RU2760558C2 - 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-HT2A/5-HT2C receptor or antagonist/reverse agonist activity of 5-HT2A 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 new compositions, combinations, therapeutic formulations, agents for symptomatic treatment and agents for altering the course of the disease, therapies, kits based on them, and methods of using them.

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, and are causing rapid increases in health care costs. Diseases affecting the brain and central nervous system are one of the most significant public health problems and require the maximum amount of care due to the devastating personal and economic consequences for patients, carers and society. An estimated 55 million people worldwide suffer from neurodegenerative diseases, and there are currently no approved disease-modifying therapies. As current therapeutic interventions lengthen 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 and other forms of dementia, low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury, and Parkinson's, have resulted in a total cost of $ 789 billion. dollars in 2014 is currently valued at $ 818 billion and is estimated to be 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%, non-medical direct costs 23%, and indirect 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 specific needs in 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). Rather than pushing for a "cure" indication, regulators have addressed the continuing high demand for drugs by opening up a range of approved drugs for syndromic-labeling therapies. Such syndromic indications may include, for example, behavioral and mental symptoms in dementia (BPSD), subsyndromal signs such as aggression or apathy in Alzheimer's disease, hallucinations and delusions in Parkinson's disease dementia (PDD). Accordingly, there is a need to develop such novel syndromic labeling therapies for new compositions, combinations, therapeutic formulations, symptomatic and disease modifying therapies, and therapies that utilize 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 formulations, symptomatic treatment and disease modifying therapies, therapies, kits based on it, and methods for preparing such compositions, combinations , therapeutic compositions, treatment agents, therapy agents and kits containing biological agents, chemical agents, food additives, pharmaceutical agents, compositions, treatment agents, therapy agents, medications, prophylactic agents, additives and formulations; including allopathic, alternative, Ayurvedic remedies, herbal remedies, complex, homeopathic, natural, medicinal, pharmaceutical, unnatural remedies, adjuvants, adjuvants, decoctions, chemicals, compositions, combinations, mixtures, medicines, elements, extracts, extractions , compositions, kits, mechanisms, drugs, medicines, potions, tinctures, preparations, prophylactic agents, recipes, soluble substances, solutions, solvents, substances, systems, teas, therapy agents, extracts and treatment agents; biological agents and vaccines; medicines; diagnostic kits, reagents and analyzes; 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 introduction, cleaning, treatment, diagnosis, healing, disinfection, drug impregnation, prevention and treatment of acute or chronic situations, namely: drug addiction, pathological conditions, developmental defects, types of disabilities, diseases, disorders, dysfunctions, infections, problems, poisoning , pollution and ailments; arising from or associated with the corresponding accidental, allergic, auditory, anti-cancer, cardiovascular, cardiopulmonary, chemotherapy, cognitive, congenital, dermatological, endocrine, gastrointestinal, genetic, genital, genitourinary, hereditary, hormonal, hepatological, immunological, side, intellectual, karmic, lymphatic, metabolic, mental, muscular, musculoskeletal, neurological, oncological, visual, ophthalmological, osteological, osteopathic, mental, psychological, psychopathic, psychosomatic, physical, physiological, respiratory, reproductive, sexual urological, virtual and visual functions, systems and processes.

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

[006] One embodiment of the present invention is a composition comprising 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 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, 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 yuheteroaryl, 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 prodrugs based on it, 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 thereof; or 2) compounds of formula II

, где, R₆, R₇, и R₈ представляют собой независимо Н, D, С_1-10алкил, галоген-С_1-10алкил, где галоген представляет собой F, Cl или Br, R₉ и R₁₀ представляют собой независимо Н; С_1-10алкил; галоген-С_1-10алкил, где галоген представляет собой F, Cl или Br; ОН; или R₉ и R₁₀ вместе образуют пятичленный гетероцикл, где гетероатом представляет собой О, S или N; его энантиомеров, метаболитов, производных, пролекарств на его основе, его солей, диастереомеров, фармацевтически приемлемых солей или N-оксидов, или их комбинации; или 3) комбинации 1 и 2; или их комбинаций.

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; _C1-10 alkyl; halogen-C _1-10 alkyl, where halogen is F, Cl or Br; 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 combinations thereof.

[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, 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, salts, diastereomers, pharmaceutically acceptable salts or N-oxides thereof, 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 options for their use.

[0010] In one embodiment, the method is a method of decreasing the number of doses and / or the total daily dose of a compound of Formula II that can be administered while increasing efficacy and maintaining tolerance and safety; a method of alleviating an adverse event associated with treatment with a compound of formula II, wherein the subject is at risk of developing an adverse event as a result of treatment with a compound of formula II; a method of decreasing plasma levels of metabolites of a compound of formula II, a method of treating a neurological disorder, a method of increasing plasma levels of a compound of formula II in a subject in need of treatment with a compound of formula II, wherein the subject is a rapid metabolizer of a compound of formula II; a method for inhibiting the metabolism of a compound of formula II; a method for increasing the metabolic life 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; a cough treatment method. Another embodiment is a method wherein the disease or disorder is a neurological disorder, wherein the composition is administered at least once a day 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, 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, 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 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, from about 15 mg / day to about 60 mg / day, from about 15 mg / day to about 120 mg / day, from about 0.1 mg / day to about 200 mg / day or the required amount of a compound of formula II to a subject in need thereof.

[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 activity (DA) agent having both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor properties. In another embodiment, DA is a compound of Formula I.

BRIEF DESCRIPTION OF THE GRAPHIC MATERIALS

[0013] Figures 1A, 1B and 1C show Dixon plots for determining Ki values for CYP2D6 compounds of formula I, examples of which are sarpogrelate and M-1, as well as quinidine. Dextromethorphan concentrations were determined as 2.5 (filled circles), 5 (open circles) and 10 (triangles) mM, respectively. V represents the rate of dextrorphan formation (pmol / minute / mg protein). Data represent the average of the determinations in triplicate. Solid lines of the compound of formula I, examples of which are sarpogrelate and M-1, as well as quinidine, correspond well to all competitive types of inhibition (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 neuropsychiatric questionnaire arousal / aggression domain scores as stage and visit averages for patients enrolled in serial side-by-side comparison and 10-week analyzes. A, stage 1 (weeks 1-5); B, stage 2 (weeks 6-10) for placebo nonresponders re-randomized after stage 1; C, 10 weeks results (10-week secondary analysis includes only those patients who continued to receive the same 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 stage 2], thus mimicking a parallel group design). Covariance analysis models with treatment as the fixed effect and baseline as the covariate were used to compare the mean change from baseline between groups at each time point. The baseline for stage 2 is the patient scores at the beginning of stage 2. The mean least squares 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 - 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, from -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. A full sample analysis includes all patients who received ≥1 doses and had SAPS at baseline and at least one thereafter. Least squares means (standard error) are shown for data points. (A) Improvement in SAPS-PD. (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 (Feb 8, 2014), fully incorporated via link).

[0016] Figures 4A, 4B and 4C are Lineweaver-Burk plots depicting 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 binaries.

[0017] Figures 4D, 4E and 4F show the effects of major phytocannabinoids, Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC), CBD and cannabinol (CBN), on AMMC 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 varying amounts of Δ ⁹ -THC, CBD and CBN; and (F) HLM was incubated with 4 μM dextromethorphan in the presence of varying 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 the mean (± SEM) of the 60-min averaged activity. testing session. N = 5-9 per group.

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

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

[0021] Figure 8 shows blood plasma dextromethorphan curves of male Wistar rats that received dextromethorphan (50 mg / kg, orally) immediately after an intravenous bolus injection of sarpogrelate (1, 3, or 10 mg / kg; racemate or one of enantiomers) or carrier medium through the port system for vascular access 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 combination of dextromethorphan with racemate of 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 sarpogrelate on blood glucose levels. Data are presented as area under the curve (mean ± SEM) blood glucose levels over a time period of 30-180 minutes. after oral glucose load (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 buspirone after 8 days of pretreatment with 60 mg of compound 829 (filled square; n = 16) or placebo (filled circle; n = 16) once daily.

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

[0026] Figure 13 shows the principles of prodrug formation for the most common functional groups of the parent drug compounds of formulas I and II, represented by R, while the general schemes 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 discriminatory stimulus. Data are presented as mean (± S.E.M.) percent drug response rate as lever pressed (top panel) and response rate (responses per second; bottom 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 Geller-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 unpunished response in the Geller-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 blood plasma and brain tissue. Total brain and plasma concentration following intraperitoneal administration of a composition of the present invention containing a compound of formula I, exemplified by compound 146. Data are presented as mean (± SEM) amount of compound in brain tissue extracts measured using UPLC assay / MS. N = 4.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0034] Various embodiments of Targeted Drug Rescue (TDR) ™, provide suitable new compositions and combinations, therapeutic formulations, symptomatic and disease modifying agents, therapies, kits, and methods for preparing such compositions, combinations, therapeutic compositions, therapies, therapies, and kits containing biologics, chemicals, nutritional supplements, pharmaceuticals, compositions, treatments, therapies, drugs, prophylactic agents, additives and formulations, including the disclosures of US patent applications 62/501693 filed 05/04/2017, PCT / US2017 / 048748, filed 08/25/2017, WO 2018/039642 A1, published 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 comprising 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 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-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, 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 wherein R ₅ is 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-acyl aspartate, aspartate. butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, N-acylglutarate, glutarate, isophthalate, maleate, malonate, methionate, N-acylmethionate oxalate, pelargonate, pimelate, propionate, phthalate, salicinate, sebacetic acid. 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, halogen-C _1-10 alkyl, where halogen represents F, C1 or Br; R ₉ and R ₁₀ independently represent H; _C1-10 alkyl; halogen-C _1-10 alkyl, where halogen is F, O or Br; 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 a pure enantiomer of Formula I selected from a compound of Formula Ia or Ib.

[0044] Another embodiment is a compound of Formula I wherein R ₁ , R ₂ and R ₃ are methyl, with the proviso that X is not ethyl.

[0045] In another embodiment, a composition comprising a compound of Formula I is a sarpogrelate (SARPO), wherein R ₁ , R _2, and R ₃ are methyl, X is ethyl, and R ₄ is a succinyl radical comprising the following compounds : SGL, SGL-E1 and SGL-E2.

[0046] In another embodiment, a composition comprising a compound of Formula I is a metabolite of sarpogrelate M1, wherein R ₁ , R _2, and R ₃ are methyl, X is ethyl, and R ₄ is OH, comprising the following compounds: M1 , M1-E1 and M1-E2.

[0047] In another embodiment, a composition comprising a compound of Formula I is a metabolite of sarpogrelate M1, wherein 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 based on it, or a combination thereof. Derivatives include, but are not limited to, deuterated derivatives such as DEX-H3, DEX-D3, DO, and DO-D3.

[0050] The term "SARPO" means one or more compounds selected from the group consisting of sarpogrelate (SGL), its enantiomers, its metabolite M1, SG1, SG2, SMG1, SMG2, SMG3, its derivative, prodrugs based on it, and combinations.

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

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

where R ₃ is a bicyclic system and the remainder of formula I is represented by R ₇ shown in 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 represents

-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 , _{-CO-C 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, —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; 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 ™ means a 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 comprising a compound of Formula I and DEX-H3, DEX-D3, DO, or DO-D3.

[0056] In another embodiment, a compound of Formula I or analogs may be prepared 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 acid 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, wherein the compound is sarpomalate, wherein R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is malate; connections 25-29. One embodiment of the present invention is a compound of Formula I wherein the compound is a sarpomethionate wherein R ₁ , R ₂ and R ₃ are methyl, X is ethyl and R ₄ is methionate; connections 30-34. One embodiment of the present invention is a compound of Formula I wherein the compound is a sarpophthalate wherein R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is phthalate; connections 35-37. One embodiment of the present invention is a compound of Formula I wherein the compound is a sarpomalonate wherein R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is malonate; connections 38-40. One embodiment of the present invention is a compound of Formula I wherein the compound is a sarpotirosinate wherein R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is tyrosinate; connections 41-43. One embodiment of the present invention is a compound of Formula I, wherein the compound is sarpotryptophanate, wherein R ₁ , R ₂ and R ₃ are methyl, X is ethyl, and R ₄ is tryptophanate; connections 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 a sarpogrelate, and dextromethorphan.

[0058] One embodiment of the present invention is a composition comprising a compound of Formula I, wherein the compound is a sarpogrelate, and dextromethorphan, wherein the sarpogrelate and dextromethorphan form a diastereomeric mixture.

[0059] One embodiment of the present invention is a composition comprising a compound of Formula I, wherein the compound is a sarpogrelate, and dextromethorphan, wherein the sarpogrelate and dextromethorphan form a salt, wherein the salt is a diastereomeric mixture. One embodiment of the present invention is a composition comprising a compound of Formula I, wherein the compound is a sarpogrelate, and dextromethorphan, wherein the sarpogrelate and dextromethorphan form a salt, wherein 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 metabolite of sarpogrelate M1, 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 a 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 comprising a compound of Formula I, wherein the compound is a 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 a sarpotirosinate, 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 comprising a compound of Formula I, wherein the compound is SGL, and dextromethorphan-HCl, 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 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 comprising a compound selected from the group consisting of SGL, its enantiomers, its metabolite M1, SG1, SG2, SMG1, SMG2, SMG3, a derivative thereof, a prodrug thereof, and a combination 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, prodrugs based on it, 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, wherein compounds 110-145 are exemplary. 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, prodrugs based on it, 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 represented by 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, wherein the 5-membered heterocycle is unsaturated.

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

[0065] In another embodiment, the composition comprises a compound of Formula I. wherein 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 comprises a compound of Formula I wherein R ₁ , R _2, and R ₃ are methyl, X is ethyl, and R ₄ is a succinyl radical represented by the following compounds: SGL, SGL-E1, and SGL -E2.

[0067] In one embodiment, the composition comprises a compound of Formula I wherein R ₅ is —O (CO) —CH ₂ —CH ₂ - (CO) OY, where alkyl, cycloalkyl, aryl, heteroaryl, α-alkenylaryl, α-aralkyl, alkyl-ONO ₂ , cycloalkyl-ONO ₂ , aryl-ONO ₂ , heteroaryl-ONO ₂ , -alkenylaryl-ONO ₂ and -aralkyl-ONO ₂ , by way of example and without limitation, are selected from the following compounds: 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-ylmethyl succinate, 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) propane- 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 comprises 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 comprises a combination of a compound of Formula I and a compound of Formula II comprising DEX-H ₃ , DEX-D ₃ , DO, DO-D ₃ , levometorphan, 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, wherein the compound of formula I is racemic compound 50 (sarpogrelate), racemic compound 146 (M1 ) or compound 829 (deramciclane). In another embodiment, the composition comprises memantine. In another embodiment, the composition comprises sarpogrelate and memantine. In another embodiment, the composition comprises enantiomerically pure S-compound 51 (S-sarpogrelate) and R-compound 52 (R-sarpogrelate) and memantine. In another embodiment, the composition comprises enantiomerically pure S-compound 147 (S-M1), R-compound 148 (R-M1), and memantine. In another embodiment, the composition comprises enantiomerically pure deramciclane and memantine.

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

[0072] In another embodiment, a compound of formula I or analogs may be prepared using the following carboxylic acids: difluorosuccinic acid HO ₂ C-CF ₂ -CH ₂ -CO ₂ H (201-206), trifluoro-succinic acid HO ₂ C-CF ₂ -CHF-CO ₂ H (207-212), tetrafluoro-succinic acid HO ₂ C- (CF ₂ ) ₂ -CO ₂ H, difluoro-succinic acid (213-215), HO ₂ C-CHF-CHF-CO ₂ H (216- 219), difluoro glutaric acid HO ₂ C- (CH ₂ ) ₂ -CF ₂ -CO ₂ H (219-221), difluoro glutaric 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, the compound of Formula I is a compound of Formula Ic or Formula Id as defined above, and derivatives thereof, including 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-acyltyrosinate, N-acyltrypto fanate, N-acylmethionate, citrate, galactonate, glucaric acid (sugar acid), mannonate, munate.

[0074] In another embodiment, the compound of formula I is a compound of formula Ic or formula Id as defined above, and derivatives thereof, including acid addition salts formed from di- and tricarboxylic acids selected from: adipic acid, aspartic acid, N -acyl aspartic acid, citric acid, fumaric acid, galactonic acid, glutaric acid, glutamic acid, N-acylglutamic acid, glucaric acid (sugar acid), malic acid, maleic acid, mannonic acid, mucinic acid, oxalic acid, pimelic acid 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: 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-acyl-aspartate, hydrogen-N-acylglutamate, hydrogen-N-acyltyrosinate, hydrogen-N-acyltryptophanate, hydrogen-N-acylmethionate, hydrogen citrate, hydrogen galactonate, hydrochloric acid oty (sugar acid), hydrogenmannonate, hydrogenmucat, hydrogenramnonate and hydrogenartrate.

[0076] Another embodiment is a composition comprising an acid addition salt of dextromethorphan and M1 selected from: dextromethorphan dihydrogenadipate and M1, dextromethorphan dihydrogenaspartate and M1, dextromethorphan dihydrogen fumarate and M1, dextromethorphan dihydrogen fumarate and M1, dextromethorphan dihydrogen fumarate and M1, dextromethorphan dihydrogenglutamate and M1 dyhydrogenglutamate, dextromethorphan and M1 , 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 dihydrogen citrate and M1, dextromethorphan dihydrogen galactonate and M1, dextromethorphan dihydrogen glucarate and M1, dextromethorphan dihydrogenacarate on and M1, dextromethorphan dihydrogenmannonate and M1, dextromethorphan dihydrogen mucate and M1, dextromethorphan dihydrogen mannonate 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 fluoro derivatives thereof. In another embodiment, the compound of formula I is a compound of formula Ic or formula Id, wherein the compound is a fluorine 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 provides a composition comprising an acid addition salt of dextromethorphan and FDIc, selected from: digidrogenadipata dextromethorphan FDIc, digidrogenaspartata dextromethorphan FDIc, digidrogenfumarata dextromethorphan FDIc, digidrogenglutamata dextromethorphan FDIc, digidrogenglutarata dextromethorphan FDIc, digidrogenizoftalata dextromethorphan 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 dihydrogen citrate and FDIc, dextromethorphan dihydrogen galactonate and FDIc, dextromethorphan dihydrogen glucarate and FDIc, dextromethorphan dihydrogenacarate and FDIc, dextromethorphan dihydrogen mannonate and FDIc, dextromethorphan dihydrogen mucate and FDIc, dextromethorphan dihydrogen ramnonate and FDIc, and dextromethorphan dihydrogen mannonate 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 dihydrogen aspartate, dextromethorphan dydrogenfu, dextromethorphan dydrogenfu, and FDId, FDIdorhydromethomethazide dihydrogenate and FDId, FDIdhydromethomethomethazyl dihydrogenate 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 dihydrogen citrate and FDId, dextromethorphan dihydrogen galactonate and FDId, dextromethorphan dihydrogen glucarate and FDId, dextromethorphan dihydrogenacarate and FDId, dextromethorphan dihydrogen mannonate and FDId, dextromethorphan dihydrogen mucate and FDId, dextromethorphan dihydrogen mannonate and FDId and dextromethorphan dihydrogen mannonate and FDId.

[0080] In another aspect of the present invention, the compound is a derivative of a compound of Formula I comprising 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, the compound of Formula Ic or Formula Id is M1, wherein Y is CH ₃ ; R4 is OH. In some embodiments, the 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 comprising a compound of formula I.

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

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

-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 , _{-CO-C 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, —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; 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 wherein 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, a compound of Formula I includes, without limitation, the following examples: RS4 - ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3.3 β-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- (trifluoromethyl) 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- (trifluoromethoxy) 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- (tert-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- (naphthalen-1-ylmethoxy) propan-2-ol; S1- (isopropyl amino) -3- (naphthalen-1-ylmethoxy) propan-2-ol; R1- (isopropylamino) -3- (naphthalen-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-l, 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- (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-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-methylnaphthalen-1-yl) oxy) propan-2-ol; S1- (isopropylamino) -3 - ((4-methylnaphthalen-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- (naphthalen-2-yloxy) propan-2-ol; S1- (isopropylamino) -3- (naphthalen-2-yloxy) propan-2-ol; R1- (isopropylamino) -3- (naphthalen-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- (isopropylamino) -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- (tert-butylamino) -3- (3-methyl-2-nitrophenoxy) propan-2-ol; R1- (tert-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- (cyutobutylmethoxy) 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 '- (butylazanediyl) bis (l-phenoxypropan-2-ol); S3,3 '- (butylazanediyl) bis (1-phenoxypropan-2-ol); R3,3 '- (butylazanediyl) 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) -1,2,3,4,4а, 7,8,8а-octahydro-1,4-ethanonaphthalen-5-yl) methanesulfonamide; SN- (8- (2-hydroxy-3- (isopropylamino) propoxy) -1,2,3,4,4а, 7,8,8а-octahydro-1,4-ethanonaphthalen-5-yl) methanesulfonamide; RN- (8- (2-hydroxy-3- (isopropylamino) propoxy) -1,2,3,4,4а, 7,8,8а-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- (tert-butylamino) -3 - ((3-methyl-1H-indol-4-yl) oxy) propan-2-ol; R1- (tert-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 wherein R ₆ and R _{7 are} independently substituted with one, two or three halogens, wherein halogen is F, Cl, or Br. Examples of halogenated compounds of Formula I include, but are not limited to:

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- (trifluoro methyl) 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 comprising 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'-dim-methylaminopropoxy) -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) ethane-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- (trifluoro methyl) 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-dimethylethan-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 comprising an acid addition salt of a compound of Formula If comprising hydrogen acetate, hydrogen acetylsalicylate, hydrogen adipate, hydrogen aspartate, hydrogen butyrate, hydrogen aprate, hydrogen proate, hydrogen prilat, hydrogen enanthate, hydrogen formate hydrogenate, hydrogen hydrogen phenate , hydrogen pelargonate, hydrogen pimelate, hydrogen propionate, hydrogen phthalate, hydrogen salicylate, hydrogen sebacate, hydrogen succinate, hydrogen terephthalate, hydrogen pentosinate, hydrogen propionate, hydrogen methionate; hydrogen-N-acyl methionate and hydrogen valerate.

[0089] Another embodiment is a composition comprising 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 , deramcyclane hydrogen maleate, deramcyclane hydrogenmalonate, deramcyclane hydrogenoxalate, deramcyclane hydrogen pelargonate, deramcyclane hydrogen pimelate, deramcyclane hydrogen propionate, deramcyclane hydrogen phthalate, deramycyclane hydrogen phthalate, deramycyclane hydrogen phthalate, deramycyclane hydrogen peroxide, deramycyclane hydrogen peroxide , deramcyclane hydrogenmethionate, deramcyclane hydrogenmethionate; deramcyclane hydrogen-N-acyl methionate; or deramcyclane hydrogenvalerate.

[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-methoxy-phenyl) -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 (deramcyclane); or their acid addition salts.

[0091] One embodiment of the present invention is a composition comprising dextromethorphan or an acid addition salt thereof and deramciclane, deramciclane acetate, deramciclane acetyl salicylate, deramciclane adipate, deramciclane butyrate, deramciclane caprate, deramciclane caproate, deramciclane caprylate, deramcyclane formate, deramciclane enanthate 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 both.

[0092] In some embodiments, the compound of formula II is a fluoro derivative such as, without limitation: (4bS, 8aS, 9S) -11-methyl-3- (trifluoromethoxy) -6,7,8,8a, 9,10-hexahydro -5H-9.4b- (epiminoetano) phenanthrene; (4bS, 8aS, 9S) -3- (trifluoromethoxy) -11- (trifluoromethyl) -6,7,8,8a, 9,10-hexahydro-5H-9,4b- (epiminoetano) phenanthrene; (4bS, 8aS, 9S) -3-methoxy-11- (trifluoromethyl) -6,7,8,8а, 9,10-hexahydro-5H-9,4b- (epiminoetano) 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-acyl tyrosinate, N-acyl tyrosinate 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, tryptophacylate-ateraphanate, N-asp , N-acyl tyrosinate, N-acyl tryptophanate, N-acyl methionate, citrate, galactonate, glucaric acid (sugar acid), mannonate, mucate, rhamnonate and tartrate.

[0095] In some embodiments, the compound of Formula II is an acid addition salt selected from N-acyl aspartate, N-acyl glutarate, 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 entryptophanate 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 comprising an acid addition salt of deramcyclane and an acid addition salt of dextromethorphan.

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

[0099] aspartate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, camphorsulfonate, camsylate, chloride, citrate, decanoate, edetate, lauryl sulfate, estolate, ethanesulfonate, esylate, fumarate, gluexcollate, gluconatelate, gluconate , hexylresorcinol, hydroxynaphthoate, isethionate, iodide, lactate, galactopyranosyl-d-gluconate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, octanoate 4, oleate 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, camsylic acid, chloride, citric acid, decanoic acid, edetate, laurylsulfonic acid, estolic acid, ethanesulfonic acid, esilic acid, fumaric acid, gluceptic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexanoic acid, hydroxylresorcinol acid 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, mucinic acid, napsylic acid, nitric acid , octanoic acid, oleic acid, pamic 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 acid, terephthalic acid, salicylic acid, difluoro-succinic acid, trifluoro-succinic acid, tetrafluoro-succinic acid, difluoro-glutaric acid, difluoroacetic acid acid, trifluoroacetic acid and dextromethorphan; or a combination of both.

[00101] In some aspects of the present invention, the compound of formula I is a prodrug according to, wherein the compound is an ester or an addition formed with the following acids: 3- (nitrooxy) propanoic acid (suppliers: AKos (AKOS006377427) and 1717 CheMall (OR235109)), 4-nitrooxybutanoic acid (suppliers: AKos (AKOS006378268) and iChemical (EBD3415162)), 3- (nitroxy) butanoic acid (AKos (AKOS006376331, AKOS016035558), MolMall (21929)). Examples include, but are not limited to, 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, 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 the 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 compounds of formulas I and II include salts formed with the following acid groups:

[00104] The 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, celecoxiba, chlorofenyvazine lasoprazole, levomepromazine, lopinavir, loratadine, mechitazine, methadone, metoclopramide, mibefradil, moclobemide, nelfinavir, nevirapine, nicardipine, norfluoxetine, perphenazine, pimozide, terfenadine, cytoridine, cytazapine, deszapine, terfinitocaride, cytoridinazine, cytoridine risperidone, ritonavir, saquinavir, sertraline, terbinafine, ticlopidine, trifluperidol, yohimbine, clomipramine, doxepin, mianserin, imipramine, 2-chlorimipramine, amitriptyline, amoxapine, protriptyline, tramilipramidine, isoxapine, protriptyline, tramilipramine sertraline, aryloxyindanamine a, benactisin, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tezofensin, brazofenzine, moclobemide, rasagiline, nialamide, butypronzepone, lpronpolapin, 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, aymaline, amiodarone, amitriptyline, aprindine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, doxorubicin, fluphenazine, fluvastatin, haloperidol, imipramine, indinavir, loporadiramine, lasopromadine Nelfinavir, Nevirapine, Nicardipine, Norfluoxetine, Perphenazine, Pimozide, Terfenadine, Thioridazine, Cimetidine, Quinidine, Cisapride, Citalopram, Clomipramine, Clozapine, Cocaine, Ranitidine, Risperidone, Serfacvinevirin, Terfenavir, mianserin, imipramine, 2 lorimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, trazodone, citalopram, sertraline, aryloxyindanamine, benactalaxine nefaxylamoxine, desyloxyindanamine, flactizuvilaxine, escytamoxine milnacipran, tesofensine, brazofensin, moclobemide, rasagiline, nialamide, iproniazide, iprocloside, toloxatone, butriptyline, dosulepine, dibenzepine, iprindol, lofepramine, opipramol and dapoxetine.

[00107] In one embodiment, the composition comprises a compound of Formula I, wherein the compound wherein R ³ is a conjugate or covalent compound formed either by esterification or esterification with derivatives of one or more AChIs 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 (metriphonate), (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 (galantamine) and 1,2,3,4-tetrahydroacridin-9-amine (tacrine), O, S-dimethylacetylamidothiophosphate , O, O-dimethyl-S - ((4-oxobenzo [d] [1,2,3] triazin-3 (4Н) -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 diethylphosphate, 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 - ((dimethoxypho sforothioyl) 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-dichloroethyl dimethylphosphate, 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-dimethyl phosphate, O, O, O ', O'-tetramethyl-O, O' - (thiobis (4,1-phenylene)) bis (thiophosphate), tetraethyl diphosphate, S- ((tert-butylthio) methyl) -O, O-diethyl phosphorodithioate, 2-chloro-1- (2,4,5-trichlorophenyl) vinyl dimethyl phosphate and dimethyl (2,2,2-trichloro-1-hydroxyethyl) phosphonate or pharmaceutically acceptable derivatives, metabolites, and taxes or salts obtained using the principles of prodrug formation described in Figure 13, where the starting compounds of the drugs of formulas I and II are represented by R, while the general schemes represent various embodiments of prodrugs based on compounds of formulas I and II (see. e.g. Rautio et al., The expanding role of prodrugs in contemporary drug design and development, Nature Reviews Drug Discovery, published 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). Antivir. 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. Antivir. 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, but are not limited to:

[00109] In another embodiment, prodrugs based on a compound of Formula I, exemplified by, but not limited to, compounds 901-978 represented by formulas P1-P11, PA-1 and PA-2, PF1-PF9, PT1-PT34, wherein P = phosphate , PA = phosphoramidate, PF = fluorophosphonate and PT = thiophosphate, are also acetylcholinesterase inhibitors due to the presence of phosphate, phosphoramidate, fluorophosphonate and phosphothioate moieties that confer this activity (McGleenon et al., Acetylcholines Jimer. , 471-480 (1999); Acetylcholinesterase Inhibitors and Memantme. Acetylcholinesterase Inhibitors for the Treatment of Mild to Moderate Dementia, and Memantine for the Treatment of Moderate to Severe Dementia in Alzheimer's disease (AD) (June 2013), available at http://www.fifeadtc.scot.nhs.uk/media/8535/cholinesterase-inhibitors-and-memantine-scp.pdf; incorporated by reference).

METHODS OF APPLICATION

) 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: 22164 euros; psychotic disorders: 16,717 euros; mood disorders: € 19,238; dependency: € 11,719; anxiety disorders: € 11,687 In addition to psychosis, these five disorders are among the disorders that have 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 (Jan 19, 2011), incorporated by reference in its entirety). More than a decade ago, it was estimated that the total cost of bipolar disorder (BP), also known as manic-depressive illness, reached $ 45 billion a year. Most of these costs are indirect costs associated with reduced functionality and loss of work. Patients with BP have higher rates of health care resource utilization compared to the general population and compared to patients with other types of psychiatric conditions. Comorbidities add to the heavy burden that BP places on society. Brain diseases represent a significant social and economic burden in Europe. At an annual cost of 800 billion euros and an estimated 179 million people suffering from these diseases in 2010, brain diseases are 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 it is projected to 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 growth will be 66%. In the United States of America, depression is the second most common cause of disability among women, and those who do not respond to antidepressant treatment are among the largest consumers of health care resources. Despite the apparent declines in quality of life and productivity associated with depression, depression is often rarely diagnosed and inadequately treated.

[00111] Drug and alcohol dependence is a serious public health problem. An estimated 26.4 to 36 million people worldwide abuse opioids (UNODC, World Drug Report 2012), with an estimated 2.1 million people in the United States of America suffering from substance use disorders associated with prescription opioid analgesics in 2012, and an estimated 467,000 people are addicted to heroin (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 pain relievers has skyrocketed in the United States of America, more than fourfold since 1999. There is growing evidence that in the United States of America there is a growing body of evidence of an association between the increase in the abuse of opioid analgesics for non-medical purposes and the abuse of heroin (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] The link between metabolic disturbances in chronic diabetes and the risk and pathophysiology characteristic of AD has long been suggested and confirmed in recent years (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 postmortem studies, more than a third of all subjects clinically diagnosed with typical AD had signs of cerebrovascular disease and should be classified 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, it is clinically desirable to extend the therapy of AD beyond the currently approved drugs and mechanisms, and also to combat cognitive impairment by optimizing for metabolic impairment in latent diabetes or the fairly common type 2 diabetes in the elderly. Indeed, exercise of 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). Due to the specific antidiabetic action of a compound of formula I described above, in one embodiment, the present invention provides advantages in both symptoms and disease progression in AD and in cognitive impairment mainly of vascular origin (multi-infarction dementia, vascular dementia, vascular cognitive violations, etc.).

[00113] In Parkinson's disease, the anticholinergic effects of antipsychotics are highly undesirable since they inevitably lead to a deterioration in addition to the level of motor activity and symptoms of the autonomic nervous system. In all forms of dementia, lowering the seizure threshold is another infrequent but highly undesirable possible undesirable effect of antipsychotics. Approximately 10 million people worldwide have Parkinson's disease. Parkinson's disease is a synucleopathy resulting in 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 manifests itself primarily in the form of hallucinations and delusions, which can cause severe distress in patients and their caregivers. These episodes pose a significant challenge to treatment and care, increase the likelihood of being placed in a disabled home, and are associated with increased mortality. Best treatment guidelines provide early consideration of comorbidities and the 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 growing. Depression is currently 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; Even worse, people who already have either acute or chronic illness are even more likely to develop depression, with the incidence of depression 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 several decades. According to this hypothesis, depression is associated with decreased monoamine function. Consequently, efforts to enhance the transfer of monoamines by inhibiting the transporters of serotonin (5-HT) and norepinephrine (NE) 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 of the latest trends in antidepressant research has been to clarify monoaminergic mechanisms by targeting monoaminergic receptors and accessory transporters (for example, with combination drugs and triple reuptake inhibitors) or by adding atypical antipsychotics when treated with SSRIs or SNRIs. In addition, in the course of preclinical and clinical studies, several other hypotheses for the occurrence of depression have been put forward, based on the biological characteristics of the disease and the effectiveness of pharmacological interventions. The main strategy has been to target glutamate receptors (eg, by intravenous infusion of ketamine, which is an N-methyl-D-aspartate (NMDA) receptor antagonist). Other strategies have been based on modulation of cholinergic transmission and transmission by gamma-aminobutyric acid (GABA), neuronal plasticity, stress / hypothalamic-pituitary-adrenal (HPA) axis, reinforcing system, and neuroinflammation. Thus, there is a need for the development of new drugs with complex pharmacological profiles obtained by simultaneously targeting multiple neurotransmitter and neuromodulatory systems.

[00116] BP often occurs in conjunction with other mental disorders, especially anxiety disorders and substance abuse. In addition, BP is associated with various medical conditions that further complicate the treatment of mental health problems (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 the ability to perform daily tasks. BP is characterized by mood disturbances, impulsivity, aggressive behavior, and interpersonal problems. BP is a recurrent and often chronic psychiatric disorder associated with functional impairment, increased suicide rates, and the use of mental health systems. BP is commonly underestimated, and up to 40% of BP patients are initially misdiagnosed, leading to an increased risk of suicide, mania, and chronic psychosocial distress. With correct diagnosis, successful treatment is possible in <50% of diagnosed patients, and 10-15% of patients eventually die by suicide (NIMH 2002).

[00118] Although pharmacological treatment guidelines are well known, BP treatment remains far from ideal. Most people, even with medication, still experience episodes of illness or significant residual symptoms (NIMH 2002). In addition, functional deficits often persist even during remission (NIMH 2002). Because many BP patients remain symptomatic even though they adhere to their drug regimens fully, the need for a deeper understanding of the pathogenesis of this disease from studies of the pharmacological mechanisms of drug action in bipolar disorder is becoming increasingly urgent. The main drug 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 evaluating the potential involvement of various brain structures in regulating mood, can be used to test neuroanatomical models of mood disorders. Imaging studies have shown that BP is associated with persistent neuronal atrophy. For example, PET images of cerebral blood flow and glucose metabolic rates related to brain activity revealed decreased activity in the subgenual prefrontal cortex during bipolar depression. This decrease in activity was, at least in part, attributed to a corresponding decrease in cortical volume, in the same way as magnetic resonance imaging, which shows the average volume of gray matter. 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 a part 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 syndrome, and nevoid basal cell carcinoma syndrome. Neuroblastoma is a cancer found in developing nerve cells, usually in children under the age of 10. Almost 90% of cases are diagnosed before the age of 5 years. Various factors can influence the type of neuroblastoma in a child 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; the degree of the condition and other individual factors. Typically, treatment for patients with brain or spinal cord cancer includes surgery, chemotherapy, radiation therapy, and / or steroids to treat and prevent edema, especially in the brain; anticonvulsant drugs to treat and prevent seizures associated with increased intracranial pressure; Placement of a shunt (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 (restoring lost motor skills and muscle strength) and / or antibiotics (to treat and prevent infections). Chemotherapy is the use of anticancer drugs to treat cancer. In most cases, chemotherapy affects the ability of the cancer cell to grow or multiply. These medicines can be injected into a 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 but not limited to Lewy body dementia (DLB), vascular dementia (VaD) and fronto -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 at very early stages of 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 Dementias 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, are of 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 causes of disease (hence multiple drug targets) represents 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 nevertheless have common mechanisms. This similarity in general mechanisms can manifest itself at the neurochemical and / or neuroanatomical levels and serves as a basis for the development of targeted, but not mechanism-specific, therapies aimed at more than one BPSD symptom.

[00125] General mechanisms are illustrated by similar neurochemical structures of nerve pathways from the cortical regions to the basal ganglia to the thalamus and back to the cerebral cortex. For example, the dorsolateral area of the prefrontal cortex transmits a signal to the dorsolateral region of the caudate nucleus, which in turn targets the lateral dorsal regions of the inner globus pallidus, which directs signals to the main part of the ventral anterior or mediodorsal thalamus, which returns signals to the cortex. In contrast, the orbitofrontal cortex transmits signals to the ventromedial caudate, which transmits signals to the medial dorsomedial portions of the inner globus pallidus, which directs signals to the large cell 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 different BPSD symptoms. The heterogeneity of the clinical manifestations of neurodegenerative disorders is determined by the dominant location of the pathological focus (i.e., affected networks). For example, the dorsal anterior cingulate cortex and the dorsolateral prefrontal cortex are more affected in apathetic patients, while 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] Regarding 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 the pyramidal cells of layer V of the prefrontal cortex (Aghajanian GK, Marekin Ser. , 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)). This 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 different regions 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] Regarding glutamatergic signaling, which is targeted by dextromethorphan and memantine, it is well known that it mediates thalamocortical signaling by inducing activation of the corresponding regions of the cortex (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 are characterized by a systematic, progressive, possibly transsynaptic spread of neurodegeneration. This means not only the loss of more cells in a certain area of the brain, but also the spread of the pathology to other parts of the brain. Since different parts of the brain play different functional roles, this explains why 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 Questionnaire (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: delusional states, hallucinations, agitation / aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability / lability, impaired motor activity, night-time behavior disorders, and appetite and eating disorders.

[00130] Patients rarely exhibit all of these NPI symptoms at the same time because there are elements of NPI such as euphoria that are rare even at a CDR score of 3. Conversely, clinical experience shows that it is rare for a patient to exhibit only one particular element and none of the others. Instead, BPSD symptoms occur in various combinations or clusters. For example, a common cluster in AD may, for example, represent aggression, agitation, wandering, repetition, while a common cluster in vascular dementia may, for example, represent confusion and movement anxiety, but the frequency and severity of NPI elements may vary. , for example, day to 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 the patient in question can exhibit such a set of several symptoms that are clinically significant simultaneously, there is an urgent need in the medical field for therapies that can target different clusters of symptoms or the entire spectrum of BPSD symptoms, regardless of any currently prevailing. the time of the pathophysiological hypothesis of 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 noticeably increases 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- 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 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 unapproved indications for such symptoms; however, with rare exceptions, both "typical" and "atypical" antipsychotics increase the incidence of CV adverse events and have shown significantly increased mortality rates when used for off-label dementia. Therefore, the FDA issued a black box warning prohibiting their off-label use in non-schizophrenia, leaving few therapeutic options for treating such BPSD symptoms in dementia. Against this background, a completely different class, namely antagonists and inverse agonists of 5-HT2A receptors, have shown 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 have been under development for use in neuropsychiatric indications, and there have been 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 randomized, 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 and 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 can 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 exclude the possibility that dextromethorphan also has antipsychotic properties in certain circumstances. Indeed, it has been reported that dextromethorphan, but not its metabolite dextrorphan, has been reported to attenuate phencyclidine-induced motor behaviors in rats (Szekely JI et al. Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan. Pharmacol Biochem Behav 40 (2) : 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 caused significant improvement in relation to delusional states (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 element. 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 NPI element is one of the most common and at the same time is a clinical BPSD symptom that is 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 HTR2A T allele 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 5-HT _2A receptor polymorphisms 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 blockers have been shown to attenuate 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 dextromethorphan-quinidine combination provided a decrease in arousal / aggression scores according to NPI (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 channel blocker, memantine, in patients with Alzheimer's disease showed that memantine also induces significant improvements 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 reward through brain stimulation have shown that antagonizing the 5-HT2A receptor can neutralize dysphoria caused by typical antipsychotics such as haloperidol (Benaliouad F et al. Blockade of 5-HT2a receptors reduces haloperidol-induced attenuation of reward Neuropsychopharmacology 32 (3): 551-61 (2007)). 5-HT _2A receptor antagonists exhibit antidepressant-like effects in preclinical models responsive to antidepressant drugs used in clinical practice (Marek GJ et al. The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluyoxetine. : 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. Synapse 52: 73-75 (2004)).

[00139] It has been shown that blockers of NMDA receptor channels, such as dextromethorphan, 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 dextthorphan in mice forced swimming test and tail suspension test. Biomed Pharmacother 85: 627-634 (2017)). Among the blockers of NMDA receptor channels, ketamine has been proven to have a rapid and pronounced antidepressant activity in patients with therapeutically 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 treatment resistant depression: A proof of concept clinical trial. J Affect Disord 218: 277-283 (2017)) ... Dextromethorphan is not a selective blocker of the NMDA receptor channel and is more effective in combination with serotonin and norepinephrine transporters and sigma-1 receptors, which may contribute to the therapeutic effect of dextromethorphan (Stahl SM. Mechanism of action of dextromethorphan / quinidine: comparison with ketamine. CNS Spectrums 18: 225-227 (2013)). Although most currently used antidepressants target monoamine transporters, 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 dextthorphan. 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. 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)). In a case-control study of Chinese subjects with AD, apathy in AD was significantly associated with 5-HT2A receptor polymorphisms 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 commonly seen in schizophrenic patients and belongs to a 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); Meltzer HY et al. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161 (6 ): 975-84 (2004)).

[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 in 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] Antagonists of 5-HT _2A receptors exhibit anxiolytic action in various preclinical models, in particular in models of conditioned reflex 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 orbitofrontal activation during processing of fearful and angry faces in healthy subjects. 47: S39 S41 (2009)). The 5-HT2 receptor antagonist serazepine (CGS-15040A) has been shown to be effective 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 induce anxiolytic effects in laboratory animals in a defined 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 interactions with sigma-1 receptors (Kamei H et al. (+) - SKF-10,047 and dextromethorphan ameliorate conditioned 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 channel blocker, memantine, significantly reduces the NPI 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 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)).

[00146] Human PET studies have shown a positive correlation between psychostimulant-induced changes in analogue euphoria scores and a decrease in the binding potential (BP) of the [11C] raclopride receptor in the caudate nucleus and shells 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 [11C] of racloprid in the ventral striatum, which correlated with euphoric 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 transmit signals to the dorsal suture nuclei and the 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 dopaminergic system of the midbrain is also under the control of cholinergic neural pathways, such as pathways originating in the leash, and the activity of these 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 towards α3β4-containing nicotinic acetylcholine receptors is associated with various effects attributable 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 represent 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. 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)).

[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 maladaptive impulsivity scores. (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 the point of view of neuroanatomy, it is known that the neocortex is rich in 5-HT2A receptors and disinhibition of behavior 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 beneficial therapeutic effects in patients with pseudobulbar affect (PBA), (Pioro EP. Review of Dextromethorphan 20 mg / Quinidine 10 mg (NUEDEXTA®) for Pseudobulbar Affect. Neurol Ther): 17; 3 (1 15-28 (2014)). PVA can occur in association with a variety of neurological diseases such as amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer's disease, stroke, and brain tumors. PBA is a disinhibition syndrome in which 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 channel blocker, memantine, in patients with Alzheimer's disease showed that memantine caused 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 the specific involvement of the 5-HT2A receptor in the regulatory projection of prefrontal cortical feedback (PFC) to the amygdala. Since this receptor is characterized by a high level of expression in areas of the prefrontal cortex, it affects 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-HTgA 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, uncontrolled crying or laughing, which 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 channel blocker, memantine, significantly reduces the scores for the irritability / lability element NPI (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 has shown 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. 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19 ( 6): 523-6 (2004); Pritchard AL et al. Role of 5HT 2A and 5HT 2C polymorphisms in behavioural and psychological symptoms of Alzheimer's disease. Neurobiol Aging 29 (3): 341-7 (2008)).

[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 manifest as behavioral sensitization that is sensitive to blockade of glutamate / NMDA receptors (Chase TN et al. Striatal glutamatergic mechanisms and extrapyramidal movement disorders. Neurotox Res 5 (1-2): 139-46 (2003)) and antagonism at α3β4-containing receptors (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)), two of the receptor targets for dextromethorphan (Taylor CP et al. Pharmacology of dextromethorphan: Relevance to dextromethorphan / quinidine (Nuedexta®) clinical use. Pharmacol Ther 164 : 170-82 (2016)).

[00158] The prevalence of night-time behavior disorders 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 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)).

[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 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 randomized, placebo-controlled phase 3 trial. Lancet 383: 533-40 (2014). Another 5-HT2A receptor inverse agonist, eplivanserin, has been shown to be clinically effective 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 channel blocker, memantine, in patients with Alzheimer's disease showed that memantine caused 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 AD patients, memantine was effective in reducing the incidence of fragmented sleep, and polysomnography showed an increase in total sleep duration, an increase in sleep efficiency and an increase in the time spent in stage II, as well as a decrease in the likelihood of awakening at night, the index of periodic limb movements. and the 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 for 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 the target receptors for dextromethorphan, a serotonin transporter that 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, involves multiple neuroanatomical substrates, with neurochemical and neuropharmacological mechanisms leading to the following: i) one therapeutic mechanism of action (TMA) can be used to treat more than one clinically diagnosable BPSD element (eg, a symptom or NPI symptom group); ii) one TMA can be used to treat the symptoms of two or more clinically different neurodegenerative diseases (eg, AD, PD, DLB, FTLD, etc.), as shown by the emerging efficacy profile of Nuplazid®; iii) coverage of the entire spectrum of BPSD symptoms with one 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 exhibited by therapy with pimavanserin, which is a single MTA 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, randomized, placebo-controlled, double-blind study. Lancet Neurology (2018) 17: 213-22), a combination therapy that includes several MTAs represented by compounds of formula I and compounds of formula II, provides both broader and more intense efficiency profile.

[00165] One embodiment is a method of treating 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 , an inverse agonist of the 5-HT2A receptor and a CYP2D6 inhibitor. In another embodiment, the agent is a dual activity (DA) agent having both a 5-HT2A receptor antagonist and a CYP2D6 inhibitor. In another embodiment, the agent is DA having both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor 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 a3p4 nicotinic receptor antagonist. The uptake of norepinephrine and serotonin is also inhibited. Several neuropsychiatric diseases and syndromes such as Alzheimer's disease and the behavioral and psychological symptoms of dementia include dysregulation of the glutamatergic, cholinergic, serotonergic, and norepinephrinergic 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 comprises 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 comprising SARPODEX ™, DERADEX ™ or DERAPHAN ™.

[00168] Psychological symptoms of dementia include dysregulation of the glutamatergic, cholinergic, serotonergic, and norepinephrinergic neurotransmitter systems. Therefore, one embodiment is a method for treating the behavioral and psychological symptoms of dementia. Another embodiment is treating a person in need thereof, comprising administering a composition comprising a compound of Formula I and a compound of Formula II to provide improvement in EEG disorders, behavior, cognition and seizure relief, and to provide improvement in respiratory disorders, motor ability, bone density and gastrointestinal dysfunction. Another embodiment is treating a person in need thereof, comprising administering a composition comprising DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ to provide improvement in EEG, behavior, cognitive and seizure reduction, as well as providing improvement in breathing disorders, movement ability, bone density and gastrointestinal dysfunction. Another embodiment is treating a person in need thereof, comprising administering a composition comprising DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ for the treatment of other diseases and conditions, including IEED or pseudobulbar affect ( PBA), neurodegenerative diseases, neuropathic pain, and brain injury.

[00169] Another embodiment is a composition comprising a compound DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ 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 with the formation of the primary metabolites DO and 3-methoxymorphinan, which are then 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 reaction of dextromethorphan and 3-methoxymorphinan. N-demethylation of dextromethorphan and DO is catalyzed by enzymes of the related CYP3A family. DO and 3-hydroxymorphinan conjugates can be detected in human plasma and urine for several hours after administration. DO is a substance best known for its psychoactive effects. [00171] SGL is a 5-HT2A receptor inverse agonist and a CYP2D6 inhibitor. SGL inhibits 5-HT2A receptor-mediated responses to 5-HT, such as platelet aggregation, vasoconstriction, and vascular smooth muscle proliferation. SGL (MCI-9042) has been shown to have the same affinity for 5-HT2A receptors 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 thrombus formation, inhibit platelet aggregation, and inhibit vascular smooth muscle cell proliferation (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 suffers 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 for 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 completeness).

[00173] DO is a substance best known for its psychoactive effects, which are likely to result from blockade of NMDA receptors. DO has a significantly higher affinity for NMDA receptors compared to DEX. The undesirable 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 comprising 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 having 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 comprising (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 that are commonly prescribed to patients with mental disorders, such as tricyclic antidepressants (nortriptyline, desipramine, amitriptyline, imipramine, and clomipramine) and selective serotonin reuptake inhibitors, including fluoxetine and paroxetine, 1996; Sproule et al., 1997; incorporated by reference in its entirety). It is expected that drugs that inhibit these enzymes will cause increases in plasma concentrations of co-administered antipsychotic drugs (Goff, 1993; Ereshefsky, 1996; Michalets, 1998; incorporated by reference in their entirety). These increases can, in turn, lead to the development or aggravation of antipsychotic-induced side effects, including cardiotoxicity, anticholinergic side effects, or orthostatic hypotension (Ereshefsky, 1996; Desta et al., 1999; incorporated by reference in their entirety).

[00176] Many antipsychotic drugs 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 the control activity at 10 μM and to 11.4 and 10.7% of the control activity at 25 μM, respectively. The inhibitory efficacy of these drugs against DEX O-demethylation was compared with the inhibitory effect of 10-25 μM quinidine. The 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 of chlorpromazine, fluphenazine and haloperidol were 9.7, 16.3 and 14.4 μM, respectively. Cisthiothixene, clozapine and risperidone showed weaker inhibition than the other drugs tested, with mean IC50 values assessed as 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, aymalin, amiodarone, amitriptyline, aprindine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, doxorubicin, fluvofluxenazetine, fluvoxetine , haloperidol, imipramine, indinavir, lasoprazole, levomepromazine, lopinavir, loratadine, mechitazine, methadone, metoclopramide, mibefradil, moclobemide, nelfinavir, nevirapine, nicardipine, norfluoxetine, paroxysine, tsidiamidine, tsitin, tsis, tsis, , 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 advantage of simultaneous 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 advantage of simultaneous 5HT2A 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 the concurrent use of the antiarrhythmic drug quinidine with DEX. Accordingly, an embodiment is a composition comprising 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 the total daily dose of dextromethorphan, its metabolite, derivative or prodrug (DEX), which can be administered while increasing efficacy and ensuring tolerability and safety, including oral administration of an effective amounts 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 an adverse event associated with treatment 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, and / or a compound 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 for lowering plasma DO levels 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 DEX treatment, with a decrease in plasma DO levels occurring in 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 for lowering 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 DEX treatment, 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 a compound of Formula I for eight consecutive days.

[00183] 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 decreasing DEX metabolism in some subjects by coadministration of 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 and DEX receptor antagonist / inverse agonist, wherein the subject is a rapid metabolizer of DEX.

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

[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 metabolizer of DEX, 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 wherein DEX is present in the subject at the same time as the compound of Formula I.

[00188] Another embodiment is a method of increasing the metabolic life of a 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 wherein DEX is present in the subject's body simultaneously with a compound of Formula I.

[00189] Another embodiment is a method of correcting a rapid metabolism 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 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 for treating cough, comprising administering a combination of a compound of Formula I and a compound of Formula II 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 a compound of Formula II or DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ should be administered at least once a day 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, 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 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 about 0.5 mg / day to about 15 mg / day, from about 15 mg / day to about 60 mg / day, from about 15 mg / day to about 120 mg / day, from 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 metabolizer, 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 metabolizer, and wherein DEX is present in the subject concurrently with the compound of Formula I.

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

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

[00198] Another embodiment is a method of increasing plasma DEX levels, comprising administering a compound of Formula I and DEX together for at least five consecutive days to a subject in need of DEX treatment, wherein on the fifth day the plasma DEX level is 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 a 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, wherein on day six the plasma DEX level is 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 a compound of formula I for six consecutive days.

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

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

[00202] Another embodiment is a method of reducing the residual effect of DEX comprising co-administering a compound of Formula I with DEX to a subject in need of DEX treatment, wherein the plasma DEX level 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 if the same amount of DEX were administered without a compound of Formula I.

[00203] Another embodiment is a method of reducing the likelihood of an adverse event or other undesirable consequences such as dependence associated with DEX treatment, comprising administering a compound of Formula I and DEX together to a subject in need of DEX treatment, where the subject is exposed risk of 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 compound of formula I comprising co-administering DEX and a compound of formula I to a subject in need of treatment with a compound of formula I, wherein the subject is at risk of the adverse event as a result of treatment with a compound of formula I.

[00205] Another embodiment is a method for 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 for 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 is administered at least once a day 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 compound of Formula I, DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ to a subject in need thereof, wherein the compound of Formula I and DEX administered at least once a day for at least 8 days.

[00210] Another embodiment is an oral sustained release DEX delivery system comprising a composition comprising 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 comprising DEX and a compound of Formula I or DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ to a subject in need of DEX treatment.

[00212] Another embodiment is a pharmaceutical composition, dosage form, or medicament 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, there is provided a method of increasing the metabolic lifespan of a DEX 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 the CYP2D6 enzyme, and wherein DEX is present in the subject at the same time as a CYP2D6 inhibitor. In another embodiment, the composition comprises DEX and a compound of Formula I or DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™.

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

[00215] In another aspect, there is provided a method of 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 and DEX receptor antagonist to a subject in need thereof. In another embodiment, the composition comprises DEX and a compound of Formula I or DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™.

[00217] In another aspect, there is provided a method of 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 naloxone-blocked withdrawal trait (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 is capable of weakening not only the physical but also the affective and motivational components of the withdrawal conditions, 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 Dependence. 67 (2): 177-83 (2002); incorporated by reference in its entirety). By reducing withdrawal symptoms, such drugs should be beneficial for 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 a drug dependence and substance abuse disorder or disease, comprising administering DEX and a compound of Formula I or DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™.

[00220] Chronic exposure to morphine leads to a number of biochemical adaptations of the glutamatergic receptor system in the limbic system (Fitzgerald et al., Drugs of abuse and stress increase the expression of GluRl and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross- sensitizing agents J. Neurosci 16: 274-282 (1996); incorporated by reference in its entirety). Excitatory amino acids are involved in mediating many neurochemical and behavioral effects resulting from chronic drug abuse, some of which can be prevented or regressed by 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 reward centers in the brain and to an 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 opioid 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 animal models of Parkinson's disease based on inflammation (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); 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); Zhang et al., 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity. FASEB Journal. 19 (3): 395-7 (2005); incorporated by reference in its 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 the cultures treated with LPS, in addition to the decrease in the number of dopamine neurons, the dendrites of the remaining dopamine neurons were significantly less developed than the dendrites in the controls. In cultures pretreated with DEX (10 μM) prior to stimulation with LPS, dopamine neurons were significantly more numerous and dendrites were less damaged. Significant neuroprotection was noted in cultures when DEX was added within 60 minutes after LPS was added. Thus, DEX significantly protects monoamine neurons not only during pretreatment, 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 inhibition of over-activation of microglia by inhibition of superoxide anion formation 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 the neuroprotection of dopamine receptors mediated 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 acute excitotoxicity induced by glutamate. 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-related 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 opioid dependence. 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 moderate 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). It has been reported that, in particular among the Han Chinese in Taiwan, DEX is metabolized by the "dextromethorphan-metabolizing enzyme CYP2D6", which is significantly different from that of the Western population (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. 116 (3): 214-7 (2009); incorporated by reference into in its entirety).

[00225] At necropsy, the frontal cortex of BP cadavers showed significantly higher levels of IL-1 beta receptor protein and mRNA and neuroinflammatory markers induced by 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, leading subsequently to an inflammatory response of neurons, may be associated with the progression of cerebral atrophy and exacerbation of BP symptoms. Treatment of BP with immunity-targeted therapies has been shown to have antidepressant effects. For example, unmasked acetylsalicylic acid, when added to fluoxetine, resulted in an increased remission rate in severely depressed individuals who had previously failed to respond 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 stabilizing agents have been shown to activate interconnected intracellular signaling pathways that mediate neurogenesis and synaptic plasticity. Found that the decrease in brain volume in BP patients 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 neurotrophic factor (BDNF), and heat shock protein 70. In addition, VPA activates neurite outgrowth, while VPA has been reported in therapeutic levels inhibits histone deacetylase (HDAC), an enzyme that catalyzes the removal of the acetyl group from histone lysine residues, promoting local BDNF biosynthesis in neurons. Accordingly, an embodiment is a method of treating a subject in need of treatment for 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 of reducing the adverse events of DEX in a subject in need, comprising:

a. introduction to the subject of 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 person in need thereof.

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

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

[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 the DEX is present in the subject concurrently with 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 metabolizer, and wherein the DEX is present in the subject concurrently with the 5-HT2A receptor antagonist / inverse agonist.

[00233] Some embodiments include a method of correcting a 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 neuropsychiatric disorder treatment.

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

[00236] DEX is used as a cough suppressant. In accordance with the FDA-accepted requirements of the DEX instructions for use according to the OTC monograph [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 can limit systemic drug exposure in individuals who are fast metabolizers. Subjects may be: 1) DEX metabolizers rapidly — those who metabolize DEX rapidly; 2) poor DEX metabolizers - those who poorly metabolize DEX; or 3) DEX intermediate metabolizers - those whose DEX metabolism is somewhere between the metabolism of the fast and the weak metabolizer. Rapid metabolizers can also be ultra-rapid metabolizers. Rapid metabolizers of DEX make up a large proportion 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 metabolizers of DEX. Low plasma concentrations of DEX may limit its clinical utility as a sole agent for rapid metabolizers and possibly intermediate metabolizers of DEX. Certain antidepressants, such as a compound of Formula I, inhibit the metabolism of DEX and are thus capable of improving its therapeutic efficacy. Likewise, antidepressants can provide DEX with less frequent use, 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, compounds of Formula I, include, but are not limited to, mood disorders, mental disorders, disorders of brain function, movement 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, compounds of Formula I include, without limitation, depression, major depressive disorder, therapeutically resistant depression and therapeutically 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 conditions, obsessive-compulsive disorder, bulimia, anorexia , obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug or substance abuse, nicotine dependence, psychosexual dysfunction, pseudobulbar affect, and emotional lability. [00242] Depression can manifest as mood changes, feelings of deep sadness, despair, slowed thinking, sleep disturbances, 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] Mental 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 behavior change in Alzheimer's disease (AD). This is true for the entire spectrum of cognitive impairment, from mild cognitive impairment to severe Alzheimer's disease (AD), as well as in a number of other neuropsychiatric disorders. Apathy is a form of executive cognitive dysfunction. Patients with apathy suffer from decreased performance of daily activities and specific cognitive deficits and rely on families to provide more care, resulting in increased stress for families. Apathy is one of the primary syndromes associated with frontal and subcortical pathology, with apathy in AD apparently having several neuroanatomical correlates that involve components of the frontal subcortical networks. Despite the profound implications of this common syndrome, only a few instruments have been developed to specifically measure apathy, and these instruments have not been directly compared. Assessment of apathy in AD requires clinicians to distinguish loss of motivation from loss of disability due to cognitive decline. Although apathy can be misdiagnosed as depression due to the overlap of symptoms, current research has shown that apathy is a distinct syndrome. Differentiating apathy from depression plays an important role in treatment, as these disorders are treatable with different types of interventions.

[00245] The Apathy Questionnaire (IA), which is a scoring scale for the overall assessment of apathy and the separate assessment of emotional dullness, lack of initiative and lack of interest, is a reliable method for assessing several parameters of apathy in dementia and non-dementia elderly subjects. as well as the awareness of the subject about these symptoms. IA is as effective in assessing apathy as in the apathy domain of the neuropsychiatric questionnaire (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 (Nov 01, 2005), incorporated by reference in its entirety). Apathy can result from damage to one or more areas of the brain, such as the frontal cortex, thalamus, striatum, and amygdala. In most cases, direct involvement of the frontal lobes or subcortical nuclei, which are associated with the frontal lobes, causes apathy. The apathy associated with Alzheimer's disease is difficult to treat. Antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors, etc., only alleviated the course of apathy 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 , metriphonate, 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 are incorporated by reference in their entirety).

[00247] Acetylcholinesterase is one of the most important components of the central cholinergic pathways. It stops the synaptic action of acetylcholine through hydrolysis, which leads to the formation of a choline fragment, 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 (AChEI) are effective because they accelerate acetylcholine-mediated signaling between neurons. This is achieved by increasing the concentration of acetylcholine due to reversible inhibition of its hydrolysis by acetylcholinesterase. (USFDA Reference ID: 3096907; Guidance on Donepezil Hydrochloride, completed Aug 2017, incorporated by reference in its entirety).

[00248] Accordingly, in one embodiment, the composition comprises AChIs 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 (metriphonate), (4aS, 6R, 8aS) -3-methoxy-11-methyl-4а, 5,9,10,11,12-hexahydro-6Н-benzo [2, 3] benzofuro [4,3-cd] azepin-6-ol (galantamine) and 1,2,3,4-tetrahydroacridin-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-diethyl phosphorodithioate, 2-chloro-1- (2,4-dichlorophenyl) vinyl diethyl phosphate, O, O-diethyl-O- (3,5,6-trichloropyridin-2-yl) phosphorothioate, O- (3-chloro-4-methyl-2-oxo-2H-chromen-7-yl) -O, O-diethyl phosphorothioate, 1-phenylethyl- (E) -3 - ((dimethoxyphosphoryl) oxy) but- 2-enoate, 4- (tert-butyl) -2-chlorophenyl methyl meth ylf os for amide at, O, O-d iethyl-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-yl-dimethylphosphate, 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- 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-dichloroethyl dimethyl phosphate, 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-diethyl phosphorodithioate, 2-chloro-1- (2,4,5-trichlorophenyl) vinyl dimethyl phosphate and dimethyl (2,2,2- trichloro-1-hydroxyethyl) phosphonate or pharmaceutically acceptable derivatives, metabolites, analogs or salts thereof.

[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, meta), nicotine, alcohol, opioids, anxiolytic and hypnotics, cannabis (marijuana), amphetamine, hallucinogens, phencyclidine, volatile solvents and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking cigarettes, cigars and / or pipes, and tobacco chewing.

[00250] Brain dysfunctions treatable 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, disorders including forms of mental retardation such as vascular dementia, dementia in Alzheimer's disease , Lewy body dementia, frontotemporal lobar degeneration, memory loss, amnesia / amnesic syndrome, epilepsy, consciousness disorders, coma, decreased attention, speech disorders, voice cramps, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome and schizophrenia ... Cerebral dysfunction also includes disorders caused by cerebrovascular disease, including but not limited to stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries and the like, with symptoms including 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, ballism, hemiballism, bradykinesia, cerebral paralysis, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spastic torticollis, dopamine-sensitive 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, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, fronto -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, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS) , progressive muscle atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), forms of motor neuron atrophy of the spinal cord, 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 muscle atrophy (SMA), bulbar muscle atrophy, Friedrich's ataxia, Huntington's disease, Levy's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple systemic atrophy, Shay-Dreager syndrome, corticobasal degeneration , progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (SMT), familial neuromuscular neuropathy or spastic disease , strionigral degeneration, syndrome Guillain-Barré 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, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile seizures; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and partial continuous epilepsy; generalized seizures, including but not limited to generalized tonic-clonic seizures, minor epileptic seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and also 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, but are not limited to migraine, trigeminal irritation cephalalgia, 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, a metabolite of any of these compounds, or a prodrug based on any of these compounds include Rett syndrome, autism , tinnitus, disturbances of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disturbances due to uncontrolled spasms of the laryngeal muscles, including, but not limited to, spastic dysphonia of the abductive type, spastic dysphonia of the adduction type, dysphonia of muscle tension and tremors of the voice; chemotherapy-induced diabetic neurotoxicity such as methotrixate-induced neurotoxicity; urinary incontinence, including but not limited to stress urinary incontinence, urge incontinence and fecal incontinence, and erectile dysfunction.

[00258] The analgesic properties of DEX can be improved by a method involving co-administration of DEX and a 5-HT2A receptor antagonist / inverse agonist, such as a compound of Formula I, a metabolite derived from 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 coadministration of DEX with a compound of Formula I.

[00260] These methods can be used to treat or provide relief from any pain, including but not limited to musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, and the like.

[00261] Examples of musculoskeletal pain include lower back pain (i.e., lumbosacral pain), primary dysmenorrhea, and arthritic 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 pain in amputated limbs, central pain, and the like. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio- or chemotherapy-associated neuropathy, etc.

[00264] The term "treating" or "treating" includes diagnosing, curing, ameliorating, treating, or preventing a disease in humans or other animals, or any activity that otherwise affects the structure or any function of the body of humans or other animals.

[00265] Any 5-HT2A receptor antagonist / inverse agonist can be used in combination with DEX to enhance the therapeutic properties of DEX. DEX and the 5-HT2A receptor antagonist / inverse agonist can be administered as separate compositions or dosage forms, or can 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, amoxapin, desipramine, trimipramine , nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindanamine, benactisine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, mocloxinzipranzetili, mirtaodinezine , nialamide, iproniazide, iprocloside, 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 any of these compounds.

[00267] The combination of a compound of Formula I with DEX may provide greater efficacy, such as greater pain relief, than would be achieved with either component alone. In fast metabolizers, DEX can be rapidly and actively 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, derivative, 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 a compound of Formula I.

[00268] As explained above, this inhibition can increase plasma levels of DEX, resulting in additive or synergistic efficacy such as ameliorating neurological disorders including pain, depression, smoking cessation, and so on. Thus, while inhibition of DEX metabolism is only one of the many potential benefits of the combination, coadministration 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 in many conditions. Co-administration of DEX with a compound of Formula I can also enhance the antidepressant properties of a compound of Formula I in many conditions, including providing a more rapid onset of action.

[00269] Another potential advantage of coadministration 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 can be useful, for example, for subjects at risk of developing an adverse event as a result of DEX treatment.

[00270] Another potential advantage of co-administration of DEX and a compound of Formula I is that it can be useful to reduce the likelihood of an adverse event, such as a seizure, associated with treatment with a compound of Formula I. This can be useful for, for example, subjects with the risk of an adverse event occurring as a result of treatment with a compound of formula I.

[00271] Regarding DEX, co-administration with a compound of Formula I can 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, coordination disorder, fatigue, euphoria, nervousness, insomnia, sleep disturbances, seizures, agitation, catatonic-like conditions, hysteria, hallucinations, delusions, paranoia, headaches and / or migraine and extrapyramidal symptoms such as oculogyric crisis, torticollis, hyperexcitability, increased muscle tone, ataxia and protrusion of the tongue.

[00272] Adverse events in the gastrointestinal tract include, but are not limited to, 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, hyperacidity, dry mouth, gastrointestinal upset 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 the two compounds to be administered in the same dosage form. For example, the two compounds can be administered in a single dosage form, or can be administered in two separate dosage forms. In addition, two compounds can be administered simultaneously, but this is not necessary. The compounds can be administered at different times, provided that they are in the human body simultaneously for at least a portion of the time during which the co-administration 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 a compound of Formula I alone or over DEX alone, including potentially faster onset of action.

[00275] In some embodiments, the combination may have at least about 0.5% improved pain relief, at least about 1%, at least about 10%, at least about 20%, at least at least about 30%, at least about 50%, 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 as compared to the compound of Formula I alone.

[00276] In some embodiments, the combination may have at least about 0.5% improved analgesic properties, at least about 1%, at least about 10%, at least about 20%, at least at least about 30%, at least about 50%, 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 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 DEX and compounds of Formula I include, but are not limited to, the compounds shown below.

[00278] The dosage form or composition can be a combination or mixture of DEX and a compound that inhibits the metabolism of DEX, such as a compound of Formula I, either alone or in a carrier medium. For example, DEX and a compound of Formula I can be dispersed in each other or dispersed together in a carrier medium. The dispersion can include a mixture of solid materials, where the fine individual particles are actually one compound, but the fine particles are dispersed in each other, which can happen when two powders of two different drugs are mixed with a solid material of the carrier medium and mixing 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 present in separate zones or phases in a composition or dosage form. For example, one drug can be in a coating and another drug can be in a coated core. For example, one drug can be formulated for sustained release and another drug can be formulated for immediate release.

[00279] Some embodiments include administering a tablet that contains a compound of Formula I in a sustained release form and DEX in an immediate release form, or vice versa. While there are many ways in which 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, hydrochloride particles of a compound of Formula I can be mixed with microcrystalline cellulose and hydroxypropyl methylcellulose (eg METHOCEL ™) to form a mixed powder mixture. 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, can be combined with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice, as described, for example, in Remington's Pharmaceutical Sciences. 2005. The relative ratios of active ingredient to carrier can be determined, for example, by the solubility and chemical nature of the compounds, the route of administration chosen, and standard pharmaceutical practice.

[00281] The 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 can be administered using conventional means available for use in combination with pharmaceuticals, either as separate therapeutic agents or in a 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] The therapeutic compounds can be administered to a subject in various forms adapted to the chosen route of administration, for example, 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, skin, ocular, rectal and nasal inhalation by insufflation, aerosol and rectal systemic.

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

[00284] The amount of DEX in the therapeutic composition can 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), about 1% (w / v) to about 3% (w / v), about 3% (w / v) to about 5% (w / v), about 5% ( w / v) to about 7% (w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v ), about 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v) or about 40% (w / v) to about 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 DEX, or any amount of DEX within a range limited by any of these values or dressing 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% (weight / weight), at least about 70% (weight / weight), at least about 80%, from about 10% (weight / weight) to about 30% (weight / weight), from about 10% (weight / 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) , about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to approximately 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, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about PO mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg DEX, or any amount of DEX within a range limited 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 the plasma DEX level is desired, the compound of Formula I must be administered in an amount that increases the plasma DEX level. 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 with the same amount of DEX administered without a compound of Formula I.

[00289] In some embodiments, a compound of Formula I can be administered to a subject in an amount that provides the area under the curve 12 hours after dosing (AUC _0-12 ) or the subject's mean plasma concentration over 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 can 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 for 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, an increase in plasma DEX level may occur on the first day of administration of a compound of formula I, compared to the same amount of DEX administered without a compound of formula I. For example, plasma DEX level on the first day the introduction of a compound of formula I can 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 have been achieved by administering the same amount of DEX without the compound of Formula I.

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

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

[00294] In some embodiments, the implementation of the residual level of DEX (eg, the level in blood plasma 12 hours after administration) on the first day of administration of a compound of formula I may be at least twice the residual level that would be achieved with the introduction of the same amount 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 DEX treatment, wherein a decrease in plasma DO levels occurs on the first day of co-administration of a compound of Formula I and DEX, compared to the same amount of DEX. administered without a compound of Formula I. For example, plasma DO levels on the first day can be reduced by at least 5% compared to plasma DO levels that would be achieved with the same amount of DEX without a 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 higher than the plasma DEX level, which is would be achieved by administering the same amount of DEX administered without a compound of Formula I over five consecutive days. For example, the plasma DEX level on the fifth day (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can 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 with the same amount of DEX without a 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 day six, the plasma DEX level is higher than the plasma DEX level, which is would be achieved by administering the same amount of DEX administered without a compound of Formula I over six consecutive days. For example, the plasma DEX level on the sixth day (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5 times, at least 10 times, 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 day 7 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 a compound of Formula I over seven consecutive days. For example, the plasma DEX level on the seventh day (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5 times, at least 10 times, 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 such that DEX is reached in plasma on day eight, for example, after 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, 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 the administration of such the same amount of DEX without a 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 DEX treatment, wherein on day eighth, the plasma DO level is below the plasma DO level, which is would be achieved by administering the same amount of DEX administered without a compound of Formula I over eight consecutive days. For example, plasma DO levels on the eighth day (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be reduced by at least 10%, by at least 20%, by at least 30%, at least 40%, or at least 50% compared to the plasma DO level that would be achieved by administering the same amount of DEX without a compound of formula I for eight consecutive days.

[00301] In some embodiments, a compound of formula I can be administered to a subject in an amount that provides an AUC _{0-12 of a} compound of formula I in a subject on day 8 of 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 / ml, at least about 1200 ng h / ml, at least 1600 ng h. / ml or up to approximately 15000 ng⋅h / ml.

[00302] In some embodiments, a compound of Formula I can be administered to a subject in an amount that provides a C _{avg of a} compound of Formula I in a subject on day 8 of 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), about 0.01% to about 10% (w / v), about 1% (w / v) to about 3% (w / v), 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), about 10% (w / v) to about 15% (w / v), 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% (w / v) a compound of formula I or any amount of a compound of formula I in a range bounded 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, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 110 mg to about 140 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, whether limited to or between 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% (weight / weight), at least about 70% (weight / weight), at least about 80%, from about 10% (weight / weight) to about 30% (weight / weight), from about 10% (weight / 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) , about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) up to about 90% (w / w) of a compound of formula I or any an amount of a compound of Formula I within a range limited or between any of these values.

[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, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 110 mg to about 140 mg, 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 range any of these values or 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 from about 0.1 μM to about 10 μM, from about 0.1 μM to about 5 μM, from 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 can be administered to a subject in an amount that provides an AUC _{0-12 of a} compound of formula I in a subject on day 8 of at least about 200 ngh / ml, at least about 400 ng H / ml, at least about 700 ng h / ml, at least about 1000 ng h / ml, at least about 3000 ng h / ml, at least about 7000 ng 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 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 between or limited to any of these values.

[00309] In some embodiments, a compound of formula I is administered to a subject in an amount that provides a subject's C _{max of a} compound of formula I on day 8 of 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 between or limited to any of these values.

[00310] In some embodiments, a compound of formula I is administered to a subject in an amount that provides a C _{avg of a} compound of formula I in a subject on day 8 of at least about 20 ng / ml, at least about 30 ng / ml, according to 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 between or limited to any of these values.

[00311] For compositions containing both DEX and a compound of Formula I, some fluids 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), 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), about 5% (w / v) to about 7% (w / v), about 5% (w / v) to about 15% ( w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / volume) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), 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 in the range limited to any of these values or between them. 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 / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), 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), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), about 80% (w / wt) up to about 90% (w / w) DEX and a compound of formula I in combination and whether any number in the range limited by any of these values or in between. In some embodiments, the weight ratio of DEX to a compound of Formula I in one composition or dosage form can 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] The therapeutically effective amount of a therapeutic compound can vary depending on the circumstances. For example, the daily dosage of DEX in some cases can 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 flax 200 mg, about 200 mg to about 300 mg, about 220 mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg to about 380 mg, about 400 mg to about 500 mg, 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 limited to 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 half, one third, one fourth, or one sixth, respectively daily dose.

[00313] The daily dose of a compound of formula I in some cases may range 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 in the range limited or between 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 about half or one third of the daily dose, respectively.

[00314] In some embodiments, a subject in need thereof is administered 1) from about 50 mg / day to about 100 mg / day, from about 100 mg / day to about 150 mg / day, from 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 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 compound of Formula I and about 30 mg / day of DEX, about 150 mg / day of a compound of Formula I and about 60 mg / day of DEX, about 150 mg / day of a compound of Formula I, 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, about 200 mg / day of a compound of formula I and about 90 mg / day of DEX, about 200 mg / day of a compound of formula I and about 120 mg / day of DEX, about 300 mg / day of a compound of formula I and about 30 mg / day DEX, about 300 mg / day of a compound of formula I and about 60 mg / day of DEX, about 300 mg / day of a compound of formula I and about 90 mg / day of DEX or about 300 mg / a day of a 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, followed by 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 compound of Formula I and about 30 mg / day of DEX for 1, 2, or 3 days, followed by about 200 mg / day of a compound of Formula I 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, can be administered as long as necessary to treat a neurological condition such as pain, depression, or cough. In some embodiments, a 5-HT2A receptor antagonist / inverse agonist, such as a compound of Formula I, and DEX are administered at least once a day, such as once a day or twice a day, for at least 1 day, for 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 can be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or they can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or included directly in food from the diet. For oral administration for the purpose of therapy, the active compound can be combined with an excipient and used in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.

[00320] Tablets, troches, pills, capsules and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia gum, corn starch or gelatin; an excipient such as dicalcium phosphate; 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, gaulteria oil, or cherry flavor. If the unit dosage form is a capsule, it may contain, in addition to materials of the type indicated above, a liquid carrier. Various other materials can be present as a coating, for example, tablets, pills or capsules can 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 color 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 suitably mixed with a surfactant such as hydroxypropyl cellulose. The dispersion can also have an oil dispersed in glycerin or dispersed with glycerin, liquid polyethylene glycols, and mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

[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 the burden of care 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 commercially available therapeutic agents for dementia leave much room for improvement when it comes to treating BPSD, but also other non-cognitive problem areas. With long-term 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 in (costly) accommodation in a home for the disabled.

[00325] Prescribing ("typical or atypical") antipsychotics to facilitate care and maintenance is global standard practice. However, the FDA has determined that off-label prescribing of antipsychotics poses a serious health threat to subjects with dementia and has issued a black box warning in the guidelines citing serious cardiovascular adverse events and an increased risk of death. The EU approval of risperidone permits short-term use by patients with moderate AD only if they have harmed themselves or others. In Parkinson's disease, the anticholinergic effects of neuroleptics are extremely undesirable, since they inevitably worsen, among other things, motor impairment, as well as impairments in the functioning of the autonomic nervous system. In all dementias, lowering the seizure threshold is another infrequent but highly undesirable potential side effect of antipsychotics. These concerns about the use of antipsychotics in dementia lead to a decrease in the use of antipsychotics in this patient population, leaving BPSD symptoms in the vast majority of patients with mild to moderate AD, essentially untreated.

[00326] Accordingly, some embodiments provide new compositions and methods useful in the symptomatic and disease-modifying treatment of neurodegenerative diseases and brain damage, including their consequences such as organic brain syndrome and chronic traumatic encephalopathies; chronic or intractable pain, ophthalmic signs associated with retinopathies, 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, ischemic heart disease, angina pectoris, atherosclerosis, including CNS-like multi-infarction dementia, vascular cognitive impairment, vascular dementia or Binswanger's disease, and nephropathy.

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

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

[00329] In a third aspect, there is provided a method of using 5HT2A receptor antagonists of Formula I to improve the therapeutic properties of DEX in the treatment of neuropsychiatric disorders.

[00330] In a fourth aspect, there is provided a method of treating a neuropsychiatric disorder 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 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 an 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, there is provided a method of 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, the specific enantiomer of a 5HT2A receptor antagonist with potent CYP2D6 inhibitory activity has a higher penetration rate across 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 blood glucose-based methods.

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

[00338] In one embodiment of the fifth aspect, DEX is administered in 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 of enhancing the therapeutic properties of DEX by administering it with a 5HT2A receptor antagonist, which 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, 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 / s tki, 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 to any of these values or in between, or the required amount of DEX to a 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 can be formulated in any pharmaceutical dosage form for oral, topical, rectal, vaginal, nasal, or ophthalmic administration, and include syrups and suspensions using commonly known ingredients, as well as procedures and methods (U.S. Patent Application Nos. 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 can be formulated in any pharmaceutical dosage form for oral, topical, rectal, vaginal, nasal or ophthalmic administration and include syrups and suspensions, and the generally known ingredients and procedures for formulating a pharmaceutical composition are within the skill of the art. technical fields, including various known methods (US patent applications No. 4221778, 4762709, 4788055, 4959219, 4996047, 5071646, 4221778 and 5186930; are fully incorporated herein by reference) that 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, cutaneous or local, intra-articular, intra-serum , intrafocal, intramuscular, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical. intravitreal, transdermal or transmucosal.

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

METHODS OF SYNTHESIS

[00344] SGL hydrochloride (CAS No: 135159-51-2), named according to the systematic nomenclature hydrochloride complex mono (2- (dimethylamino) -1 - ((2- (2- (3-methoxyphenyl) ethyl) phenoxy) methyl) ethyl) ester of butanediol acid, can be obtained through many synthesis 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 its entirety).

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

[00346] As shown in the scheme below, the reaction of 2-hydroxy-3'-methoxybenzyl with epichlorohydrin via a NaH base in DMF gives 2- (2,3-epoxypropoxy) -3'-methoxybenzyl, condenser in THF gives 2- [3- (dimethylamino) -2-hydroxypropoxy] -3'-methoxybenzyl. Finally, this compound is treated with succinic anhydride with heating under 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 salicylic aldehyde by 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 reactions.

[00348] To achieve an acceptable level of purity of the SGL hydrochloride drug used in the preparation of the desired SGL hydrochloride tablets, one hetero-containing compound must meet the requirements. US patent application 4,485,258 discloses a method for synthesizing a first SGL hydrochloride and recrystallization 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 recrystallization of SGL. CN 101239920 A discloses acetonitrile, propionitrile, 1,4-dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, sulfolane, dimethylsulfoxide or a mixture of more than two of them with methanol, ethanol, acetone, ethyl acetate, diethyl ether, diisopropyl ether can be used in as a solvent for recrystallization of SGL hydrochloride, while the purity of the product can reach 98%. C _2-10 alkanes, C _3-10 ketones, esters of C _2-10 carboxylic acids, C _1-10 halogenated alkanes, aromatic hydrocarbons or aromatic derivatives at temperatures from room temperature to reflux temperature are characterized by low solubility in hydrochloric acid, therefore should not be used as a solvent for SGL or SGL hydrochloride, in addition, when using water or 5% or more aqueous organic solvent, a high purity product cannot be obtained. The existing literature does not mention the issue of controlling the content of an individual impurity.

[00349] Enantiomerically pure form 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 useful biological activity. Enzymes and other natural binding sites recognize substrates with specific chiralities to create a range of biological functions. These enzymes or receptor sites are specific for their action, since 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 efficacy, or both enantiomers have the same or equal activity. Thus, the preparation of enantiomerically pure drug molecules is of interest, and the technique has three main strategies: 1) separation, (2) use of chiral constituents, and (3) asymmetric synthesis. Asymmetric synthesis allows one chiral material to be used much more efficiently to produce another.

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

[00352] In another embodiment, 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 universal and suitable chiral carboxylic acid ligands are available in the literature, such as mandelic acid, 2-methylmandelic acid, 2-chloromandelic acid, 3-chloromandic acid, 4-methoxymandelic acid, O-acetylmandelic acid, α-methoxyphenylacetic acid, malic acid, tartaric acid, etc. Chiral ligands can be obtained 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); Ishihara et al., An extremely simple, convenient, and selective method for acetylating primary alcohols in the presence of secondary alcohols , J. Org. Chem., 58 (15), pp. 3791-3793 (1993); Edwards et al., The stereoselective replacement of hydroxyl groups by chlorine, using the mesyl chloride-N, N-dimethylformamide reagent, Carbohydrate Research , Volume 35, Issue 1, pages 111-129 (July 1974); incorporated by reference throughout its completeness).

[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 isobutyryl , 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 their entirety).

[00356] Linkers that can be used in the synthesis of SARPODEXAMIDE ™ derivatives in the above scheme include, but are not limited to, 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); US patent application No. 20130053301, patent applications No. WO 2011089216 A1 ; WO 2006136586 A2; US Patent Applications Nos. 7932294; 20060046967 A1; 8357723; 8349901; 8354455; 9550734; 20160220694; 20160002167; 20150328323; 9090563; 20140058063; 20130158271; Patent # 827846957; 20110 in its entirety).

[00357] Formation of an ester. Esters are derived from carboxylic acids. The carboxylic acid contains a —COOH— group, and in the ester, the hydrogen in this group is replaced by a hydrocarbon group R 'such as an alkyl, cycloalkyl, aryl and heteroaryl group. Esters are prepared 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 (tosylic acid) is also often used.

[00358] The esterification reaction is both slow and reversible at the same time. The reaction equation between acid RCOOH and alcohol R'OH (where R and R 'can 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 19980 by reference in its entirety).

SARPODEXTER ™

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

EXAMPLES

Preparation of SARPODEXAMIDE ™ Derivatives

[00360] The compound of Formula I or Sarpodexamide ^tm derivatives can be prepared by reacting dextromethorphan either as a single isomer or as a mixture thereof with 2,2,2-trichloroethyl chloroformate under reflux in toluene, thereby producing the N-demethylated compound.

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

[00362] N-desmethyldextromethorphan, obtained 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, amides (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl-4 - ((4bS, 8aS, 9S) -3-methoxy- 6,7,8,8а, 9,10-hexahydro-5Н-9,4b- (epiminoethano) phenanthrene-11-yl) -4-oxobutanoate (compound 167) and (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl-4 - ((4bS, 8aS, 9S) -3-methoxy-6,7,8,8а, 9,10-hexahydro-5Н-9,4b - (epiminoetano) phenanthrene-11-yl) -4-oxobutanoate (compound 168) can be obtained from sarpogrelate by amidation with N-desmethyldextromethorphan using HBTU in combination with Hunig's base for 1-2 hours. Reagents such as uronic hexafluorophosphate salt (1-cyano-2-ethoxy-2-oksoetilidenaminooksi) dimetilaminomorfolinokarbeniya (COMU), ethyl 2-cyano-2- (2-nitrobenzolsulfoniloksiimino) 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 of Formula I, SARPODEX ™, DERADEX ™ or DERAPHAN ™

Compound 50 and compound 149 form a mixture of diastereomeric salts based on the salt of dextromethorphan (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 chromatographic techniques referred to and described in this description.

[00363] In one embodiment, a method is provided for separating the 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 an 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 more soluble. degree than the other diastereomer, and separating the diastereomer of lower solubility from the mixture. The present invention disclosed herein thus includes methods for separating diastereomers, the use of such methods, and products obtained and obtained using such methods.

[00365] In another embodiment, this separation method can be carried out with a compound such as a diastereomeric mixture of a DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ salt, 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 the separation of the diastereomer with lower solubility from the mixture.

[00366] In yet another embodiment, there is provided a method for isolating 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 of carrying out an industrial operation selected from the group consisting of a standardization operation, a cleaning operation, a washing operation, a drying operation, a particle removal operation, a dissolution operation, a dispersing operation, a heat transfer operation, and an isolation operation involving bringing a mixture containing a pair of diastereomers DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™, 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 the use of the isolated diastereomer in the 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 the 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 isolating the diastereomer of lower solubility 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. Extraction of a liquid by a liquid involves transferring a mass from one liquid phase to a second immiscible liquid phase and is carried out using an extractant or solvent.

[00371] The components in the liquid mixture can be separated by a method, such as liquid-liquid extraction, in a single equilibrium (or theoretical) stage, or in multiple stages. The equilibrium or theoretical stage is a device that provides thorough mixing of the raw material with an immiscible liquid so that the concentrations reach equilibrium, followed by physical separation of the two immiscible liquid phases. The one-stage device can be a separating funnel or a shaking vessel that provides thorough mixing of the raw material with an immiscible extractant. After thorough mixing, one or both of the liquid phases can be recovered, for example by decantation.

[00372] Multi-stage liquid separation devices can be cross-flow devices or counter-flow devices. In a multistage device, the raw material enters the first equilibrium stage and contacts the extractant. The two liquid phases are mixed, the droplets of one phase are suspended in the second phase, and then the two phases are separated, and DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ from the first stage are contacted with an 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 achieved, and (3) liquid separation is repeated until the desired purity of the component of interest is achieved. The number of equilibrium stages will depend on the desired purity, as well as the solubility of the components in the extractant and the consumption of raw materials and extractant.

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

[00374] Equipment used for liquid-liquid extraction can be classified as "staged" or "continuous (differential) contact" equipment. Staged equipment is also called mixer-settler. Mixing of liquids occurs by contact of the feedstock with the extractant, and the resulting dispersion settles as the two phases separate. Mixing can take place using baffles or stirrers, and the separation process can be carried out batchwise or in a continuous flow. The settling tanks can be simple gravity settling tanks such as decanters, or they can be cyclones or centrifuges that increase the sedimentation rate.

[00375] Continuous contact equipment is typically configured for multi-stage countercurrent contacting of immiscible liquids without re-separating the liquids from each other between stages. Instead, liquids remain in continuous contact as they pass through the equipment. The counterflow is maintained by the density difference of the liquids and either by gravity (vertical towers) or centrifugal force (wringing-out centrifuges). Gravity extractors can be classified as spray towers, packed towers, or perforated trays (sieve trays) towers. Gravity towers also include rotating stirrer towers and pulsed towers as is known in the art.

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

[00377] Mass transfer from one liquid phase to a separate immiscible phase by liquid-liquid extraction and equipment for use therein are discussed further in references such as Robbins and Cusack, "Liquid-Liquid Extraction Operations and Equipment" in Perry's Chemical Engineers' Handbook , 7 ^th 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 employed in the separations described herein include the recovery of acetic acid from water using ethyl ether or ethyl acetate as extractant (Brown, Chem. Engr. Prog. (1963) 59:65) and extraction of phenolic compounds from water using methyl isobutyl ketone as an extractant as described Scheibel in "Liquid-Liquid extraction" (Perry and Weissburg (eds), Separation and Purification, 3 ^rd 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 a solvent (if solvent is used in separations) alters the formation, composition, and recognition of crystal enantiomers (Sakai et al., Tetrahedron: Asymmetry, 14, 3716 (2003); incorporated by reference in its entirety). The composition of the crystalline diastereoisomers is also influenced by the pH of the reaction mixture (Fogassy et al., J. Chem. Res., S 11, 346 (1981); Fogassy et al., J. Chem. Soc. Perkin Trans. 2. (1988), incorporated by reference in its entirety). The purity of the (de) diastereoisomer can be improved with a mixture of structurally related resolving agents. This is often referred to in the literature as "Dutch separation" (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 the solvent unsuitable for the separation of diastereoisomers contains partially structurally similar compounds with the solvate-forming solution (US Patent Application Nos. 214720, Chem. Abs. 124, 117097 (1995); US 2133894; Chem. Abs. 139, 90595 (2001) ), incorporated by reference), separation of enantiomers was made possible by fractional precipitation of the diastereoisomeric 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 the racemate melts crystallize to form enantiomeric mixtures, the eutectic composition usually 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 a binary system. If the original isomeric composition (e0) 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 the diastereomers of a compound. If, for example, the diastereomers of DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ 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 liquid over a wide range of temperatures. They are also generally insoluble in non-polar hydrocarbons; not miscible with water (depending on the anion); and are highly ionized (but have a low dielectric density). Ionic liquids have essentially no vapor pressure, most are stable in air and water, and can be either neutral, acidic, or basic.

[00381] The cation or anion of an ionic liquid useful herein can in principle be any cation or anion with the proviso that the cation and the anion together form an organic salt that is liquid at about 100 ° C or below. The properties of the ionic liquid can, however, be adjusted by changing the type of cation and / or anion. For example, the acidity of the ionic liquid can be controlled by varying molar 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 (eg, an alkyl halide) to form a quaternary ammonium salt and ion exchange or other suitable reactions with various Lewis acids or their conjugated 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 since larger groups can form fusible solids rather than ionic liquids. Various triarylphosphines, thioethers and cyclic and acyclic 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 anhydride, tetrachloroaluminate anhydride, tetrachloroaluminium peroxide anhydride, tetrachloroaluminium peroxide iron, zinc trichloride anion, 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 a neutralization reaction of an acid 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 useful ionic liquids are described in sources 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, an ionic liquid library can be obtained, for example, by making various alkyl derivatives of a particular cation (such as a quaternary ammonium cation) and varying the bound anions (US 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 the combined sorbent in a solid phase extraction (SPE) procedure.

[00386] In one embodiment, diastereomers can be separated by extractive distillation, where an adjuvant that changes the partial pressure of the different diastereomers to be separated to varying degrees provides easier separation of the diastereomers by distillation in good yield. The separation can be carried out using fractionation 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 chromatography (NP-HPLC) separations can be used to separate the diastereomers of the present invention. Columns that can be used in enantiomeric separation may be Primesep C, NUCLEOSIL, cellulose based chiral HPLC columns, SHISEIDO Chiral CD-Ph, etc. (Fekete et al., Comparative Study Separation of Diastereomers by HPLC, Chromatographia, 57, No.

(February 2003), U.S. Patent Application No. 7119211 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 a suitable solvent and dissolving therein. The solution thus obtained is added to the complex magnesium aluminosilicate to obtain a pasty mass. Although the above steps are carried out at about room temperature, elevated temperatures can be used as needed. 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 a solution of a compound of Formula I, DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ that is prepared in the first step. The paste thus obtained can be easily incorporated into a traditional caramel-forming mass, which in turn can be processed using traditional 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 herein are within the scope of the present invention. For example, in preparing the compositions of the present invention, a racemate or enantiomerically pure compound of Formula I, DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ and a complex magnesium aluminosilicate can be mixed and then added to a suitable solvent to form a paste therewith. Sodium chloride and sodium saccharin can be added to the dextromethorphan-complex magnesium aluminosilicate mixture before the mixture is converted to a paste. Alternatively, sodium chloride and sodium saccharin can be added to the paste. In addition, suitable flavors and colors can be added either to the dry mix or to the paste. In carrying out the present invention, any medicinally suitable organic solvent can be used which is suitable for pharmaceutical use and in which the compound of Formula I, DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ is soluble. Thus, for example, organic solvents such as propylene glycol, glycerin, 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, etc. As the colorant, any colorant that is suitable for use in food and medicine can be used. The amount of colorant and the amount of flavoring used in formulating the composition of the present invention vary.

[00392] In an embodiment, the composition comprises about 0.3 g to about 1.5 g, about 1.0 g, of a thickening agent; about 1 g to about 10 g, about 2.5 g, 1,2-propylene glycol as solvent; from about 0.12 g to about 0.19 g or 0.15 g of at least one paraben preservative, such as methylparaben; 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 a sugar alcohol solution; 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 about 2.10 g (amount 1: 6 of the 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 a sufficient amount of water to bring the volume up to 100 ml.

[00393] In another embodiment, suitable thickening agents include tragacanth; bentonite; gum arabic and lower alkyl ethers of cellulose (including hydroxy and carboxy derivatives of cellulose ethers). Illustrative 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 methyl paraben to propyl paraben ratio of from about 2.5: 1 to about 7.5: 1. In another embodiment, the ratio of methyl paraben to 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 can 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 for delivery, when administered in one dose every 12 hours, of an antitussive effective amount of a compound of Formula I, DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™ for a period of approximately 12 hours, to a patient who needs such an administration.

[00396] In an embodiment, the formulation comprises an adult dose of 20 ml, which contains about 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 agent to the resin is 1: 6, and 2.10 g of resinate is present for every 100 ml of the composition. The dosage can be varied in a manner similar 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 a day.

[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 dysocilpine (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-phenylpropane-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) decahydroisoquinoline-3-carboxylic acid, (S) -а-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 its entirety).

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

SYNTHESIS OF THE COMPOUNDS OF THE PRESENT INVENTION

[00400] All reactions were carried out in an argon atmosphere with dry solvents, unless otherwise indicated. 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 (ethanol solution of phosphoromolybdic acid) or ANIS (ethanol solution of para-anisaldehyde) as an imaging agent. The products were purified by column chromatography through silica gel 60 (0.060-0.200 mm). NMR spectra were acquired on a Bruker AVANCE III 500 MHz (Bruker Corporation, Billerica, MA, USA) using residual non-deuterated solvent or TMS (tetramethylsilane) as 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 (with a planar structure) by Greve cyclization to give the corresponding morphinane, 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-methylmorphinane. Dextromethorphan is readily soluble in 96% ethanol and substantially insoluble in water. Dextromethorphan can be a monohydrated 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 left to crystallize. The compound of Formula I and the positive dextromethorphan cation will 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 sarpogrelate in chloroform at 70 ° C. Salt was precipitated from the hot solution by the addition of 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 ] oxy-4-oxobutanoate salt and recrystallized from aqueous dimethylformamide (DMF) to obtain 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 of carbon tetrachloride. Receiving. Glyceryl tristearate was dissolved in warm carbon tetrachloride at 55-60 ° C. The compound of formula I, its derivative, SARPODEX ™ or its derivative is then added and suspended in solution. The slurry was then spray dried using an inlet temperature of 90 ° C and an outlet temperature of 40 ° C. The resulting coated compound of Formula I with DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or DERAPHAN ™, having an average particle size of about 10 to about 200 microns, is then suspended in the following aqueous carrier medium.

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 Sucaril, 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. The tragacanth was then added to this solution and dispersed evenly. The dispersion was heated again, cooled, and the sorbitol solution, methylcellulose solution in water, and artificial "black currant" flavor were then added with stirring to form a carrier medium. The coated compound of formula I, DERATINE ™, SARPOTINE ™, SARPODEX ™, DERADEX ™ or coated DERAPHAN ™ is then added to the above carrier medium and mixed until the particles are completely wetted and evenly dispersed.

[00406] The controlled release composition of the present invention was characterized by a content of 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, for example, a biodegradable aliphatic polyester, or aliphatic poly (carbonate), poly (lactic acid), copolymer of lactic acid and glycolic acid, poly (caprolactone), poly (hydroxybutyric acid) and the like.

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

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

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

[00411] The polymer material applied to the surface of the stent is amorphous. The polymer material applied to the surface of the stent is an amorphous biodegradable polymer material. The polymer material is poly (lactic acid) or a copolymer of lactic acid and glycolic acid, which is biodegradable. The polymeric material also contains a release-promoting aid that aids in the release of the drug that has been applied. The auxiliary agent that aids in the release of the drug is a tartrate ester or malate ester, or a monoester or diester of glycerol. The surface of the metal forming 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 SARPOMALATE. Malic acid is a component of many foods that we eat every day. Although it occurs as a naturally occurring organic compound in a variety of fruits, many are starting to take malic acid supplements to improve overall health as well as treat a variety of conditions. Currently, this acid is most often 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 be beneficial to health and is found 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 asymmetric carbon usually exist in the form of an optically active material and exhibit physiological activity that is 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 over 30 min 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 racemic 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 SARPOMETHIONATE. 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 racemate or enantiomerically pure M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated over 30 min to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 diastereomerically 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic or optically pure sarpophthalate, respectively depending on 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 racemate or enantiomerically pure M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated over 30 min to 25 ° С, stirred the mixture at 25 ° С 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 racemic or optically pure sarpotirosinate, respectively depending on M1, to give compounds 41-43. Racemic sarpotirosinate can be purified by crystallization and / or chiral chromatography to provide optically pure sarpotirosinate.

[00418] EXAMPLE 10. OPTICALLY PURE SARPOTRIPTOPHANATE. 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 racemate or enantiomerically pure M1 (0.50 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml), heated over 30 min to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 provide 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 SARPHEAT. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 PURE SARPOADIPATE. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 provide optically pure sarpopimelate.

[00424] EXAMPLE 16. OPTICALLY PURE SARPOSEBACINATE. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic or optically pure sarposebacate, respectively depending on M1, to give compounds 62-64. Racemic sarposebacate can be purified by crystallization and / or chiral chromatography to give optically pure sarposebacate.

[00425] EXAMPLE 17. OPTICALLY PURE SARPOFORMIATE. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 provide 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic or optically pure sarpopropionate, respectively depending on M1, to give compounds 71-73. Racemic sarpopropionate can be purified by crystallization and / or chiral chromatography to provide optically pure sarpopropionate.

[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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 SARPOENANTATE. 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 min 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 racemic 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 SARPOPELARGONAT. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 provide optically pure sarpopelargonate.

[00434] EXAMPLE 26. OPTICALLY PURE 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 SARPOISOPHTHALATE. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 SARPOTEREPHTHALATE. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 SARPOSALICYLATE. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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 SARPOACETYL SALICYLATE. 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 racemate or enantiomerically pure M1 (0, 50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 ml), heated for 30 minutes to 25 ° С, stirred the mixture at 25 ° С 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 racemic 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) and CH ₃ CN (5 mL) was added Aspirin (0.55 mmol, 1.1 eq.) and 1, '- carbonyldiimidazole (CDI, 0.60 mmol, 1.2 eq.) at 25 ° C. The mixture was stirred for 12 h 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 sarpoacetylsalicylate, which is compound 107, can be purified by crystallization and / or chiral chromatography to provide optically pure sarpoacetylsalicylates 108 and 109.

[00441] EXAMPLE 33. 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 h, 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 sarpoacetylsalicylate, which is compound 107, can be purified by crystallization and / or chiral chromatography to provide optically pure sarpoacetylsalicylates 108 and 109.

[00442] EXAMPLE 34 To a stirred solution of acetyle 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 increased to 25 ° C. The mixture was stirred at the same temperature for 12 hours. Then, to another M1 stirred solution of 3 (0.50 mmol, 1.0 eq.) In CH ₂ Cl ₂ (5 mL) was added pyridine (0.24 mL, 3.0 mmol, 6.0 equiv.) and a previously prepared aspirinyl chloride solution. The mixture was stirred for an additional 12 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 compound 107. Racemic sarpoacetyl salicylate, which is compound 107, can be purified by crystallization and / or chiral chromatography to provide optically pure sarpoacetylsalicylates 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, which is compound 107, can be purified by crystallization and / or chiral chromatography to provide optically pure sarpo acetyl acidicylates 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-ietoxyphenethyl) phenoxy) propan-2-yl acetate (compound 164): colorless oil; R _f = 0.19 (silicate, 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 = 7.4 Hz, 1H), 6.84 (t, J = 8.9 Hz 2H), 6.78 (t, J = 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 = 0.9 Hz J ₂ = 8.4 Hz 1H), 6.91-6.88 (m, 2H), 6.81-6.77 (m, 1H), 6.76-6, 72 (m, 3H), 5.70-5.66 (m, 1H), 4.30-4.29 (m, 2H), 3.76 (s, 3H), 2.91-2.82 ( m, 6H), 2.40 (s, 6H) ppm; ¹³ C-NMR (125 MHz CDCl ₃ ): δ = 169.6, 161.8, 159.7, 156.3, 144.0, 136.0, 130.5, 130.4, 130.1, 129 , 4, 127.4, 121.2, 120.9, 119.4, 117.8, 114.3, 112.5, 111.3, 111.2, 71.2, 67.6, 59.4 , 55.2, 46.1, 36.5, 32.8 ppm; HRMS (EI): 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 Deutering an H-Compound to Form a D-Compound. 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 with 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 of 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% total volume) was diluted with 5 ml saturated NaHCO ₃ and 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 the addition of a few drops of 4M HCl in dioxane. The salt was triturated with ether and the solvents were evaporated to give the HCl salt of the deuterated compound. A 9.6 ml aliquot (80% total volume) was diluted with 40 ml saturated 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 a refrigerator.

[00450] EXAMPLE 41 PREPARATION OF UNPURISHED SARPOGRELAT 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-neck 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 sarpogrelate hydrochloride product and dried under reduced pressure (-0.08-0.1 MPa) at 45-55 ° C to obtain crude sarpogrelate hydrochloride in an amount of 14.7 g, yield 86%, HPLC purity 98.6%.

[00451] EXAMPLE 42. PURIFICATION OF UNPURIFIED SARPOGRELATE HYDROCHLORIDE. 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, stirring continued 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 UNPURCHASED SARPOGLATE HYDROCHLORIDE. Crude sarpogrelate hydrochloride in an 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 little the amount of methyl ethyl ketone to give a white fluffy solid, 55-65 ° C and dried under reduced pressure for 24 hours to obtain 4.55 g of sarpogrelate hydrochloride, 91% yield, HPLC purity 99.7%.

[00453] EXAMPLE 44. PURIFICATION OF UNPURIFIED SARPOGRELATE HYDROCHLORIDE. 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 little the amount of methyl ethyl ketone to give a white solid, 55 ~ 65 ° C, and dried under reduced pressure for 24 hours to obtain 4.5 g of sarpogrelate hydrochloride, 90% yield, 99.8% HPLC.

[00454] EXAMPLE 45. PURIFICATION OF UNPURIFIED SARPOGRELATE HYDROCHLORIDE. The crude product, which is sarpogrelate hydrochloride in an amount of 5 g, was combined with 20 ml of butanone, heated with stirring until dissolved 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 chromatography on chiral stationary phases (CSP) is considered as a suitable alternative to most traditional 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, 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 (Jan 23, 2009); Maier et al., Separation of enantiomers: needs, challenges, perspectives, Journal of Chromatography A, Volume 906, Issues 12, pages 3-33 (Jan 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 309-3 17 (Jul 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 (Dec 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 on a scale ranging from analytical to preparative by this technique.

[00456] Fluid moving bed chromatography can be used to separate the enantiomers of the compounds of the present invention, suitable for all production scales, from laboratory to pilot 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) Sarpogrelate 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 yielding 5.30 mg enantiomer (99% purity 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, 1 H) 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 DEXTROMETORPHANE MALATE. Dextromethorphan 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 DEXTROMETORPHANE METHIONATE. Dissolve the free base dextromethorphan (0.05 mol) in 20 ml acetone, add the solution to a solution of methionine or N-acylmethionine (0.05 mol) in 60 ml hot water, and then cool the reaction mixture to separate crystals by filtration, and dried.

[00460] EXAMPLE 49 DEXTROMETORPHANE PHTHALATE. Dextromethorphan 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 DEXTROMETORPHANE MALONATE. Dextromethorphan 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. DEXTROMETORPHANE TYROSIATE. Dissolve the free base dextromethorphan (0.05 mol) in 20 ml acetone, add the solution to a solution of tyrosine or N-acyltyrosine (0.05 mol) in 60 ml hot water, and then cool the reaction mixture to separate crystals by filtration, and dried.

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

[00464] EXAMPLE 53 DEXTROMETORPHANE MALEATE. Dextromethorphan 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 DEXTROMETORPHANE SUCCINATE. Dextromethorphan 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 GLUTARATE / DEXTROMETORPHANE 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 ADIPATE OF DEXTROMETORPHANE. Dextromethorphan 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 DEXTROMETORPHANE PIMELATE. Dextromethorphan 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 DEXTROMETORPHANE SEBACINATE. Dextromethorphan 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 DEXTROMETORPHANE FORMIATE. Dextromethorphan 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 DEXTROMETORPHANE ACETATE. Dextromethorphan 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. PROPIONATE OF DEXTROMETORPHANE. Dextromethorphan 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 DEXTROMETORPHANE BUTYRATE. Dissolve dextromethorphan free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of butyric acid (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.

[00474] EXAMPLE 63 VALERATE OF DEXTROMETORPHANE. Dissolve dextromethorphan free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of valeric acid (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.

[00475] EXAMPLE 64. DEXTROMETORPHANE CAPROATE. Dissolve dextromethorphan free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of caproic acid (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.

[00476] EXAMPLE 65 DEXTROMETORPHANE ENANTHATE. Dissolve dextromethorphan as the 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.

[00477] EXAMPLE 66 DEXTROMETORPHANE CAPRILATE. Dextromethorphan 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. PELARGONATE OF DEXTROMETORPHANE. Dextromethorphan 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 DEXTROMETORPHANE CAPRATE. Dextromethorphan 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 DEXTROMETORPHANE OXALATE. Dextromethorphan 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 DEXTROMETORPHANE ISOPHTHALATE. Dextromethorphan 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. DEXTROMETORPHANE TEREPHTHALATE. Dissolve dextromethorphan free base (0.05 mol) in 20 ml of acetone, add the solution to a solution of terephthalic acid (0.05 mol) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.

[00483] EXAMPLE 72 DEXTROMETORPHANE 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 ACETYL DEXTROMETORPHANE 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. DEXTROMETORPHANE DYACID ADDITION SALT AND COMPOUNDS SELECTED FROM COMPOUNDS OF FORMULA I CONTAINING FDIc AND FDId (COMPOUNDS 219-269).

The free base (FDIc or FDId) (0.25 mol) and dextromethorphan (0.05 mol) were dissolved in 20 ml of acetone, the solution was added to a solution of di- or triacid (0.05 mol) in 60 ml of hot water, and then the reaction was cooled mixture to separate crystals by filtration and dried. Di- and triacids include, but are not limited to, adipic acid, aspartic acid, N-acylaspartic acid, citric acid, fumaric acid, galactonic acid, glutaric acid, glutamic acid, N-acylglutamic acid, glucaric acid, malic 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 - Adipic acid addition salt (FDIc or FDId) and dextromethorphan;

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

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

[00489] EXAMPLE 77 — Citric acid addition salt (FDIc or FDId) and dextromethorphan;

[00490] EXAMPLE 78 — Fumaric acid addition salt (FDIc or FDId) and dextromethorphan;

[00491] EXAMPLE 79 — An addition salt of galactic acid (FDIc or FDId) and dextromethorphan;

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

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

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

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

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

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

[00498] EXAMPLE 86 — Mannonic acid addition salt (FDIc or FDId) and dextromethorphan;

[00499] EXAMPLE 87 — An addition salt of mucinic acid (FDIc or FDId) and dextromethorphan;

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

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

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

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

[00504] EXAMPLE 92 — Terephthalic acid addition salt (FDIc or FDId) and dextromethorphan;

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

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

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

[00508] EXAMPLE 96 — Tartaric acid addition salt (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-methylthiophosphate;

[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-ethyldithiophosphate;

[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 - ((tert-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- (dimethylamino) -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) oxy) 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) oxy) 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 2-chloro-1- (2,4,5-trichlorophenyl) vinyl - (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propane-2- yl) oxy) methyl) hydrogen phosphate;

[00546] EXAMPLE 133 - compound 938 2-chloro-1- (2,4,5-trichlorophenyl) vinyl - ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;

[00547] EXAMPLE 134 - compound 939 2-chloro-1- (2,4,5-trichlorophenyl) vinyl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propane -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 2-chloroethyl - ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) - (R ) -fluorophosphate;

[00562] EXAMPLE 149 - compound 954 2-chloroethyl - ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) - (R ) -fluorophosphate;

[00563] EXAMPLE 150 - compound 955 3-chlorobutan-2-yl - (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) - (R ) -fluorophosphate;

[00564] EXAMPLE 151 - Compound 956 3-chlorobutan-2-yl - ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl ) - (R) -fluorophosphate;

[00565] EXAMPLE 152 - compound 957 3-chlorobutan-2-yl - ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl ) - (R) -fluorophosphate;

[00566] EXAMPLE 153 - compound 958 ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl- (S) - ((((E) -chlorofluoromethylene ) 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 2-chloroethyl - (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) - (E) - (( (chlorofluoromethylene) amino) oxy) fluorophosphate;

[00570] EXAMPLE 158 - Compound 962 2-chloroethyl - ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) - (E ) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;

[00571] EXAMPLE 159 - compound 963 2-chloroethyl - ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) - (E ) - (((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 1-chloropropan-2-yl - ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl ) - (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;

[00574] EXAMPLE 162 - Compound 966 1-chloropropan-2-yl - ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl ) - (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;

[00575] EXAMPLE 163 - compound 967 3-chlorobutan-2-yl - (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) -propan-2-yl) oxy) methyl) - ( E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;

[00576] EXAMPLE 164 - compound 968 3-chlorobutan-2-yl - ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl ) - (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;

[00577] EXAMPLE 165 - compound 969 3-chlorobutan-2-yl - ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl ) - (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate.

[00578] EXAMPLE 166 - compound 970 ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl- (2,2,2-trichloro-1-hydroxyethyl ) phosphonate.

[00579] EXAMPLE 167 - compound 971 ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl- (2,2,2- trichloro-1-hydroxyethyl) phosphonate;

[00580] EXAMPLE 168 - compound 972 ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl- (2,2,2- 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 compound 4- (tert-butyl) -2-chlorophenyl - ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propane-2- 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) isopropyl phosphoramidate;

[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 (US 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 according to a three-stage synthesis scheme using readily available and inexpensive starting materials (camphor) with very high enantiomeric purity (> 99.9%). 3.9 g (0.1 g atoms) of metallic potassium are added to 100 ml of anhydrous xylene and the mixture was 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 made alkaline to pH 10 with 20% aqueous potassium hydroxide solution while 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%) of a pale yellow oil, BP: 131 ° -135 ° C / 26.7 Pa, hydrogen fumarate, mp: 180 ° -182 ° C. Enantiomeric separation is 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-acting inverse agonist of 5-HT _2A / 5-HT2C receptors at clinically relevant doses and does not induce 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 dopamine D2 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 to these receptors. Compound 829 was found not to increase prolactin levels at least over the dose range that encompasses therapeutically significant 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 well characterized preclinically, and a large body of evidence points to a CNS target (s) for the pharmacodynamic activity of deramcyclane.

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) describe the profile of effects 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 the binding of [3H] -mesulergin to the choroidal 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). Doses of compound 829, which cause almost maximum inhibition of the binding of [3H] -mesulergin (0.5 mg / kg), are in the lower dose range providing 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). Consequently, compound 829 is expected to induce antidepressant, anxiolytic, appetite stimulating, and other effects in humans, all of which are of therapeutic value 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] With regard to compound 829, there are data on therapeutic effects from clinical studies of 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), confirming the claim that compound 829 is a compound active in the CNS that is capable of reaching its target (s). In the intervention population (n = 208), doses of 30 mg / day and 60 mg / day deramcyclane provided clinically significant improvements in the overall score on the Hamilton HAM-A Anxiety Scale after 8 weeks of treatment, reaching statistical significance on 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 treatment groups at 30 mg / day and 60 mg / day compared to patients in the placebo group.

[00593] Compound 829 is also a CYP 2D6 inhibitor based on human studies using desipramine as a substrate. In this double-blind, randomized, 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 a 100 mg single dose of desipramine. Re-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- (dimethalamino) -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 mass: 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; Oh, 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 [cm ³ / mol]; Gibbs energy: 126.8 [kJ / mol]; Log P: 5.06; MR: 160.74 [cm ³ / 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 mass: 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; Oh, 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 [cm ³ / mol]; Gibbs energy: 126.8 [kJ / mol]; Log P: 5.06; MR: 160.74 [cm ³ / 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-oxobutanoate.

Chemical formula: C ₃₄ H ₄₆ N ₂ O ₅ ; exact mass: 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; Oh, 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 [cm ³ / mol]; Gibbs energy: 126.8 [kJ / mol]; Log P: 5.06; MR: 160.74 [cm ³ / 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-methoxyphene1yl) phenoxy) propan-2-yl-4 - ((3,5-dimethyladamantan-1-yl) amino) -4-oxobutanoate. Chemical formula: C ₃₆ H ₅₀ N ₂ O ₅ ; exact mass: 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 [cm ³ / mol]; Gibbs energy: 132.66 [kJ / mol]; Log P: 6; MR: 169.53 [cm ³ / 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 1- (dimethylamino) -3- (2- (3-methoxyphene1yl) phenoxy) propan-2-yl-4 - ((3,5-dimethyladamantan-1-yl) amino) -4 -oxobutanoate. Chemical formula: C ₃₆ H ₅₀ N ₂ O ₅ ; exact mass: 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 [cm ³ / mol]; Gibbs energy: 132.66 [kJ / mol]; Log P: 6; MR: 169.53 [cm ³ / 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-methoxyphene1yl) phenoxy) propan-2-yl-4 - ((3,5-dimethyladamantan-1-yl) amino) -4-oxobutanoate. Chemical formula: C ₃₆ H ₅₀ N ₂ O ₅ ; exact mass: 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 [cm ³ / mol]; Gibbs energy: 132.66 [kJ / mol]; Log P: 6; MR: 169.53 [cm ³ / 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) ettsh) succinate. Chemical formula: C ₂₈ H ₃₇ Cl ₃ NO ₉ P; exact mass: 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; Oh, 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 mass: 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; Oh, 21.53; P, 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 mass: 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; Oh, 21.53; P, 4.63.

BIOLOGICAL RESEARCH

[00603] Biological studies were carried out using compounds of formula I. an example of which is 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 BASIC EFFECTS OF 5HT2A RECEPTOR BLOCKADE. Neuroleptic drugs weaken motor hyperactivity caused by psychostimulants and psychotomimetic drugs in laboratory rodents. Although hyperactivity caused by dopaminergic agents such as d-amphetamine is reversible with both typical and atypical antipsychotics currently used in treatment, 5HT2A receptor antagonists are more effective against hyperactivity caused 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). Locomotion data were collected over a 15 minute period in a lighted room. Mice were not previously housed in cages to study motor activity. Immediately before placing the mice in the motor test chambers, muscle relaxation / ataxia effects were determined by bringing each of the front paws of the mouse into contact with a horizontal wire while holding the mouse by the base of the tail. Mice were required to bring at least one hind paw into contact with the wire for 10 seconds to gain the "passed" status, and those unable to do so were considered ataxic. Each dose or combination of doses was tested in 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 subcutaneously. [F (7.63) = 6.010; p <0.0001], corresponding to a similar neuroleptic 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; included 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 thrice daily (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 sarpogrelate is significantly higher than that of dextromethorphan. Given that the molecular weight of sarpogrelate is approximately 429 and the molecular weight of dextromethorphan is approximately 271, the combination of dextromethorphan and sarpogrelate at current clinical doses does not result in a 1: 1 molar ratio. However, such a molar ratio of 1: 1 is a prerequisite for the preparation and use of dextromethorphan sarpogrelate salts. Since the current clinical use of sarpogrelate is for indications related to the peripheral system (not CNS) (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 coadministration with dextromethorphan as arpogrelate dextromethorphan salt or as a 1: 1 molar mixture. In laboratory animals, sarpogrelate is usually given at doses of 25 mg / kg or more to induce peripheral effects (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 (6): 833-844 (2016); incorporated by reference in its entirety). An example of a higher CNS activity of sarpogrelate is provided in the example where sarpogrelate is administered to Spreg-Doley rats at doses of 0.3, 1 and 3 mg / kg over 30 minutes. before administration of the 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 when a compound of formula I is co-administered, SARPODEX ™, DERADEX ™ or DERAPHAN ™.

[00606] The compound of formula I, as well as both enantiomers of its primary metabolite M1, are antagonists of the 5HT2A receptor (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 5HT2A receptors in the CNS, rats were pre-treated with 0.1 mg / kg MK801, and the attenuation of MK801-induced locomotor hyperactivity was monitored over the dose range of the compound of Formula I in a 120 min test conducted with conventional devices for monitoring motor activity.

[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 metabolite DO. Therefore, DEX is less likely to induce phencyclidine-like locomotion than DO. 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) produced mild hyperactivity only at higher doses after approximately 45 minutes. after treatment. DEX and DO reversed the 10 mg / kg PCP-induced locomotor stimulation. DO pretreatment 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 A 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 metabolic studies for the detection of inhibitory activity against 2D6 biologically active substances and drugs. In a specially designed series of studies, a compound of Formula I was administered prior to DEX and locomotor activity in rats was monitored for 120 minutes to show that the compound of Formula I prevented the onset of hyper activity 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 provide the most optimal balance of hyperactivity inhibition and DEX metabolism inhibition effects.

[00609] EXAMPLE 187. BLOOD GLUCOSE AND INSULIN SENSITIVITY. Unlike sulfonylurea drugs, which induce significantly higher basal insulin secretion compared to carrier medium 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, application of DEX with drinking water (4 mg / ml) overnight did not alter either basal blood plasma insulin or fasting blood glucose concentration in mice, but resulted in significantly higher glucose-induced plasma insulin concentrations and tolerance to glucose than that observed in controls without DEX treatment (glucose was administered intraperitoneally at 1.5 mg / kg body weight).

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

[00611] To test whether DEX can 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, crossover phase proofing trial was performed 2a with a 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 took 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 after drug intake 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 higher fasting serum insulin concentrations or lower fasting blood glucose concentrations compared to placebo, and did not induce any severe hypoglycemic events up to the 270 mg dose. In contrast, after oral glucose administration, both DEX doses of 60 and 270 mg resulted in significantly (P <0.05) higher maximum serum insulin concentrations compared to those observed with placebo.

[00612] In addition, the major endpoint was reached for 270 mg DEX; namely, the area under the blood glucose concentration curve during the first 2 hours. OGTT (AUC1 glucose-3 hours) was significantly (P <0.05) less in people who received a 270 mg dose of DEX than in the same people who received a placebo on the other 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 prior treatment with a 5-HT2A receptor antagonist ketanserin and a peripheral 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 double antagonism of dopamine and serotonin receptors have been associated with an increased risk of impaired glucose tolerance and diabetes mellitus. While this is largely attributed 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 recruited into a double-blind, placebo-controlled, crossover study with a single dose of 40 mg of the 5-HT2 antagonist ketanserin versus placebo. Insulin sensitivity was measured by means of the euglycemic hyperinsulinemic clamp test. Subjects were treated with the alpha 1-adrenergic receptor antagonist phenoxybenzamine in both parts of the study to monitor the effects of ketanserin at the 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 .; p = 0.047).

[00615] Thus, the combination of DEX and 5-HT2A receptor antagonists can lead to synergistic effects on blood glucose and insulin sensitivity, which may be undesirable in the case of long-term treatment, as it can have unwanted metabolic side effects, qualitatively similar to those observed in patients who have been treated with antipsychotic drugs. These effects may limit the dose of DEX and 5-HT2A receptor antagonists that can be safely administered in 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 blockers of NMDA receptor channels, and it has been suggested that inhibition of the NMDA receptor on pancreatic islets is 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 stronger blocker of NMDA receptor channels 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 manifestation of DEX's effects on glucose-stimulated insulin secretion and glucose tolerance and thus the risks of metabolic side effects.

[00618] The second approach is to select an inverse agonist or antagonist of the 5HT2A receptor that has the best filling ratio of central to peripheral 5HT2A receptors. Therefore, an inverse agonist or antagonist of the 5HT2A receptor is chosen to obtain a therapeutically significant filling of central 5HT2A receptors at doses that have the lowest risk of producing unwanted metabolic effects such as without limiting 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 hereditary obesity rat strain, which is a model of type 2 diabetes, was randomly divided into 2 groups; a group treated with 30 mg / kg bw / day of a compound of formula I for 4 weeks (HTB group) and no treatment (control group). The glucose infusion rate was significantly increased in the HTB group compared to the control group. Blood glucose levels after 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 caused 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 men, 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 versus 9.2 +/- 2.0 microU / ml, p = 0.03).

[00622] The compound of formula I is rapidly metabolized to a metabolite that also has the properties of both a 5HT _2A receptor antagonist and a 2D6 inhibitor. Both enantiomers of the metabolite are biologically active and have the ability to block 5HT2A and 2D6 receptors. To find out which of the enantiomers has the most optimal properties for combining 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. Test substances were administered to male Sprague-Dawley rats (group size: 8 per group). Animals were tested after being deprived of food overnight and housed separately. The test substances were administered 60 minutes before the glucose load, i. E. after measuring baseline blood glucose. The animals were injected with glucose at 2 g / kg orally by gavage in TO after measuring blood glucose. Blood glucose was measured in a drop of blood collected from the tail tip incision using a commercially available glucosimeter at 8 time points: baseline (before treatment), TO (before glucose), and then after 15, 30, 60, 90, 120 and 180 minutes after glucose load.

[00623] EXAMPLE 188. EFFECTS OF FORMULA I SEPARATELY ON PATHOPHYSIOLOGY AD. The existence of links between chronic diabetic metabolic situation and risk and the emergence of pathophysiology of AD has long been suspected and 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 autopsy series, more than one third of all subjects clinically diagnosed with typical AD had signs 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 the therapy of AD beyond the currently approved drugs and mechanisms, as well as to address cognitive impairment by optimizing the latent diabetic metabolic situation or the fairly common type 2 diabetes in elderly subjects. Glycemic control is clearly believed to have an impact on 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 antidiabetic actions of the compounds of formula I described above, it is thus possible to try to obtain additional beneficial effects both in terms of symptoms and disease progression in AD and cognitive impairment predominantly of vascular origin (multiinfarction 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 to 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 to be justified also in the elderly population with several comorbidities.

[00626] EXAMPLE 189. STEREOSELECTIVE ELIMINATION OF PSYCHOSTIMULATOR-INDUCED IN VIVO HYPERACITY BY USING A CONNECTION. Locomotion data were collected over a 15 minute period in a lighted room. Mice were not previously housed in cages to study motor activity. Immediately before placing the mice in the motor test chambers, muscle relaxation / ataxia effects were determined by bringing each of the front paws of the mouse into contact with a horizontal wire while holding the mouse by the base of the tail. Mice were required to bring at least one hind paw into contact with the wire for 10 seconds to gain the "passed" status, and those unable to do so were considered ataxic. Each dose or combination of doses was tested in 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 subcutaneously. [F (7.63) = 6.010; p <0.0001], corresponding to a similar neuroleptic effect.

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

Inhibition constants (Ki) were calculated using the Cheng-Prusoff equation. Both enantiomers of sarpogrelate 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 sarpogrelate enantiomers (Table 1). There is no significant difference between enantiomers with respect to binding of the 5-HT2A receptor for sarpogrelate or its major metabolite.

[00628]

[00629] To confirm the ability of M1 enantiomers to induce effects that are significant for CNS diseases and which are known for agonists and inverse agonists of the 5-HT2A receptor, separate groups of female Wistar rats (n = 6-9), housed 4-5 per cage at standard colonial conditions in a room with free access to food and water, pretreated 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 medium, and then immediately placed in computer-controlled movement recording cameras (25 × 35.5 × 34 cm, L × W × H; transparent Plexiglas walls and opaque plastic floor; enclosed in sound-absorbing ventilated cells) for 60 minutes, during which cases of interruption of the infrared photocell (5 cm and 14 cm above the floor) were recorded as a measure of locomotor activity. MK-801 is a phencyclidine-like blocker of NMDA receptor channels commonly used in psychopharmacological research for new therapeutic agents, including new antipsychotics. Analysis of variance (ANOVA) revealed the presence of major M1 dose effects and interactions between M1 dose and MK-801 treatment factors for the (-) - enantiomer M1 [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, despite the absence of significant differences between the M1 enantiomers in binding to 5-HT _2A receptors, surprisingly, only one of the enantiomers showed efficacy in a preclinical model of psychomotor activation, which is known to be sensitive to blockade of the 5-HT2A receptor.

[00630] EXAMPLE 190. ELIMINATION OF MOTOR HYPERACTION CAUSED BY REMOVAL OF OLFACTOR BULBS IN RATS. In a specially designed series of studies, adult male Spreg-Dawley rats (Charles River, Germany) were subjected to bilateral removal of olfactory bulbs, performed under ketamine / xylazine anesthesia. The animals were allowed a recovery period of 14 days after surgery, while being cared for every day to avoid any aggressiveness that would otherwise have occurred. Sham-operated animals were treated in the same way, but the olfactory bulbs were left intact. Drug administration and locomotion testing were performed 4 times for each rat with a 72 hour gap between successive tests. Before each test, animals were first treated with dextromethorphan (0, 15, 30 or 60 mg / kg orally) and then 15 minutes later. sarpogrelate (1, 3 and 10 mg / kg, intraperitoneally), and after another 15 minutes. were placed in Opto-Varimex cages to record locomotor activity for 30 min. Hyperactivity in rats after removal of the olfactory bulbs was observed mainly during the early testing phase. 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 surgery factor and the dose factor of sarpogrelate [F (l, 88) = 5.04, p = 0.0273; F (3.88) = 5.02, p = 0.0029, respectively]. Post hoc paired comparisons (Sidak's multiple comparison test) confirmed that significant differences between rats with removed olfactory bulbs and sham-operated rats were observed only in rats that were pre-treated with a carrier medium instead of sarpogrelate before the test. Rats with removed olfactory bulbs, which were pretreated with 3 or 10 mg / kg sarpogrelate, spent less time walking after surgery compared to corresponding controls that received carrier medium instead of sarpogrelate. These anti-hyperactivity effects of sarpogrelate have been observed at doses that do not affect the activity of sham-operated rats and thus do not reflect a general non-specific motor impairment. Thus, unexpectedly, despite the fact that it was previously called a peripherally limited 5-HT2A receptor antagonist, characterized only by 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)), sarpogrelate has been observed to exhibit behavioral specific effects in reversing hyperactivity in rats following removal of the olfactory bulbs, a model commonly used for research drugs for the CNS, such as antidepressants.

[00631] EXAMPLE 191. INHIBITION OF METABOLISM OF DEXTROMETORPHANE IN VITRO AND IN VIVO. Dextromethorphan-O-demethylase activity was determined in human liver microsomes. Sarpogrelate (1.0E-8 M to 3.0E-5 M) or M-1 (concentration: 3.0E-9 M to 1.0E-5 M) and dextromethorphan were dissolved in acetonitrile and subsequently diluted with acetonitrile to the required concentrations to obtain a final concentration of the organic solvent of 1.0% in the incubation mixture. Incubation mixtures contained mixed human liver microsomes (final concentrations: 0.25 mg / ml), dextromethorphan and a NADPH-generating system (1.3 mM NADP +, 3.3 mM glucose-6-phosphate, 3.3 mM 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 means were used for analysis. IC50 values (concentration causing half of the maximum inhibition of control specific binding) and Hill's coefficients (nH) were determined by non-linear regression analysis of the competition curves obtained with the means of replicates using a curve fit according to Hill's equation. Both enantiomers of sarpogrelate inhibited CYP2D6 mediated O-demethylation of dextromethorphan (Table 4).

[00632]

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

[00634] A pharmacokinetic study was performed in male Wistar rats, which were cannulated in the jugular vein. Sarpogrelate hydrochloride was formulated in Pharmasolv: PBS buffer (5:95) and administered at a dose of 2 mg / kg IV. Blood samples were collected from the jugular vein using heparin as an anticoagulant at the specified time points: 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, and 6 hours. The bioanalytical LC-MS / MS method was used to simultaneously quantify sarpogrelate and M1 in blood plasma samples. After a 2 mg / kg intravenous bolus, the plasma level curves showed little interindividual 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 sarpogrelate was rapid as the highest M1 concentrations were measured at the first sampling time points. Despite the rapid formation, the concentrations of the free metabolite M1 were orders of magnitude lower in the bloodstream than that of the parent compound (the Ml / c ratio of arpogregates was 2.98 ± 0.597%). Thus, although the M1 enantiomers were significantly more potent inhibitors of 2D6 than the parent compound, the potential effect of M1 was reduced due to the low relative exposure of Ml, as evidenced by the plasma AUC ratio for M1 and sarpogrelate.

[00635] EXAMPLE 191. In a separate series of studies, the ability of sarpogrelate to inhibit dextromethorphan metabolism 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 hour light / 12 hour dark cycle with access to food and water as desired. Two to three days before sampling, the rats received a jugular vein catheter, and then the rats were treated once with carprofen (5 mg / kg) immediately after surgery, and the catheters were rinsed 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 a tube, followed immediately by an intravenous bolus injection of sarpogrelate (1, 3, or 10 mg / kg; racemate or one of the enantiomers) or carrier medium via the vascular access port at t = 0 h. Blood samples were collected at four time points up to 6 hours after dextromethorphan administration. The sample size was 80 μL of Li-heparin whole blood / time point, i.e. 40 μL of blood plasma with Li-heparin / time point. Whole blood samples were stored on ice until centrifugation (10 min at 3000 g, 4 ° C). Blood plasma was obtained within 45 minutes. after collection, frozen at -20 ° C and stored at this temperature until processed for LC-MS analysis.

[00636] As shown in Figure 10, in rats treated with sarpogrelate (racemate or enantiomers), plasma dextromethorphan levels 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] Surprisingly, quantification of the AUC for dextromethorphan showed that at the highest tested dose of 10 mg / kg, sarpogrelate increased the AUC of dextromethorphan by 5.3-6.9-fold. Even at a lower dose of 3 mg / kg, the AUC of dextromethorphan increased in the range from 2.7 times (for the (-) - enantiomer) to 3.3 times (for the (+) - enantiomer).

[00638]

[00639] EXAMPLE 192. INHIBITION OF FENCYCLIDINE-INDUCED HYPERACITY IN RAT TREATED WITH A COMBINATION OF SARPOGRELATE AND DEXTROMETORPHANE. 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) produced mild hyperactivity only at higher doses after approximately 45 minutes. after treatment. DEX and DO reversed the 10 mg / kg PCP-induced locomotor stimulation.

[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 counteract psychomotor activation and hyperactivity. Male Sprague-Dawley rats were injected intraperitoneally with Compound 50 (racemate of sarpogrelate), (-) sarpogrelate, (+) sarpogrelate or carrier medium, as well as subcutaneously (experiment with racemate) or orally (experiments with enantiomers) dextromethorphan or vehicle (water) and were placed separately in the Opto-Varimex-4 automatic tracking system. Fifteen minutes later, the rats were removed from the boxes, injected with phencyclidine (PCP; 5 mg / kg, subcutaneous) and returned to the auto-tracking system for an additional 105 minutes. (i.e. up to a total recording time of 120 minutes). Data analysis focused on the second half of the test (60-120 minutes). ANOVA revealed the presence of a significant interaction between the dose of sarpogrelate and the dose of dextromethorphan (Figure 11, top 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). A posteriori analysis showed that in the presence of dextromethorphan, 3 mg / kg sarpogrelate racemate and 1 mg / kg or 3 mg / kg (-) - sarpogrelate inhibited motor hyperactivity in PCP-treated rats (Dunnett's multiple comparison test). This pattern of results unexpectedly revealed that the (-) - enantiomer of sarpogrelate is less effective than the (+) - enantiomer in inhibiting dextromethorphan metabolism both in vitro (Table 4) and in vivo (Table 5).

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

[00643] EXAMPLE 193. METHOD FOR ESTIMATING BLOOD GLUCOSE LEVELS AND GLUCOSE TOLERANCE DURING ORAL ADMINISTRATION. 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 glucosimeter (OneTouch®, Lifescan), and then the rats were injected intraperitoneally with sarpogrelate and / or dextromethorphan, and after 30 minutes. blood glucose was measured again, and the rats were immediately administered glucose at 2 g / kg orally. Then blood glucose was measured at 6 time points until 180 minutes after the glucose load. As shown in Figure 12, there was a main effect of drug treatment (F (4.59 = 12.0, p <0.0001). Post hoc pairwise comparisons of groups showed that when administered alone, dextromethorphan significantly reduced blood glucose, and this the effect of dextromethorphan was reversed when it was administered in combination with the racemate of sarpogrelate 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 orally administered 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. With regard to general conditions, vomiting was observed 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. Weight gain was reduced in males and females receiving 320 mg / kg / day. Food intake was inhibited in females receiving 80 mg / kg / day or more. Females receiving 320 mg / kg / day also showed a decrease 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. In urine analysis, an increase in protein levels was found in females receiving 320 mg / kg / day, a hematology study showed an increase in platelet count in males receiving 320 mg / kg / day, and a biochemical study 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 drug withdrawal. The relative weight of thyroid and liver was increased in males given 80 mg / kg / day and above, but no treatment-related changes were found on histopathological examination. Histopathological examination revealed fatty degeneration in the cortico-medullary border zone of the kidney in males receiving 320 mg / kg / day. However, during the recovery period, this change was not detected. The no-effect dose level of Compound 50 hydrochloride found in a 52-week study was 20 mg / kg.

[00645] While the features of the present invention have been shown and described herein, many modifications, substitutions, alterations, and equivalents will now be apparent to those of ordinary skill in the art. Thus, it will be understood that the appended claims are intended to cover all such modifications and variations as falling within the true spirit of the present invention. Those skilled in the art will understand that various changes in shape and detail can be made in relation to the present invention without departing from the spirit and scope of the present invention as set forth in the appended claims. Those skilled in the art will recognize or be able to establish using only routine experimentation, many equivalents to the specific embodiments of the present invention described herein. Such equivalents are to be encompassed within the scope of the claims. Reasonable changes should not be construed as a departure from the scope of the present invention. It will be apparent that the invention thus described can be varied, and that various modifications, additions, substitutions and variations of the illustrative examples set forth herein can be made without departing from the spirit of the present invention, and thus are considered to be within the scope of the present invention. All documents referenced above, including without limitation printed publications and preliminary and ordinary patent applications, are incorporated herein by reference in their entirety.

[00646] EXAMPLE 195. ELIMINATION OF MOTOR HYPERACTION INDUCED BY NMDA RECEPTOR BLOCKADE IN RATS. To confirm the ability of the present invention (compounds of formula I) to induce antipsychotic effects that are related to efficacy against the behavioral and psychological symptoms of dementia and which are known for agonists and inverse agonists of 5-HT2A receptors, separate groups of rats that were kept in standard colony rooms with free access to food and water, were pretreated with various doses of deramcyclane (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 locomotor activity cameras. NMDA receptor channel blockers are commonly used in psychopharmacological research for new therapeutic agents, including new antipsychotics. Analysis of variance (ANOVA) was used to identify the main effects of the deramcyclane dose and the interaction between the deramcyclane dose and treatment with NMDA receptor treatment factors.

[00647] EXAMPLE 196. ELIMINATION OF MOTOR HYPERACTION CAUSED BY REMOVAL OF OLFACTOR BULBS IN RATS. In a special series of studies, adult male rats were subjected to bilateral removal of the olfactory bulbs, a model commonly used to study drugs that act on the CNS, such as antidepressants. The 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. Before each test session, animals were treated with dextromethorphan (up to 60 mg / kg, orally) in combination with a compound of formula I (up to 30 mg / kg) and then placed on locomotion monitors to record locomotion.

[00648] EXAMPLE 197. INHIBITION OF DEXTROMETORPHANE METABOLISM. Dextromethorphan-O-demethylase activity was determined in human liver microsomes. The compound of formula I (concentration: up to 3.0E-5M) and dextromethorphan were dissolved in acetonitrile and subsequently diluted with acetonitrile to the desired concentrations to give a final organic solvent concentration of about 1.0% in the incubation mixture. The incubation mixtures contained pooled human liver microsomes, dextromethorphan, and a 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 mean values were used for analysis. IC50 values (concentration causing half of the maximum inhibition of control specific binding) and Hill's coefficients (pH) were determined using methods such as non-linear regression analysis of competition curves obtained with the means of replicates using a curve fit according to 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 (i.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 performed in rats, the ability of a compound of formula I to inhibit the metabolism of dextromethorphan was studied in vivo. Adult rats were housed in a controlled room with a 12 hour light / 12 hour dark cycle, with access to food and water at will. On the day of the experiment, dextromethorphan (50 mg / kg) was administered orally by gavage, followed by immediate administration of deramciclane (up to 30 mg / kg) or carrier medium (t = 0 h). Blood samples were collected at various time points within 24 hours after the administration of dextromethorphan. The sample size was approximately 80 μL of Li-heparin whole blood / time point, i.e. 40 μL of blood plasma with Li-heparin / time point. Whole blood samples were stored on ice until centrifugation (10 min at 3000 g, 4 ° C). Blood plasma was obtained within 45 minutes. after collection, frozen at -20 ° C and stored at this temperature until processed for LC-MS analysis. In rats treated with a compound of Formula I, plasma dextromethorphan levels continued to remain high even at later time points, while in rats treated with vehicle media, dextromethorphan levels decreased more rapidly.

[00651] EXAMPLE 199. EFFECTS OF THE COMPOUND OF FORMULA I ON THE EFFECTS OF THE DISTRIBUTING STIMULUS OF DEXTROMETORPHANE AND MEMANTINE. Drug recognition is commonly used to assess the control of interoceptive stimuli caused by psychoactive drugs (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 blockers of NMDA receptor channels, to induce 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, and feeding occurred after behavioral testing to maintain constant body weight (300-330 g). Behavioral learning and testing was performed using standard double-arm conditioned response chambers connected to a microcomputer via an interface and controlled by 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, rats were peritoneally injected with either 0.056 mg / kg disocilpine or saline, returned to their cages, and then placed 15 minutes later in the chambers to generate a specific response for a total of 15 minutes. During the test sessions, 10 consecutive responses on either arm triggered delivery of the pellets. Two injections were given prior to the test sessions; one peritoneal injection of deramcyclane (3 mg / kg) or its carrier medium (pre-injection period 60 minutes) and one injection of disocilpine (0.056 mg / kg), memantine (10 mg / kg), dextromethorphan (30 mg / kg) or physiological solution (pre-injection period 15 minutes). The percentage of responses to the dysocilpine-designated lever (DLR) and response rates (responses / sec) were calculated for each test session to establish that deramciclane significantly reduced the intensity of the discriminative stimulus effects of NMDA channel blockers (Figure 14A) at a dose that had no significant effect. to generate a specific response (Figure 14B). The decrease in the intensity of the effects of the discriminatory stimuli of memantine in the presence of deramcyclane (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 by inhibiting 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. ANTI-DEPRESSANT LIKE EFFECTS OF COMPOUND OF FORMULA I IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL BLOCKER. Tail suspension is one of the classic tests used to study antidepressants and has also been used to evaluate 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). The 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 prior to initiation of drug treatment. Immobility was induced by tail hanging by individually attaching the mice to paper sticky tape 65 cm above the table. The tape was about 1 cm from the tip of the tail. The animals were suspended for 6 minutes. and the duration of immobility was recorded. Mice were considered immobile only when they did not show any signs of movement. Two injections were given prior to the test sessions; one peritoneal injection of deramcyclane (3 mg / kg) or its carrier medium (pre-injection period 60 minutes) and one injection of memantine (3 mg / kg), dextromethorphan (10 mg / kg) or saline (pre-injection period 30 minutes) ... Although none of the treatments at these dose levels had statistically significant effects, the combined administration of deramcyclane with dextrimethorphan significantly reduced immobility time, indicating the antidepressant-like potential of this combination (Figure 15A). The combination of deramcyclane 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 (Figure 15B). Instead, ritanserin was able to neutralize the antidepressant-like effects of an effective dose of memantine (10 mg / kg). These results indicate that, when used in combination with NMDA receptor channel blockers, deramciclane is capable of producing 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 CONNECTING FORMULA I IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL BLOCKER. Conflict tests, such as the Geller-Seifter test, are commonly used to study the anxiolytic effects of drugs and are also used to assess 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 chambers to generate a specific response, connected to a computer via an interface and controlled by MED-PC software, rats were trained to press levers in a multiple fixed ratio (FR) 20 (food only), FR 20 (food and shock), in which three 7-minute components, not accompanied by punishment, alternated with three 3-minute components, accompanied by punishment, the total duration of the session was 30 minutes. The intensity and duration of the shock were adjusted for each individual rat. The data were analyzed as response rates (responses per second) during the punished and unpunished components of each session. For analytical purposes, response rate data from drug tests were expressed as changes in response rate from a 5-day baseline. Two injections were given prior to the test sessions; one peritoneal injection of deramcyclane (1 mg / kg) or its carrier medium (pre-injection period 60 minutes) and one injection of memantine (3 mg / kg) or saline (pre-injection period 30 minutes). Both deramciclane and memantine were administered at doses that themselves had a marked effect on the implementation of the response, with or without punishment (Figures 16A and 16B). However, when subeffective doses of memantine and deramcyclane were given in combination, rats experienced significantly more pronounced responses to punishment, indicating synergistic interactions between deramciclane and memantine that lead to decreased anxiety.

[00656] EXAMPLE 202. ANTI-AGGRESSIVE EFFECTS OF THE COMPOUND OF FORMULA I IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL BLOCKER. Isolated male mice easily develop and display aggression towards individuals that invade their territory. Such paradigms have been used to assess the anti-aggressiveness 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, the mice were housed separately and, starting from the first two weeks of isolation, they were allowed several times (twice a week) to attack for 4 minutes the mice contained in the group and invading their territory. Only resident mice, which consistently exhibit aggressive behavior towards individuals invading their territory, have been used for drug testing. Drug tests began when resident mice demonstrated attack by invading mice in at least three consecutive tests and lived in isolation for at least 35 days. Mice that invaded other mice were previously housed 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 behavior (attacks, bites, threats, tail banging, standing or sideways, pushing and retreating). However, when memantine was combined with deramciclane (but not with ritanserin), the mice attacked significantly less often in the absence of any visible ataxia (Figure 17). Thus, while deramciclane or NMDA receptor antagonists may be ineffective when taken alone, they can exhibit potent anti-aggressive properties when used in combination.

[00657] EXAMPLE 203 The 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, a 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. The incubation was carried out at 37 ° C for 10 min. and stopped by adding 10 μl of 70% (w / v) perchloric acid. After removing the protein by centrifugation, 50 μL of the supernatant was subjected to high performance liquid chromatography (integrator D7500, pump L-7100, automatic dispenser L-7200, column thermostat L-7300 and fluorescence detector L-7485) using a Mightysil RP-18 GP column (4.6 μ 250 mm, 5 μm). 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 at a flow rate of 1.0 ml / min. Dextrorphan production was monitored at 280 nm excitation and 310 nm emission.

[00658] The preincubation mixture consisted of recombinant CYP2D6 (2 pmol), each of the major cannabinoids (2.5-50 μM), a 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, reactions were initiated by the addition of a 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. The incubation was carried out in the same manner as described in the section "Analysis of enzymes for the manifestation of O-demethylase activity against AMMS". Predicting drug interactions in vivo for CYP2D6. Evaluation of in vivo inhibition efficacy was determined by the methods of Obach et al. (2006). The maximum concentration of unbound substance entering the liver, Cmax, and, was determined using the following equation:

C _{max., U, act.} = 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, ka 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 counted. Thus, Cmax, u, 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 associated with blood plasma proteins, mainly lipoproteins (Grotenhermen, 2003). The ratio of the area under the curve (AUC) of the inhibitor to the 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 the inhibitor is the area under the curve for a given substrate sample in the presence of the inhibitor, and the AUC _control 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 value of the inhibitor potential are presented as fm (CYP2D6) and Ki, respectively. The fm (CYP2D6) value for the urinary dextromethorphan / dextrorphan ratio was set at one (Obach et al., 2006). Thus, the ratio of the AUC of the _inhibitor to the AUC of the _{dextromethorphan control} 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) was determined in plasma, pituitary and 14 regions of the brain, as well as in the spinal cord of a rat after a single oral treatment (acute experiments) and after repeated administration of one dose daily for six days (subacute experiments). Tissue levels of compound 829 were calculated from the 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. The H-3 activity could be measured over the entire period of the acute experiment (95 hours), while the C-14 radioactivity dropped below the detection limit within 24 hours. The AUC values (0.96) for H-3 were 10-15 times higher than for C-14. I, for all tested samples, the concentration-time curves of the peak enterohepatic circulation can be seen after 12 hours. Studies have shown that intact molecules enter brain tissue from the bloodstream. The results of subacute experiments show that compound 829, labeled with C-14, or its metabolites), bearing (e) 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 admission. In subacute experiments, peak concentrations were reached 0.5 h after final treatment. However, their values for 3H were higher than in acute experiments. The latter trend was not observed for the C-14 label. The 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. Enterohepatic circulation observed after a single dose was also observed after repeated administration. The time-related values of the concentration of compound 829 in the pituitary gland were at least two times higher than in blood plasma and brain tissues. No significant difference was found in the concentrations of compound 829 in symmetric (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. ANALYSIS of 5HT2a. The assessment of the affinity of compounds for the human 5-HT2A receptor in transfected HEK-293 cells was determined using a 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 the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4). Non-specific binding was determined in the presence of 1 μM ketanserin. After incubation, the samples were quickly filtered under vacuum through glass fiber filters presoaked with 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 lag time elapsed before licking of the front paws was measured. Reaction times were checked twice before processing. Animals were not included in the experiment if the time of the first basal delay was> 5 sec., Or the difference between two control measurements exceeded 3 sec. Mice were treated with either saline or 1 mg / kg morphine HCl subcutaneously and at the same time with either vehicle or deramciclane or buspirone, 30 mg / kg HCl intraperitoneally, respectively. After treatment (15, 30, 45 and 60 minutes), the reaction time was measured again. 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 the combination of morphine and compound 129 showed a statistically significant analgesic effect compared to administration of one of these compounds alone (patent application EP1734940 B1, incorporated by reference in its entirety).

[00662] EXAMPLE 207. EFFICIENCY OF THE COMPOUND OF FORMULA I IN THE CNS MAY BE MEDIATED BY 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 a peripheral. Eur J Pharmacol (2000) 404: 95-102) and there is direct evidence using compound 50 labeled [14C] in such a way that sarpogrelate may be unable to cross the rat's 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 blood plasma were collected 30, 60, 120 and 240 minutes after M1 administration. The amount of compound in the brain tissue extracts was measured using the UPLC / MS assay. As shown in figure XYZ, the total concentration of M1 in the brain was significantly higher than 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, containing in an effective amount a dual activity agent exhibiting CYP2D6 inhibitor activity and 5-HT2A / 5-HT2C receptor inverse agonist activity or 5-HT2A receptor antagonist / inverse agonist activity, where said dual activity agent is N, N-dimethyl-2 - [[(1R, 3S, 4R) -4,7,7-trimethyl-3-phenyl-3-bicyclo [2.2.1] heptanyl] oxy] ethanamine ; and an NMDA receptor antagonist selected from the group consisting of memantine and dextromethorphan (DEX), or their enantiomers, pharmaceutically acceptable salts, or a combination thereof. 2. The pharmaceutical composition according to claim 1, wherein the composition further comprises: a. polymer, b. emulsifier, s. binder, d. disintegrating agent and / or e. lubricant. 3. A pharmaceutical composition according to claim 1, wherein the composition is a combination of a fumarate and / or a hydrobromide salt of the following compounds:

4. The use of a pharmaceutical composition according to claim 1 in a method for increasing plasma DEX levels 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 of _0-12 DEX that is higher than AUC _0-12 DEX, which 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. The 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 / hr / ml, or about 500 ng / hr / ml, or about 600 ng / hr / ml, or about 700 ng / hr / ml, or about 800 ng / hr / ml, or about 900 ng / h / ml, or approximately 1000 ng / h / ml. 7. Use according to claim 4, wherein the administration is cutaneous, oral, nasal, anal, rectal, vaginal, sublingual, buccal, sublabial, muscular, intramuscular, intravenous, peritoneal, epidural, intracerebral, intracerebroventricular, cutaneous or local, intraarticular, intraarticular , intracavernous, intradermal, intrafocal, intramuscular, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal or transmucosal. 8. The use of a pharmaceutical composition according to any one of claims. 1-3 in a method of treating a neuropsychiatric or neurodegenerative disease or disorder or traumatic brain injury, including behavioral and psychological symptoms of dementia (BPSD), in a patient in need thereof, comprising a) the introduction of a therapeutically effective amount of the composition according to any one of paragraphs. 1-3; b) targeting the CYP2D6 enzyme and NMDA receptors, 5-HT _2A and 5HT _2c ; and c) achieving symptom relief and / or altering the course of the disease.

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