

[00460] EXAMPLE 49 DEXTROMETHORPHAN PHTHALATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of phthalic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00461] EXAMPLE 50 DEXTROMETHORPHAN MALONATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of malonic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00462] EXAMPLE 51 DEXTROMETHORPHAN TYROSIATE. Dissolve dextromethorphan as a free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of tyrosine or N-acyltyrosine (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration, and dried up.

[00463] EXAMPLE 52. DEXTROMETHORPHAN TRYPTOFANATE. Dissolve dextromethorphan as a free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of tryptophan or N-acyltryptophan (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration, and dried up.

[00464] EXAMPLE 53 DEXTROMETHORPHAN MALEAT. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of maleic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00465] EXAMPLE 54 DEXTROMETHORPHAN SUCCINATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of succinic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00466] EXAMPLE 55. DEXTROMETHORPHAN GLUTARATE/GLUTAMATE. Dissolve dextromethorphan as a free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of glutaric acid, glutamic acid or N-acylglutamic acid (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration, and dried.

[00467] EXAMPLE 56 DEXTROMETHORPHAN ADIPATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of adipic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00468] EXAMPLE 57 DEXTROMETHORPHAN PIMELATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of pimelic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00469] EXAMPLE 58 DEXTROMETHORPHAN SEBACATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of sebacic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00470] EXAMPLE 59 DEXTROMETHORPHAN FORMAT. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of formic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00471] EXAMPLE 60 DEXTROMETHORPHAN ACETATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of acetic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00472] EXAMPLE 61 DEXTROMETHORPHAN PROPIONATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of propionic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00473] EXAMPLE 62 DEXTROMETHORPHAN BUTYRATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of butyric acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00474] EXAMPLE 63 DEXTROMETHORPHAN VALERATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of valeric acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00475] EXAMPLE 64 DEXTROMETHORPHAN CAPROATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of caproic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00476] EXAMPLE 65. DEXTROMETHORPHAN ENANTATE. Dissolve dextromethorphan as a free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of enanthic (heptanoic) acid (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration, and dried up.

[00477] EXAMPLE 66 DEXTROMETHORPHAN CAPRILATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of caprylic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00478] EXAMPLE 67. DEXTROMETHORPHAN PELARGONATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of pelargonic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00479] EXAMPLE 68 DEXTROMETHORPHAN CAPRATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of capric acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00480] EXAMPLE 69 DEXTROMETHORPHAN OXALATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of oxalic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00481] EXAMPLE 70 DEXTROMETHORPHAN ISOPHTHALATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of isophthalic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00482] EXAMPLE 71. DEXTROMETHORPHAN TEREPHTHALATE. Dextromethorphan as a free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of terephthalic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00483] EXAMPLE 72 DEXTROMETHORPHAN SALICYLATE. The free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of salicylic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00484] EXAMPLE 73. DEXTROMETHORPHAN ACETYL SALICYLATE. The free base (0.05 mol) was dissolved in 20 ml of acetone, the solution was added to a solution of acetylsalicylic acid (0.05 mol) in 60 ml of hot water, and then the reaction mixture was cooled to separate crystals by filtration, and dried.

[00485] EXAMPLE 74-96. ADDITION SALT OF DEXTROMETHORPHAN DICID AND A COMPOUND SELECTED FROM COMPOUNDS OF FORMULA I CONTAINING FDIc AND FDId (COMPOUNDS 219-269).

Dissolve the free base (FDIc or FDId) (0.25 mol) and dextromethorphan (0.05 mol) in 20 ml of acetone, add the solution to a solution of di- or triacid (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration, and dried. Di- and tri-acids include, without limitation, adipic acid, aspartic acid, N-acylaspartic acid, citric acid, fumaric acid, galactonic acid, glutaric acid, glutamic acid, N-acylglutamic acid, glucaric acid (sugaric acid), malic acid, maleic acid , mannonic acid, mucinic acid, oxalic acid, pimelic acid, phthalic acid, isophthalic acid, terephthalic acid, rhamnonic acid, sebacic acid, succinic acid and tartaric acid. Thus, addition salts are formed, such as:

[00486] EXAMPLE 74 - addition salt of adipic acid (FDIc or FDId) and dextromethorphan;

[00487] EXAMPLE 75 - addition salt of aspartic acid (FDIc or FDId) and dextromethorphan;

[00488] EXAMPLE 76 - addition salt of N-acylaspartic acid (FDIc or FDId) and dextromethorphan;

[00489] EXAMPLE 77 - addition salt of citric acid (FDIc or FDId) and dextromethorphan;

[00490] EXAMPLE 78 - addition salt of fumaric acid (FDIc or FDId) and dextromethorphan;

[00491] EXAMPLE 79 - addition salt of galactonic acid (FDIc or FDId) and dextromethorphan;

[00492] EXAMPLE 80 - addition salt of glutaric acid (FDIc or FDId) and dextromethorphan;

[00493] EXAMPLE 81 - addition salt of glutamic acid (FDIc or FDId) and dextromethorphan;

[00494] EXAMPLE 82 - addition salt of N-acylglutamic acid (FDIc or FDId) and dextromethorphan;

[00495] EXAMPLE 83 - addition salt of glucaric acid (sugar acid) (FDIc or FDId) and dextromethorphan;

[00496] EXAMPLE 84 - addition salt of malic acid (FDIc or FDId) and dextromethorphan;

[00497] EXAMPLE 85 - addition salt of maleic acid (FDIc or FDId) and dextromethorphan;

[00498] EXAMPLE 86 - addition salt of mannonic acid (FDIc or FDId) and dextromethorphan;

[00499] EXAMPLE 87 - addition salt of mucic acid (FDIc or FDId) and dextromethorphan;

[00500] EXAMPLE 88 - addition salt of oxalic acid (FDIc or FDId) and dextromethorphan;

[00501] EXAMPLE 89 - addition salt of pimelic acid (FDIc or FDId) and dextromethorphan;

[00502] EXAMPLE 90 - addition salt of phthalic acid (FDIc or FDId) and dextromethorphan;

[00503] EXAMPLE 91 isophthalic acid addition salt (FDIc or FDId) and dextromethorphan;

[00504] EXAMPLE 92 - addition salt of terephthalic acid (FDIc or FDId) and dextromethorphan;

[00505] EXAMPLE 93 - addition salt of rhamnonic acid (FDIc or FDId) and dextromethorphan;

[00506] EXAMPLE 94 - addition salt of sebacic acid (FDIc or FDId) and dextromethorphan;

[00507] EXAMPLE 95 - addition salt of succinic acid (FDIc or FDId) and dextromethorphan;

[00508] EXAMPLE 96 - addition salt of tartaric acid (FDIc or FDId) and dextromethorphan;

[00509] EXAMPLE 97 Compound 901 ((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methylisopropyl-(S)-fluorophosphate;

[00510] EXAMPLE 98 - Compound 902 (((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methylisopropyl-(S)-fluorophosphate;

[00511] EXAMPLE 99 - compound 903 (((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methylisopropyl-(S)-fluorophosphate;

[00512] EXAMPLE 100 - compound 904 ((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl-(3,3-dimethylbutan-2-yl)- (R)-fluorophosphate;

[00513] EXAMPLE 101 - Compound 905 sec-butyl-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-(R )-fluorophosphate;

[00514] EXAMPLE 102 - compound 906 sec-butyl ((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-(R) -fluorophosphate;

[00515] EXAMPLE 102 - Compound 907 O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyl-O-(4 -nitrophenyl)thiophosphate;

[00516] EXAMPLE 103 - Compound 908 O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyl- O-(4-nitrophenyl)thiophosphate;

00517] EXAMPLE 104 Compound 909 O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyl-O -(4-nitrophenyl)thiophosphate;

[00518] EXAMPLE 105 - Compound 910 O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-((1,3- dioxoisoindolin-2-yl)methyl)(dimethyl-13-oxidanyl)dithiophosphonate;

[00519] EXAMPLE 106 - Compound 911 O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-(( 1,3-Dioxoisoindolin-2-yl)methyl)-(dimethyl-13-oxidanyl)dithiophosphonate;

[00520] EXAMPLE 107 Compound 912 O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-(( 1,3-Dioxoisoindolin-2-yl)methyl)-(dimethyl-13-oxidanyl)dithiophosphonate;

[00521] EXAMPLE 108 Compound 913 (E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yl-(((1-(dimethylamino)-3-(2-(3 -methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)methyl phosphate;

[00522] EXAMPLE 109 Compound 914 (E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yl-((((S)-1-(dimethylamino)-3-( 2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)methyl phosphate;

[00523] EXAMPLE 110 Compound 915 (E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yl-((((R)-1-(dimethylamino)-3-( 2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)methyl phosphate;

[00524] EXAMPLE 111 - compound 916 O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-(2-(ethylsulfinyl) ethyl)-O-methylthiophosphate;

[00525] EXAMPLE 112 - Compound 917 O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-(2 -(ethylsulfinyl)ethyl)-O-methylthiophosphate;

[00526] EXAMPLE 113 - Compound 918 O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-(2 -(ethylsulfinyl)ethyl)-O-ethylthiophosphate;

[00527] EXAMPLE 114 - Compound 919 O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyl-S-(( ethylthio)methyl)dithiophosphate;

[00528] EXAMPLE 115 - Compound 920 O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyl-S-(( ethylthio)methyl)dithiophosphate;

[00529] EXAMPLE 116 - compound 921 O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyl-S-(( ethylthio)methyl)dithiophosphate;

[00530] EXAMPLE 117 Compound 922 S-((6-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-O-(((1-(dimethylamino)-3-(2- (3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyl dithiophosphate;

[00531] EXAMPLE 118 - compound 923 S-((6-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-O-((((S)-1-(dimethylamino)-3 -(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyldithiophosphate;

[00532] EXAMPLE 119 - compound 924 S-((6-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-O-((((R)-1-(dimethylamino)-3 -(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-ethyldithiophosphate;

[00533] EXAMPLE 120 Compound 925 S-((tert-butylthio)methyl)-O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy) methyl)-O-ethyldithiophosphate;

[00534] EXAMPLE 121 Compound 926 S-((tert-butylthio)methyl)O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl )oxy)methyl)-O-ethyldithiophosphate;

[00535] EXAMPLE 122 Compound 927 S-((t-butylthio)methyl)-O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propane-2- yl)oxy)methyl)-O-ethyldithiophosphate;

[00536] EXAMPLE 123 - Compound 928 O-(4-((4-(((((1-(dimethyllamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methoxy) (methoxy)phosphorothioyl)oxy)phenyl)thio)phenyl)-O,O-dimethylthiophosphate;

[00537] EXAMPLE 124 - Compound 929 O-(4-((4-(((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl) hydroxy)methoxy)(methoxy)phosphorothioyl)oxy)phenyl)thio)phenyl)-O,O-dimethylthiophosphate;

[00538] EXAMPLE 125 - Compound 930 O-(4-((4-(((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl) hydroxy)methoxy)-(methoxy)phosphorothioyl)oxy)phenyl)thio)phenyl)-O,O-dimethylthiophosphate;

[00539] EXAMPLE 126 Compound 931 ((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyltriethyl diphosphate;

[00540] EXAMPLE 127 Compound 932 (((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyltriethyl diphosphate;

[00541] EXAMPLE 128 Compound 933 (((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyltriethyl diphosphate;

[00542] EXAMPLE 129 Compound 934 ((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methylmethyl-(2,2,2-trichloro-1-hydroxyethyl )phosphonate;

[00543] EXAMPLE 130 Compound 935 (((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methylmethyl-(2,2,2-trichloro -1-hydroxyethyl)phosphonate;

[00544] EXAMPLE 131 Compound 936 (((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methylmethyl-(2,2,2-trichloro -1-hydroxyethyl)phosphonate;

[00545] EXAMPLE 132 Compound 937 yl)oxy)methyl)hydrogen phosphate;

[00546] EXAMPLE 133 - Compound 938 propan-2-yl)oxy)methyl)hydrogen phosphate;

[00547] EXAMPLE 134 - Compound 939 -2-yl)oxy)methyl)hydrogen phosphate;

[00548] EXAMPLE 135 - Compound 940 O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-methylacetylphosamidothiophosphate;

[00549] EXAMPLE 136 Compound 941 O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-methylacetylphosamidothiophosphate;

[00550] EXAMPLE 137 Compound 942 O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-methylacetylphosamidothiophosphate;

[00551] EXAMPLE 138 - compound 943 (O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-propylphosphorothio)-(O ,O-dipropylphosphorothio) anhydride;

[00552] EXAMPLE 139 - Compound 944 (O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-propylphosphorothio )-(O,O-dipropylphosphorothio) anhydride;

[00553] EXAMPLE 140 - Compound 945 (O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-propylphosphorothio )-(O,O-dipropylphosphorothio) anhydride;

[00554] EXAMPLE 141 Compound 946 O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-methylacetylphosamidothiophosphate;

[00555] EXAMPLE 142 - Compound 947 O-((((S)-1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-methylacetylphosamidothiophosphate;

[00556] EXAMPLE 143 Compound 948 O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-S-methylacetylphosamidothiophosphate;

[00557] EXAMPLE 144 - compound 949 compound O-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-methyl-S-( (4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)methyl)dithiophosphate with methane (1:1);

[00558] EXAMPLE 145 - compound 950 compound O-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-methyl -S-((4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)methyl)dithiophosphate with methane (1:1);

[00559] EXAMPLE 146 - compound 951 compound O-((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-O-methyl -S-((4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)methyl)dithiophosphate with methane (1:1);

[00560] EXAMPLE 147 Compound 952 2-chloroethyl-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)-(11)-fluorophosphate;

[00561] EXAMPLE 148 - Compound 953 )-fluorophosphate;

[00562] EXAMPLE 149 - Compound 954 )-fluorophosphate;

[00563] EXAMPLE 150 - Compound 955 )-fluorophosphate;

[00564] EXAMPLE 151 Compound 956 )-(R)-fluorophosphate;

[00565] EXAMPLE 152 Compound 957 )-(R)-fluorophosphate;

[00566] EXAMPLE 153 - Compound 958 )amino)oxy)fluorophosphonate;

[00567] EXAMPLE 154 - Compound 959 ((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl-(S)-((( (E)-chlorofluoromethylene)amino)oxy)fluorophosphonate;

[00568] EXAMPLE 156 - compound 960 ((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl-(S)-((( (E)-chlorofluoromethylene)amino)oxy)fluorophosphonate;

[00569] EXAMPLE 157 Compound 961 (chlorofluoromethylene)amino)oxy)fluorophosphate;

[00570] EXAMPLE 158 Compound 962 )-(((chlorofluoromethylene)amino)oxy)fluorophosphate;

[00571] EXAMPLE 159 Compound 963 )-(((chlorofluoromethylene)amino)oxy)fluorophosphate;

[00572] EXAMPLE 160 - compound 964 1-chloropropan-2-yl-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)(E) -(((chlorofluoromethylene)amino)oxy)fluorophosphate;

[00573] EXAMPLE 161 Compound 965 )-(E)-(((chlorofluoromethylene)amino)oxy)fluorophosphate;

[00574] EXAMPLE 162 - Compound 966 )-(E)-(((chlorofluoromethylene)amino)oxy)fluorophosphate;

[00575] EXAMPLE 163 - Compound 967 E)-(((chlorofluoromethylene)amino)oxy)fluorophosphate;

[00576] EXAMPLE 164 Compound 968 )-(E)-(((chlorofluoromethylene)amino)oxy)fluorophosphate;

[00577] EXAMPLE 165 Compound 969 )-(E)-(((chlorofluoromethylene)amino)oxy)fluorophosphate.

[00578] EXAMPLE 166 Compound 970 )phosphonate.

[00579] EXAMPLE 167 Compound 971 trichloro-1-hydroxyethyl)phosphonate;

[00580] EXAMPLE 168 - Compound 972 trichloro-1-hydroxyethyl)phosphonate.

[00581] EXAMPLE 169 - compound 973 compound 4-(tert-butyl)-2-chlorophenyl-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy) methyl)methylphosphoramidate with methane (1:1);

[00582] EXAMPLE 170 - compound 974 compound 4-(tert-butyl)-2-chlorophenyl-((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propane-2- yl)oxy)methyl)methylphosphoramidate with methane (1:1).

[00583] EXAMPLE 171 - Compound 975 yl)oxy)methyl)methylphosphoramidate with methane (1:1).

[00584] EXAMPLE 172 Compound 976 ((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl-(3-methyl-4-(methylthio)phenyl) isopropylphosphoramidate;

[00585] EXAMPLE 173 - compound 977 ((((S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl-(3-methyl-4- (methylthio)phenyl)isopropylphosphoramidate.

[00586] EXAMPLE 174 - compound 978 ((((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl-(3-methyl-4- (methylthio)phenyl)isopropylphosphoramidate.

[00587] EXAMPLE 175 - Compound 829 ((2, (-)-[1R,2S,4R]-2-(2-dimethylaminoethoxy)-2-phenyl-1,7,7-trimethylbicyclo-[2.2.1]heptane ) fumarate (U.S. Patent Application No. 4,342,762 A; Ladanyi L et al., Stereochemistry and enantiomeric purity of a novel anxiolytic agent, deramciclane fumarate. Chirality 11:689-93 (1999), incorporated by reference). 829 can be prepared in a three-step synthesis using readily available and inexpensive starting materials (camphor) with very high enantiomeric purity (>99.9%) 3.9 g (0.1 g atom) of potassium metal is added to 100 ml of anhydrous xylene and the mixture is reacted with 23.04 g (0.1 mol) of (+)-2-phenyl-1,7,7-trimethylbicyclo(2,2,1)heptan-2-ol with vigorous stirring. stops, with further stirring add 10.3 g (0.11 mol) of a solution of 1-dimethylamino-2-chloroethane in 30 ml of anhydrous xylene.The reaction mixture is kept at 100°C for 6 hours, then washed three times with 50 ml of water and extracted with 15 g (0.1 mol) of a solution of tartaric acid in 80 ml of water or 0.11 mol of dilute aqueous hydrochloric acid. The aqueous phase is alkalinized to pH 10 with 20% aqueous potassium hydroxide solution under cooling (0 to 5°C). The base, separated as an oil, is extracted with ether. After distillation of the solvent, the residue is either purified by fractional distillation in vacuo or used to form a salt. Yield: 25.2 g (D.6%) pale yellow oil, BP: 131°-135°C/26.7 Pa, hydrogen fumarate, mp: 180°-182°C. Enantiomeric separation was carried out by HPLC on OD Chiralcel (250 x 4.6 mm; 10 μm) and hexane-ethanol (99.5:0.5) as mobile phase at room temperature. Chemical formula: C ₂₄ H ₃₅ NO ₅ . Molecular weight: 417.55. Elemental analysis: Calculated: C: 69.03%, H: 8.45%, N: 3.35%, found: C: 69.05%, H: 8.59%, N: 3.44%;

[00588] Compound 829 is a dual inverse agonist of 5- _HT2A /5-HT2C receptors at clinically relevant doses and does not cause inhibition of these receptors (Palvimaki EP et al., Deramciclane, a putative anxiolytic drag, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation Psychopharmacology (1998) 136:99-104). Deramciclane is at least 10 times more selective for D2 dopamine receptors (Gacsalyi I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997) 40:333-348 ). Extensive evaluation of Compound 829 using dopaminergic models did not reveal any functional significance of binding these receptors. Compound 829 was found not to increase prolactin levels, at least over a dose range that encompasses therapeutically relevant effects (Laine K et al., Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone. Eur J Clin Pharmacol (2003) 59: 761-766).

и коллеги (

I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997) 40:333-348) описали профиль эффектов, индуцируемый дерамцикланом, который представляет собой типичный профиль обратных агонистов рецепторов 5-HT_2A/5-HT_2C. N-десметилпроизводное соединения 829 представляет собой биологически активный метаболит, имеющий профиль, аналогичный профилю соединения 829.[00589] Compound 829 has been extensively characterized preclinically, and a large body of evidence points to a CNS target(s) for the pharmacodynamic activity of deramcilan.

and colleagues (

I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997) 40:333-348) described the effect profile induced by deramciclane, which is a typical profile of 5-HT _2A /5-HT _2C receptor inverse agonists. The N-desmethyl derivative of compound 829 is a biologically active metabolite with a profile similar to that of compound 829.

ЕР et al., Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation. Psychopharmacology (1998) 136:99-104), так и на людях (Kanerva Н et al., Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration-a positron emission tomography study. Psychopharmacology (1999) 145:76-81).[00590] The ability of compound 829 to target 5-HT _2A receptors in the CNS has been directly demonstrated in both animals (

EP et al., Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation. Psychopharmacology (1998) 136:99-104) and in humans (Kanerva H et al., Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration-a positron emission tomography study. Psychopharmacology (1999) 145: 76-81).

I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997) 40:333-348). Следовательно, ожидается, что соединение 829 будет вызывать у людей антидепрессивный, анксиолитический, стимулирующий аппетит и другие эффекты, все из которых имеют терапевтическое значение для пациентов с деменцией (Jensen NH et al., Therapeutic potential of 5-HT2C receptor ligands. ScientificWorldJournal. 14 сентября, 2010 r.;10:1870-85; Meltzer HY et al., Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia. Curr Pharm Biotechnol., июнь, 2012 r.;13(8): 1572-86).[00591] The ability of compound 829 to target 5-HT _2A receptors in the CNS has been directly demonstrated in rats by binding [3H]-mesulergin to the choroid plexus (Palvimaki EP et al., Deramciclane, a putative anxiolytic drug, is a serotonin 5- HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation Psychopharmacology (1998) 136:99-104). The doses of compound 829 that cause near-maximal inhibition of [3H]-mesulergin binding (0.5 mg/kg) are in the lower dose range for efficacy in animal models (

I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997) 40:333-348). Therefore, Compound 829 is expected to induce antidepressant, anxiolytic, appetite stimulating and other effects in humans, all of which are of therapeutic importance in patients with dementia (Jensen NH et al., Therapeutic potential of 5-HT2C receptor ligands. Scientific World Journal. 14 September, 2010;10:1870-85; Meltzer HY et al., Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia. Curr Pharm Biotechnol., June, 2012;13(8): 1572-86).

[00592] For compound 829, there is evidence of therapeutic effects from clinical studies in patients with generalized anxiety disorder (Naukkarinen H et al., Deramciclane in the treatment of generalized anxiety disorder: a placebo-controlled, double-blind, dose-finding study. Eur Neuropsychopharmacol (1999) 15:617-23), supporting the claim that compound 829 is a compound active in the CNS that is able to reach its target(s). In the intervention population (n=208), deramcilan doses of 30 mg/day and 60 mg/day provided clinically relevant improvements in overall HAM-A Hamilton Anxiety Rating Scale score after 8 weeks of treatment, reaching statistical significance for compared with placebo (n=51) in the 60 mg/day group (p=0.024, n=54) and a clear trend in the 30 mg/day group (p=0.059, n=53), but not in the group with a dose of 10 mg/day (n=54). With regard to the mental anxiety factor HAM-A, there were significant improvements in patients in the deramciclane 30 mg/day and 60 mg/day treatment groups compared with patients in the placebo group.

[00593] Compound 829 is also an inhibitor of CYP 2D6 based on human studies using desipramine as a substrate. In this randomized, double anonymous crossover study, fifteen healthy subjects received either compound 829 at 60 mg/day or placebo for 8 days. On day 8 of each phase of the study, subjects received 100 mg of a single dose of desipramine. Repeated administration of compound 829 doubles the AUC of desipramine (Laine K et al., Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol (2004) 59:893-898, incorporated by links).

[00594] EXAMPLE 176 Compound 1001 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-(adamantan-1-ylamino)-4-oxobutanoate. Chemical formula: C ₃₄ H ₄₆ N ₂ O ₅ ; exact weight: 562.34; molecular weight: 562.75; mass/charge: 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1, 0%); elemental analysis: C, 72.57; H, 8.24; N, 4.98; O, 14.21; boiling point: 1300.87 [K]; melting point: 890.75 [K]; critical temperature: 1176.29 [K]; critical pressure: 8.99 [bar]; critical volume: 1685.5 [ ^cc /mol]; Gibbs energy: 126.8 [kJ/mol]; Log P: 5.06; MR: 160.74 [ ^cc /mol]; Henry's law: 16.03; heat of formation: -719.51 [kJ/mol]; tPSA: 77.1; CLogP: 6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.

[00595] EXAMPLE 177 Compound 1002 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-(adamantan-1-ylamino)-4-oxobutanoate.

Chemical formula: C ₃₄ H ₄₆ N ₂ O ₅ ; exact weight: 562.34; molecular weight: 562.75; mass/charge: 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1, 0%); elemental analysis: C, 72.57; H, 8.24; N, 4.98; O, 14.21; boiling point: 1300.87 [K]; melting point: 890.75 [K]; critical temperature: 1176.29 [K]; critical pressure: 8.99 [bar]; critical volume: 1685.5 [ ^cc /mol]; Gibbs energy: 126.8 [kJ/mol]; Log P: 5.06; MR: 160.74 [ ^cc /mol]; Henry's law: 16.03; heat of formation: -719.51 [kJ/mol] tPSA: 77.1; CLogP: 6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.

[00596] EXAMPLE 178 Compound 1003 (R)1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-4-(adamantan-1-ylamino)-4-oxobut tanoate.

Chemical formula: C ₃₄ H ₄₆ N ₂ O ₅ ; exact weight: 562.34; molecular weight: 562.75; mass/charge: 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1, 0%); elemental analysis: C, 72.57; H, 8.24; N, 4.98; O, 14.21; boiling point: 1300.87 [K]; melting point: 890.75 [K]; critical temperature: 1176.29 [K]; critical pressure: 8.99 [bar]; critical volume: 1685.5 [ ^cc /mol]; Gibbs energy: 126.8 [kJ/mol]; Log P: 5.06; MR: 160.74 [ ^cc /mol]; Henry's law: 16.03; heat of formation: -719.51 [kJ/mol] tPSA: 77.1; CLogP: 6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.

[00597] EXAMPLE 179 Compound 1004 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenyl)phenoxy)propan-2-yl-4-((3,5-dimethyladamantan-1-yl) amino)-4-oxobutanoate. Chemical formula: C ₃₆ H ₅₀ N ₂ O ₅ ; exact weight: 590.37; molecular weight: 590.81; mass/charge: 590.37 (100.0%), 591.38 (38.9%), 592.38 (7.4%), 592.38 (1.0%); elemental analysis: C, 73.19; H, 8.53; N, 4.74; Oh, 13.54; boiling point: 1347.11 [K]; melting point: 961.09 [K]; critical temperature: 1191.88 [K]; critical pressure: 8.46 [bar]; critical volume: 1793.5 [ ^cc /mol]; Gibbs energy: 132.66 [kJ/mol]; Log P: 6; MR: 169.53 [ ^cc /mol]; Henry's law: 15.78; heat of formation: -730.31 [kJ/mol]; tPSA: 77.1; CLogP: 7.5534; CMR: 17.0669; LogS: -7.773; pKa: 8.362.

[00598] EXAMPLE 180 Compound 1005 -oxobutanoate. Chemical formula: C ₃₆ H ₅₀ N ₂ O ₅ ; exact weight: 590.37; molecular weight: 590.81; mass/charge: 590.37 (100.0%), 591.38 (38.9%), 592.38 (7.4%), 592.38 (1.0%); elemental analysis: C, 73.19; H, 8.53; N, 4.74; Oh, 13.54; boiling point: 1347.11 [K]; melting point: 961.09 [K]; critical temperature: 1191.88 [K]; critical pressure: 8.46 [bar]; critical volume: 1793.5 [ ^cc /mol]; Gibbs energy: 132.66 [kJ/mol]; Log P: 6; MR: 169.53 [ ^cc /mol]; Henry's law: 15.78; heat of formation: -730.31 [kJ/mol]; tPSA: 77.1; CLogP: 7.5534; CMR: 17.0669; LogS: -7.773; pKa: 8.362.

[00599] EXAMPLE 181 Compound 1005 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenyl)phenoxy)propan-2-yl-4-((3,5-dimethyladamantan-1-yl) amino)-4-oxobutanoate. Chemical formula: C ₃₆ H ₅₀ N ₂ O ₅ ; exact weight: 590.37; molecular weight: 590.81; mass/charge: 590.37 (100.0%), 591.38 (38.9%), 592.38 (7.4%), 592.38 (1.0%); elemental analysis: C, 73.19; H, 8.53; N, 4.74; Oh, 13.54; boiling point: 1347.11 [K]; melting point: 961.09 [K]; critical temperature: 1191.88 [K]; critical pressure: 8.46 [bar]; critical volume: 1793.5 [ ^cc /mol]; Gibbs energy: 132.66 [kJ/mol]; Log P: 6; MR: 169.53 [ ^cc /mol]; Henry's law: 15.78; heat of formation: -730.31 [kJ/mol]; tPSA: 77.1; CLogP: 7.5534; CMR: 17.0669; LogS: -7.773; pKa: 8.362.

[00600] EXAMPLE 182 Compound 1007 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-(2,2,2-trichloro-1-(damethoxyphosphoryl)etsh)succinate. Chemical formula: C ₂₈ H ₃₇ Cl ₃ NO ₉ P; exact weight: 667.13; molecular weight: 668.93; mass/charge: 667.13 (100.0%), 669.12 (95.9%), 671.12 (30.6%), 668.13 (30.3%), 670.13 (29, 0%), 672.12 (9.3%), 671.13 (4.2%), 673.12 (3.3%), 669.13 (2.7%), 669.13 (1, 8%), 669.13 (1.7%), 671.13 (1.6%), 673.13 (1.4%); Elemental analysis: C, 50.28; H, 5.58; C1, 15.90; N, 2.09; O, 21.53; P, 4.63.

[00601] EXAMPLE 183 Compound 1008 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-(2,2,2-trichloro-1-(dimethoxyphosphoryl) ethyl) succinate. Chemical formula: C ₂₈ H ₃₇ Cl ₃ NO ₉ P; exact weight: 667.13; molecular weight: 668.93; mass/charge: 667.13 (100.0%), 669.12 (95.9%), 671.12 (30.6%), 668.13 (30.3%), 670.13 (29, 0%), 672.12 (9.3%), 671.13 (4.2%), 673.12 (3.3%), 669.13 (2.7%), 669.13 (1, 8%), 669.13 (1.7%), 671.13 (1.6%), 673.13 (1.4%); Elemental analysis: C, 50.28; H, 5.58; C1, 15.90; N, 2.09; O, 21.53; R, 4.63

[00602] EXAMPLE 184 Compound 1009 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl-(2,2,2-trichloro-1-(dimethoxyphosphoryl) ethyl) succinate. Chemical formula: C ₂₈ H ₃₇ Cl ₃ NO ₉ P; exact weight: 667.13; molecular weight: 668.93; mass/charge: 667.13 (100.0%), 669.12 (95.9%). 671.12 (30.6%), 668.13 (30.3%), 670.13 (29.0%), 672.12 (9.3%), 671.13 (4.2%), 673.12 (3.3%), 669.13 (2.7%), 669.13 (1.8%), 669.13 (1.7%), 671.13 (1.6%), 673.13 (1.4%); Elemental analysis: C, 50.28; H, 5.58; C1, 15.90; N, 2.09; O, 21.53; P, 4.63.

BIOLOGICAL RESEARCH

[00603] Biological studies were performed using compounds of formula I, exemplified by 4-((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)-4-oxobutanoic acid (represented by compounds 50, 51 and 52); 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-ol (represented by compounds 146, 147, 148);

N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]ethanamine or N,N-dimethyl- 2-(((1R,2S,4S)-1,7,7-trimethyl-2-phenylbicyclo-[2.2.1]heptan-2-yl)oxy)ethan-1-amine (compound 829, deramciclane) and compounds formula II, exemplified by dextromethorphan, its derivatives and metabolites.

[00604] EXAMPLE 1 85. DEX METABOLISM AND MAIN EFFECTS OF 5HT2A RECEPTOR BLOCK. Antipsychotic drugs attenuate motor hyperactivity caused by psychostimulants and psychotomimetic drugs in laboratory rodents. Although hyperactivity induced by dopaminergics such as d-amphetamine is reversible with both typical and atypical antipsychotics currently used in treatment, 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 to mice in combination with 0.3 mg/kg MK-801 (ip) over 15 minutes. before testing (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 (May 2006); incorporated by links). Movement data were collected over a 15 minute period in a lighted room. Mice were not previously kept in cages for studying motor activity. Immediately prior to placing the mice in the motor test chambers, muscle relaxation/ataxia effects were determined by bringing each of the mouse's forepaws into contact with a horizontal wire while holding the mouse at the base of the tail. Mice were required to bring at least one hind paw into contact with the wire for 10 s to achieve "passed" status, and those unable to do so were considered ataxic. Each dose or combination of doses was tested on a separate group of mice. ACP-103 significantly reduced MK-801-induced hyperactivity in mice at doses of 0.1 and 0.3 mg/kg sc. [F(7.63)=6.010; p<0.0001], corresponding to a similar antipsychotic effect.

[00605] When used in combination with quinidine in patients with neurological disorders (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; incorporated by references in its entirety), dextromethorphan was used at a dose of 10 mg, which can be administered twice a day. The currently known clinical dose of sarpogrelate is 100 mg, which is usually given three times a day (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical potential, expert opinion in Investigational Drugs, 13:7, 865-874; incorporated by reference in its entirety ). Thus, the current clinical dose of sarpogrelat is significantly higher than that of dextromethorphan. Given that the molecular weight of sarpogrelat is approximately 429 and the molecular weight of dextromethorphan is approximately 271, the combined use of dextromethorphan and sarpogrelat at current clinical doses does not result in a 1:1 molar ratio. However, this 1:1 molar ratio is a prerequisite for the preparation and use of dextromethorphan sarpogrelate salts. Because the current clinical use of sarpogrelate is for peripheral system (non-CNS) indications (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, 13:7, 865-874; incorporated by reference throughout its completeness), the use of sarpogrelate for CNS-related indications may require lower doses and thus allow co-administration with dextromethorphan as dextromethorphan arpogrelate salt or as a 1:1 molar mixture. In laboratory animals, sarpogrelat is usually given at doses of 25 mg/kg and above to induce effects on the peripheral system (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); incorporated by reference in its entirety). An example of the superior CNS activity of sarpogrelat is provided in an example where sarpogrelat is given to Sprague-Dawley rats at doses of 0.3, 1 and 3 mg/kg over 30 minutes. prior to administration of a direct acting 5-HT2A agonist DOI (3 mg/kg; (1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)hydrochloride), and the frequency of DOI-induced head twitching is reduced by co-administration of a compound of formula I, SARPODEX™, DERADEX™ or DERAPHAN™.

[00606] The compound of formula I, 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, 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 (April 1995); incorporated by reference in its entirety). To confirm the ability of the S- and R enantiomers of M1 to reach the 5HT2A receptors in the CNS, rats were pretreated with 0.1 mg/kg MK801 and the attenuation of MK801-induced motor hyperactivity was monitored over the dose range of the formula I compound in a 120-minute test conducted with conventional motion control devices.

[00607] DEX acts on 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 (August, 2016); incorporated by reference in its entirety). However, DEX is a less potent NMDA receptor antagonist than its DO metabolite. Therefore, DEX is less likely to cause phencyclidine-like locomotor activity than DO. The effects of DEX, DO and PCP on behavior were compared in rats. The effect of DO (15-120mg/kg) was similar to PCP (1.25-20mg/kg) in inducing dose-dependent motor hyperactivity, stereotypy and ataxia. DEX (15-120 mg/kg) only induced moderate hyperactivity at higher doses after approximately 45 minutes. after treatment. DEX and DO reversed motor stimulation induced by 10mg/kg PCP in reverse. Pretreatment with DO stimulated while DEX dose-dependently inhibited PCP-induced hyperactivity (Szekely et al., Induction of phencyclidine-like behavior in rats by DO but not DEX, Pharmacol Biochem Behav, 40(2):381-6 (Oct. 1991); incorporated by reference in its entirety).

[00608] EXAMPLE 186 The compound of formula I, as well as both enantiomers of its primary metabolite, are inhibitors of CYP2D6. DEX is a widely used substrate in in vitro metabolism studies to detect 2D6 inhibitory activity for biologically active substances and drugs. In a specially designed series of studies, the formula I compound was administered prior to DEX and the locomotor activity of the rats was monitored for 120 minutes to show that the formula I compound prevented the development of hyperactivity in DEX-treated subjects. These studies were conducted in parallel with measurements of plasma DEX levels. A combination of pharmacokinetic (plasma DEX concentration) and pharmacodynamic (MK-801 and DEX induced hyperactivity) studies were used to determine the M1 enantiomer and dose level(s) that give the most optimal balance of the effects of suppressing hyperactivity and suppressing DEX metabolism.

[00609] EXAMPLE 187 BLOOD GLUCOSE AND INSULIN SENSITIVITY. Unlike sulfonylurea drugs, which induce significantly higher basal insulin secretion compared to vehicle treatment, DO and its prodrug, DEX, did not significantly alter basal insulin secretion from murine 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); incorporated by reference in its entirety). More specifically, administration of DEX with drinking water (4 mg/mL) overnight did not alter either plasma basal insulin or fasting blood glucose concentrations in mice, but resulted in significantly higher glucose-induced plasma insulin concentrations and tolerance to glucose than those observed in untreated controls with DEX (glucose administered intraperitoneally at 1.5 mg/kg body weight).

[00610] Marguard et al. (2015) suggested that the effects of DEX are mediated by an NMDA receptor channel blocker and specifically noted the rapid metabolism of DEX to DO, which is a potent inhibitor of NMDA receptors. For evidence of NMDA receptor involvement, Marguard et al. showed that glucose-stimulated insulin secretion and glucose tolerance are not observed in mice genetically engineered to lack NMDA receptor function.

[00611] 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 double-blind, placebo-controlled, randomized, cross-over, phase proof-of-concept study was performed. 2a single dose (Marquard et al., Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 21(4):363-72 (2015); incorporated by reference in its entirety). Twenty men with T2DM were recruited on metformin monotherapy (age 59 (46-66) years (mean (range)), with a mean body mass index (BMI) of 29.2 (25.2-34.1) kg m ^-2 ; with glycosylated hemoglobin (HbAlc) 6.9 (6.5-7.4)%). 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 hour post-dose for four days of treatment separated by a washout period of 7-14 days. Consistent with the results in mice, DEX did not result in either higher fasting serum insulin concentrations or lower fasting blood glucose concentrations compared to placebo and did not cause any severe hypoglycemic events up to the 270 mg dose. In contrast, following oral glucose administration, both 60 and 270 mg DEX doses resulted in significantly (P<0.05) higher peak serum insulin concentrations compared to those observed with placebo.

[00612] In addition, the main endpoint was achieved for 270 mg DEX; namely, the area under the curve for blood glucose concentrations during the first 2 hours of OGTT (glucose AUC1-3 hours) was significantly (P<0.05) smaller in people who received the 270 mg dose of DEX than in the same people. who received placebo on a different day of treatment.

[00613] Blood glucose is also controlled by 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); incorporated by reference in its entirety). More specifically, administration of a non-selective 5HT receptor agonist such as 5-methoxytryptamine caused hyperglycemia, which was prevented by pretreatment with the 5-HT2A receptor antagonist ketanserin as well as the peripherally acting 5-HT2 receptor antagonist xylamidine. These results indicate that 5-methoxytryptamine-induced hyperglycemia is mediated by peripheral 5-HT2A receptors.

[00614] Second-generation antipsychotics with dual dopamine and serotonin receptor antagonism have been associated with an increased risk of impaired glucose tolerance and diabetes mellitus. Although this is largely due to weight gain, there is also a direct, receptor-mediated effect of antipsychotics on glucose tolerance. Some 5HT2A receptor antagonists, such as ketanserin, impair insulin sensitivity (Grilles et al., Antagonism of the serotonin (5-HT)-2 receptor and insulin sensitivity: implications for atypical antipsychotics. Psychosom Med. 67(5):748- 51 (2005)); incorporated by reference in its entirety). In a study by Gilles et al., ten healthy male volunteers were enrolled in a double-blind, placebo-controlled, single-dose, 40 mg crossover study of the 5-HT2 antagonist ketanserin versus placebo. Insulin sensitivity was measured by the euglycemic hyperinsulinemic clamp test. Subjects were treated with the alpha-1 adrenergic receptor antagonist phenoxybenzamine in both parts of the study to control the effects of ketanserin at this receptor level. Compared to placebo, subjects showed significantly reduced insulin sensitivity after ketanserin (placebo: 9.4+/- 3.6 mg/kg/min; ketanserin: 7.7+/- 2.1 mg/kg/min). min; p=0.047).

[00615] Thus, the combination of DEX and 5-HT2A receptor antagonists may lead to synergistic effects on blood glucose and insulin sensitivity, which may be undesirable in the case of long-term treatment, as it may have undesirable metabolic side effects qualitatively similar to those observed. in patients treated with neuroleptic drugs. These effects may limit the doses of DEX and 5-HT2A receptor antagonists that can be safely administered as a combination.

[00616] There are two approaches that are part of the present invention that facilitate the therapeutic use of combinations of DEX and 5HT2A receptor antagonists while reducing the risks of peripheral metabolic adverse effects.

[00617] One approach is based on the use of an inverse agonist or antagonist of the 5HT2A receptor, which inhibits CYP2D6 and thereby reduces the conversion of DEX to DO. Both DEX and DO are NMDA receptor channel blockers, and inhibition of the NMDA receptor on the pancreatic islets has been hypothesized 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); incorporated by reference in its entirety). Because DO is a 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); incorporated by reference in its entirety), inhibition of DEX metabolism by CYP2D6 may reduce the effects of DEX on glucose-stimulated insulin secretion and glucose tolerance, and thus the risk of metabolic side effects.

[00618] The second approach is to select the 5HT2A receptor inverse agonist or antagonist that has the best filling ratio of central to peripheral 5HT2A receptors. Therefore, the 5HT2A receptor inverse agonist or antagonist is chosen to produce therapeutically meaningful occupancy of the central 5HT2A receptors at doses that have the lowest risk of producing unwanted metabolic effects, such as, but not limited to, glucose intolerance.

[00619] The compound of formula I is an inverse agonist or antagonist of the 5HT _2A receptor which has 2D6 inhibitory properties. Studies have been conducted on the acute and chronic effects of a compound of formula I on glucose tolerance and insulin resistance (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), incorporated by reference in its entirety). In these studies, the Otsuka Long-Evans Tokushima genetically obese rat model of type 2 diabetes was randomly divided into 2 groups; a group treated with 30 mg/kg body weight/day of a compound of formula I for 4 weeks (HTB group) and no treatment (control group). The rate of glucose infusion was significantly increased in the HTB group compared to the control group. Blood glucose levels after an oral glucose tolerance test and plasma insulin and lipid levels were significantly lower in the HTB group than in the control group. A compound of formula I has been shown to reverse insulin resistance induced by various agents, including treatment with glucocorticoid drugs (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; incorporated by reference in its entirety).

[00620] Synergistic effects of a compound of Formula I 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); incorporated by reference in its entirety) and pioglitazone (Iizuka et al., Beneficial effects of a compound of sarpogrelate hydrochloride , a 5-HT2A receptor antagonist, supplemented with pioglitazone on diabetic model mice (Endocr Res. 34(1-2): 18-30 (2009); incorporated by reference in its entirety).

[00621] Insulin-sensitizing effects of a compound of formula I have also been found 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); incorporated by reference in its entirety). Insulin resistance indices (fasting immunoreactive insulin) were measured before and after 2 weeks of administration of a compound of formula I (300 mg/day) in 24 patients (19 males, 76+/-9 years old) with peripheral arterial disease. Sixteen of 24 patients were also examined 3 months after treatment. After 2 weeks of treatment, a significant decrease in fasting immunoreactive insulin was observed (p=0.03). After 3 months of treatment, there was a significant decrease in fasting immunoreactive insulin (16.0+/-10.3 vs. 9.2+/-2.0 microU/mL, p=0.03).

[00622] The compound of formula I is rapidly metabolized to a metabolite that also has both 5HT _2A receptor antagonist and 2D6 inhibitory properties. Both enantiomers of the metabolite are biologically active and have the ability to block 5HT2A and 2D6 receptors. To find out which enantiomer has the best properties to combine with DEX, the effects of these substances alone and in combination with DEX were evaluated in an oral glucose tolerance test (Taniguchi et al., Diabetes, 55, 2371-2378 (2006); incorporated by reference in its entirety). This method is based on the measurement of glucose in whole blood and insulin in blood plasma. The test substances were administered to male Sprague-Dawley rats (group size: 8 per group). Animals were tested after being deprived of food overnight and placed individually. The test substances were administered 60 minutes before the glucose load, ie. after measuring baseline blood glucose. Animals were administered glucose at 2 g/kg orally by gavage in the TO after measuring blood glucose. Blood glucose was measured in a drop of blood collected from a tail-tip incision using a commercially available glucose meter at 8 time points: baseline (before treatment), TT (before glucose), and then at 15, 30, 60, 90, 120, and 180 minutes after glucose loading.

[00623] EXAMPLE 188 EFFECTS OF FORMULA I SEPARATELY ON THE PATHOPHYSIOLOGY OF AD. The existence of links between the chronic diabetic metabolic situation and the risk and occurrence of AD pathophysiology has long been suspected and has been confirmed in 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 (August 1, 2016); incorporated by reference in its entirety). In several large postmortem series, more than a third of all subjects clinically diagnosed with typical AD had evidence of cerebrovascular disease and had to be reclassified as mixed dementia (Grandal Leiros et al., Prevalence and concordance between the clinical and the post-mortem diagnosis of dementia in a psycho geriatric clinic, Neurologia S0213-4853(16)30070-6 (2016); incorporated by reference in its entirety). From a clinical perspective, it is desirable to expand AD therapy beyond currently approved drugs and mechanisms, as well as address cognitive impairment by optimizing the latent diabetic metabolic situation or the relatively common type 2 diabetes in elderly subjects. Certainly, glycemic control is believed to influence the severity of cognitive impairment (Zilliox et al., Diabetes and Cognitive Impairment. Curr Diab Rep, 16 (9): 87 (2016); incorporated by reference in its entirety).

[00624] Due to the specific anti-diabetic actions of the compound of formula I described above, thus, one can try to obtain an additional beneficial effect both in terms of symptoms and disease progression in AD, and cognitive impairment of predominantly vascular origin (multi-infarct dementia, vascular dementia, vascular cognitive impairment, etc.).

[00625] Based on the Japanese regulatory indication, the incidence of adverse events in therapy with a compound of formula I in internal medicine is quite low compared with placebo, and the nature of the recorded AEs was found to be acceptable; thus, the benefit-risk ratio of added therapy with a compound of formula I seems justified also in an elderly population with multiple comorbidities.

[00626] EXAMPLE 189. STEREOSELECTIVE REMOVAL OF PSYCHOSTIMULATOR-INDUCED HYPERACTIVITY IN VIVO WITH THE USE OF THE COMPOUND. Movement data were collected over a 15 minute period in a lighted room. Mice were not previously kept in cages for studying motor activity. Immediately prior to placing the mice in the motor test chambers, muscle relaxation/ataxia effects were determined by bringing each of the mouse's forepaws into contact with a horizontal wire while holding the mouse at the base of the tail. Mice were required to bring at least one hind paw into contact with the wire for 10 s to achieve "passed" status, and those unable to do so were considered ataxic. Each dose or combination of doses was tested on a separate group of mice. ACP-103 significantly reduced MK-801-induced hyperactivity in mice at doses of 0.1 and 0.3 mg/kg sc. [F(7.63)=6.010; p<0.0001], corresponding to a similar antipsychotic effect.

[00627] HEK-293 cells expressing the recombinant human 5HT2A receptor have been used in antagonist radioligand binding studies. A compound of formula I, such as the racemate of compound 50 and both enantiomers, was used at concentrations ranging from 3.0E-11M to 1.0E-07M. The M1 enantiomers were used at concentrations ranging from 1.0E-11M to 3.0E -08 M. IC50 values (concentration causing half maximum inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of competition curves obtained with average replicate values using curve fitting by Hill's equation.

Inhibition constants (Ki) were calculated using the Cheng-Prusoff equation. Both enantiomers of sarpogrelat were potent inhibitors of [3H]ketanserin binding (Table 1). M1 enantiomers also bind strongly to 5HT2A receptors with Ki values that are about one order of magnitude higher than those of sarpogrelat enantiomers (Table 1). There is no significant difference between the enantiomers in terms of 5-HT2A receptor binding for sarpogrelat or its major metabolite.

[00628]

[00629] To confirm the ability of the M1 enantiomers to induce effects that are significant for CNS diseases and that are known for agonists and inverse agonists of the 5-HT2A receptor, separate groups of female Wistar rats (n=6-9) placed 4-5 per cage at standard colonial conditions in a room with free access to food and water, pre-treated intraperitoneally with different doses of one of the two M1 enantiomers (0.3 or 10 mg/kg) followed by treatment 15 minutes later with 0.1 mg/kg MK801 or its carrier medium, and then immediately placed in computer-controlled motion recording chambers (25 × 35.5 × 34 cm, L × W × H; transparent Plexiglas walls and opaque plastic floor; enclosed in noise-absorbing ventilated cells) for 60 minutes, during which the interruptions of the infrared photocell (5 cm and 14 cm above the floor) were recorded as a measure of motor activity. MK-801 is a phencyclidine-like NMDA receptor channel blocker commonly used in psychopharmacological research into new therapeutics, including new antipsychotics. Analysis of variance (ANOVA) revealed the presence of major M1 dose effects and an 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], but not for the (+)-enantiomer M1 [F(2.42)=0.5211; p=0.5977, F(2.42)=0.5229; p=0.5966, respectively]. As shown in FIG. 7, both doses of the (-)-enantiomer M1 as well as 3 mg/kg of the prototype 5-HT2A receptor antagonist M-100,907 reduced MK-801-induced hyperactivity (Dunnett's multiple comparison test). Thus, while there is no significant difference between the M1 enantiomers in binding to 5- _HT2A receptors, surprisingly, only one of the enantiomers was effective in a preclinical psychomotor activation model known to be sensitive to 5-HT2A receptor blockade.

[00630] EXAMPLE 190. ELIMINATION OF MOTOR HYPERACTIVITY CAUSED BY OLFACTORY BULBS REMOVAL IN RATS. In a specially designed series of studies, adult male Sprague-Dawley rats (Charles River, Germany) were subjected to bilateral olfactory bulb removal performed under ketamine/xylazine anesthesia. Animals were provided with a recovery period of 14 days after surgery, while grooming them every day to eliminate any aggressiveness that would otherwise occur. Sham-operated animals were treated in the same way, but the olfactory bulbs were left intact. Drug administration and testing of locomotor activity was performed 4 times for each rat with a 72 hour gap between consecutive tests. Prior to each test, animals were first treated with dextromethorphan (0, 15, 30, or 60 mg/kg po) and then 15 min later. sarpogrelat (1, 3 and 10 mg/kg, intraperitoneally), and after another 15 minutes. were placed in Opto-Varimex cages to record motor activity for 30 min. Hyperactivity in rats after removal of the olfactory bulbs was observed mainly during the early phase of testing. In FIG. 8 shows the average activity calculated in the first 15 minutes. test, when the activity of animals with removed olfactory bulbs was significantly higher than that of sham operated controls. ANOVA revealed the presence of significant main effects for both the operation factor and the dose factor of sarpogrelat [F(l,88)=5.04, p=0.0273; F(3.88)=5.02, p=0.0029, respectively]. Post hoc pairwise comparisons (Sidak's multiple comparison test) confirmed that significant differences between olfactory bulb removed and sham operated rats were observed only in rats that were pretreated with vehicle instead of sarpogrelat before the test. Olfactory bulb ablated rats pretreated with 3 or 10 mg/kg sarpogrelat spent less time locomotion after surgery compared to matched controls that received vehicle medium instead of sarpogrelat. These effects of sarpogrelat on the elimination of hyperactivity were observed at doses that did not affect the activity of sham-operated rats and thus did not reflect a general non-specific impairment of motor abilities. Thus, surprisingly, despite being previously referred to as a peripherally limited 5-HT2A receptor antagonist characterized by only minimal penetration of 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)), sarpogrelat has been observed to exhibit behaviorally specific effects in reversing hyperactivity in rats after removal of the olfactory bulbs, a model commonly used for research drugs for CNS, such as antidepressants.

[00631] EXAMPLE 191 IN VITRO AND IN VIVO DEXTROMETHORPHAN METABOLISM INHIBITION. The activity of dextromethorphan-O-demethylase was determined in human liver microsomes. Sarpogrelat (from 1.0E-8 M to 3.0E-5 M) or M-1 (concentration: from 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 obtain a final concentration of the organic solvent of 1.0% in the incubation mixture. The incubation mixtures contained mixed human liver microsomes (final concentrations: 0.25 mg/ml), dextromethorphan and NADPH-generating system (1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 3.3 mM MgCl ₂ 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 the averages were used for analysis. IC50 values (concentration causing half the maximum inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of competition curves obtained with average replicate values using curve fitting by Hill's equation. Both enantiomers of sarpogrelat inhibited CYP2D6 mediated O-demethylation of dextromethorphan (Table 4).

[00632]

[00633] Although both M1 enantiomers markedly inhibited 2D6 activity with IC50 values of 0.038-0.096 μM, the sarpogrelat enantiomers were about 10-15 times less effective (Table 4). Based on previous in vivo studies, sarpogrelat has been classified as a weak inhibitor of 2D6. This classification is based on less than a 2-fold increase in substrate AUC (m.e. according to 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/GuidanceComplianceRegulatorylnformati on/Guidances/ucm292362.pdf).

[00634] A pharmacokinetic study was performed on male Wistar rats equipped with cannulas in the jugular vein. Sarpogrelat hydrochloride was formulated in Pharmasolv:PBS buffer (5:95) and administered at a dose of 2 mg/kg intravenously. Blood samples were collected from the jugular vein using heparin as the anticoagulant at the given time points: 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h and 6 h. Bioanalytical method LC-MS/MS was used for simultaneous quantitative determination of sarpogrelat and M1 in blood plasma samples. Following 2 mg/kg intravenous bolus administration, plasma level curves showed little inter-individual variability (Figure 9). The apparent terminal elimination half-life was estimated to be 1.21±0.159 hours. The formation of the M1 metabolite of sarpogrelat was rapid as the highest M1 concentrations were measured at the first sampling time points. Despite rapid formation, circulating concentrations of the free metabolite M1 were orders of magnitude lower than those of the parent compound (Ml/s arpogrelat ratio of 2.98 ± 0.597%). Thus, although the M1 enantiomers were significantly more potent inhibitors of 2D6 than the parent compound, the possible effect of M1 is reduced due to the low relative effect of Ml, as evidenced by the ratio of plasma AUC for M1 and sarpogrelat.

[00635] EXAMPLE 191 In a separate series of studies, the ability of sarpogrelat to inhibit the metabolism of dextromethorphan in vivo was investigated in rats. Adult male Sprague Dawley rats (RjHan:SD) purchased from Janvier Labs (France) were housed in a controlled room with a 12 h light/12 h dark cycle with access to food and water as desired. Two to three days prior to sampling, the rats were catheterized into the jugular vein, and then the rats were treated once with carprofen (5 mg/kg) immediately after surgery, and the catheters were flushed every day with heparin (500 IU/ml) (20 μl/rat/ day). On the day of the experiment, dextromethorphan (50 mg/kg) was administered orally via gavage followed immediately by an intravenous bolus injection of sarpogrelat (1, 3, or 10 mg/kg; racemate or one of the enantiomers) or vehicle medium via the vascular access port at t= 0 hours Blood samples were collected at four time points up to 6 hours after administration of dextromethorphan. The sample size was 80 µl whole blood with Li-heparin/time point, i.e. 40 µl of blood plasma with Li-heparin / time point. Whole blood samples were kept on ice until centrifugation (10 min. at 3000 g, 4°C). Blood plasma was obtained within 45 min. after collection, frozen at -20°C and stored at this temperature until processing for LC-MS analysis.

[00636] As shown in Figure 10, in sarpogrelat (racemate or enantiomers) treated rats, plasma levels of dextromethorphan continued to be high even at the last time points, while in vehicle-treated rats, dextromethorphan levels decreased by the 6 hour time point.

[00637] Unexpectedly, AUC quantification for dextromethorphan showed that at the highest tested dose of 10 mg/kg, sarpogrelat increased the AUC of dextromethorphan by 5.3-6.9 times. Even at a lower dose of 3 mg/kg, the AUC of dextromethorphan increased in the range of 2.7 (for the (-)-enantiomer) to 3.3-fold (for the (+)-enantiomer).

[00638]

[00639] EXAMPLE 192. INHIBITION OF PHECYCLIDINE-INDUCED HYPERACTIVITY IN RATS TREATED WITH A COMBINATION OF SARPOGRELAT AND DEXTROMETHORPHAN. The effects of DEX, DO and phencyclidine (PCP) on behavior were compared in rats. The effect of DO (15-120 mg/kg) was similar to PCP (1.25-20 mg/kg) in inducing dose-dependent motor hyperactivity, stereotypy and ataxia. DEX (15-120 mg/kg) only induced moderate hyperactivity at higher doses after approximately 45 minutes. after treatment. DEX and DO reversed motor stimulation induced by 10mg/kg PCP in reverse.

[00640] In a specially designed series of studies, the racemate and enantiomers of Compound 50 were co-administered with DEX to demonstrate the ability of such drug combination(s) to counter psychomotor arousal and hyperactivity. Male Sprague-Dawley rats were treated with compound 50 (racemate sarpogrelate), (-) sarpogrelate, (+) sarpogrelate, or vehicle medium, and subcutaneously (racemate experiment) or orally (enantiomer experiments) dextromethorphan or vehicle (water), and were placed individually in an Opto-Varimex-4 auto-tracking system. Fifteen minutes later, the rats were removed from the boxes, injected with phencyclidine (PCP; 5 mg/kg, s.c.) and returned to the automatic tracking system for another 105 minutes. (m.e. up to a total recording time of 120 minutes). Data analysis focused on the second half of the test (60-120 min.). ANOVA revealed the presence of a significant interaction between the dose of sarpogrelat and the dose of dextromethorphan (Figure 11, upper panel; F(9.120)=2.38, P=0.015).

[00641] A similar statistically significant interaction with dextromethorphan dose was observed for (-)-sarpogrelate (Figure 11, middle panel; F(9.141)=3.07, P=0.002), but not for (+)-sarpogrelate (Figure 11, bottom panel; F(9.120)=1.65, P=0.1). Post hoc analyzes showed that, in the presence of dextromethorphan, 3 mg/kg racemate sarpogrelat, as well as 1 mg/kg or 3 mg/kg (−)-sarpogrelat, inhibited motor hyperactivity in PCP-treated rats (Dunnett's multiple comparison test). This pattern of results surprisingly revealed that the (-)-enantiomer of sarpogrelat is less effective than the (+)-enantiomer in inhibiting the metabolism of dextromethorphan both in vitro (Table 4) and in vivo (Table 5).

[00642] When administered in the absence of dextromethorphan, neither racemate sarpogrelate nor enantiomers of sarpogrelate reduced activity in PCP-treated rats. When administered in combination with dextromethorphan, inhibitory effects of sarpogrelat were observed regardless of whether dextromethorphan alone decreased (subcutaneous administration, sarpogrelat racemate experiment) or increased (oral administration, sarpogrelat enantiomer experiments) locomotor activity in PCP-treated rats. Thus, the presence of dextromethorphan may be required for sarpogrelat to exhibit inhibitory effects in subjects with psychomotor arousal, such as hyperactive rats after exposure to the psychotomimetic drug PCP. This pattern of superadditive interactions between dextromethorphan and sarpogrelat is unexpected.

[00643] EXAMPLE 193. METHOD FOR ASSESSING BLOOD GLUCOSE LEVELS AND ORAL GLUCOSE TOLERANCE. The test substances were administered to male Wistar (Han) rats (180-280 g at the beginning of the experiments; Janvier Labs), which were housed in groups with free access to food and water. After fasting overnight, the tip of the tail was incised, each rat was weighed, housed individually, and left stress-free in a quiet room. After about 1 hour, baseline blood glucose was measured in a drop of blood collected from the tip of the tail using a commercially available glucose meter (OneTouch®, Lifescan), and then sarpogrelat and/or dextromethorphan were administered intraperitoneally to the rats, and after 30 min. blood glucose was measured again, and the rats were immediately administered glucose at 2 g/kg po. Then, blood glucose was measured at 6 time points until 180 minutes after the glucose load. As shown in Figure 12, the main effect of drug treatment was present (F(4.59=12.0, p<0.0001). Post hoc pairwise comparisons of the groups showed that when administered alone, dextromethorphan significantly lowered blood glucose, and this the effect of dextromethorphan was abolished when it was administered in combination with sarpogrelat racemate or any of the enantiomers.

[00644] EXAMPLE 194 52-WEEK CHRONIC TOXICITY TEST AND 5-WEEK RECOVERY TEST USING BEAGLE DOGS (Suzuki et al., Pharmacology & Therapeutics Vol 19 Supplement '91). Compound 50 hydrochloride was administered orally to beagle dogs at dose levels of 5, 20, 80 and 320 mg/kg/day for 52 consecutive weeks. No animal died or was euthanized in a terminal state regardless of gender. Regarding general conditions, vomiting was noted in males and females receiving 320 mg/kg/day and males receiving 80 mg/kg/day, and salivation in females receiving 320 mg/kg/day. Body weight gain was reduced in males and females receiving 320 mg/kg/day. Food intake was suppressed in females receiving 80 mg/kg/day or more. Females receiving 320 mg/kg/day also showed a reduction in water intake. During the recovery period, the overall observed conditions showed no difference between the control and treatment groups. No treatment-related change was observed on electrocardiographic or ophthalmoscopic examination. Urinalysis showed an increase in protein levels in females receiving 320 mg/kg/day, hematology showed an increase in platelets in males receiving 320 mg/kg/day, and biochemistry showed an increase in potassium levels in males receiving 80 mg/kg/day and above, and females receiving 320 mg/kg/day. These changes were restored after discontinuation of the drug. The relative weight of thyroid and liver was increased in males treated with 80 mg/kg/day and above, but histopathological examination showed no treatment-related changes. Histopathological examination revealed fatty degeneration in the cortico-medullary border zone of the kidney in males treated with 320 mg/kg/day. However, during the recovery period, this change was not detected. The dose level of Compound 50 hydrochloride found to have no effect during the 52-week study was 20 mg/kg.

[00645] While features of the present invention have been shown and described herein, many modifications, substitutions, changes, and equivalents will now be apparent to those skilled in the art. Thus, it will be understood that the appended claims are to cover all such modifications and changes as fall within the true spirit of the present invention. Those skilled in the art will appreciate that various changes in form and detail may be made with respect to the present invention without departing from the spirit and scope of the present invention as defined in the appended claims. Those skilled in the art will recognize or be able to ascertain, using only routine experimentation, many equivalents to the specific embodiments of the present invention described herein. Such equivalents are intended to be within the scope of the claims. Reasonable changes should not be considered as a deviation from the scope of the present invention. It will be apparent that the invention thus described is subject to change and that various modifications, additions, substitutions and variations of the illustrative examples referred to herein may be made without departing from the spirit of the present invention and are thus considered to be within the scope of the present invention. All documents referenced above, including without limitation printed publications and provisional and conventional patent applications, are incorporated herein by reference in their entirety.

[00646] EXAMPLE 195 REMOVAL OF MOTOR HYPERACTIVITY INDUCED BY NMDA RECEPTOR BLOCK IN RATS. To confirm the ability of the present invention (compounds of formula I) to induce antipsychotic effects that are relevant to efficacy against behavioral and psychological symptoms of dementia and that are known for agonists and inverse agonists of 5-HT2A receptors, separate groups of rats that were kept in standard rooms for colonies with free access to food and water, pre-treated with various doses of deramcilan (up to 30 mg/kg), followed by treatment with an NMDA receptor channel blocker or its carrier medium, and immediately thereafter placed in computer-controlled movement recording chambers. NMDA receptor channel blockers are commonly used in psychopharmacological research into new therapeutic agents, including novel antipsychotics. Analysis of variance (ANOVA) was used to identify the main effects of the dose of deramcilan and the interaction between the dose of deramcilan and treatment with treatment factors in relation to NMDA receptors.

[00647] EXAMPLE 196 REMOVAL OF MOTOR HYPERACTIVITY CAUSED BY OLFACTORY BULBS REMOVAL IN RATS. In a special series of studies, adult male rats were subjected to bilateral olfactory bulb ablation, a model commonly used to investigate drugs that act on the CNS, such as antidepressants. Animals were allowed to recover for at least 14 days after surgery. Sham-operated animals were treated in the same way, but the olfactory bulbs were left intact. Prior to each test session, animals were treated with dextromethorphan (up to 60 mg/kg, po) in combination with a compound of formula I (up to 30 mg/kg) and then placed on a locomotor monitor to record locomotor activity.

[00648] EXAMPLE 197. INHIBITION OF DEXTROMETHORPHAN METABOLISM. The activity of dextromethorphan-O-demethylase was determined in human liver microsomes. The compound of formula I (concentration: up to 3.0E-5M) and dextromethorphan were dissolved in acetonitrile and diluted sequentially with acetonitrile to the required concentrations to give a final organic solvent concentration of approximately 1.0% in the incubation mixture. The incubation mixtures contained pooled human liver microsomes, dextromethorphan and the NADPH generating system. 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 the averages were used for analysis. IC50 values (concentration causing half the maximum inhibition of control specific binding) and Hill coefficients (pN) were determined using methods such as non-linear regression analysis of competition curves obtained with average replicate values using curve fitting by Hill's equation. Deramciclane has been observed to inhibit CYP2D6 mediated O-demethylation of dextromethorphan.

[00649] Based on the results of previous studies in humans with desipramine as a substrate, the compound of formula I can be classified as a weak inhibitor of 2D6 (Laine K et al., Effect of the novel anxiolytic drug deramciclane on cytochrome P450 2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol (2004) 59: 893-898). This classification is based on an approximately 2-fold increase in substrate AUC (m.e., according to 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/Guidance ComplianceRegulatoryInformation/Guidances/ucm292362.pdf).

[00650] In a pharmacokinetic study conducted in rats, the ability of a compound of formula I to inhibit the metabolism of dextromethorphan was studied in vivo. Adult rats were placed in a controlled room with a 12 hour light/12 hour dark cycle, with access to food and water as desired. On the day of the experiment, dextromethorphan (50 mg/kg) was administered orally by gastric tube, followed immediately by deramciclane (up to 30 mg/kg) or carrier medium (t=0 h). Blood samples were collected at various time points within 24 hours of dextromethorphan administration. The sample size was approximately 80 µl of whole blood with Li-heparin/time point, i.e. 40 µl plasma with Li-heparin/time point. Whole blood samples were kept on ice until centrifugation (10 min. at 3000 g, 4°C). Blood plasma was obtained within 45 min. after collection, frozen at -20°C and stored at this temperature until processing for LC-MS analysis. In rats treated with the compound of formula I, plasma levels of dextromethorphan continued to remain high even at later time points, while in rats treated with vehicle medium, dextromethorphan levels decreased more rapidly.

[00651] EXAMPLE 199. EFFECTS OF THE COMPOUND OF FORMULA I ON THE EFFECTS OF THE DIFFERENTIAL STIMULUS OF DEXTROMETHORPHAN AND MEMANTHINE. Drug recognition is commonly used to assess the control of psychoactive drug-induced interoceptive stimuli (Sukhotina IA et al., Effects of calcium channel blockers on behaviors induced by the N-methyl-D-aspartate receptor antagonist, dizocilpine, in rats. Pharmacol Biochem Behav ( 1999) 63:569-80). These methods are used to determine the ability of certain classes of drugs that act on the CNS, such as NMDA receptor channel blockers, to cause adverse events (Nicholson KL et al., Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D -aspartate channel blocker memantine Behav Pharmacol (1998) 9:231-43).

[00652] Adult male Wistar rats were housed individually with water available at will. Food intake was limited to 14-16 g/day, feeding followed behavioral testing to maintain a constant body weight (300-330 g). Behavioral training and testing was carried out using standard dual-arm air-conditioned chambers for specific response, connected to a microcomputer via an interface and controlled by the MED-PC software. Each chamber was equipped with a dispenser that delivered 45 mg of food pellets. At the start of each drug discrimination test session, rats were peritoneally injected with either 0.056 mg/kg of dizocilpine or saline, returned to their cages, and then placed in specific response chambers 15 minutes later for a total of 15 minutes. During the test sessions, 10 consecutive responses on any arm elicited pellet delivery. Prior to the test sessions, two injections were given; one peritoneal injection of deramciclane (3 mg/kg) or its carrier medium (pre-injection period 60 min.) and one injection of dizocilpine (0.056 mg/kg), memantine (10 mg/kg), dextromethorphan (30 mg/kg) or saline solution (pre-injection period 15 minutes). Percentage of responses to dizocilpine-labeled leverage (DLR) and response rates (responses/sec) were calculated for each test session to establish that deramciclane significantly reduced the intensity of the effects of discriminative stimuli of NMDA receptor channel blockers (Figure 14A) at a dose that had no significant effect to generate a specific response (Figure 14B). The reduction in the intensity of memantine discriminative stimulus effects in the presence of deramcilan (Figure 1, top panel) indicates that deramciclane is able to control the unwanted effects of NMDA receptor channel blockers such as dextromethorphan (Nicholson KL et al., Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys. Psychopharmacology (1999) 146:49-59) not only through inhibition of dextromethorphan metabolism (Zawertailo LA et al., Effect of metabolic blockade on the psychoactive effects of dextromethorphan. Hum Psychopharmacol ( 2010) 25:71-9), but also through pharmacodynamic mechanisms. Thus, given the 206-inhibitory properties of deramciclane, deramciclane most effectively controls the subjective effects of NMDA receptor channel blockers that are metabolized by CYP 2D6, such as dextromethorphan.

[00653] EXAMPLE 200 ANTIDEPRESSANT-LIKE EFFECTS OF A FORMULA I COMPOUND IN COMBINATION WITH A NMDA RECEPTOR CHANNEL BLOCKER. Tail suspension is one of the classic tests used to study antidepressants, this test has also been used to assess the antidepressant-like effects of NMDA receptor channel blockers (Kos T et al., Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice European Neuropsychopharmacology (2006) 16:297-310). Mice were transferred from the room in which they were kept to the testing area in their cages and allowed to adapt to the new environment for at least 1 hour before drug treatment. Immobility was induced by tail suspension, for which mice were individually attached to paper tape 65 cm above the table. The tape was about 1 cm from the tip of the tail. Animals were suspended for 6 min. and recorded the duration of immobility. Mice were considered immobile only when they showed no signs of movement. Prior to the test sessions, two injections were given; one peritoneal injection of deramciclane (3 mg/kg) or its carrier medium (pre-injection period 60 min.) and one injection of memantine (3 mg/kg), dextromethorphan (10 mg/kg) or saline (pre-injection period 30 min.) . Although none of the treatments at these dose levels had statistically significant effects, the combined administration of deramciclane with dextrimethorphan significantly reduced immobility time, indicating the antidepressant-like potential of this combination (Figure 15A). The combination of deramciclane with memantine also reduced immobility time by 57% (P=0.1). Surprisingly, when an ineffective dose of memantine (3 mg/kg) was administered in combination with another 5-HT2A/2C receptor antagonist, ritanserin (1 mg/kg), no reduction in immobility time was observed (FIG. 15B). Instead, ritanserin was able to reverse the antidepressant-like effects of an effective dose of memantine (10 mg/kg). These results suggest that when used in combination with NMDA receptor channel blockers, deramciclane is able to induce pharmacodynamic effects that distinguish it from at least some other members of the 5-HT2A/2C receptor antagonist and inverse agonist class.

[00654] EXAMPLE 201 ANXIOLYTIC EFFECTS OF THE COMPOUND OF FORMULA I IN COMBINATION WITH A NMDA RECEPTOR CHANNEL BLOCKER. Conflict tests such as the Heller-Seifter test are commonly used to study the anxiolytic effects of drugs and are also used to evaluate the anxiolytic effects of glutamate receptor antagonists (Pietraszek M et al., Anxiolytic-like effects of mGlul and mGlu5 receptor antagonists in rats. Eur J Pharmacol (2005) 514:25-34).

[00655] Using standard conditioned response chambers connected to a computer via an interface and controlled by MED-PC software, rats were trained to press levers in multiple fixed ratio (FR) 20 (food only), FR 20 (food and shock) in which three 7-minute non-punishment components alternated with three 3-minute punishment components, for a total session duration of 30 minutes. the intensity and duration of shock exposure were adjusted for each individual rat. Data were analyzed as response rates (responses per second) during the punished and non-punished components of each session. For analysis purposes, response rate data from drug trials were expressed as change in response rate from a 5-day baseline. Prior to the test sessions, two injections were given; one peritoneal injection of deramciclane (1 mg/kg) or its carrier medium (60 min pre-injection period) and one injection of memantine (3 mg/kg) or saline (30 min pre-injection period). Both deramciclane and memantine were administered at doses that themselves had a marked effect on the implementation of the response, accompanied or not accompanied by punishment (figures 16A and 16B). However, when subeffective doses of memantine and deramciclane were given in combination, rats exhibited significantly greater responses to punishment, indicating synergistic interactions between deramciclane and memantine leading to a reduction in anxiety.

[00656] EXAMPLE 202 ANTI-AGGRESSIVE EFFECTS OF THE COMPOUND OF FORMULA I IN COMBINATION WITH A NMDA RECEPTOR CHANNEL BLOCKER. Male mice in isolation easily develop and show aggression towards individuals that invade their territory. Such paradigms were used to assess the anti-aggression of NMDA receptor channel blockers (Belozertseva IV, Bespalov AY, Effects of NMDA receptor channel blockade on aggression in isolated male mice, Aggressive Behavior (1999) 25: 381-396). In these experiments, mice were kept individually and, starting from the first two weeks of isolation, they were given the opportunity to attack a mouse that was kept in a group and invaded their territory several times (twice a week) for 4 minutes. Only resident mice that consistently exhibit aggressive behavior towards intruders were used for drug testing. The drug trials began when the resident mice showed attack by intruders in at least three consecutive tests and lived in isolation for at least 35 days. Mice that invaded the territory of other mice were previously kept in groups of five. Thirty minutes before the test, mice were treated with memantine (10 mg/kg) in combination with deramciclane (3 mg/kg) or ritanserin (1 mg/kg). When given alone, none of the compounds at the selected doses had a significant effect on agonistic behaviors (attacks, bites, threats, tail banging, standing up or sideways, pushing and retreating). However, when memantine was combined with deramciclane (but not ritanserin), mice were significantly less likely to attack in the absence of any visible ataxia (Figure 17). Thus, while deramciclane or NMDA receptor antagonists may not be effective when taken alone, they can exhibit potent anti-aggressive properties when used in combination.

[00657] EXAMPLE 203 O-demethylation activity of dextromethorphan was measured (Yu et al., Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A activities? Drug Metab Dispos, 29:1514 1520 (2001)) with minor modifications. Recombinant CYP2D6 (0.25 pmol) and HLM (12.5 µg protein) were used as enzyme sources. The incubation mixture consisted of an enzyme source, dextromethorphan, an NADPH generating system (500 μM NADP, 10 mM 6 glucose-6-phosphate, 10 mM magnesium chloride, and 1 U/ml glucose-6-phosphate dehydrogenase), and a buffer based on 100 mM potassium phosphate (pH 7.4) in a final volume of 200 µl. Incubation was carried out at 37°C for 10 min. and terminated by adding 10 μl of 70% (w/v) perchloric acid. After protein was removed by centrifugation, 50 µl of the supernatant was subjected to high performance liquid chromatography (D7500 integrator, L-7100 pump, L-7200 autosampler, L-7300 column oven, and L-7485 fluorescence detector) using a Mightysil RP-18 GP column (4.6 microns 250 mm, 5 microns). The mobile phase was an acetonitrile/methanol mixture: 10 mM potassium phosphate buffer was adjusted to pH 3.5 with phosphoric acid (200:160:630). Elution was carried out with a flow rate of 1.0 ml/min. Dextrorphan formation was monitored at 280 nm excitation and 310 nm emission.

[00658] The pre-incubation mixture consisted of recombinant CYP2D6 (2 pmol), each of the main cannabinoids (2.5-50 μM), NADPH generating system (8.2 μM NADP, 0.41 mM 6 glucose-6-phosphate, 0 41 mM magnesium chloride and 1 U/ml glucose-6-phosphate dehydrogenase) and 100 mM potassium phosphate buffer (pH 7.4) in a final volume of 180 µl. After preheating at 37° C. for 5 minutes, the reactions were initiated by adding the NADPH generating system. After a 20-minute pre-incubation, 20 µl of AMMS solution (final substrate concentration 0.6 µM) was added to the pre-incubation mixture. Incubation was carried out in the same manner as described in the section "Assay of enzymes for the manifestation of O-demethylase activity against AMMS". Prediction of drug interactions in vivo for CYP2D6. Evaluation of the effectiveness of inhibition in vivo was determined by the methods of Obach et al. (2006). The maximum concentration of unbound substance entering the liver, Cmax, u, was determined using the following equation:

C _{max., u, progress.} = f _u * (C _max. + D * F _a * k _a / Q _h )

Cmax is the maximum systemic concentration, fu is the fraction of unbound substance in the blood, D is the oral dose, Fa is the fraction of the absorbed oral dose, k a is the first order absorption rate constant, and Qh is the blood flow rate in the liver. In the case of smoking marijuana, absorption from the gastrointestinal tract is not taken into account. Thus, Cmax, and, for inhaled cannabinoids is equal to fu Cmax. The fu value for cannabinoids is no more than 0.05, since 95 to 99% of THC in blood plasma is bound to plasma proteins, mainly lipoproteins (Grotenhermen, 2003). The ratio of area under the curve (AUC) of inhibitor to control AUC can be estimated using the following equation:

_Inhibitor AUC /AUC _control =1/{[ f _m(CYP2D6) /(1+[I] _{in vivo} /K _i )]+(1- f _m(CYP2D6) )}

In the above equation, the AUC of an inhibitor is the area under the curve for a given substrate sample in the presence of the inhibitor, and _{the control} AUC is the area under the curve for the same substrate sample without the inhibitor. The fraction of the substrate sample metabolized by CYP2D6 and the magnitude of the inhibitor potential are presented as fm (CYP2D6) and Ki, respectively. The fm value (CYP2D6) for the urinary dextromethorphan/dextrorphan ratio was taken as one (Obach et al., 2006). Thus, the ratio _{of inhibitor} AUC to _control AUC of dextromethorphan is 1+[I] _{in vivo} /Ki.

[00659] EXAMPLE 204 The temporal distribution and pharmacokinetics of doubly labeled compound 829 (compound 829-phenyl-C-14 and -ethyl-H-3) were determined in plasma, pituitary and 14 brain regions, as well as in the spinal cord of rats after single oral treatment (acute trials) and after repeated administration of a single dose daily for six days (subacute trials). Compound 829 levels in tissues were calculated from simultaneously determined dpm values and the specific activity of the two radioisomers present in the administered dose. EGIS-38 85 was rapidly absorbed from the gastrointestinal tract (t(max)=1.0 h). Tissue concentration-time curves can be described using an open model with two compartments. H-3 activity could be measured during the entire period of the acute experiment (95 hours), while C-14 radioactivity fell below the detection limit within 24 hours. AUC values (0.96) for H-3 were 10-15 times higher than for C-14. I, for all studied samples in the concentration-time curves, the peak characteristic of the enterohepatic circulation can be seen after 12 hours. Studies have shown that intact molecules enter the brain tissue from the bloodstream. The results of subacute experiments show that compound 829, labeled with C-14, or its metabolites) carrying the label, reaches equilibrium already on the second or third day, while the level of H-3 radioactivity is constant increases within six days of repeated administration. In subacute experiments, peak concentrations were reached 0.5 hours after final treatment. However, their values for 3H were higher than in acute experiments. The latter trend was not observed in the case of the label C-14. AUC values for compound 829 labeled with H-3, determined in subacute experiments, prevailed over C-14; ratios ranged from 50 to 60 in all areas of the brain. The enterohepatic circulation observed after a single dose was also observed after a second dose. Time-related concentrations of compound 829 in the pituitary gland were at least twice as high as those in blood plasma and brain tissues. No significant difference was found in compound 829 concentrations in symmetrical (left and right) brain regions (Magyar et al., Distribution Of Deramciclane In Rat-Brain Regions, European journal of drug metabolism and pharmacokinetics, 23(2), p. 125 -131 (1998), included in its entirety).

[00660] EXAMPLE 205 5HT2a assay. The affinity of the compounds for the human 5-HT2A receptor in transfected HEK-293 cells was determined by radioligand binding assay. Cell membrane homogenates (30–50 μg of protein) were incubated for 15 min. at 37° C. with 0.5 nM [3H]ketanserin in the absence or presence of test compound in buffer containing 50 mM Tris-HCl (pH 7.4). Non-specific binding was determined in the presence of 1 μM ketanserin. After incubation, samples were quickly filtered under vacuum through glass fiber filters pre-soaked in 0.3% PEI and washed several times with ice-cold 50 mM Tris-HCl using a 96 sample cell collector. The filters were dried and then the radioactivity was determined in a scintillation detector using a scintillation mixture (patent applications WO 200501395 A1, EP 1500391 A1, incorporated by reference in their entirety).

[00661] EXAMPLE 206 Male NMRI mice (body weight 20-25 g) were placed on a heating plate (56±0.5°C) and the delay time elapsed before forepaw licking was measured. processing. Animals were not included in the experiment if the first basal retention time was >5 sec, or the difference between the two control measurements was greater than 3 sec. Mice were treated with either saline or 1 mg/kg morphine HCl s.c. and at the same time either vehicle or deramciclane or buspirone, 30 mg/kg HCl ip, respectively. After treatment (15, 30, 45 and 60 minutes) the reaction time was again measured. Animals were considered positive if they showed a 2.5-fold increase in reaction time and it was at least twice their first control values. Administration of a combination of morphine and compound 129 showed a statistically significant analgesic effect compared to administration of either of these compounds alone (patent application No. EP1734940 B1, incorporated by reference in its entirety).

[00662] EXAMPLE 207 EFFECTIVENESS OF FORMULA I COMPOUND IN CNS MAY BE MEDIATED BY A BIOLOGICALLY ACTIVE METABOLITE. Compound 50 is a peripherally acting 5-HT2A receptor antagonist (Obata H et al., Antinociception in rat by sarpogrelate, a selective 5-HT(2A) receptor antagonist, is peripheral. Eur J Pharmacol (2000) 404:95-102) and there is direct evidence using compound 50 labeled with [14C] so that sarpogrelat may be unable to cross the rat blood-brain barrier (Komatsu T et al., Studies on the Metabolic Fate of (+)-2(Dimethylamino)-1 -CCo(m-methoxyphenethyl) phenoxyDmethyl] ethyl hydrogen siccinate hydrochloride (MCI-9042) (II): Absorption, Distribution, Metabolism and Excretion after a Single Administration to Rats).

[00663] Adult male SD rats were pretreated with Compound 146 or M1 (10 mg/kg ip) and brain tissue and plasma were collected 30, 60, 120 and 240 minutes after M1 administration. The amount of the compound in the brain tissue extracts was measured using UPLC/MS analysis. As shown in figure XYZ, the total concentration of M1 in the brain significantly exceeded the concentration in the blood. Thus, unlike Compound 50, M1 readily enters the brain and may be responsible for the unexpected effects of Compound 50 on the CNS.

Claims (12)

1. A pharmaceutical composition for the treatment of a neuropsychiatric or neurodegenerative disease or disorder, comprising, in an effective amount, a dual activity agent exhibiting CYP2D6 inhibitor activity and 5-HT _2A /5-HT _2C receptor inverse agonist activity or 5-HT receptor antagonist/inverse agonist activity _2A wherein said dual activity agent is N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl] hydroxy]ethanamine; and an NMDA receptor antagonist selected from the group consisting of memantine and dextromethorphan (DEX), or their enantiomers, pharmaceutically acceptable salts, or combinations thereof. 2. The pharmaceutical composition according to claim 1, wherein the composition further comprises: a. polymer b. emulsifier, s. binder, d. a disintegrating agent; and/or e. a lubricant. 3. Pharmaceutical composition according to claim 1, where the composition is a combination of fumarate and/or hydrobromide salt of the following compounds:

4. The use of a pharmaceutical composition according to claim 1 in a method for increasing plasma levels of DEX in a subject in need thereof, the method comprising administering said composition. 5. Use according to claim 4, wherein the composition is administered once or twice a day, wherein the daily dose of DEX is from about 0.1 mg to about 1000 mg, providing an AUC value of _0-12 DEX that is higher than the value AUC _0-12 DEX that would be achieved by administering the same amount of DEX without N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo [2.2.1]heptanyl]oxy]ethanamine. 6. Use according to claim 4, where the AUC value is _0-12 N,N-dimethyl-2-[[(1R,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2. 1]heptanyl]oxy]ethanamine is at least about 10 ng/h/ml, about 100 ng/h/ml, 200 ng/h/ml, about 300 ng/h/ml, or about 400 ng /h/ml, or about 500 ng/h/ml, or about 600 ng/h/ml, or about 700 ng/h/ml, or about 800 ng/h/ml, or about 900 ng /hour/ml, or approximately 1000 ng/hour/ml. 7. Use according to claim 4, wherein the administration is dermal, oral, nasal, anal, rectal, vaginal, sublingual, buccal, sublabial, muscular, intramuscular, intravenous, peritoneal, epidural, intracerebral, intracerebroventricular, dermal or local, intraarticular, intracardiac , intracavernous, intradermal, intralesional, intramuscular, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal or transmucosal. 8. The use of a pharmaceutical composition according to any one of paragraphs. 1-3 in a method of treating a neuropsychiatric or neurodegenerative disease or disorder, including behavioral and psychological symptoms of dementia (BPSD), in a patient in need thereof, comprising a) administering a therapeutically effective amount of a composition according to any one of paragraphs. 1-3; b) targeting the CYP2D6 enzyme and NMDA, 5-HT _2A and 5HT _2c receptors; And c) achieving relief of symptoms and/or change in the course of the disease.

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