CN110831584A - Targeted drug rescue with novel compositions, combinations and methods thereof - Google Patents

Targeted drug rescue with novel compositions, combinations and methods thereof Download PDF

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CN110831584A
CN110831584A CN201880037396.3A CN201880037396A CN110831584A CN 110831584 A CN110831584 A CN 110831584A CN 201880037396 A CN201880037396 A CN 201880037396A CN 110831584 A CN110831584 A CN 110831584A
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phenoxy
oxy
propan
methyl
dimethylamino
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CN110831584B (en
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斯瑞尼瓦萨饶·韦帕切杜
汉斯·J·莫比乌斯
安东·贝斯帕洛夫
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Si RuiniwasaraoWeipaqiedu
Exeva Co Ltd
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Si RuiniwasaraoWeipaqiedu
Exeva Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Abstract

There is provided a compound of formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a metabolite thereof, a derivative thereof, a prodrug thereof, an acid addition salt thereof, a pharmaceutically acceptable salt thereof, or an N-oxide thereof; or a combination thereof, processes and intermediates for preparing the same, compositions thereof, and uses thereof. Pharmaceutical compositions are provided that include a compound of formula I, or an enantiomer thereof, a metabolite thereof, a derivative thereof, a prodrug thereof, an acid addition salt thereof, a pharmaceutically acceptable salt thereof, or an N-oxide thereof; or a combination thereof, wherein the compound is a dual and/or triple agent or ligand for a CYP2D6, 5-HT2A, and/or 5HT2C receptor, and/or acetylcholinesterase.

Description

Targeted drug rescue with novel compositions, combinations and methods thereof
Technical Field
The present disclosure relates to targeted drug rescue (T) with novel compositions, combinations, therapeutic formulations, symptomatic and disease modifying treatments, therapies, kits thereofDR)TMAnd a method thereof.
Background
Being overweight alters the body, increases the levels of certain hormones and inflammation leading to metabolic disorders, cancer and brain disorders (including developmental, psychiatric and neurodegenerative diseases) which represent a significant disease burden with respect to human suffering and economic costs, and leads to a rapid increase in the cost of therapeutic health care. Diseases affecting the brain and central nervous system represent one of the largest global healthcare challenges and the largest therapeutic needs due to devastating personal and economic consequences to patients, caregivers, and society. There are five thousand five million people estimated to have neurodegenerative diseases worldwide and no approved disease modifying therapy is currently available. As modern therapeutic interventions increase life expectancy, it is expected that the number of patients with these diseases will double every 20 years. Only the nine most common neurological diseases, such as alzheimer's disease and other dementias, lower back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury, and parkinson's disease, are startling, totaling $ 7890 billion in 2014, currently estimated to $ 8180 billion, and estimated to be over $ 1 trillion by 2030. The total expenditure of European brain disease in 2010 was 7980 billion Euros with a direct healthcare cost of 37%, a direct non-healthcare cost of 23%, and an indirect cost of 40% (Olesen et al, The ecological cost of brain disorders in Europe [ economic cost of European brain disorders ], EJN [ J European neurology ], 19, 1, 155-.
Over the past two decades, the therapeutic needs for dementia in particular have progressed slowly, and since the approval of memantine (memantine) by EMA (2002) and FDA (2003), almost all alzheimer's disease development programs have failed. Regulatory agencies have addressed the continuing high therapeutic need by opening a range of approved drugs to treat the indications of the syndrome without adhering to a "treatment" indication. Such symptomology indication may encompass indications such as Behavioral and Psychiatric Symptoms of Dementia (BPSD), sub-symptomology, like aggression or apathy of alzheimer's disease, hallucinations and delusions of parkinson's disease (PDD). Thus, it is possible to provideThe EXCIVA TDR is required to be usedTMThe art develops such novel therapies with indications for syndrome indications for novel compositions, combinations, therapeutic formulations, symptomatic and disease modifying treatments, and therapies.
Disclosure of Invention
Various embodiments of the present disclosure relate to Targeted Drug Rescue (TDR) with novel compositions, combinations, therapeutic formulations, symptomatic and disease modifying treatments, therapies, kits thereofTMAnd methods of making such compositions, combinations, therapeutic formulations, treatments, therapies and kits, including biologies, chemicals, nutraceuticals, pharmaceuticals, compositions, treatments, therapies, cures, preventions, supplements and formulations; including allopathic therapy, alternative therapy, ayurvedic therapy, herbal therapy, holistic therapy, homeopathic therapy, natural therapy, pharmacotherapy, unnatural agents, adjuvants, drugs (brews), chemicals, compositions, combinations, blends, drugs, elements, extracts, formulations, kits, mechanisms, drugs, medicaments, mixtures, lotions, preparations, prophylactics, formulas, solutes, solutions, solvents, substances, systems, teas, therapies, medicated liquors, and treatments; biologics and vaccines; curing; diagnostic kits, reagents and assays; diet, cate and nutritional agents, lotions and supplements; a health care product; and a nutritional food; and its related products and services; for administration, cleaning, healing, diagnosis, healing, disinfection, administration, prevention and treatment of acute or chronic conditions, namely: addiction, condition, deficiency, disability, disease, disorder, dysfunction, infection, problem, poisoning, contamination, and malfunction thereof; it is due to and related to, i.e., accidental, allergic, auditory, anticancer, cardiovascular, cardiopulmonary, chemotherapeutic, cognitive, congenital, dermatological, endocrine, gastrointestinal, genetic, genital, urogenital, genetic, hormonal, hepatic, immunological, casual, intellectual, industrial, lymphatic, metabolic, psychiatric, muscular, musculoskeletal, neurological, oncological, optical, ophthalmological, orthopedic, osteopathic, psychiatric, psychological, psychiatricPhysical, mental, physical, physiological, respiratory, reproductive, sexual, skeletal, urinary, virtual and visual functions, systems and causes thereof.
In various embodiments, the invention is a composition comprising a combination of one or more agents, each agent having a unique Therapeutic Mode of Action (TMA), wherein the agent is an NMDA receptor antagonist, 5-HT2AReceptor antagonists, 5-HT2AReceptor inverse agonists, 5-HT2CA receptor antagonist, and/or an inhibitor of CYP2D 6.
One embodiment of the invention is a composition comprising a compound of formula I:
Figure GDA0002354989720000021
wherein R is1And R2Independently is H, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C5-10Aryl, substituted or unsubstituted C3-10cycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10Bicycloalkyl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Heteroaryl, substituted or unsubstituted C4-10Tricycloalkyl, substituted or unsubstituted C4-10tricycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10tricycloalkyl-C5-10Heteroaryl, or substituted or unsubstituted C5-10Heteroaryl, or R1And R2Taken together with the nitrogen to form a saturated or unsaturated heterocyclic ring having one or more heteroatoms selected from N, O, and S;
R3independently is H, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C5-10Aryl, substituted or unsubstituted C5-10Heteroaryl, substituted or unsubstituted C3-10cycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10Bicycloalkyl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Aryl, substituted orUnsubstituted C4-10bicycloalkyl-C5-10Heteroaryl, substituted or unsubstituted C4-10bicycloalkyl-C1-10-alkyl-C5-10Aryl, substituted or unsubstituted C4-10bicycloalkyl-C1-10-alkyl-C5-10Heteroaryl, substituted or unsubstituted C4-10Tricycloalkyl, substituted or unsubstituted C4-10tricycloalkyl-C1-10-alkyl-C5-10Aryl, substituted or unsubstituted C4-10tricycloalkyl-C1-10-alkyl-C5-10Heteroaryl, substituted or unsubstituted C4-10tricycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10tricycloalkyl-C5-10Heteroaryl, or substituted or unsubstituted C5-10Heteroaryl, or substituted or unsubstituted C5-10A heteroaryl group;
n is an integer from 0 to 5; r4Is H, NH-R5、S-R5、-OH、O-R5、–CO-R5、–O-CO-R5or-CO-O-R5Wherein R is5Is an acyl group; or R5And R2Forming a heterocyclic ring; or an enantiomer thereof, a metabolite thereof, a derivative thereof, and/or a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a combination thereof.
Some embodiments include compositions comprising effective amounts of: 1) a composition comprising a compound of formula I as defined above, an enantiomer thereof, a metabolite thereof, a derivative thereof, and/or a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a combination thereof; or 2) compounds of the formula II
Figure GDA0002354989720000031
Wherein R is6、R7And R8Independently is H, D, C1-10Alkyl, halo C1-10-alkyl, wherein halogen is F, Cl, or Br; r9And R10Independently is H; c1-10-an alkyl group; halogen substituted C1-10-alkyl, wherein halogen is F, Cl, or Br; OH; or R9And R10Together form a 5-membered heterocyclic ring in which the heteroatom is O, S, or N; an enantiomer, metabolite, derivative, prodrug, salt, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof, or a combination thereof; or 3) a combination of 1and 2; or a combination thereof.
Some embodiments include a method of treating a disease or disorder in a subject in need thereof, the method comprising an effective amount of: 1) a composition comprising a compound of formula I as defined above; an enantiomer thereof, a metabolite thereof, a derivative thereof, and/or a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a combination thereof; or 2) a compound of formula II as defined above, an enantiomer, metabolite, derivative, prodrug, salt, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof, or a combination thereof; or 3) a combination of 1and 2.
Some embodiments include a method of treating a disease or disorder in a subject in need thereof, the method comprising an effective amount of a composition comprising dextromethorphan, an enantiomer, metabolite, derivative, or prodrug thereof, or a combination thereof; salts and diastereomers thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, processes and intermediates for their preparation, compositions thereof, and uses thereof.
In one embodiment, the method is a method of reducing the number of doses of the compound of formula II that can be administered and/or the total daily dose, while increasing efficacy and ensuring tolerability and safety; a method of reducing adverse events associated with treatment with a compound of formula II, wherein the subject is at risk of experiencing an adverse event caused by treatment with a compound of formula II; a method of reducing a plasma level metabolite of a compound of formula II, a method of treating a neurological disorder, a method of increasing a plasma level of a compound of formula II in a subject in need of treatment with a compound of formula II, wherein the subject is a rapidly metabolizer of a compound of formula II (extensive metabolite); a method of inhibiting the metabolism of a compound of formula II; a method of increasing the metabolic lifespan of a compound of formula II; a method of correcting for rapid metabolism of a compound of formula II; a method of improving the antitussive properties of a compound of formula II; a method for treating cough is provided. Another embodiment is the method, wherein the disease or disorder is a neurological disorder, wherein the composition is administered once a day for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 8 days.
Some embodiments include methods of treating a neurological disorder comprising administering about 5 mg/day to about 600 mg/day, about 5 mg/day to about 300 mg/day, about 5 mg/day to about 400 mg/day, about 5 mg/day to about 500 mg/day, about 5 mg/day to about 600 mg/day, about 5 mg/day to about 1,000 mg/day, about 50 mg/day to about 1000 mg/day, about 100 mg/day to about 1000 mg/day, about 150 mg/day to about 5000 mg/day, about 150 mg/day to about 300 mg/day, or about 150 mg/day to about 100 mg/day, or a desired amount of a compound of formula I, and about 0.1 mg/day to about 1 mg/day, about 0.5 mg/day to about 15 mg/day, about 1 mg/day, or a combination thereof, 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 a desired amount of a compound of formula II to a subject in need thereof.
Another embodiment is a pharmaceutical composition comprising a compound of formula II and one or more agents selected from the group comprising 5-HT2A receptor antagonists/inverse agonists and CYP2D6 inhibitors. In another embodiment, the agent is an agent that has both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor properties. In another embodiment, the agent is a Dual Agent (DA) having both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor properties. In another embodiment, DA is a compound of formula I.
Drawings
FIGS. 1A, 1B and 1C show Dixon plots (Dixon plots) for measuring the Ki values of CYP2D6 for compounds of formula I, exemplified by sarpogrelate and M-1, and quinidine. Dextromethorphan concentrations were determined to be 2.5mM (filled circles), 5mM (open circles), and 10mM (triangles), respectively. V represents the rate of formation of dextrorphan (pmol/min/mg protein). Data are the average of triplicate determinations. The solid lines of the compounds of formula I (exemplified by sarpogrelate) and M-1, and quinidine) fit closely to all competitive inhibition types (Cho et al, Effect of the potential CYP2D6 inhibitor, on the pharmacological kinetics and pharmacological responses, [ Effect of potent CYP2D6 inhibitors on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers ] Xenobiotica [ symbiotics ], 45(3):256-63 (3 months 2015), the entire contents of which are incorporated by reference).
Figures 2A, 2B and 2C show mean neuropsychiatric scale activation/aggression domain scores by stage and visit and 10-week analysis for patients included in the sequential parallel comparison design. A, stage 1 (weeks 1-5); phase 2 (weeks 6-10), placebo non-responders randomized again after phase 1; c, 10-week results (the 10-week secondary analysis included only patients who lasted the same treatment assignment throughout study participation; i.e., patients randomized to receive dextromethorphan-quinidine only or placebo only [ excluding patients who were randomized again at stage 2 to switch from placebo to dextromethorphan-quinidine ], thereby mimicking the parallel group design). The covariance analysis model with treatment as the fixed effect and baseline as the covariate was used to compare the mean change from baseline between time point groups. The baseline for stage 2 is the score of the patient at the beginning of stage 2. The least squares average treatment difference is as follows: for stage 1, week 1, -0.8 (95% CI, -1.5 to-0.03; P ═ 04), week 3, -1.0 (95% CI, -1.8 to-0.2; P ═ 01), and week 5, -1.5 (95% CI, -2.3 to-0.7; P <. 001); for stage 2, week 6, 0.7 (95% CI, -0.4 to 1.9; P ═ 19), week 8, -0.1 (95% CI, -1.3 to 1.2; P ═ 93), and week 10, -1.6 (95% CI, -2.9 to-0.3; P ═ 02); for 10-week analysis, week 1, -0.9 (95% CI, -1.8 to-0.04; P ═ 047), week 3, -1.3 (95% CI, -2.2 to-0.3; P ═ 01), week 5, -1.8 (95% CI, -2.7 to-0.9; P <.001), week 6, -0.9 (95% CI, -2.0 to 0.1; P ═ 06), week 8, -1.3 (95% CI, -2.4 to-0.3; P ═ 01), and week 10, -1.8 (95% CI, -2.8 to-0.7; P ═ 003). Observation cases (Cummings et al, Effect of dextromethorphan quinidine on imaging with Alzheimer Disease severity: a random clinical trial for the effects of dextromethorphan quinidine on agitation in Alzheimer's Disease dementia patients: A randomized clinical trial ] JAMA [ journal of American medical society ]314(12):1242-1254(2015), the entire contents of which are incorporated by reference).
Figures 3A, 3B, and 3C show the therapeutic effect on the reduction of severity of psychiatric abnormalities over the 6 week study period of the complete analysis set. The complete analysis set included all patients receiving a dose of ≧ 1and at least one SAPS assessment at baseline and thereafter. Data points show the least squares means (standard error). (A) SAPS-PD improves. (B) CGI-change in severity score. (C) CGI-improvement score. SAPS ═ scale of assessment of positive symptoms. CGI (Cummings et al, Pimavanserin for patients with parkinsons's disease therapy: a randomised, placebo-controlled phase 3trial [ Lancet ] for Parkinson's disease patients randomized, placebo controlled phase 3trial ] Lancet [ Lancet ], 383(9916):533-40(2014, 8 days), the entire contents of which are incorporated by reference).
FIGS. 4A, 4B and 4C show Lineweaver-Burk plots of inhibition of CYP2D6 and Human Liver Microsomes (HLM) by compound 847 (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 (fig. 4A), (B) dextromethorphan in the presence of CBD (fig. 4B), and (C) in the absence of CBD (fig. 4C), HLM was incubated with dextromethorphan in the presence or absence of CBD. Each point is the average of duplicate determinations.
FIGS. 4D, 4E and 4F represent the major phytocannabinoids Δ9-tetrahydrocannabinol (Δ)9-THC), CBD and Cannabinol (CBN) on dextromethorphan O-demethylase activity of AMMC and CYP2D6 and HLM. At different amounts of delta9-incubating recombinant CYP2D6 with (D)0.6 μ M AMMC (fig. 4D), (E)0.6 μ M dextromethorphan (fig. 4E) in the presence of THC, CBD, and CBN; and (F) in different amounts Δ9-incubating HLM with 4 μ M dextromethorphan in the presence of THC, CBD, and CBN. Each point is the mean of two determinations (Yamaori et al, Cannabidial, a Major phytocannabinoids, As a potential pathological Inhibitor for CYP2D6[ Cannabidiol, a Major Phytocannabinoid, As a potent atypical Inhibitor of CYP2D6]Drug Metabolism and DispositionDevice for placing]Vol 39, No. 11 (2011), the entire contents of which are incorporated by reference).
FIG. 5 shows the (-) and (+) enantiomer of M1 and the effect of M-100, 907 on MK-801 induced hyperactivity in rats. Data are presented as mean (± SEM) average activity over the 60-min test period. Each group N is 5-9.
Figure 6 shows the effect of sarpogrelate on locomotor activity of rats after olfactory bulb resection (OBX) or SHAM Surgery (SHAM). Data are presented as mean (± SEM) average activity for the 5-min test segment. Each group N is 12.
FIG. 7 shows the plasma level curves of sarpogrelate and M1 following a single intravenous administration of sarpogrelate hydrochloride (2mg/kg) in male West rats. Data are presented as mean (± SD) concentrations (ng/ml). N is 4.
Fig. 8 shows the plasma level curves of dextromethorphan in male winster rats receiving dextromethorphan (50mg/kg, oral) shortly after intravenous bolus injection of sarpogrelate (1, 3 or 10 mg/kg; one of the racemates or enantiomers) or vehicle administration via the vascular inlet at t ═ 0 h. Data are presented as mean (± SD) concentrations (ng/ml). N-2-3.
Figures 9A, 9B, and 9C show the effect of a combination of dextromethorphan and compound 50 racemate (upper panel), (-) compound 51 (middle panel), or (+) compound 52 on PCP-induced hyperactivity in rats.
Figure 10 shows the effect of dextromethorphan and sarpogrelate racemate on blood glucose levels. Data are presented as the area under the blood glucose level curve (mean ± SEM) over a 30-180min time period following oral glucose (2g/kg) challenge. Each group N is 8.
Fig. 11A and 11B show the mean (SEM) concentrations of (a) buspirone and (B)1-PP after administration of 20mg buspirone following 8 days of pretreatment with 60mg compound 829 (filled squares; n ═ 16) or placebo (filled circles; n ═ 16) once daily.
Fig. 12A and 12B show the mean (SEM) plasma prolactin concentrations after (a) 7 days of once daily treatment with compound 829, 60mg (filled squares; n ═ 16) or placebo (filled circles; n ═ 16), and (B) 8 days of pretreatment with 60mg compound 829 (filled squares; n ═ 16) or placebo (filled circles; n ═ 16) once daily, following a concomitant administration of 20mg buspirone.
Fig. 13 shows the prodrug strategy of the most common functional groups on the parent drug compounds of formulas I and II, represented by R, with the general scheme representing various embodiments of prodrugs of the compounds of formulas I and II.
Figures 14A and 14B show the effect of compound 829 on the differential stimulatory effect of NMDA receptor channel blockers. Data are presented as percent drug lever response (± s.e.m.) (upper panel) and response rate (response per second; lower panel). N is 6.
Figure 15A shows the effect of compound 829 in combination with memantine and with dextromethorphan in the tail suspension test. Data are presented as mean (± s.e.m.) immobility time. N-8.
Figure 15b shows the effect of ritanserin (ritanserin) in combination with memantine in a tail suspension test. Data are presented as mean (± s.e.m.) immobility time. And N is 7-8.
FIG. 16A shows the effect of compound 829 and Memantine in a Leeller-Seffert (Geller-Seifter) assay in response to a penalty (punlished) stimulus. Data are presented as the mean (± s.e.m.) number of responses per segment. N is 4.
Figure 16B shows the effect of compound 829 and memantine in the geller-schiff test in response to an unpruned mark (unpinnpressed). Data are presented as the mean (± s.e.m.) number of responses per segment. N is 4.
Figure 17 shows the effect of compound 829 in combination with memantine, and ritanserin in combination with memantine, on the challenge induced by the isolation. Data are presented as mean (± s.e.m.) latency for the first challenge. N-7.
Figure 18 shows the total concentration of compound 146(M1) in plasma and brain tissue. Total brain and plasma concentrations following intraperitoneal administration of a composition of the invention comprising a compound of formula I, e.g., compound 146. Data are presented as mean (± s.e.m.) amounts of compound in brain tissue extracts (measured using UPLC/MS analysis). N is 4.
Detailed Description
Targeted Drug Rescue (TDR) of the present inventionTMThe Targeted Drug Rescue (TDR)TMIncluding novel compositions and combinations, therapeutic formulations, treatments for symptoms and disease modification, therapies, kits thereof, and methods of making such compositions, combinations, therapeutic formulations, treatments, therapies, and kits, including biologies, chemicals, nutraceuticals, pharmaceuticals, compositions, treatments, therapies, cures, prevents, supplements, and formulations, including patent application US 62/501, 693 filed 05/04/2017, PCT/US2017/048748 filed 08/25/2017, published WO 2018/039642a103/01/2018, TW 106129169 filed 08/28/2017, US 62/634, 162 filed 02/22/2018, US 62/636,171 filed 02/22/2018, US 62/635,554, 02/27/2018, and methods of making such compositions, combinations, therapeutic formulations, treatments, therapies, and kits, And US 62/636,099 filed 02/27/2018, all of which are incorporated herein by reference.
One embodiment of the invention is a composition comprising a compound of formula I:
Figure GDA0002354989720000071
wherein R is1And R2Independently is H, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C5-10Aryl, substituted or unsubstituted C3-10cycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10Bicycloalkyl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Heteroaryl, or substituted or unsubstituted C5-10Heteroaryl, or R1And R2Taken together with the nitrogen to form a saturated or unsaturated heterocyclic ring having one or more heteroatoms selected from N, O, and S;
R3independently is H, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C5-10Aryl, substituted or unsubstituted C5-10Heteroaryl, substituted or unsubstituted C3-10cycloalkyl-C5-10Aryl, heteroaryl, and heteroaryl,Substituted or unsubstituted C4-10Bicycloalkyl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Heteroaryl or substituted or unsubstituted C5-10A heteroaryl group; n is an integer from 0 to 5; r4Is H, NH-R5、S-R5、-OH、O-R5、–CO-R5、–O-CO-R5or-CO-O-R5Wherein R is5Is an acyl group; or R5And R2Forming a heterocyclic ring; or an enantiomer thereof, a metabolite thereof, a derivative thereof, and/or a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a combination thereof.
One embodiment are compounds of formula I, wherein C is substituted or unsubstituted4-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. In another embodiment, the cycloalkyl group contains one or more heteroatoms N, S, or O.
Another embodiment are compounds of formula I, wherein C is substituted or unsubstituted3-10Bicycloalkyl is bicyclobutyl, dicyclopentyl, dicyclohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl or bicyclodecyl. In another embodiment, bicycloalkyl contains one or more heteroatoms N, S, or O.
Another embodiment are compounds of formula I wherein aryl is phenyl, naphthyl, anthryl or phenanthryl.
In another embodiment, the compound is a compound of formula I, wherein R5 is an acyl group selected from the group consisting of: mono-, di-, and tricarboxylic acid radicals.
In another embodiment, the compound is a compound of formula I, wherein R5 is an acyl group selected from the group consisting of: acetate, acetylsalicylate, adipate, N-acyl-aspartate, butyrate, decanoate, hexanoate, octanoate, heptanoate, formate, fumarate, N-acyl-glutarate, isophthalate, maleate, malonate, methionine, N-acyl-methionate, oxalate, nonanoate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, tyrosine, N-acyl-tyrosine, tryptophan, N-acyl-tryptophan, and valerate.
Another embodiment is a compound of formula II,
Figure GDA0002354989720000081
wherein R is6、R7And R8Independently is H, D, C1-10Alkyl, halo C1-10-alkyl, wherein halogen is F, Cl, or Br; r9And R10Independently is H; c1-10-an alkyl group; halogen substituted C1-10-alkyl, wherein halogen is F, Cl, or Br; OH; or R9And R10Together form a 5-membered heterocyclic ring in which the heteroatom is O, S, or N.
Another embodiment are compounds of formula I wherein R5 and R2 form a heterocycle selected from, for example, morpholine, dihydrooxazine, oxazine, piperazine, dihydropiperazine, and tetrahydropyrazine. The compounds of this example include, but are not limited to, the following compounds 10-24:
Figure GDA0002354989720000082
another embodiment is a pure enantiomer of formula I selected from formula Ia or Ib.
In another embodiment, the compounds of formula I, wherein R1、R2And R3Is methyl, provided that X is not ethyl.
In another embodiment, the composition comprises formula I as Sarpogrelate (SARPO), wherein R is1、R2And R3Is methyl, X is ethyl, and R4Is succinyl having the following compounds SGL, SGL-E1, and SGL-E2.
In another embodiment, the composition comprises formula I as sarpogrelate metabolite M1, wherein R1、R2And R3Is methyl, X is ethyl, and R4Is OH with the following compounds M1, M1-E1, and M1-E2.
In another embodiment, the composition comprises formula I as sarpogrelate metabolite M1, wherein R1And R2Taken together with the nitrogen to form a saturated or unsaturated heterocyclic ring having one or more heteroatoms selected from N, O, and S; and R is3Is methyl, X is ethyl, and R4 is OH. In another embodiment, the heterocyclic ring is a five-membered ring. Another embodiment is where the heterocycle is a six membered ring. In another embodiment, the heterocycle is saturated. Another embodiment has an unsaturated heterocycle. In one embodiment, the heterocyclic ring has one heteroatom. In another, the heterocyclic ring has two heteroatoms.
In another embodiment, the compounds of formula I, wherein R is1And R2The heterocyclic ring taken together with the nitrogen is selected from the heterocyclic rings listed below:
Figure GDA0002354989720000091
the term "DEX" denotes a compound of formula II, such as dextromethorphan, an enantiomer thereof, a metabolite thereof, a derivative thereof, and/or a prodrug thereof, or a combination thereof. Derivatives include, but are not limited to, deuterated derivatives such as DEX-H3, DEX-D3, DO, and DO-D3.
The term "saprophos" means one or more compounds selected from the group consisting of: sarpogrelate (SGL), its enantiomers, its metabolites, M1, SG1, SG2, SMG1, SMG2, SMG3, its derivatives, its prodrugs, and combinations thereof.
The term SARPODEXTMRepresents 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 invention is a composition comprising a compound of formula I and DEX-H3, DEX-D3, DO, or DO-D3. One embodiment of the invention is a composition comprising: m1, M1-E1, M1-E2, SGL-E1, or SGL-E2; and DEX-H3, DEX-D3, DO, or DO-D3.
The term DERAGEXTMOr DERAPANTMRepresents a combination of DEX and a compound of formula I, wherein the compound is bicyclo [2.2.1] having formula I]Derivatives of heptanol:
Figure GDA0002354989720000092
wherein R is3Is a bicyclic ring system and the remainder of formula I is represented by R7Represents: as shown in formula If
Figure GDA0002354989720000093
Wherein R is6Is H, substituted or unsubstituted-C1-10Alkyl, substituted or unsubstituted-C3-10Cycloalkyl, substituted or unsubstituted-C5-10Aryl, substituted or unsubstituted-C1-10alkyl-C5-10Aryl, substituted or unsubstituted-C5-10Heteroaryl, or substituted or unsubstituted-C1-10alkyl-C5-10A heteroaryl group;
R7is that
Figure GDA0002354989720000101
-C1-10alkyl-X- (Y)n、-C3-10cycloalkyl-X- (Y)m、-C5-10aryl-X- (Y) m, or-C5-10heteroaryl-X- (Y)m(ii) a Wherein X is a bond, N, O, S, -C1-10Alkyl, -C3-10Cycloalkyl, -C5-10Aryl, -CO-C1-10Alkyl, -CO-C3-10Cycloalkyl, -COC5-10Aryl, -CO-C5-10Heteroaryl, -CO-NH-C1-10Alkyl, -CO-NH-C3-10Cycloalkyl, -CO-NH-C5-10Aryl, or-CO-NH-C5-10A heteroaryl group; y is H, C1-10Alkyl radical, C3-10Cycloalkyl radical, C5-10Aryl, -CO-C1-10Alkyl, -CO-C3-10Cycloalkyl, -COC5-10Aryl, CO-C5-10Heteroaryl, -CO-NH-C1-10Alkyl, -CO-NH-C3-10Cycloalkyl, -CO-NH-C5-10Aryl, or-CO-NH-C5-10A heteroaryl group; and m is an integer 1 or 2; or a pharmaceutically acceptable salt thereof orAn N-oxide; or a prodrug thereof.
The term DERATINETMRepresents a combination of an NMDA receptor antagonist and a compound of formula I as defined above.
The term SARPOTINETMRepresents a combination of an NMDA receptor antagonist and a compound of formula I as defined above.
One embodiment of the invention is a composition comprising a compound of formula I and DEX-H3, DEX-D3, DO, or DO-D3.
In another embodiment, a compound of formula I or analog can be prepared using the following carboxylic acids: malic acid HO2C-CH2-CH(OH)-CO2H (Compound 25-29), methionine H3C-S-(CH2)2-CH(NH2)-CO2H (Compound 30-34), phthalic acid C6H4(CO2H)2(Compound 35-37) malonic acid HO2C-CH2-CO2H (Compounds 38-40), tyrosine HO-C6H4-CH2-CH(NH2)-CO2H (Compounds 41 to 43), Tryptophan C8H6N-CH2-CH(NH2)-CO2H (Compounds 44 to 46), maleic acid HO2C-CH＝CH-CO2H (Compounds 47 to 49), succinic acid HO2C-(CH2)2-CO2H (Compounds 50-52), glutaric acid HO2C-(CH2)3-CO2H (Compounds 53 to 55), adipic acid HO2C-(CH2)4-CO2H (Compounds 56 to 58), pimelic acid HO2C-(CH2)5-CO2H (Compounds 59 to 61), sebacic acid HO2C-(CH2)6-CO2H (Compounds 62-64), formic acid HCO2H (Compounds 65-67), acetic acid CH3CO2H (Compounds 68-70), propionic acid CH3CH2CO2H (Compound 71-73), butyric acid CH3(CH2)2CO2H (Compounds 74-76), pentanoic acid CH3(CH2)3CO2H (Compounds 77-79), hexanoic acid CH3(CH2)4CO2H (compound 80-82), heptanoic acid CH3(CH2)5CO2H (Compound 83-85), octanoic acid CH3(CH2)6CO2H (compound 86-88), nonanoic acid CH3(CH2)7CO2H (compound 89-91), capric acid CH3(CH2)8CO2H (compounds 92 to 94), oxalic acid HO-CO-CO2H (Compound 95-97), isophthalic acid C6H4(CO2H)2(Compound 98-100) terephthalic acid C6H4(CO2H)2(Compound 101-103) salicylic acid HO-C6H4-CO2H (compound 104-106), acetylsalicylic acid CH3-CO-O-C6H4-CO2H (compound 107-109).
An embodiment of the invention is a compound of formula I, wherein the compound is sapelomalate (sartomelate), wherein R is1、R2And R3Is methyl, X is ethyl, and R4 is malate; compounds 25-29. An embodiment of the invention is a compound of formula I, wherein the compound is saparathionine, wherein R is1、R2And R3Is methyl, X is ethyl, and R4 is methioninate; 30-34. An embodiment of the invention is a compound of formula I wherein the compound is sapephthalate, wherein R is1、R2And R3Is methyl, X is ethyl, and R4 is phthalate; compounds 35-37. An embodiment of the invention is a compound of formula I, wherein the compound is sabalonate, wherein R1、R2And R3Compound 38-40 which is methyl, X is ethyl, and R4 is malonate. An embodiment of the invention is a compound of formula I, wherein the compound is a salt of sapercetin, wherein R is1、R2And R3Is methyl, X is ethyl, and R4 is tyrosine; compounds 41 to 43. An embodiment of the invention is a compound of formula I wherein the compound is a salt of safrole, wherein R is1、R2And R3Is methyl, X is ethyl, and R4 is tryptophan; compounds 44-46. At one endIn an embodiment, the composition is a combination of DEX and at least one compound selected from compounds 10-46, 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 sarpogrelate, and dextromethorphan.
One embodiment of the present invention is a composition comprising a compound of formula I, wherein the compound is sarpogrelate, and dextromethorphan, wherein the sarpogrelate and dextromethorphan form a diastereomeric mixture.
Figure GDA0002354989720000111
One embodiment of the present invention is a composition comprising a compound of formula I, wherein the compound is sarpogrelate, and dextromethorphan, wherein the sarpogrelate and dextromethorphan form a salt, wherein the salt is a mixture of diastereomers. One embodiment of the present invention is a composition comprising a compound of formula I, wherein the compound is 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 sarpogrelate metabolite M1, and dextromethorphan. One embodiment of the invention is a composition comprising dextromethorphan and a compound of formula I, wherein the compound is a salt of sapelo malate, forming a salt comprising a diastereomeric mixture or pure diastereomer thereof; one embodiment of the present invention is a composition comprising a compound of formula I, wherein the compound is a salt of saprobamate, and dextromethorphan, forming a salt comprising a diastereomeric mixture or pure diastereomer thereof. One embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is a salt of saprophthalic acid, and dextromethorphan, forming a salt comprising a diastereomeric mixture or pure diastereomer thereof. One embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is a salt of sapalonic acid, and dextromethorphan, forming a salt comprising a diastereomeric mixture or pure diastereomer thereof. One embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is a salt of sapercetin and dextromethorphan, forming a salt comprising a diastereomeric mixture or pure diastereomer thereof. One embodiment of the present invention is a composition comprising a compound of formula I, wherein the compound is a salt of saperchromic acid, and dextromethorphan, forming a salt comprising a diastereomeric mixture or pure diastereomer thereof.
One embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is SGL, and dextromethorphan HCl, forming a salt comprising a diastereomeric mixture or pure diastereomer thereof. One embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is SGL, and dextromethorphan HBr, forming a salt comprising a diastereomeric mixture or pure diastereomer thereof. One embodiment of the invention is a composition comprising a compound selected from the group consisting of: SGL, its enantiomers, its metabolites, M1, SG1, SG2, SMG1, SMG2, SMG3, its derivatives, its prodrugs, and combinations thereof. One embodiment of the invention is a composition comprising a compound selected from the group consisting of: SGL, its enantiomers, its metabolites, M1, SG1, SG2, SMG1, SMG2, SMG3, its derivatives, its prodrugs, and combinations thereof, and dextromethorphan.
Another embodiment are compounds of formula 1 wherein Ra and R2 form a 5-or 6-membered heterocyclic moiety, exemplary compounds are compounds 110-145. One embodiment of the invention is a composition comprising a compound selected from the group consisting of: SGL, its enantiomers, its metabolites, M1, SG1, SG2, SMG1, SMG2, SMG3, its derivatives, its prodrugs, and combinations thereof, and dextromethorphan.
Figure GDA0002354989720000121
In another embodiment, the compound of formula I is exemplified wherein the heterocycle is represented by R1And R2Together with nitrogen, represented by compounds of formula Ic-Is comprising saturated (shown below) and unsaturated heterocycles:
Figure GDA0002354989720000132
in another embodiment, the compound Is a compound of formula Ic-Is, wherein the 5-membered heterocyclic ring Is unsaturated.
In another embodiment, the composition comprises DEX and a compound of formula I and/or perhexiline, flecainide, quinidine, (R) -propafenone ((R) -propapholone), (S) -propafenone, isonicotinyl (isoniazide), (R) -fluoxetine, (S) -fluoxetine, nefazodone, paroxetine, ketoconazole (ketoconazole), chloroquine (chloroquine), oxaniquine (oxaninazine), primaquine (primaquine), quinine (quinine), acebutolol (acetobutolol), betaxolol (betaxolol), bufalol (bufuralol), oxprenol (oxaprenolol), pindolol (pindolol), propranolol (propinolol), budipine (budipine), simvastatin (simvastatin), lovastatin (lovastatin), simvastatin (simvastatin), simvastatin (lovastatin), guastatin (lovastatin), picloratadine (atorvastatin), picloratadine (lovastatin), or (lovastatin), picloratadine (lovastatin), piclorane (lovastatin), picloratadine (lovastatin), or a, Or a derivative thereof.
In another embodiment, the composition comprises formula I, wherein R1、R2And R3Is methyl, X is ethyl, and R4 is OH, which is represented by the following compounds M1, M1-E1, and M1-E2.
Figure GDA0002354989720000141
In another embodiment, the composition comprises formula I, wherein R1、R2And R3Is methyl, X is ethyl, and R4 is succinyl, represented by the following compounds SGL, SGL-E1, and SGL-E2.
In one embodiment, the composition comprises formula I, wherein R5is-O (CO) -CH2-CH2- (CO) O-Y, wherein alkyl, cycloalkyl, aryl, heteroaryl, -alkenyl-aryl, -aralkyl, alkyl-ONO2cycloalkyl-ONO2aryl-ONO2Hetero aryl-ONO2-alkenyl-aryl-ONO2and-aralkyl-ONO2Such as, but not limited to, the following: 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) propan-2-yl (3- (nitrooxy) propyl) succinate Yl) phenoxy) propan-2-yl (4- (nitrooxy) butyl) succinate, 4- ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) -4-oxobutanoic acid nitric anhydride, and the like.
Figure GDA0002354989720000142
In one embodiment, the composition comprises DEX-H3、DEX-D3、DO、DO-D3Levomethaphen (levomethorphan), morphine, codeine (codeine), thebaine (thebaine), benzocaine (benzocaine), ketamine (ketamine), mexadol (methadone), memantine (3, 5-dimethyladamantane-1-amine), amantadine (amantadine), dextropropoxyphene ((2R) -4- (dimethylamino) -3-methyl-1, 2-diphenylbutan-2-ylpropionate), ketonide (1- (4- (3-hydroxyphenyl) -1-methylpiperidin-4-yl) propan-1-one), tropane alkaloids such as cocaine, atropine (atropine), scopolamine (scopolamine), and the like.
In another embodiment, the composition comprises a combination of a compound of formula I and a compound of formula II, the combination comprising DEX-H3、DEX-D3、DO、DO-D3Levomethaphen, morphineCodeine, thebaine, benzocaine; and/or ketamine, mesartan, memantine, amantadine, dexpropoxyphene, ketomidone, cocaine, atropine, or scopolamine.
In another embodiment, a composition comprises a combination of a compound of formula I and ketamine, mesartan, memantine, amantadine, dextropropoxyphene, ketonide, 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 ester) and R-compound 52 (R-sarpogrelate ester) 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.
In another embodiment, the compounds of the invention are compounds of formula I wherein R1, R2, and R3 are independently substituted with one, two, or three halogens, wherein the halogen is F, Cl, or Br. Examples of fluoro derivatives of formula I are:
Figure GDA0002354989720000151
in another embodiment, a compound of formula I or analog can be prepared using the following carboxylic acids: difluorosuccinic acid, HO2C-CF2-CH2-CO2H (201-2C-CF2-CHF-CO2H (207-2C-(CF2)2-CO2H. Difluorosuccinic acid (213-215), HO2C-CHF-CHF-CO2H (216-219), difluoroglutaric acid, HO2C-(CH2)2-CF2-CO2H (219- & ltSUB & gt 221- & gt), difluoroglutaric acid, HO2C-CF2-(CH2)2-CO2H (222-2C-CF2H (226-2C-CF3(229-231)。
Figure GDA0002354989720000152
In another embodiment, the compound of formula I is a compound of formula Ic or formula Id as defined above and derivatives thereof, comprising an acid addition salt selected from: acetate, acetylsalicylate, adipate, aspartate, butyrate, caprate, hexanoate, octanoate, heptanoate, formate, fumarate, glutamate, glutarate, isophthalate, maleate, malonate, methionate, oxalate, nonanoate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, galactonate (galctonate), glucaric acid (saccharic acid), mannonate, mucate, rhamnosate, rhamnonate, capryloate, caprylate, heptanoate, formate, fumarate, glutamate, glutarate, isophthalate, maleate, fumarate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, galactonate (galctonate), glucaric acid (saccharic acid), manno, And a tartrate salt.
In another embodiment, the compound of formula I is of formula Ic or formula Id as defined above and derivatives thereof comprising acid addition salts formed from dicarboxylic and tricarboxylic acids selected from: adipic acid, aspartic acid, N-acyl aspartic acid, citric acid, fumaric acid, galactonic acid, glutaric acid, glutamic acid, N-acyl glutamic acid, glucaric acid (sugar acid), malic acid, maleic acid, mannonic acid, mucic acid, oxalic acid, pimelic acid, phthalic acid, isophthalic acid, terephthalic acid, rhamnose acid, sebacic acid, succinic acid, and tartaric acid.
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 derivatives of formula Ic, formula Id, and formula II are independently acid addition salts: hydroacetate, hydroacetylsalicylate, hydroadipate, hydroaspartate, hydrobutyrate, hydrocaprate, hydrohexanoate, hydrooctanoate, hydroheptanoate, hydroformate, hydrofumarate, hydroglutamate, hydroglutarate, hydroisophthalate, hydromaleate, hydromalonate, hydromethionate, hydrooxalate, hydrononanoate, hydropimelate, hydropropionate, hydrophthalate, hydrosalicylate, hydrosebacate, hydrosuccinate, hydroterephthalate, hydrocaseinate, hydrotryptophan, hydrovalerate, hydroN-acyl-aspartate, hydroN-acyl-glutamate, hydroN-acyl-caseinate, hydroN-acyl-tryptophan, hydroN-acyl-methionine, hydrocitrate, hydrohexanoate, hydrooctanoate, hydroN-acyl-glutamate, hydroN-acyl-caseinate, hydroN-acyl-tryptophan, hydroN-acyl-methionine, hydrocitrate, hydrohexanoate, Hydrogalactose, hydroglucaric acid (saccharic acid), hydromannose acid salt, hydromucic acid salt, hydrorhamnose acid salt, and hydrotartaric acid salt.
Another embodiment is a composition comprising dextromethorphan and an acid addition salt of M1 selected from the group consisting of: dextromethorphan and M1 dihydroadipate, dextromethorphan and M1 dihydroaspartate, dextromethorphan and M1 dihydrofumarate, dextromethorphan and M1 dihydroglutamate, dextromethorphan and M1 dihydroglutarate, dextromethorphan and M1 dihydroisophthalate, dextromethorphan and M1 dihydromaleate, dextromethorphan and M1 dihydromalonate, dextromethorphan and M1 dihydrooxalate, dextromethorphan and M1 dihydropimelate, dextromethorphan and M1 dihydrophthalate, dextromethorphan and M1 dihydrosebacate, dextromethorphan and M1 dihydrosuccinate, dextromethorphan and M1 dihydroterephthalate, dextromethorphan and M1 dihydroN-acyl-aspartate, dextromethorphan and M1 dihydroN-acyl-glutamate, dextromethorphan and M1 dihydrocitrate, dextromethorphan and M1 dihydrogalactose, Dextromethorphan and M1 dihydrogluconate, dextromethorphan and M1 dihydrogluconate, dextromethorphan and M1 dihydromannonate, dextromethorphan and M1 dihydromucate, dextromethorphan and M1 dihydrorhamnosate, and dextromethorphan and M1 dihydrotartrate.
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 a compound of formula Id, wherein the compound is a Fluorine Derivative (FD) of formula Ic (FDic) or formula Id (FDId) selected from the group consisting of compounds 221-.
Another embodiment is a composition comprising an acid addition salt of dextromethorphan and FDIc selected from the group consisting of: dextromethorphan and FDic dihydroadipate, dextromethorphan and FDic dihydroaspartate, dextromethorphan and FDic dihydrofumarate, dextromethorphan and FDic dihydroglutamate, dextromethorphan and FDic dihydroglutarate, dextromethorphan and FDic dihydroisophthalate, dextromethorphan and FDic dihydromaleate, dextromethorphan and FDic dihydromalonate, dextromethorphan and FDic dihydrooxalate, dextromethorphan and FDic dihydropimelate, dextromethorphan and FDic dihydrophthalate, dextromethorphan and FDic dihydrosebacate, dextromethorphan and FDic dihydrosuccinate, dextromethorphan and FDic dihydroterephthalate, dextromethorphan and FDic dihydroN-acyl-aspartate, dextromethorphan and FDic dihydroN-acyl-glutamate, dextromethorphan and FDic dihydrocitrate, dextromethorphan and FDic dihydrogalactose, Dextromethorphan and FDIc dihydrogluconate, dextromethorphan and FDIc dihydromannonate, dextromethorphan and FDIc dihydromucate, dextromethorphan and FDIc dihydrorhamnonate, and dextromethorphan and FDIc dihydrotartrate.
Figure GDA0002354989720000171
Another embodiment is a composition comprising dextromethorphan and an acid addition salt of FDId selected from the group consisting of: dextromethorphan and FDId dihydroadipate, dextromethorphan and FDId dihydroaspartate, dextromethorphan and FDId dihydrofumarate, dextromethorphan and FDId dihydroglutamate, dextromethorphan and FDId dihydroglutarate, dextromethorphan and FDId dihydroisophthalate, dextromethorphan and FDId dihydromaleate, dextromethorphan and FDId dihydromalonate, dextromethorphan and FDId dihydrooxalate, dextromethorphan and FDId dihydropimelate, dextromethorphan and FDId dihydrophthalate, dextromethorphan and FDId dihydrosebacate, dextromethorphan and FDId dihydrosuccinate, dextromethorphan and FDId dihydroterephthalate, dextromethorphan and FDId dihydroN-acyl-aspartate, dextromethorphan and FDId dihydroN-acyl-glutamate, dextromethorphan and FDId dihydrocitrate, dextromethorphan and FDId dihydrogalactose, Dextromethorphan and FDId dihydrogluconate, dextromethorphan and FDId dihydromannose, dextromethorphan and FDId dihydromucate, dextromethorphan and FDId dihydrorhamnosate, and dextromethorphan and FDId dihydrotartrate.
In another aspect of the invention, the compound is a compound of formula I, and derivatives include the following:
Figure GDA0002354989720000181
Figure GDA0002354989720000191
in some embodiments, the compound of formula I is formula Ic or formula Id.
In some embodiments, the compound of formula Ic or formula Id is M1, wherein Y is CH3(ii) a R4 is OH. In some embodiments, the compound of formula Ic or formula Id as defined above is a fluoro derivative, wherein R4 is OCF3。
Figure GDA0002354989720000192
One embodiment of the present invention is a composition comprising a compound having formula I:
Figure GDA0002354989720000193
wherein R is3Is a bicyclic ring system and the remainder of formula I is represented by R7Represents: as shown in formula If
Figure GDA0002354989720000194
Wherein R is6Is H, substitutedOr unsubstituted-C1-10Alkyl, substituted or unsubstituted-C3-10Cycloalkyl, substituted or unsubstituted-C5-10Aryl, substituted or unsubstituted-C1-10alkyl-C5-10Aryl, substituted or unsubstituted-C5-10Heteroaryl, or substituted or unsubstituted-C1-10alkyl-C5-10A heteroaryl group;
R7is that
Figure GDA0002354989720000201
-C1-10alkyl-X- (Y)n、-C3-10cycloalkyl-X- (Y)m、-C5-10aryl-X- (Y) m, or-C5-10heteroaryl-X- (Y)m(ii) a Wherein X is a bond, N, O, S, -C1-10Alkyl, -C3-10Cycloalkyl, -C5-10Aryl, -CO-C1-10Alkyl, -CO-C3-10Cycloalkyl, -COC5-10Aryl, -CO-C5-10Heteroaryl, -CO-NH-C1-10Alkyl, -CO-NH-C3-10Cycloalkyl, -CO-NH-C5-10Aryl, or-CO-NH-C5-10A heteroaryl group; y is H, C1-10Alkyl radical, C3-10Cycloalkyl radical, C5-10Aryl, -CO-C1-10Alkyl, -CO-C3-10Cycloalkyl, -COC5-10Aryl, CO-C5-10Heteroaryl, -CO-NH-C1-10Alkyl, -CO-NH-C3-10Cycloalkyl, -CO-NH-C5-10Aryl, or-CO-NH-C5-10A heteroaryl group; and m is an integer 1 or 2; or a pharmaceutically acceptable salt or N-oxide thereof; or a prodrug thereof.
In certain embodiments, the compound is a compound of formula If, wherein R is6Is aryl, and R7Is substituted or unsubstituted-C1-10alkyl-X- (Y)n.. In certain embodiments, R6Is substituted or unsubstituted C1-10alkyl-C5-10Aryl, and R7Is substituted or unsubstituted-C1-10alkyl-X- (Y)n.. In certain embodiments, R6Is phenyl, R7is-C1-10alkyl-N- (C)1-10Alkyl radical)2。
In one embodiment, compounds of formula I include, but are not limited to, the following examples: RS4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid; s4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid; r4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid; RS4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid; s4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid; r4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid; RS4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2, 3-trifluoro-4-oxobutanoic acid; s4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2, 3-trifluoro-4-oxobutanoic acid; r4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2, 3-trifluoro-4-oxobutanoic acid; RS4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 3, 3-trifluoro-4-oxobutanoic acid; s4- ((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 salt; s4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl 2, 2, 2-trifluoroacetate salt; r4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl 2, 2, 2-trifluoroacetate salt; 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) -1- (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) -1- (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) -1- (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; r S1- (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) -N- (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- (difluoromethoxy) -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) ethanyl ) 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; r3- (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; r3- (difluoromethoxy) -N- (difluoromethyl) -N-methyl-4- (2- (3- (trifluoromethoxy) phenethyl) phenoxy) butan-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-dimethylbut-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; RS 3-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; RS 3-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; RS1- (4- (3-methoxyphenyl) piperazin-1-yl) -3-phenoxypropane-2-ol S1- (4- (3-methoxyphenyl) piperazin-1-yl) -3-phenoxypropane-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; RS 1-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' - (phenylalkanediyl) bis (1-phenoxypropane-2-ol); s3, 3' - (phenylalkanediyl) bis (1-phenoxypropane-2-ol); r3, 3' - (phenylalkylalkanediyl) bis (1-phenoxypropane-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-1-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-phenoxypropane-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; RS 1-amino-3- (3, 5-dimethylphenoxy) propan-2-ol; s1-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; RS 1-amino-3-phenoxypropane-2-ol; s1-amino-3-phenoxypropane-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- (isopropylamino) -3- (naphthalen-1-ylmethoxy) propan-2-ol; r1- (isopropylamino) -3- (naphthalen-1-ylmethoxy) propan-2-ol; RS1- (isopropylamino) -3- ((3- (4-methylpiperazin-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; s1- (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; s1- (isopropylamino) -3- (pyrimidin-2-yloxy) propan-2-ol; r1- (isopropylamino) -3- (pyrimidin-2-yloxy) propan-2-ol; RS1- ((3, 4-dimethoxyphenethyl) amino) -3-phenoxypropan-2-ol; s1- ((3, 4-dimethoxyphenethyl) amino) -3-phenoxypropan-2-ol; r1- ((3, 4-dimethoxyphenethyl) amino) -3-phenoxypropan-2-ol; RS1- (4- (3- (1H-1, 2, 4-triazol-1-yl) propoxy) phenoxy) -3- (isopropylamino) propan-2-ol; s1- (4- (3- (1H-1, 2, 4-triazol-1-yl) propoxy) phenoxy) -3- (isopropylamino) propan-2-ol; r1- (4- (3- (1H-1, 2, 4-triazol-1-yl) propoxy) phenoxy) -3- (isopropylamino) propan-2-ol; RS1- (isopropylamino) -3-phenoxypropan-2-ol; s1- (isopropylamino) -3-phenoxypropan-2-ol; r1- (isopropylamino) -3-phenoxypropan-2-ol; RS1- (4- (3- (1H-1, 2, 4-triazol-1-yl) propoxy) phenoxy) -3- (isopropylamino) propan-2-ol; s1- (4- (3- (1H-1, 2, 4-triazol-1-yl) propoxy) phenoxy) -3- (isopropylamino) propan-2-ol; r1- (4- (3- (1H-1, 2, 4-triazol-1-yl) propoxy) phenoxy) -3- (isopropylamino) propan-2-ol; RS1- (isopropylamino) -3- (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) -1- (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- (trimethylphenoxy) propan-2-ol; s1- (isopropylamino) -3- (trimethylphenoxy) propan-2-ol; r1- (isopropylamino) -3- (trimethylphenoxy) 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-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- (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-toluenesulfonyl) butan-2-ol; s1- (isopropylamino) -4- (p-toluenesulfonyl) butan-2-ol; r1- (isopropylamino) -4- (p-toluenesulfonyl) butan-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- ((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- (cyclobutylmethoxy) ethoxy) phenoxy) -3 (isopropylamino) propan-2-ol; s1- (4- (2- (cyclobutylmethoxy) ethoxy) phenoxy) -3- (isopropylamino) propan-2-ol; r1- (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; r1- (4- (2- (cyclopropylmethoxy) ethyl) phenoxy) -3- (isopropylamino) propan-2-ol; RS3, 3' - (butylazaldiyl) bis (1-phenoxypropane-2-ol); s3, 3' - (butylazaldiyl) bis (1-phenoxypropane-2-ol); r3, 3' - (butylazaldiyl) bis (1-phenoxypropane-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-1-ol; RS5- (2-hydroxy-3- (isopropylamino) propoxy) chroman-3-yl nitrate; s5- (2-hydroxy-3- (isopropylamino) propoxy) chroman-3-yl nitrate; r5- (2-hydroxy-3- (isopropylamino) propoxy) chroman-3-yl nitrate; RS1- (isopropylamino) -3- ((6-methylpyrazin-2-yl) oxy) propan-2-ol; s1- (isopropylamino) -3- ((6-methylpyrazin-2-yl) oxy) propan-2-ol; r1- (isopropylamino) -3- ((6-methylpyrazin-2-yl) oxy) propan-2-ol; RS1- (isopropylamino) -3- ((3-morpholinopyrazin-2-yl) oxy) propan-2-ol; s1- (isopropylamino) -3- ((3-morpholinopyrazin-2-yl) oxy) propan-2-ol; r1- (isopropylamino) -3- ((3-morpholinopyrazin-2-yl) oxy) propan-2-ol; RS1- (isopropylamino) -3- ((6-methylpyrazin-2-yl) oxy) propan-2-ol; s1- (isopropylamino) -3- ((6-methylpyrazin-2-yl) oxy) propan-2-ol; r1- (isopropylamino) -3- ((6-methylpyrazin-2-yl) oxy) propan-2-ol; RSN- (8- (2-hydroxy-3- (isopropylamino) propoxy) -1, 2, 3, 4, 4a, 7, 8, 8 a-octahydro-1, 4-ethanonaphthalen-5-yl) methanesulfonamide; SN- (8- (2-hydroxy-3- (isopropylamino) propoxy) -1, 2, 3, 4, 4a, 7, 8, 8 a-octahydro-1, 4-ethanonaphthalen-5-yl) methanesulfonamide; RN- (8- (2-hydroxy-3- (isopropylamino) propoxy) -1, 2, 3, 4, 4a, 7, 8, 8 a-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-1-yl) propan-2-ol; RS3, 3' - ((2-hydroxyethyl) azanediyl) bis (1-phenoxypropane-2-ol); s3, 3' - ((2-hydroxyethyl) azaalkanediyl) bis (1-phenoxypropane-2-ol); r3, 3' - ((2-hydroxyethyl) azanediyl) 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; r1- (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; r1- (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; r1- (((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; s1- (methylamino) -3-phenoxypropan-2-ol; r1- (methylamino) -3-phenoxypropan-2-ol; RS1- ((2-hydroxyethyl) amino) -3-phenoxypropan-2-ol; s1- ((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; r1- ((4-methylthiazol-5-yl) oxy) -3- (4- (2- (neopentyloxy) phenyl) piperazin-1-yl) propan-2-ol; RS1- (4- (2-ethoxyphenyl) piperazin-1-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; RS 1-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; r1- (4- (3-chlorophenyl) piperazin-1-yl) -3- ((4-methylthiazol-5-yl) oxy) propan-2-ol; RS1- (((6, 7-dimethoxyisochroman-1-yl) methyl) (methyl) amino) -3-phenoxypropan-2-ol; s1- (((6, 7-dimethoxyisochroman-1-yl) methyl) (methyl) amino) -3-phenoxypropan-2-ol; r1- (((6, 7-dimethoxyisochroman-1-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-1-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-1-yl) -3- ((4-methylthiazol-5-yl) oxy) propan-2-ol; RS1- (4- (2-isobutoxyphenyl) piperazin-1-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-1-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; RS 1-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; s1- ((4-methoxybutyl) amino) -3-phenoxypropan-2-ol; r1- ((4-methoxybutyl) amino) -3-phenoxypropan-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 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; r1- ((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; r1- ((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; r1- ((2- ((2-nitrophenyl) amino) ethyl) amino) -3-phenoxypropan-2-ol; RS1- (isopropylamino) -3- ((1-tosyl-1H-indol-4-yl) oxy) propan-2-ol; s1- (isopropylamino) -3- ((1-tosyl-1H-indol-4-yl) oxy) propan-2-ol; r1- (isopropylamino) -3- ((1-tosyl-1H-indol-4-yl) oxy) propan-2-ol.
Another embodiment are compounds of formula If, wherein R6And R7Independently by one, two or three halogen, wherein the 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- (trifluoromethyl) ethan-1-amine,
n, N-dimethyl-2- ((1-methyl-2-phenyl-7, 7-bis (trifluoromethyl) bicyclo [2.2.1] heptan-2-yl) oxy) ethan-1-amine,
2- ((1, 7-dimethyl-2-phenyl-7- (trifluoromethyl) bicyclo [2.2.1] heptan-2-yl) oxy) -N, N-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.
Another embodiment is a composition comprising a compound of formula If listed 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-methoxy-phenyl) -2- (3' -dimethylaminopropoxy) -1, 7, 7-trimethyl-bicyclo (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-trimethyl-bicyclo [2, 2, 1] heptane;
2-benzyl-2- (2-diisopropylaminoethoxy) -1, 7, 7-trimethyl-bicyclo [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-trimethyl-bicyclo [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 ] ethylamine (deramciclane); N-methyl-N- (trifluoromethyl) -2- ((1, 7, 7-trimethyl-2-phenylbicyclo [2.2.1] heptan-2-yl) oxy) ethan-1-amine,
n, N-bis (trifluoromethyl) -2- ((1, 7, 7-trimethyl-2-phenylbicyclo [2.2.1] heptan-2-yl) oxy) ethan-1-amine,
2- ((1, 7-dimethyl-2-phenyl-7- (trifluoromethyl) bicyclo [2.2.1] heptan-2-yl) oxy) -N, N-bis (trifluoromethyl) ethan-1-amine,
2- ((1-methyl-2-phenyl-7, 7-bis (trifluoromethyl) bicyclo [2.2.1] heptan-2-yl) oxy) -N, N-bis (trifluoromethyl) ethan-1-amine,
n-methyl-2- ((1-methyl-2-phenyl-7, 7-bis (trifluoromethyl) bicyclo [2.2.1] heptan-2-yl) oxy) -N- (trifluoromethyl) ethan-1-amine,
n, N-dimethyl-2- ((1-methyl-2-phenyl-7, 7-bis (trifluoromethyl) bicyclo [2.2.1] heptan-2-yl) oxy) ethan-1-amine,
2- ((1, 7-dimethyl-2-phenyl-7- (trifluoromethyl) bicyclo [2.2.1] heptan-2-yl) oxy) -N, N-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.
Another embodiment is a composition comprising an acid addition salt of a compound of formula If, said acid addition salt comprising hydrogen acetate, hydrogen acetylsalicylate, hydrogen adipate, hydrogen aspartate, hydrogen butyrate, hydrogen decanoate, hydrogen hexanoate, hydrogen octanoate, hydrogen heptanoate, hydrogen formate, hydrogen fumarate, hydrogen glutarate, hydrogen isophthalate, hydrogen maleate, hydrogen malonate, hydrogen oxalate, hydrogen nonanoate, hydrogen pimelate, hydrogen propionate, hydrogen phthalate, hydrogen salicylate, hydrogen sebacate, hydrogen succinate, hydrogen terephthalate, hydrogen caseinate, hydrogen tryptophan, hydrogen methionine; hydrogen N-acyl-methionine salt; and a hydrovalerate salt.
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 ] ethylamine (deramciclane) comprising deramciclane hydrogen acetate, deramciclane hydrogen acetylsalicylate, deramciclane hydrogen adipate, deramciclane hydrogen aspartate, deramcane hydrogen butyrate, deramcane hydrogen decanoate, deramcane hydrogen hexanoate, deramcane hydrogen octanoate, deramcane hydrogen heptanoate, deramcane hydrogen formate, deramcane hydrogen fumarate, deramcane hydrogen glutarate, deramcane hydrogen isophthalate, deramcane hydrogen maleate, deramcane hydrogen malonate, deramcane hydrogen oxalate, Deramciclane hydrogen nonanoate, deramciclane hydrogen heptanoate, deramciclane hydrogen propionate, deramciclane hydrogen phthalate, deramciclane hydrogen salicylate, deramciclane hydrogen sebacate, deramciclane hydrogen succinate, deramciclane hydrogen terephthalate, deramciclane hydrogen caseinate, deramciclane hydrogen tryptophan salt, deramciclane hydrogen methionine salt; deramciclane hydrogen N-acyl-methionine salt; or deramciclane hydrovalerate.
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-trimethyl-bicyclo [2, 2, 1] heptane;
2-benzyl-2- (2-diisopropylaminoethoxy) -1, 7, 7-trimethyl-bicyclo [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-trimethyl-bicyclo [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 ] ethylamine (deramciclane); or an acid addition salt thereof.
One embodiment of the present invention is a composition comprising dextromethorphan, or an acid addition salt thereof, and: deramciclane, deramciclane acetate, deramciclane acetylsalicylate, deramciclane adipate, deramciclane butyrate, deramciclane decanoate, deramciclane hexanoate, deramciclane octanoate, deramciclane heptanoate, deramciclane formate, deramciclane fumarate, deramciclane glutarate, deramciclane isophthalate, deramciclane maleate, deramciclane malonate, deramciclane oxalate, deramciclane nonanoate, deramcane enantharate, deramciclane propionate, deramciclane phthalate, deramciclane salicylate, deramciclane sebacate, deramciclane succinate, deramciclane terephthalate, deramciclane caseinate, deramciclane tryptophan, or deramciclane valerate; or a combination thereof.
In some embodiments, the compound of formula II is a fluoro derivative, such as, but not limited to: (4bS, 8aS, 9S) -11-methyl-3- (trifluoromethoxy) -6, 7, 8, 8a, 9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene; (4bS, 8aS, 9S) -3- (trifluoromethoxy) -11- (trifluoromethyl) -6, 7, 8, 8a, 9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene; (4bS, 8aS, 9S) -3-methoxy-11- (trifluoromethyl) -6, 7, 8, 8a, 9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene.
In some embodiments, the compound of formula II is an acid addition salt selected from: acetates, acetylsalicylates, adipates, aspartates, butyrates, caprates, caproates, caprylates, enantheses, formates, fumarates, glutamateglutarates, isophtalate, maleates, malonates, methionates, oxalates, azelates, pimelates, propionates, phthalates, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, hemi-lactobionate, glucaric acid (sugar acid), mannonate, mucate, rhamnosate, and tartrate.
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: acetates, acetylsalicylates, adipates, aspartates, butyrates, caprates, caproates, caprylates, enantheses, formates, fumarates, glutamates, glutarates, isophtalate, maleates, malonates, methionates, oxalates, azelates, pimelates, propionates, phthalate, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, hemi-lactobionate, glucaric acid (sugar acid), mannonate, mucate, rhamnosate, and tartrate.
In some embodiments, the compound of formula II is an acid addition salt selected from: n-acyl-aspartate, N-acyl-glutarate, N-acyl-caseinate, N-acyl-tryptophan, and N-acyl-methionine.
Examples include base addition salts of formula II represented by dextromethorphan, such as dextromethorphan hydrogen acetate, dextromethorphan hydrogen acetylsalicylate, dextromethorphan hydrogen adipate, dextromethorphan hydrogen aspartate, dextromethorphan hydrogen butyrate, dextromethorphan hydrogen caprate, dextromethorphan hydrogen hexanoate, dextromethorphan hydrogen octanoate, dextromethorphan hydrogen heptanoate, dextromethorphan hydrogen formate, dextromethorphan hydrogen fumarate, dextromethorphan hydrogen glutarate, dextromethorphan hydrogen isophthalate, dextromethorphan hydrogen maleate, dextromethorphan hydrogen malonate, dextromethorphan hydrogen oxalate, dextromethorphan hydrogen nonanoate, dextromethorphan hydrogen heptanoate, dextromethorphan hydrogen propionate, dextromethorphan hydrogen phthalate, dextromethorphan hydrogen salicylate, dextromethorphan hydrogen sebacate, dextromethorphan hydrogen succinate, dextromethorphan hydrogen terephthalate, Dextromethorphan hydrobromide caseinate, dextromethorphan hydroxytryptolate, and dextromethorphan hydrovalerate.
Another embodiment of the 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 deramciclane and an acid addition salt of dextromethorphan.
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 that is a trifluoromethyl derivative of M1.
Aspartate, benzenesulfonate (besylate), benzoate, bicarbonate, bitartrate, bromide, camphorsulfonate, chloride, citrate, caprate, edetate, dodecylsulfate, propionate dodecylsulfate, ethanesulfonate (esylate), fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycoluridylaronate, hexanoate, hexylresorcinol, hydroxynaphthoate, isethionate, iodide, lactate, galactose-d-gluconate, lactobionate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalenesulfonate, nitrate, octanoate, oleate, pamoate, 4' -methylenebis (3-hydroxy-2-naphthoate), 4' -methylenebis (3-hydroxy-2-naphthoate), methyl bromide, mesylate, sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, 4' -methylenebis (3-hydroxy-2-naphthoate), Pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, chlorophylline, 8-chloro-1, 3-dimethyl-7 h-purine-2, 6-dione, tosylate, malate, methionate, phthalate, malonate, caseinate, tryptophan, maleate, fumarate.
An embodiment of the invention is an addition salt of formula I, wherein is an addition salt with an organic acid, such as aspartic acid, benzenesulfonic acid (besylic acid), benzoic acid, hydrocarbonate, tartaric acid, bromide, camphorsulfonic acid (camphorsulfonic acid), chloride, citric acid, capric acid, ethylenediaminetetraacetic acid, laurylsulfonic acid, dodecylsulfonic acid (estolic acid), ethanesulfonic acid (esylic acid), fumaric acid, glucoheptonic acid (gluceptic acid), gluconic acid, glutamic acid, glycolic acid, arsonic acid, hexanoic acid, hexylresorcinol, hydroxynaphthoic acid, isethionic acid, iodine, lactic acid, galactosyl-d-gluconic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methyl bromide, methyl nitric acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid (napsic acid), nitric acid, octanoic acid, oleic acid, pamoic acid (pamoic acid), 4, 4' -methylenebis (3-hydroxy-2-naphthoic acid, pantothenic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, theachloric acid (teoclic acid), 8-chloro-1, 3-dimethyl-7 h-purine-2, 6-dione, toluenesulfonic acid, malic acid, methylenedisulfonic 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, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, oxalic acid, isophthalic acid, terephthalic acid, salicylic acid, difluorosuccinic acid, trifluorosuccinic acid, tetrafluorosuccinic acid, difluoroglutaric acid, difluoroacetic acid, trifluoroacetic acid; and dextromethorphan; or a combination thereof.
In some aspects of the invention, the compound of formula I is a prodrug according to, wherein the compound is an ester or addition formed from: 3- (nitrooxy) propionic acid (suppliers: AKos (AKOS006377427) and 1717Chemall (OR235109)), 4-nitrooxy butyric acid (suppliers: AKos (AKOS006378268) and iChemical (EBD3415162)), 3- (nitrooxy) butyric 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, the compounds of formula I form addition salts of 3- (nitrooxy) propionic acid, 3- (nitrooxy) butyric acid, and 4- (nitrooxy) butyric acid. In another embodiment, the acid addition salts are 3- (nitrooxy) propanoic acid, 3- (nitrooxy) butanoic acid, and 4- (nitrooxy) butanoic acid.
In another embodiment, pharmaceutically acceptable acid addition salts of the compounds of formula I can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid.
Other anionic salts of the compounds of formula I and formula II include salts formed from the following acidic groups:
Figure GDA0002354989720000381
the acid addition salts of formula I are represented by the following formula:
Figure GDA0002354989720000382
another embodiment is a composition comprising a compound of formula I, and at least one compound selected from the group consisting of: thioridazine (thioridazine), perphenazine (perphenazine), flufenazine (fluphenazine), clopenthixol (zuclopenthixol), risperidone (risperidone), sertindole (sertindole), nortriptyline (nortriptyline), amitriptyline (amitriptyline), imipramine (imipramine), fluoxetine (fluoxetine), paroxetine (parooxetine), ajmaline (ajmaline), amiodarone), amitriptyline (amitriptyline), aprepidine (apriline), azelastine (azetinine), celecoxib (celecoxib), chlorpheniramine (chloniamine), chlorpromazine (chlorpromazine), diphenhydramine (diphenoxyurazine), fluphenazine (fluphenazine), fluvastatin (fluvastatin), fluvastatin (fluphenazine), fluphenazine (chlorpheniramine (fluphenazine), fluphenazine (fluphenazine), fluphenazine (fluphenazine), fluphenazine (fluphenazine), fluphenazine (, Moclobemide (moclobemide), nelfinavir (nelfinavir), nevirapine (nevirapine), nicardipine (nicardipine), norfluoxetine (norfluoxetine), perphenazine (perphenazine), pimozide (pimozide), terfenadine (terfenadine), thioridazine (thioridazine), cimetidine (cimetidine), quinidine, cisapride (cisapride), citalopram (citalopram), clozapine (clozapine), cocaine (cocaine), desipramine (desipramine), ranitidine (ranitidine), risperidone (risperidone), ritonavir (ritonavir), saquinavir (saquinavir), sertraline (sertraline), nevirapine (terbinamide), thiamine (tiapridine), triamcinopine (amipridine), amipramine (2-trimine), amipramine (clopidine (2), amitriptyline (amipramine (clopamide), doxine (amipramine (clopamide), amipramine (2 (clopyraine), amiloridine (amitriptyline), amipramine (2 (amitriptyline), amipramine (clopyraline), clopramine (amipridine), closterine (2 (amipridine), clorine (amipridine), clopridine (2-2 (amipridine), clopridine (2-2), clopridine (amipridine), clopridine (amitriptyline), clopridine (doxine (clopridine), clopridine (clopridine), clopridine, Trimipramine (trimipramine), nortriptyline (nortriptyline), maprotiline (maprotiline), phenelzine (phenelzine), isocarboxazid (isocarboxazid), tranylcypromine (tranylcypromine), citalopram (citalopram), sertraline (sertraline), aryloxyaminoindane (aryloxy indamine), benazelnazine (benzactyrazine), escitalopram (escitalopram), fluvoxamine (fluvoxamine), venlafaxine (venlafaxine), desvenlafaxine (desvenlafaxine), duloxetine (dulloxacine), mirtazapine (mirtazapine), nefazodone (nefazodone), lefluseline (milbexaline), ipramine (isopropyl), clofenadine (isopropyl), clofenamipramine (isopropyl), clofenadine (isopropyl), clofenadine), clofenamipramine (isopropyl amine (isopropyl), clofenadine), clofenamipramine (isopropyl triamcinolone (isopropyl), clofenadine), clofenamipramine (isopropyl amine (isopropyl), clofenamipramine (isopropyl), lofepramine (lofepramine), opipramol (opipramol), and dapoxetine (dapoxetine).
Another embodiment of the invention is a composition comprising a compound of formula I, a compound of formula II, and at least one compound selected from the group consisting of: thilidazine, perphenazine, flufenazine, clopenthixol, risperidone, sertindole, nortriptyline, amitriptyline, imipramine, fluoxetine, paroxetine, ajmaline, amiodarone, amitriptyline, aprepidine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, erythromycin, fluphenazine, fluvastatin, haloperidol, imipramine, indinavir, lansoprazole, levomepromazine, lopinavir, loratadine, mequinatadine, mesalamine, metoclopramide, mibedill, moclobemide, nelfinavir, nevirapine, nicardipine, norfluoxetine, perphenazine, lopinamide, terfenadine, thioridazine, cimetidine, quinidine, citalopram, clozapine, lopinavir, quinacrine, pravastatin, citalopinamide, clozapine, quinacrine, clovir, quinacrine, clovir, geine, gefitinib, Sertraline, terbinafine, ticlopidine, trifluperidol, yohimbine, dolasepine, mianserin, imipramine, 2-chlorimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, trazodone, citalopram, sertraline, aryloxyamine indane, pheniramine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, bazedoxifene, moclobemine, rasagiline, niasalazine, nianililamide, isoniazide, iprochlorohydrazine, toloxazalone, butriptyline, dibenzepine, indone, idaclopramide, lopinamide, pipindomethamphetamol, and opipramine.
In one embodiment, the composition comprises a compound of formula I, wherein the compound (wherein R is3) Is a conjugated or covalent compound prepared by reacting one or more of AChI (e.g. 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 (metrapfop-ate), (4aS, 6R, 8aS) -3-methoxy-11-methyl-4 a, 5, 9, 10, 11, 12-hexahydro-6H-benzo [2, 3-c-lol-1H-benzo [2, 3-methyl ] -1H-inden-1-one (donepezil), (S) -3- (1- (dimethylamino) ethyl) phenylethyl (methyl) carbamate (]Benzofuro [4, 3-cd]Azepine-6-ol (galantamine), and 1, 2, 3, 4-tetrahydroacridine-9-amine (tacrine), O, S-dimethylacetylthiophosphoramidate, O-dimethyl S- ((4-oxobenzo [ d)][1，2，3]Triazin-3 (4H) -yl) methyl) dithiophosphate, 2-dimethyl-2, 3-dihydrobenzofuran-7-ylmethyl carbamate, S- (((4-chlorophenyl) thio) methyl) O, O-diethyldithiophosphate, 2-chloro-1- (2, 4-dichlorophenyl) ethenyldiethylsulfate, O-diethylO- (3, 5, 6-trichloropyridin-2-yl) thiophosphate, O- (3-chloro-4-methyl-2-oxo-2H-chroman-7-yl) O, O-diethylthiophosphate, 1-phenylethyl (E) -3- ((dimethoxyphosphoryl) oxy) but-2-enoate, di-methyl-2-hydroxy-ethyl-methyl-2-oxo-2H-chroman-7-yl) phosphate, and mixtures thereof, 4- (tert-butyl) -2-chlorophenylmethylaminophosphate, O-diethyl O- (2- (ethylthio) ethyl) thiophosphate, O-diethyl S- (2- (ethylthio) ethyl) thiophosphate, O-diethyl O- (2-isopropyl-6-methylpyrimidin-4-yl) thiophosphate, 2-dichlorovinyldimethyl sulfate, (E) -4- (dimethylamino) -4-oxobut-2-en-2-yldimethyl sulfate, O-dimethyl S- (2- (methylamino) -2-oxoethyl) dithiophosphate, S' - (1, 4-dioxane-2, 3-diyl) O, O, O ', O ' -tetraethylbis (dithiophosphate), O, O-diethyl S- (2- (ethylthio) ethyl) dithiophosphate, O-ethyl O- (4-nitrophenyl) phenylthiophosphonate, O, O, O ', O ' -tetraethyl S, S ' -methylenebis (dithiophosphate), O-ethyl S, S-dipropyldithiophosphate, O- (4- (N, N-dimethylaminosulfonyl) phenyl) O, O-dimethylthiophosphate, ethyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate, O-dimethylthiophosphate, N-methyl-4- (methylthio) phenyl, N-methyl-2-methyl-4- (methylthio) phenyl) isopropylaminophosphate, N-methyl, O, O-dimethyl O- (3-methyl-4-nitrophenyl) thiophosphate, O-ethyl S-phenylethyl dithiophosphonate, isopropyl 2- ((ethoxy (isopropylamino) thiophosphoryl) oxy) benzoate, diethyl 2- ((dimethoxythiophosphoryl) thio) succinate, O, S-dimethylthiophosphamide salt, S- ((5-methoxy-2-oxo-1, 3, 4-thiadiazol-3 (2H) -yl) methyl) O, O-dimethyldithiophosphate, methyl 3- ((dimethoxyphosphoryl) oxy) but-2-enoate, (E) -dimethyl (4- (methylamino) -4-oxobut-2-en-ene -2-yl) sulfate, 1, 2-dibromo-2, 2-dichloroethyldimethylsulfate, isopropyl (S) -methylfluorophosphonate, 3-dimethylbutan-2-yl (S) -methylfluorophosphonate, O-diethyl O- (4-nitrophenyl) thiophosphate, S- (2- (ethylsulfinyl) ethyl) O, O-dimethylthiophosphate, O-diethyl S- ((ethylthio) methyl) dithiophosphate, S- ((6-chloro-2-oxobenzo [ d ] b]Oxazol-3 (2H) -yl) methyl) O, O-diethyldithiophosphate, S- ((1, 3-dioxoisoindolin-2-yl) methyl) O, O-dimethyldithiophosphate, (E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yldimethylsulfate, O, O, O ', O ' -tetramethylO, O ' - (thiobis (4, 1-phenylene)) bis (thiophosphate), tetraethyldiphosphate, S- ((tert-butylthio) methyl) O, O-diethyldithiophosphate, 2-chloro-1- (2, 4, 5-trichlorophenyl) vinyldimethylsulfate, sodium chloride, potassium chloride, sodium chloride, potassium, And dimethyl (2, 2, 2-trichloro-1-hydroxyethyl) phosphonate, or a pharmaceutically acceptable derivative, metabolite, analog, or salt thereof, prepared using The prodrug strategy described in figure 13, wherein The parent drug compounds of formula I and formula II are represented by R, wherein The overall scheme represents various examples of prodrugs of compounds of formula I and II (see, e.g., Rautio et al, The expansion role of drugs in a coordinated drug delivery and deployment [ extended role of prodrugs in contemporary drug design and development ]]Nature Reviews drug discovery]At http:// dx.doi.org/10.1038/nrd.2018.46(27April2018 published online); stella, Prodrugs, Some threads and current issues [ Some ideas and current questions ]]J.pharm.Sci. [ J.Pharm.Sci. [ J.Med.Sci. ]]99, 4755-; clas et al, Chemistry-enabled drug delivery (prodrugs): recovery drugs and galleries [ chemically-facilitated drug delivery (prodrugs): recent advances and challenges]Drug Discov]19, 79-87 (2014); rautio et al, Prodrugs-Recent apvals and a glimpse of the pipeline [ prodrug-Recent approval and route of delivery overview]Eur.j.pharm.sci. [ journal of european pharmacology science ]]109, 146-161 (2017); rautio et al produgs: design and clinical applications [ Prodrugs: design and clinical applications]Nat. Rev. drug Discov. [ Nature heald.)The following steps: drug discovery]7,255-; stella et al, Prodrug variants to ovarian com pore water solubility [ Prodrug strategy to overcome poor water solubility]Drug deliv rev. [ further review of drug delivery]59, 677-694 (2007); synthesis, in vitro and in vivo characterization of novel diethyl phosphate prodrugs of propofol by Kumplainen et al Synthesis, in vitro and in vivo characterization of novel dioxyphosphoric acid prodrugs of propofol]Eur.j.pharm.sci. [ journal of european pharmacology science ]]34, 110-; phosphorylated morpholine acetate human neurokinin-1receptor antagonists as water soluble prodrugs]Med, chem. [ journal of medicinal chemistry]43, 1234-1241 (2000); ishikawa et al TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825 Synthesis, physiochemical and pharmacological properties [ novel N-phosphonyl type prodrug of anti-MRSA cephalosporin T-91825 TAK-599: synthetic, physicochemical and pharmacological Properties]Med, chem. [ bio-organic and pharmaceutical chemistry]11, 2427-; melellou et al, aryl phosphoramides triesters, energy technology for delivering monophosphonated nucleosides and sunscreens intells [ Aryloxy phosphoramidate triester: technology for delivering monophosphorylated nucleosides and sugars into cells]ChemMedchem [ chemical medicine chemistry ]]4, 1779-1791 (2009); thornton et al, nucleotide phosphate and phosphonate prodrug clinical candidates]Med, chem. [ journal of medicinal chemistry]59, 10400, 10410 (2016); pradere et al, Synthesis of nucleoside phosphate and phosphonate prodrugs]Chem.rev. [ chemical review ]]114, 9154-9218 (2014); starrett et al Synthesis and in visualization of phosphate prodrug bis (pivaloyloxymethyl)9- (2-phosphonomethoxy) adenine [ phosphonate prodrug: synthesis and in vitro evaluation of bis (pivaloyloxymethyl)9- (2-phosphonomethoxyethyl) adenine]Antiviral Res [ Antiviral study ]]19, 267-273 (1992); starrett et al Synthesis, oral bioavailability determination, and in vitro evaluationn of prodrugs of the antiviral agent9-[2-(phosphonomethoxy)ethyl]Adenine (PMEA) [ antiviral agent 9- [2- (phosphonomethoxy) ethyl ]]Adenine (PMEA) synthesis, oral bioavailability assay, and prodrug in vitro evaluation]Med chem. [ journal of pharmaceutical chemistry]37, 1857-; synthesis of certain novel carboxylate-modified phosphoramidate derivatives of [ stavudine (d4T), anti-human immunodeficiency virus activity and esterase instability of McGuigan et al Synthesis, anti-human immunodeficiency virus activity and esterase instability]Chemothers chem, antiviral chemistry and chemotherapy]9,473-; McGuigan et al, Synthesis and anti-HIV activity of novel chain-extended phosphoramidate derivatives of d4T (stavudine) Synthesis and anti-HIV activity of novel chain-extended phosphoramidate derivatives of esterified hydrolytics as a rapid predictive test for anti-viral potential [ d4T (stavudine) ]: esterase hydrolysis as a rapid predictive test of antiviral efficacy]Chemothers chem, antiviral chemistry and chemotherapy]9, 109-115 (1998); erion et al Design, synthesis, and characterization of a series of cytotoxic P (450)3A-activated drugs (HepDipiect drugs) use for targeting phosphate-based drugs to the liver [ Design, synthesis, and characterization of a series of prodrugs of cytochrome P (450)3A activation (HepDipiect prodrugs) useful for targeting phosphate-based drugs to the liver]Am, chem, soc, american society of chemistry]126, 5154-; evaluation of in vitro models for screening alkaline phosphatase-mediated bioconversion of phosphate prodrugs]Drug meta]37, 1443-; heimabach et al, adsorption rate limit formulations for oral phosphate prodrugs]Res. [ pharmaceutical studies]20, 848-856 (2003); kadow et al, Inhibitors of human immunodeficiency virus type 1(HIV-1) attachment 6, anticlinical and human pharmacological profiling of BMS-663749, a phosphonooxymethyl prodrug of the HIV-1attachmentinhibitor2-(4-benzoyl-1-piperazinyl)-1-(4，7-dimethoxy-1H-pyrrolo[2，3-c]Pyridin-3-yl) -2-oxo ethane (BMS-488043) [ inhibitors of human immunodeficiency virus type 1(HIV-1) attachment 6.Preclinical and human pharmacokinetic profiles of BMS-663749, HIV-1 attachment inhibitor 2- (4-benzoyl-1-piperazinyl) -1- (4, 7-dimethoxy-1H-pyrrolo [2, 3-c)]Phosphonooxymethyl prodrugs of pyridin-3-yl) -2-oxoethanones (BMS-488043)]Med, chem. [ journal of medicinal chemistry]55, 2048-2056 (2012); heimbach et al, Enzyme-mediated precipitation of parent drugs from the phosphate prodrugs]Int.j.pharm. [ journal of international pharmacy]261, 81-92 (2003); all of which are incorporated herein by reference in their entirety).
Figure GDA0002354989720000431
In another embodiment, the prodrug compounds of formula I include, but are not limited to:
in another embodiment, prodrugs of formula I, such as but not limited to compounds 901-; 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) (6 months of 2013), as found in http:// www.fifeadtc.scot.nhs.uk/media/8535/cholenesterase-inhibitors-and-memantine-scp; incorporated by reference).
Application method
The five most expensive obstacles (million euros) are: dementia: 22, 164; mental disorder: 16, 717; mood disorders: 19, 238; addiction: 11, 719; anxiety disorders: 11, 687. In addition to psychiatric abnormalities, these five disorders are ranked in The column with The lowest direct medical expenditure (<3000 euros) per subject (Feinberg et al, The size, garden and cost of The study in The UK scale, burden and cost of brain disease, jychopharmacol [ journal of psychopharmacology ]27(9) 761-; subjects of the cost of Cancer Care in the United States:2010-2020[ prediction of costs of Cancer Care in the United States: 2010-2020J Natl Cancer Inst. [ journal of national Cancer institute ]103(2):117-128(2011Jan 19)). It is estimated that bipolar disorder (BP), also known as manic depression, costs up to $ 450 billion per year more than a decade ago. Most of this cost is explained by the indirect cost associated with reduced functional capacity and lost work. BP patients use a higher proportion of medical resources than the general population and than patients with other types of psychiatric conditions. Complications result in a heavy burden of BP on society. Brain diseases represent a considerable social and economic burden in europe. In 2010, about 8000 billion euros were spent in the year and 1.79 million people were estimated to be afflicted, brain disease is an unquestionable emergency and a major challenge for neuroscientists. The global cost of mental health conditions in 2010 is estimated at $ 2.5 million, with an expected increase in 2030 to $ 6. Glioblastoma multiforme is the most common malignant primary brain tumor in adults, with an estimated U.S. incidence of 4.43 times per 100,000 people-year, with a median age of 64 years. Symptoms typically include headache; nausea and vomiting; and progressive memory, personality, or neurological deficits. While from 2005 to 2030, alzheimer's and other dementias are expected to show a 66% increase. In the united states, depression is the second largest source of disability in women, and antidepressant responders are among the most severe users of healthcare resources. Despite the significant decline in quality of life and decreased productivity associated with depression, adequate diagnosis and appropriate treatment is often not available.
Drug and alcohol dependence are serious public health problems. It is estimated that there are 2640 to 3600 thousands of people worldwide abusing opioids (UNODC, World Drug Report [ World Drug Report ]2012), and in 2012, 210 thousands of people in the united states are estimated to have Substance Use barriers associated with prescribed opioid analgesics and 467,000 people's addiction to heroin (Substance absences and Mental Health Services Administration [ Drug Abuse and Mental Health Services Administration ], Results from the 2012National study on Drug Use and Health: summery of National findservices [2012 National Drug Use and Health Survey Results: National Survey Results abstract ], NSDUH series H-46, HHS publication No. (SMA)13-4795, rockville city, maryland: Substance Mental Abuse and Mental Health Services [ 2013 ], and the psychological Health Administration incorporates them in a global manner. In the united states, the number of deaths due to an inadvertent overdose of prescribed analgesics has risen dramatically, by more than a factor of four since 1999. There is also increasing evidence in the United states of China that the relationship between the increased non-therapeutic Use of opioid analgesics and Heroin abuse (Pradip et al, Associations of non-therapeutic PainReliever Use and Initiation of Heroin Use in the US [ non-medical analgesic Association for Use and Initiation of Heroin Use in the United states ], Center for behavial Health Statistics and quality data Review [ Center for Behavioral Health Statistics and quality data Review ], SAMHSA (2013); incorporated by reference in its entirety).
The Link between chronic diabetic metabolic status and the risk and emergence of AD pathophysiology has been suspected and proven in recent years (Goldwaser et al, Breakdown of the Cerebrovascularity and Blood-brain Barrier: A mechanical linkage between cerebrovascular and Blood brain barrier: Mechanistic Diabetes and Alzheimer's Disease. J Alzheimer's Disease J2016 (1/8/2016), the entire contents of which are incorporated by reference). In several large necropsy series, more than one third of subjects clinically diagnosed with typical AD showed evidence of cerebrovascular disease and had to be reclassified as mixed dementia (Grandal et al, Prevalence and concordance between the clinical and the post-mortem diagnosis of dementia in psychiatric clinics, Neurology [ neurology ] (2016); the entire contents of which are incorporated by reference). From a clinical point of view, it is therefore desirable to extend AD therapy beyond the currently approved drugs and mechanisms and address cognitive impairment by optimizing the underlying diabetic metabolic state or rather frequent type 2 diabetes in elderly subjects. Indeed, glycemic control is believed to have an effect on the severity of Cognitive Impairment (Zilliox et al Diabetes and Cognitive Impairment [ Diabetes and Cognitive Impairment ] CurrDiab Rep [ recent Diabetes reports ], 16(9):87 (2016); incorporated by reference in its entirety). Due to the specific anti-diabetic effects of the compounds of formula I as described above, in one embodiment, the invention provides benefits on the symptoms and disease progression of AD, as well as cognitive disorders of predominantly vascular origin (multi-infarct dementia, vascular cognitive dysfunction, etc.).
In parkinson's disease, the anticholinergic effects of neuroleptics are highly undesirable, as those inevitably worsen motor pathology and symptoms of the trophic nervous system. Among all dementias, lowering seizure threshold is another rare but highly undesirable potential adverse effect of neuroleptics. There are about ten million people worldwide with parkinson's disease. Parkinson's disease is a synucleinopathy, leading to progressive neurodegeneration characterized by motor dysfunction and non-motor symptoms including psychiatric abnormalities. Over 50% of Parkinson's disease patients have a period of mental disorder. Psychiatric abnormalities affect up to 75% of parkinson's dementia patients and symptoms are more difficult to cure in this population. Such mental abnormalities are mainly manifested as hallucinations and delusions, which can cause great distress to the patient and their caretakers. These events constitute a significant challenge to treatment and care, increase the likelihood of being housed in nursing homes, and are associated with increased mortality. Best practice treatment guidelines promote initial consideration for complications and reduction of dopaminergic therapy. However, these approaches are often inadequate and few other treatment options exist.
Morbidity and mortality associated with depression are quite high and continue to rise. Depression is currently ranked fourth in the major cause of disability worldwide after lower respiratory tract infections, perinatal morbidity, and HIV/AIDS. Seventeen percent of people develop depression during their lifetime; worse still, people already suffering from acute or chronic diseases are even more prone to depression, where the incidence of depression in patients can be 30% to 50% depending on the particular treatment condition.
The monoamine hypothesis has been the dominant hypothesis for depression over the past decades. It indicates that depression is associated with decreased monoamine function. Therefore, efforts to increase monoamine transmission through inhibition of serotonin (5-HT) and Norepinephrine (NE) transporters have been the central subject of depression studies since 1960. The selective 5-HT reuptake inhibitors (SSRIs) and the 5-HT and NE reuptake inhibitors (SNRIs) that appear in this series of studies are currently the first line treatment options for Major Depressive Disorder (MDD). One of the recent trends in antidepressant research is perfection by targeting monoaminergic receptors and additional transporters (e.g., as multimodal drugs and triple reuptake inhibitors) to either the monoaminergic mechanism or by adding atypical antipsychotics to SSRI or SNRI treatment. In addition, several other hypotheses for depression have been proposed in preclinical and clinical studies based on the biological markers of the disease and the efficacy of drug intervention. One central strategy is for glutamate receptors (e.g., intravenous N-methyl-D-aspartate (NMDA) receptor antagonist ketamine). Other strategies are based on modulation of cholinergic and gamma-aminobutyric acid (GABA) energetic transmission, neuronal plasticity, the stress/Hypothalamic Pituitary Adrenal (HPA) axis, the reward system, and neuroinflammation. Therefore, there is a need to develop novel drugs with complex pharmacological profiles derived from the simultaneous targeting of several neurotransmitters and neuromodulation systems.
BP often occurs with other psychiatric disorders, especially anxiety disorders and substance abuse. In addition, BP has been associated with a wide variety of general medical disorders, which further complicates the management of psychiatric disorders (Am J Manag Care [ U.S. J.MAN.J.; 11: S85-S90 (2005); incorporated by reference in its entirety).
BP is a brain disorder that causes abnormal shifts in mood, energy, activity level, and ability to perform daily tasks. BP is characterized by emotional disturbances, impulsivity, dangerous behavior, and interpersonal problems. BP is a recurrent chronic psychosis associated with dysfunction, elevated suicide rates and the utilization of mental health systems. BP is generally not well understood, and as many as 40% of BP patients are initially misdiagnosed, increasing the risk of suicide, mania, and chronic psychosocial distress. When correctly diagnosed, < 50% of diagnosed patients may be successfully treated, with as many as 10% -15% of patients dying from suicide (NIMH 2002).
Despite the established pharmacological guidelines for treatment, treatment of BP remains less than ideal. During the dosing period, most people still have sudden events or significant residual symptoms (NIMH 2002). Furthermore, functional deficits are often still present in patients in remission (NIMH 2002). Since many BP patients still have symptoms even while completely complying with the medication regimen, it is more urgent to investigate the pharmacological mechanisms of bipolar administration to have a more thorough understanding of the pathogenesis of this disease. The primary drug treatment for BP is a mood stabilizer unless the pharmacological mechanism is not clear. The common neuroprotective effects of mood stabilizers play a role in brain cell dysfunction of BP, which may ultimately lead to neuronal loss. Volumetric neuroimaging-now increasingly used to assess the potential involvement of different brain structures in mood regulation-can be applied to test neuroanatomical models of mood disorders. Imaging studies have shown that ongoing neuronal atrophy is accompanied by BP. For example, PET imaging of cerebral blood flow and glucose metabolism rates related to brain activity detect a decrease in activity in the subtotal prefrontal cortex region of the brain during bipolar depression. This reduced portion of activity can be explained at least in part by a corresponding reduction in cortical volume, as magnetic resonance imaging verifies the average gray matter volume. In BP, abnormalities of the third ventricle, frontal lobe, cerebellum, and possibly also temporal lobe are also noted.
Brain tumors are formed by abnormal growth and may appear in different areas of the brain. Benign (non-cancerous) tumors may grow and compress in the vicinity of the brain, but rarely spread to other tissues. Malignant (cancerous) tumors may grow rapidly and spread into other brain tissue. A tumor that grows in or presses against a brain region may prevent the portion of the brain from doing so, whether the tumor itself is benign or malignant, and then would require treatment. The most common type of brain tumor seen is not derived from brain tissue itself, but from metastases of extracranial cancers, such as lung and breast cancer. Brain tumors include neurofibromas type 1 or type 2, von Rippel-Lindau disease, tuberous sclerosis, Li-Porneni syndrome (Li-Fraumeni syndrome), type 1and type 2 Czochralski syndrome (Turcot syndrome type 1and type 2), Klinefelter syndrome (Klinefelter syndrome), and nevus-like basal cell carcinoma syndrome. Neuroblastoma is a cancer that is 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. Different factors can affect the neuroblastoma type and prognosis of children.
The specific treatment of nervous system cancer is based on several factors, including the overall health and medical history of the patient; the type, location and size of the tumor; the extent of the pathology; and other personal factors. Generally, treatment of patients with brain or spinal cord cancer includes surgery, chemotherapy, radiation therapy, and/or steroids to treat and prevent swelling, particularly in the brain; anti-seizure agents to treat and prevent seizures associated with intracranial pressure; placement of a shunt (to help drain excess fluid from the brain); lumbar puncture/spinal fluid extraction (to measure spinal cord and brain pressure); bone marrow transplantation; recovery (regaining lost motor skills and muscle strength); and/or antibiotics (treatment and prevention of infection). Chemotherapy is the use of anti-cancer drugs to treat cancer cells. In most cases, chemotherapy works by interfering with the ability of cancer cells to grow or multiply. These drugs can be administered intravenously or orally via tablets.
Neuropsychiatric symptoms are those with Alzheimer's Disease (AD), parkinson's disease (PDD), and many other neurodegenerative disorders, including but not limited to dementia with lewy bodies (DLB), vascular dementia (VaD), and frontotemporal dementia (FTLD) (Kazui H et al, Differences of Behavior and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias the Differences in behaviours and Psychological Symptoms in dementia of Disease Severity [ PLoS ONE journal of public science [11 (8): e0161092 (2016); Van der Schyf CJ, Psychotric Drug Development Strategies in Alzheimer's Disease and Parkinson's Disease's Diseases [ 468 ] Drug Development in Drug Development for neuropsychiatric causes of Alzheimer's Disease and Parkinson's Disease [ 458 ] 2016) ].
Many Neuropsychiatric Symptoms are expressed early in The neurodegenerative Disease stage and are even considered as a precursor index or an index of Disease Progression (Kazui H et al, Differences of Behavior and psychologic Symptoms of Dementias in Disease Severity in Major Dementias [ Differences in Dementia and psychological Symptoms of Four Major Dementias ] PLoS ONE [ journal of public science library ]11(8): e0161092 (2016); Peters ME et al, Neuropsychiatric Symptoms predictios of progress in growth section Alzheimer's Dementia and Death: The Cache essence Degreement regression Study [ Neuropsychiatric Symptoms as a predictor of Progression to Alzheimer's Disease and Death [ Alzheimer's Disease Progression ] 465 ] Study of Dementia in American J.172).
In neurodegenerative diseases and conditions including, but not limited to, AD, Behavioral and Psychiatric Symptoms of Dementia (BPSD), also known as neuropsychiatric symptoms, have multifactorial origins (McClam TD et al, Interventions for neuropsychiatric disorders in neuropathological impairement to Alzheimer's disease: a review of the neuro-psychiatric symptoms of Alzheimer's disease: literature review ] Harv Rev Psychiatry [ Harvard Psychiatry ]23:377-393 (2015)). Thus, strategies aimed at targeting multiple causes of disease (hence, multiple Drug targets) simultaneously constitute the most preferred way to develop therapeutic strategies for a range of diseases including, but not limited to, AD (Nikolic K et al, Drug design for CNSdis: pharmacological profiling of compounds using chemistry, 3D-QSAR and virtual screening methods [ Drug design for central nervous system diseases: compounds subjected to multidrug analysis using chemistry informatics, 3D-QSAR and virtual screening methods ] Front Neurosci [ lead of neuroscience ]10:265 (2015)).
Individual symptoms of BPSD may appear mutually exclusive, but may still share underlying mechanisms. This shared mechanism can likewise occur at the neurochemical and/or neuroanatomical level and serve as a basis for the development of targeted, rather than mechanism-specific therapies that address more than one symptom of BPSD.
The sharing mechanism is illustrated by the similar neurochemical organization of processes from the cortical region to the basal ganglia to the thalamus and back to the cortex. For example, the dorsolateral prefrontal cortex protrudes into the dorsolateral caudate nucleus, which in turn targets the lateral dorsolateral part of the medial globus pallidus, which sends the processes to the ventral anterior thalamus or major portion of the dorsal thalamus, which returns the processes to the cortex. In contrast, the orbital frontal cortex protrudes into the ventral caudate nucleus, which protrudes into the medial dorsal aspect of the medial globus pallidus, which sends the processes to the ventral anterior thalamus or large cellular portion of the dorsal thalamus, which returns the processes to the cortex. Thus, different parts of the cortex may be responsible for different functions, but there is a common principle by which the cortical network operates (Aouizerate B et al, Pathophysiology of obsessive-complex disorder: a neuropathic link beta pathobiology, neuropsychology, imaging and physiology. [ Pathophysiology of obsessive-compulsive disorders: phenomenology, neuropsychology, inevitable links between imaging and physiology ] Prog Neurobiol [ Neurobiol progression ]72 (3: 195) 221 (2004)). Thus, lesions in different lines are the underlying basis for the appearance of different BPSD symptoms. The heterogeneity of clinical manifestations of neurodegenerative disorders is determined by the primary location of the pathology (i.e., the affected network). For example, in apathy patients, the dorsal anterior cingulate cortex and dorsal lateral prefrontal cortex are more affected, while in uncontrolled patients with abvFTLD, the medial orbital prefrontal cortex (e.g., Massimo et al, Dement Geriator Cogn disorder [ dementia and senile dementia ]27:96-104 (2009)).
5-HT targeting with Compounds of formula I2AWith respect to the receptor, it is well established that serotonin passes 5-HT2AReceptor increasing glutamate in apical dendrites of fifth pyramidal cells of the prefrontal cortex spontaneous excitatory postsynaptic currents (Aghajanian GK, Mark GJ. Serotonin, via 5-HT2A receptors, intercrases EPSCs interlayer V-pyramidal cells of prefrontal cortex by the asynchronous pattern of glutamate release via 5-HT2A receptors, serotonin increases EPSC in V-layer pyramidal cells of the prefrontal cortex]Brain research]825:161-71(1999)). Such excessive asynchronous propagation may be functionally superior depending on which part of the cortex is affected-ranging from auditory or visual hallucinations to disorganized and indifferent-but in most cases, for 5-HT involving areas of the various cortices2AManipulation of the receptors will be sensitive (van Dyck CH et al, PET qualification of 5-HT)2Areceptors in the humanbrain:a constant infusion paradigm with[18F]altanserine [5-HT in human brain2APET quantification of the receptor: in [18F ]]Constant infusion paradigm in the case of atatanserin]J Nucl Med [ Nuclear medicine journal)]41(2):234-41(2000))。
With respect to glutamatergic signalling targeted by dextromethorphan and memantine, it is known to mediate thalamocortical signalling, resulting in activation of the corresponding regions of the cortex (Kharazia VN, Weinberg RJ, Glutamate inter halamic fibers terminating in primary sensory cortex IV layer J Neurosci [ J neuroscience ]14(10):6021-6032 (1994); Sherman SM. Thalamus systems a central role in on cortical function ] Nature Neurosci [ Nature neuroscience ]19(4):533-41 (2016)).
Diseases like alzheimer's disease are characterized by a systemic, progressive, neurodegenerative phenomenon that may spread transsynaptically. This not only means that more cells are lost in one area of the brain, but also that the pathology is spread to other brain areas. Because different brain regions have different functional roles, this explains why more advanced diseases are accompanied by a broader spectrum of symptoms (Kazui et al, Differencenes of Behavior and psychological symptoms of Dementia in Disease Severity in fountain Major Dementias. [ Differences in Behavioral and psychological symptoms for Dementia of Four Major Dementias ] PLoS ONE [ journal of public science journal ]11(8): e0161092 (2016)).
Behavioral and psychiatric symptoms of dementia-also known as Neuropsychiatric symptoms-are often studied clinically using research tools, such as The Neuropsychiatric scale (NPI; Cummings JL, The Neuropsychiatric Inventory: Association of Association psychopathology in dementias Patients [ Neuropsychiatric List: assessment of psychopathology in dementia ] Neurology [ Neurology ]48: S10-S16 (1997)). The NPI scale recognizes 12 sub-domains of behavioral function: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, loss of control, irritability/instability, abnormal motor activity, nocturnal behavior disturbances, and appetite and eating irregularities.
Patients rarely develop each of these NPI symptoms at once because even when the CDR score is 3, there are rare NPI items, like euphoria. In contrast, clinical experience indicates that few patients show only one particular item, while others do not. Rather, the symptoms of BPSD occur in various combinations or clusters. For example, common AD clusters can be, for example, aggressive, agonistic, roaming, repetitive, while common vascular Dementia clusters can be, for example, disorganized and restless, but the frequency and Severity of NPI projects can change, such as day-to-day, especially during Disease progression (Kazui et al, Differences in diferences of behavious and Psychological Symptoms of Dementia in Disease Severity in mental Dementias) [ Differences in the behavioural and Psychological Symptoms of Dementia of the four major Dementias ] ospplone [ journal of public science ]11(8): e0161092 (2016); Johnson et al, neuropsychiatric profile in Dementias ] [ neuropsychiatric psychiatric profile of Dementia ] Alzheimer Disease associated [ Alzheimer Disease association ] 326 (332)). Because a given patient may exhibit clusters of several symptoms of such clinical relevance at once, there is a high medical need for treatment of a diverse cluster of symptoms or the entire range of BPSD symptoms that can be targeted, regardless of any currently prevalent pathophysiological hypothesis for the disease.
The incidence of delusions was low in The general Population, in The Population with Normal Cognitive Aging (0.4% -2.4%), but increased in subjects with Mild Cognitive Impairment (MCI; 3.1% -3.4%) and significantly increased in subjects with dementia (18.0% -31.0%) (Geda YE et al, The prediction of Neuropsychiatric Symptomsin Mild Cognitive Impatiention and Normal Cognitive Aging: [ Mild Cognitive Impairment and Prevalence of Neuropsychiatric symptoms in Normal Cognitive Aging based on Population studies ] Archgen mental archive [ general psychiatric archive ]65(10): 1193. 1198 (2008); Lykeos CG et al, prediction of Neuropsychiatric Cognitive Impairment diagnosis and cardiovascular disease [ 2002 ] Mild Cognitive Impairment: Mild Cognitive Impairment > 288. and Mild Cognitive Impairment of cardiovascular dementia [ 2002 ] 288. J. The study of cardiovascular dementia in humans [ 12 ],288. A. As shown in Mild Cognitive Impairment, the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta analysis ] JAffect disorder [ journal of affective disorder ]190:264-71 (2016)). The incidence of hallucinations is also low in The general Population, Normal Cognitive aging Population (0.4% -0.6%), but increased 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 Point-Based Study [ [ Prevalence of neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive aging ]: Based Population Study ] Arch Genzhiath [ general psychiatric profile ]65(10): 3. sup. 1198 (2008); Lykeos CG et al, The Prevalence of neuropsychiatric disorders in dementia and Mild Cognitive Impairment: cardiovascular profile Study: 250. J. 2002 ] dementia and cardiovascular disease in cardiovascular disease publication [ 12 ] (QfQ J. A. J. The. A. The Study of neuropsychiatric Symptoms in cardiovascular disease: Mild Cognitive Impairment and dementia [ 12 ]: 5. J. The. A, the prevalence of neuropsychiatric enzymes in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Afffect disorder [ J. Emotion disorder ]190:264-71 (2016)).
Both delusions and hallucinations are part or symptom of psychiatric abnormalities in various neurological and psychiatric diseases and conditions. Now, second, (faute-de-mieux), psychostabilizing agents have traditionally been used to label such symptoms of external treatment dementia; however, with few exceptions, "typical" and "atypical" neuroleptics, when used in the context of dementia as indicated, both increase the incidence of CV adverse events and show a significant increase in mortality. Thus, the FDA issued "black box" warnings against off-label uses other than schizophrenia, which leaves such symptoms of BPSD with dementia with few treatment options. In this context, a completely different class, namely 5-HT2AReceptor antagonists and inverse agonists have demonstrated antipsychotic-like efficacy profiles in preclinical studies (Weiner et al, 5-Hydroxytryptamine2A receptor agonists as antipsychotic agents [ 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics]JPharmacol Exp Ther [ journal of pharmacology and Experimental therapeutics ]]299(1):268-76(2001)). Several 5-HT2AReceptor antagonists and inverse agonists have been developed for neuropsychiatric indications and there are reports of beneficial antipsychotic effects obtained with compounds such as eleterin (epivanserin) (meltzeryh et al, placbo-controlled evaluation of four novel compounds for the treatment of the same [ Placebo-controlled evaluation of four novel compounds for treatment of neuropsychiatric and schizoafective disorders ]Schizophrenia and schizoaffective disorders]Am J Psychiatry [ American J. psychiatric journal]161:975-84(2004))。5-HT2AReceptor inverse agonist Pimavanserin (Pimavanserin) significantly reduces psychotic symptoms in patients with moderate to severe Parkinson's disease, including hallucinations and delusions (Cummings J et al, Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placbo-controlled phase 3trial [ Pimavanserin for Parkinson's disease patients: randomized, placebo-controlled phase 3trial]Lancet [ Lancet]383:533-40(2014)) and have been approved by the FDA for the exclusive treatment of these symptoms of PDD. In patients with Alzheimer ' S disease dementia, the HTR2AT102C polymorphism is a significant risk factor for psychiatric disorders, the allele OR of the C allele is 2.191, and increases to 5.143 for homozygous CC genotypes (Ramanathan S, Glatt SJ, Serotonergic system genes in psychiatric disorders of Alzheimer ' S disease: meta-analysis [ Serotonergic system genes in Alzheimer ' S disease dementia ]]Am J Geriatr Psychiatry [ American journal of geriatric Psychiatry]17(10):839-46(2009))。
Dextromethorphan has NMDA receptor channel blocking properties, and NMDA receptor channel blockers, such as phencyclidine or ketamine, are known to possess psychotropic, rather than antipsychotic, properties. There are reports of Dextromethorphan induced psychoses in humans (Miller SC, Dextromethorphhan psychosis, dependence and physical with prawal. [ Dextromethorphan psychosis, dependence and physical withdrawal ] Add Biol [ addictive biology ]10(4):325-7 (2005)). These psychotropic properties of dextromethorphan may be a function of its metabolic degradation, leading to the production of dextrorphan (Zawertailo LA et al, Effect of metabolic block on the psychoactive effects of dextromethorphan, [ Effect of metabolic retardation on psychotropic effects of dextromethorphan ] Hum Psychopharmacol [ human psychopharmacology ]25(1):71-9 (2010)). The psychotropic effects of dextromethorphan observed in some subjects do not exclude the possibility that dextromethorphan also has antipsychotic properties in certain situations. Indeed, dextromethorphan-but not its metabolite dextrorphan-reportedly attenuates phencyclidine-induced motor behavior in rats (Sz é key JI et al, Induction of phencyclidine-like behavior in rats by dextran but not by phencyclidine) Pharmacol Biochem Behav [ pharmacological biochemistry and behaviourology ]40 (2: 381-6 (1991)). Another integrated analysis of randomized controlled studies of The NMDA receptor channel blocker memantine in Alzheimer's patients indicates that memantine contributes to a significant improvement in delusions (Kishi T et al, The effects of memantine on sensory disorders in patients with Alzheimer's disease. meta-analysis [ effect of memantine on behavioral disorders in Alzheimer's patients: meta-analysis ] neuropsychiator disease Treatment [ neuropsychiatric disorders and treatments ]13: 1909-.
Agonism and aggressiveness are grouped together on the NPI scale as one item. The incidence of agonism and aggression is low in The general population, in Normal Cognitive aging populations (2.8% -2.9%), but increased 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: application-Based Study [ Mild Cognitive Impairment and Prevalence of neuropsychiatric Symptoms in Normal Cognitive aging: population-Based Study ] Arch Gensitus [ general psychiatric profile ]65(10): 3. sup. 1198 (2008); Lykeos CG et al, The Prevalence of neuropsychiatric disorders in diabetes and mental disorder [ Mild Cognitive Impairment: cardiovascular profile ] Study of dementia [ 2002 ] and cardiovascular dementia of Japanese Cognitive Impairment: Mild Cognitive Impairment: 5. J. The Study of cardiovascular disease [5 ] dementia, the prevalence of neuropsychiatric enzymes in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Afffect disorder [ J. Emotion disorder ]190:264-71 (2016)). Therefore, the NPI program is one of the most prevalent and at the same time refractory clinical symptoms of BPSD.
Preclinical studies indicate that 5-HT is blocked2AThe receptor reduced the aggressiveness of laboratory rodents (Sakaue M et al, Modulation by 5-hT2A receptors of aggressive behavior in isolated mice [ modulation of aggressive behavior via the 5-hT2A receptor]Jpn J Pharmacol [ J.Pharmacol, Japan Pharmacol]89(1):89-92(2002)). Human genetic data indicate that three scores on the four component table of the babe's offensive questionnaire (Buss-Perry agentsistioninaire) (hostility, anger and physical aggressivity) show significant correlation with the HTR2Ars7322347T allele (Banlaki Z et al, Polymorphism in the serotoninerector 2a (HTR2A) gene as a accessible regulatory factor for an aggressive trait, [ serotonin receptor 2a (HTR2A) gene Polymorphism as a susceptible factor for a possible offensive trait]Periodical of PLoS One (public science library)]10(2) e0117792 (2015)). In case control studies of Chinese AD patients, the aggressiveness of AD is and 5-HT2AReceptor polymorphisms, such as T102C, are significantly associated (Lam LC et al, 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease, [5-HT2AT102C receptor polymorphism and neuropsychiatric symptoms of Alzheimer's disease]Int J Geriatr Psychiatry [ International journal of geriatrics]19(6):523-6(2004))。
Various NMDA receptor channel blockers have been shown to attenuate aggressive behavior in mice, and these Effects may be difficult to distinguish from sedation (Belozertseva IV, Bespalov AY, Effects of NMDA receptor channel blockade on aggregation in isolated male mice [ influence of NMDA receptor channel blockade on aggressive behavior in isolated male mice ] Aggr Behav [ aggressive behavior ]25:381- (1999)). In patients With possible Alzheimer's Disease and clinically significant Agitation, the Dextromethorphan-Quinidine combination decreased the NPI activation/aggression score (Cummings JL et al, Effect of Dextromethorphan-Quinidine on activation in Patients With Alzheimer Disease Dementia: A random Clinical Trial Trientia [ Effect of Dextromethorphan-Quinidine on Agitation in patients With Alzheimer's Disease: Randomized Clinical Trial ] JAMA [ J.Med. ]314(12):1242-54 2015)). A combinatorial analysis of a randomized controlled study of another non-selective NMDA receptor channel blocker, memantine, in Alzheimer's patients indicated that memantine also contributed to a significant improvement in agonism/aggressiveness (Kishi T et al, The effects of memantine on sensory disorders in patients with Alzheimer's disease. meta-analysis [ effect of memantine on behavioral disorders in Alzheimer's patients: meta-analysis ] neuropsychiator disease Treatment [ neuropsychiatric disease and Treatment ]13: 1909-.
The incidence of dysphoria/depression is moderate in The general Population, in Normal Cognitive Aging populations (7.2% -11.4%), but increased in subjects with MCI (20.1% -27.0%), and it is one of The most common problems of dementia (32.3% -42%) (Geda YE et al, The prediction of Neuropsychiatric in Cognitive Impairment and Normal Cognitive Aging: Population-based studies ] Archochytry psychiatric [ general psychiatric archives ]65(10): 1193-) (2008); Lyketsos CG et al, prediction of Neuropsychiatric Cognitive Impairment in Cognitive Impairment and Normal Cognitive Aging [ mild Cognitive Impairment: clinical findings of cardiovascular dementia [ 2002-288 ]288 in cardiovascular studies and mild Cognitive Impairment study of cardiovascular dementia [5 ],288 ], the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Afffect disorder [ J. Emotion disorder ]190:264-71 (2016)).
Preclinical studies with brain stimulation reward point to 5-HT2AReceptor antagonism may counteract dysphoria induced by conventional neuroleptic agents, such as haloperidol (Benaliouad F et al, Block of 5-HT2 arecepts reduce haloperidol-induced impairment of reward, [ Blockade of 5-HT2a receptor reduces haloperidol-induced impairment of reward ]]Neuropsychopharmacology]32(3):551-61(2007)). In a preclinical model sensitive to clinically used antidepressants, 5-HT2AReceptor antagonists exert antidepressant-like effects (Markek GJ et al, The selective 5-HT2A receptor antagonist M100907 antibiotic inhibitors-like behavial effects of The SSRIFLOOXETINE [ Selective 5-HT2A receptor antagonists ]The agent M100907 potentiates the antidepressant-like behavioral effects of SSRI fluoxetine]Neuropsychopharmacology]30:2205-2215 (2005); patel JG et al, the high selective 5-hydroxytryptamine (5-HT)2A receptor antagnostist, EMD 281014, signalizing in research and degrading in large compatible with the 10. high selective 5-hydroxytryptamine (5-HT)2A receptor antagonists, EMD 281014, significantly increased swimming and decreased immobility in male congenital helpless rats in forced swimming tests]Synapse]52:73-75(2004))。
In preclinical models, NMDA receptor channel blockers, such as dextromethorphan, have been shown to possess antidepressant-like properties (Sakhaee E et al, The role of NMDA receptor and nitrile oxide/cycloguanosin monophosphate pathway in The anti-depressive effect of The anti-metastatic pathway in The micro-formed myocardial test and tail Suspension test [ The effects of NMDA receptor and nitric oxide/cyclic guanosine monophosphate pathways in The antidepressant-like effects of dextromethorphan in forced swim and tail suspension tests in mice ] Biomed Pharmacother [ biomedical and pharmacotherapy ]85:627 634 (2017)). NMDA receptor channel blocker ketals have been shown to have rapid and potent antidepressant activity in Patients With refractory major depressive disorder (Singh JB et al, A Double-Blind, randomised, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study in Patients With Treatment-resistant depression ] Am J Psychiatry [ American journal of Psychiatry 173 ] (8):816-26 (2016)). In humans, Dextromethorphan given in combination with quinidine also exerts antidepressant effects (Murrough JW et al, Dextromethorphan/quinidine pharmacological in drugs with treatment resistant depression: Aprof of concept clinical trial of Dextromethorphan/quinidine in patients with treatment resistant depression ] J Affect disorder [ J. Emotion disorder ]218: 277-. Dextromethorphan is not a selective NMDA receptor channel blocker and is more potent at the serotonin and norepinephrine transporters and sigma-1receptors which may contribute to the therapeutic effect of dextromethorphan (Stahl SM, Mechanism of action of dextromethorphan/quinidine: compare with ketamine. CNS spectra 18: 225-. Although the monoamine transporters are targeted by most currently used antidepressants, sigma-1receptors have also been found to contribute to the similar antidepressant effect of dextromethorphan in experimental animals (Nguyen L et al, innovation of sigma-1receptors in the antidepressant-like effects of dextromethorphan, [ sigma-1receptors are involved in antidepressant-like effects of dextromethorphan ] PLoS One [ journal of public science library ]9(2): e89985 (2014)).
The incidence of apathy is low in the general Population, in normal Cognitive Aging populations (3.2% -4.8%), but increased in subjects with MCI (14.7% -18.5%) and dementia (35.9% -49%) (Geda YE et al, the preference of Neuropsychiatric Symptoms in Cold Cognitive Impairment and Cognitive Aging: A position-Based Study [ prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and normal Cognitive Aging]Arch Gen Psychiatry general psychiatric archive]65(10) 1193 and 1198 (2008); lykentos CG et al, Presence of neuropsychiatric symptomsin definitional and fine cognitive impact from the cardiovascular health study [ Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results of cardiovascular health studies]JAMA (journal of American medical society)]288(12) 1475-83 (2002); zhao QF et al, The predictive of neuropsychiatric systems in Alzheimer's disease, Systematic review and meta-analysis, [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: system evaluation and meta-analysis]J Affect disease [ journal of affective disorder ]]190:264-71(2016)). In case control studies of Chinese AD patients, apathy of AD was consistent with 5-HT2AReceptor polymorphisms, such as T102C, are significantly associated (Lam LC et al, 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease [5-HT2AT102C receptor polymorphism and the hallucination of Alzheimer's diseaseMenstrual mental symptoms]Int J Geriatr Psychiatry [ International journal of geriatrics]19(6):523-6(2004)). Apathy is a common symptom in schizophrenic patients and belongs to the group of negative symptoms. 5-HT2AReceptor antagonists reduce the severity of negative symptoms in schizophrenic patients (Davidson M et al, Efficacy and Safety of MIN-101: A12-Week randomised, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of negative symptoms of Schizophrenia) [ Efficacy and Safety of MIN-101: A12 Week Randomized, Double-Blind, Placebo-Controlled New Drug in the Development of a Trial for the Treatment of negative symptoms of Schizophrenia]Am J Psychiatry [ American J. psychiatric journal]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 disorders [ Placebo control evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorders ]]Am J Psychiatry [ American J. psychiatric journal]161(6):975-84(2004))。
NMDA receptor channel blockers, such as memantine, have been reported to reduce apathy in certain patients with: neurodegenerative diseases (Links KA et al, A Case of apathy due to frontotemporal destructive to memantine [ cases of apathy due to memantine-responsive frontotemporal dementia ] neuroase [ neurological cases ]19(3):256-61(2013)) or negative symptoms of schizophrenia (Paraschhakis A, a. tatkling negative symptoms of schizophrenic with memantine [ negative symptoms of schizophrenia treated with memantine ] Case Psychiatry [ psychiatric Case report ]2014:384783 (2014)).
The incidence of anxiety is low in the general Population, in normal Cognitive Aging populations (5.0% -5.8%), but increased in subjects with MCI (9.9% -14.1%) and dementia (21.5% -39%) (Geda YE et al, the prediction of Neuropsychiatric Symptoms in Mild Cognitive improvement and Cognitive Aging A Point-Based Study [ the Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and normal Cognitive Aging: Population-Based Study ] Arch Gen psychiatric profile [ general psychiatric file ]65(10): 3. sup. 1198 (2008); some of Lytsos CG et al, prediction of Neuropsychiatric Symptoms in and Mild Cognitive Impairment [ Study of Neuropsychiatric Symptoms of cardiovascular disease: Mild Cognitive Impairment ]288 ] and dementia in healthy subjects [ Study of cardiovascular disease ]288 ] this Study results of cardiovascular disease: Mild Cognitive Impairment: dementia 288 ] and dementia in cardiovascular disease [ Study of cardiovascular disease: Mild Cognitive Impairment: 23 ]288 ],288, the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Affect [ J.Emotion disorder ]190:264-71 (2016)).
5-HT2AReceptor antagonists exert anxiolytic effects in various preclinical models, particularly in a conditioned fear model (Adamec R et al, therapeutic and therapeutic effects of antibiotic effects of EMD 281014, a selective serotonin2A receptor antiandrogenic and effective by regulatory stress in rats [ acute systemic EMD 281014 (a selective serotonin2A receptor antagonist) for the prevention and treatment of anxiety induced by stress in rat predators]Eur J Pharmacol [ Eur J Pharmacol]504(1-2):79-96 (2004); millan MJ, the neurobiology and control of anxiety states [ neurobiology and control of anxiety states ]]Progr Neurobiol (neurobiological progression)]70:83-244(2003)). In humans, 5-HT2AReceptor blockade attenuates emotional processing of the prefrontal cortex of the orbit that involves assessment of socially relevant stimuli (Hornbell B et al, Pharmacological block of 5-HT2A receptor associated with the reduction of orbital activity along with processing of both feerful and growth facial health subjects) [ Pharmacological blockade of 5-HT2A receptors reduces activation of the prefrontal lobe of the orbit in healthy subjects when dealing with fear and anger expression]NeuroImage]47: S39-S41 (2009)). The 5-HT2 receptor antagonist serpin (CGS-15040A) has shown efficacy in clinical trials in patients with generalized anxiety disorder (KatzRJ et al, Serotonergic (5-HT2) differentiation of acute-pathological effects of serpin in generalized anxiety disorder) [ Serotonergic (5-HT2) mediates anxiety-treating effects of serpin in generalized anxiety disorder]Biol Psychiatry[Biopsychology]34:41-44(1993))。
Like other members of the NMDA receptor antagonist class (Chojnacka-W Lolo jcik E et al, Glutamatertecter ligands as anxiolytics. [ glutamate receptor ligand as anxiolytic agent ] Curr OpinInvestig Drugs [ current view of study Drugs ]2(8) 1112-9(2001), it was observed that dextromethorphan induces similar anxiolytic effects in experimental animals in certain dose ranges (Dere E et al, NMDA-receptor amylotrophic hormone and ifenprodil modulators and expressed on C57BL/6mice by antagonism of the NMDA receptors of dextromethorphan and ifenprodil modulators for the administration of C57 BL/6. Graded anxiety receptor expression C57BL/6mice [ NMDA 35v Pharmacol [ behavioral ] 14-6 ] mice [ behavioral activity ] 245-9 ] and > 18. multidrug receptor interaction with NMDA receptors of dextromethorphan and ifenprodil [1, and [ 13 ] receptor interaction with anxiolytic effects of NMDA receptor and mex receptors of alfa-mepidil (relevant to the clinical effects of NMDA receptor class I-1, and premenopaline receptor (1. related to the effects of premenopaline receptor, (+) -SKF-10, 047and dextromethorphan ameliorate coordinated acquired failure of the activity of phenylytoin-regulated sigma 1sites [ (+) -SKF-10, 047and dextromethorphan improve conditional fear stress by activating the sigma 1site of phenytoin regulation ] Eur J Pharmacol [ European journal of pharmacology ]299(1-3):21-8 (1996)). Treatment with memantine, another non-selective NMDA receptor channel blocker, significantly reduced The NPI subscale score for anxiety in AD patients (Ishikawa I et al, The effect on memantine on sleep architecture and psychiatric disorders in patients with Alzheimer's disease [ effect of memantine on sleep architecture and psychiatric symptoms in Alzheimer's disease ] actaneurosychiator [ neuropsychiatric reports ]28(3):157-64 (2016)).
The incidence of euphoria/joy is low in The general Population and in normal Cognitive Aging populations (0.3% -0.4%), but increased 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 Cognitive Aging: A publication-Based Study [ Mild psychiatric file ]65(10): 3. 1198 (2008); Lytskeos CG et al, The Prevalence of Neuropsychiatric Symptoms in cardiovascular disorders [ 2002. J. health Study: 288 ] and Mild Cognitive dementia [ 14. J. F. J. sub. Study of cardiovascular Neuropsychiatric Cognitive disorders ]288, the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Affect [ J.Emotion disorder ]190:264-71 (2016)).
Human PET studies have established changes in stimulant drug-induced euphoria mimetic scale scores and [11C ] in caudate and putamen]A positive correlation of a decrease in the receptor Binding Potential (BP) of Raclepride (rapropride) with an increase in endogenous dopamine (dreves WC. Amphetamine-induced dopamine release in human ventral striatum with euphoria. Amphetamine-induced dopamine release in human ventral striatum]Biol Psychiatry [ biopsychiatry]49(2):81-96(2001)). The non-selective 5-HT2A receptor agonist gymnocycline (psilocybin) significantly reduces the frequency in the ventral striatum11C]Leclepride BP, which is associated with euphoric-related de-humanization (Vollenweider FX et al, 5-HT modulation of dopamine releasing inbasal ganglib in sensitive-induced pathologies in man-a PET study with [11C]racemphide [5-HT regulates dopamine release in basal ganglia in nudeomushroom-induced psychosis in humans-use [11C]PET study with Raclepride]Neuropsychopharmacology]20(5):424-33(1999))。
Preclinical data have indicated that most prefrontal cortical pyramidal neurons projecting into the dorsal raphe nucleus and ventral tegmental area express5-HT2AThe receptor (Vazzez-Bordetetti P et al, viral nerves in rat not front cellular presenting to viral regional area and nuclear expression 5-HT2Arecepitors [ pyramidal neurons in the prefrontal cortex of rats project into the ventral tegmental area and the dorsal raph nucleus of the midline express5-HT2AReceptors]Cereb Cortex]19:1678-86(2009)). Due to the fact thatThis, blocking forehead 5-HT2AReceptors modulate pyramidal neurons that project into the midbrain, thereby inhibiting the dopaminergic system of the midbrain (Erbdru BH et al, Serotonin2A receptor antagonists for the treatment of schizophrenia]Expert opinions about investigational Drugs]1211-1223(2011)) dopaminergic mesencephalon is also under the control of cholinergic projections, e.g., those derived from the reins, and the activity of these projections is modulated by nicotinic acetylcholine receptors containing α 3 β 4 (McCallum SE et al, α 3 β 4nicotinic acetylcholine receptors in the medial hairpin modified the mesoporous dopaminergic response to acute nicotine midbrain-peripheral dopaminergic receptor regulation in vivo [ medial reins in α 3 β 4nicotinic acetylcholine receptors]Neuropharmacology (Neuropharmacology)]63(3) 434-40(2012), antagonism at the nicotinic acetylcholine receptor containing α 3 β 4 and the various effects attributed to reduced dopamine tone (tone) (Maiisonave IM, Glick SD. anti-additive interactions of an iboga alkaloid generator: a novel mechanism for anti-addiction of Evosa alkaloid homologues: novel treatment]Pharmacol biochem Behav [ pharmacological biochemistry and behaviourology]75(3) 607-18(2003) Nicotine acetylcholine receptor containing α 3 β 4 is one of the primary targets of dextromethorphan (Taylor CP et al, pharmacological of dextromethorphan: Relevance to dextromethorphan/quinidine
Figure GDA0002354989720000581
clinicalose [ pharmacology of dextromethorphan: with dextromethorphan/quinidineCorrelation of clinical use]Pharmacol Ther [ pharmacology and therapeutics)]164:170-82(2016))。
The incidence of uncontrolled progression is low in the general Population, in normal Cognitive Aging populations (0.9% -1.6%), but increased in subjects with MCI (3.1% -4.7%) and dementia (12.7% -17%) (Geda YE et al, the prediction of Neuropsychiatric Symptoms in Mild Cognitive improvement and Cognitive Aging A Point-Based Study [ Prevalence of Mild Genychiatric disorders [ general psychiatric file ]65(10): 3. sup. 1198 (2008); tsos CG et al, prediction of Neuropsychiatric disorders in diabetes and mental disorder in normal Cognitive Aging [ Mild Cognitive Impairment ] neurological disease ]288, cardiovascular disease in cardiovascular disease: Mild Cognitive disorder [ 5. sup. J. 2002 ] cardiovascular disease in cardiovascular disease, the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Affect [ J.Emotion disorder ]190:264-71 (2016)).
Changes in the balance of functional activity within the 5-HT system are the basis of pulse control and preclinical studies, suggesting that 5-HT2AReceptors are involved in the regulation of impulsive behaviors, including intrinsic and induced behavioral deregulation (Anastasio NC et al, Serotonin (5-Hydroxytryptamine)5-HT (2A) receptor: association with endogenous and cocaine-induced biochemical inhibition in rats [ Serotonin (5-hydroxytryptamine)5-HT (2A) receptors: involved in the disinhibition of intrinsic and cocaine-induced behaviors in rats]Behav Pharmacol [ behavioral pharmacology]22(3):248-61(2011))。
In humans, high levels of behavioral impulses and certain 5-HT2AA significant association was found between polymorphisms, such as The C/C genotype of rs6313 (Jakubczyk A et al The CC genotype in HTR2A T102C polymorphic isostearic with latent immunological activity in alcoholic-dependent genes) [ CC genotype of HTR2AT102C polymorphism is associated with The behavioral impulsion of alcohol-dependent patients]J Psychiator Res [ journal of psychiatric research ]]46(1):44-9(2012)). Persons with an A/A genotype for the HTR2A 1438A/G polymorphism have a higher maladaptive impulse score (Tomson K et al, Effect of a human serotonin 5-HT2A receptor genetopoisms on impulsivity: dependent on cholesterol levels [ human serum 5-HT2A receptor)Impact of genetic polymorphisms on impulsion: dependence on cholesterol levels]J Affect disease [ journal of affective disorder ]]206:23-30(2016)). From a neuroanatomical point of view, neocortex is known to be rich in 5-HT2AReceptor, and that the loss of behavior in Neurodegenerative diseases such as behavioral variant frontotemporal dementia is linked to the cortical thickness of the lateral hippocampus, right orbital frontalis cortex and right cerebral islets (Santillo AF et al, Grey and White Matter Material clinical-Anatomical correlations of inhibition of Grey and White Matter clinical-Neurodegenerative diseases [ Grey and White Matter clinical-Anatomical correlations of inhibition of Neurodegenerative diseases ]]Periodical of PLoS One (public science library)]11(10):e0164122(2016))。
The combination of Dextromethorphan and Quinidine has positive therapeutic effect on pseudobulbar effect (PBA) patients (Pioro EP. review of Dextromeorphan 20mg/Quinidine 10 mg)
Figure GDA0002354989720000591
Forpseudoubulbar Affect [ dextromethorphan 20mg/quinidine 10mg
Figure GDA0002354989720000592
Overview of the pseudobulbar Effect]Neural tube (Neral nerve therapy)]3(1):15-28(2014)). PBA can occur in association with numerous 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 syndrome of deregulation in which pathways involving serotonin and glutamate are disrupted (AhmedA, Simmons Z. Pseudobulbar effect: prediction and management]Tuer Clin Risk Manag [ treatment and clinical Risk management]9:483-9(2013)). Another integrated analysis of random control studies of The NMDA receptor channel blocker memantine in Alzheimer's patients indicated that memantine is responsible for a significant improvement in deregulation (Kishi T et al, The effects of memantine on biochemical disorders in patients with diseases with Alzheimer's disease. meta-analysis [ effect of memantine on behavioral disorders in Alzheimer's patients:. meta-analysis]Neuropsychiatr Dis Treatment [ neuropsychiatric disordersAnd treatment of]13:1909-1928(2017))。
The incidence of irritability/instability is low in the general Population, in normal Cognitive Aging populations (4.6% -7.6%), but increased in subjects with MCI (14.7% -19.4%) and dementia (27% -36%) (Geda YE et al, the Prevalence of Neuropsychiatric Symptoms in Mild Cognitive improvement Aging: A publication-basis Study [ Mild Cognitive Impairment and Neuropsychiatric Symptoms in normal Cognitive Aging ] Arch Genstem disease [ general psychiatric file ]65(10):1193- > 1198 (2008); Lykens CG et al, the Prevalence of Neuropsychiatric systemic Cognitive Impairment in general psychiatric file ]65 (2008; cardiovascular disease: Mild Cognitive Impairment: 288 ] and Neuropsychiatric dementia [ 2002 ] Mild Cognitive Impairment: Mild Cognitive Impairment in cardiovascular disease ]288 in general Cognitive Impairment [ 14 ] 5 ] Study of cardiovascular dementia [ 2002-Mild Cognitive Impairment ] and cardiovascular dementia [ 14 ] Study results of cardiovascular disease [ 14-7.5 ],288 ], the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Affect [ J.Emotion disorder ]190:264-71 (2016)).
Functional magnetic resonance studies in animals and humans have indicated 5-HT2AReceptors are specifically involved in prefrontal cortex (PFC) feedback regulation projecting onto the amygdala. Since this receptor is highly expressed in the prefrontal cortex region, it affects inhibitory mood-controlling basal and mood-controlling behaviors, such as various impulse-related behaviors (Aznar S, Klein AB. Regulation front core activation: an emulsifying role for the 5-HT)2A serotonireceivers in the modulation of observation-based actions? [ modulation of prefrontal cortex activation: 5-HT2Is an emerging role for serotonin a receptor in regulating mood-based behavior?]Mol Neurobiol [ molecular Neurobiol ]]48(3):841-53(2013))。
The combination of dextromethorphan and quinidine has a positive therapeutic effect on pseudobulbar patients characterized by emotional lability, uncontrolled crying or laughing, which may be inappropriate or inappropriate against social background (Pioro ep. review of dextromeorphan 20 mg/Quinidin)e 10mg
Figure GDA0002354989720000601
for pseudo isobulbar Affect [ dextromethorphan 20mg/quinidine 10mg
Figure GDA0002354989720000602
Overview of the pseudobulbar Effect]Neural therapy]17; 3(1):15-28(2014)). Treatment with another non-selective NMDA receptor channel blocker memantine decreases The score of NPI program for irritability/instability in AD patients (Ishikawa I et al, The effect of memantine on sleep architecture and pseudo characteristics systems in patients with Alzheimer's disease [ effect of memantine on sleep architecture and mental symptoms in patients with Alzheimer's disease ]]ActaNeuropsychiatr (neuropsychiatric report)]28(3):157-64(2016)). A collective analysis of randomized controlled studies of memantine in Alzheimer's patients indicates that memantine is superior to The control group in controlling irritability/instability (Kishi T et al, The effects of memantine on sensory disorders in patients with disabilities: meta-analysis, [ effect of memantine on behavioral disorders in Alzheimer's patients]Neuropsychiatr Dis Treatment [ neuropsychiatric disorders and treatments]13:1909-1928(2017))。
The incidence of abnormal motor activity is low in The general Population, in normal Cognitive Aging populations (0.4% -0.6%), but increased in subjects with MCI (1.3% -3.8%) and dementia (16% -32%) (Geda YE et al, The prediction of Neuropsychiatric Symptoms in Mild Cognitive improvement and Cognitive Aging A Point-Based Study [ Prevalence of Mild Genychiatric disorders [ general psychiatric file ]65(10): 3. sup. 1198 (2008); Lykeos et al, prediction of Neuropsychiatric disorders and mental Symptoms in normal Cognitive Aging [ neurological file ]65 (10); cardiovascular disease of cardiovascular disease: Mild Cognitive disorder and mental disorder [5 ] dementia of Japanese Cognitive grade: Mild Cognitive disorder [5 ] cardiovascular disease of cardiovascular disease: Mild Cognitive dementia [5 ] and dementia of Japanese dementia, the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Affect [ J.Emotion disorder ]190:264-71 (2016)).
Abnormal motor behaviour and 5-HT2A receptor polymorphisms of AD were found to be significantly associated, for example T102C (Lam LC et AL, 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease, [5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms of Alzheimer's disease ] Int JGeriator Psychiatry [ International journal of Aging ]19(6) (523-6 (2004); Pritch AL et AL, Role of 5HT 2A and 5HT2C polymorphisms in biochemical and pathological symptoms of Alzheimer's disease, [5HT 2A and 5HT2C ] neurologic of Alzheimer's disease ] 341 (2008) biological Aging).
Abnormal motor behaviour in various neurological disease states, such as parkinson's disease, is due to abnormal plastic processes in the basal ganglia, which may be expressed as a sensitisation of behaviour to: glutamate/NMDA receptor blockade (Chase TN et al, Strong glutamatergic mechanisms and extrapyramidal movement disorders [ Striatal glutamatergic mechanisms and extrapyramidal dyskinesias ]]Neurotox Res (neurotoxicity study)]5(1-2):139-46(2003)) and antagonism of receptors containing α 3 β 4 (Maizoneuve IM, Glick SD, Anti-adductive interactions of an iboga alkaloid generator: a novel mechanism for Anti-addiction to Evosa alkaloid homologues: novel therapeutic mechanisms]Pharmacol biochem Behav [ pharmacological biochemistry and behaviourology]75(3):607-18(2003)), two receptor targets for dextromethorphan (Taylor CP et al, Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine
Figure GDA0002354989720000611
clinical use [ pharmacology of dextromethorphan: with dextromethorphan/quinidine
Figure GDA0002354989720000612
Correlation of clinical use]Pharmacol Ther [ pharmacology and therapeutics)]164:170-82(2016))。
The incidence of nocturnal behavioral disorders is moderate (10.9%) in the general Population, in normal Cognitive Aging populations, but increased in subjects with MCI (13.8% -18.3%) and dementia (27.4% -39%) (Geda YE et al, the prediction of Neuropsychiatric Symptoms in Mild Cognitive improvement and Cognitive Aging: A Point-Based Study [ Mild Cognitive Impairment and the Prevalence of Neuropsychiatric Symptoms in normal cognition [ Population-Based Study ] Archgen psychophysiological profile [ general psychiatric file ]65(10): 1193. 1198 (2008); ketsos CG et al, prediction of Neuropsychiatric system in diabetes and d Cognitive assessment: Mild Cognitive Impairment [ 14 ] cardiovascular disease in cardiovascular disease ] 288. and Mild Cognitive Impairment [ 14 ] cardiovascular disease in cardiovascular disease of cardiovascular disease ]288, the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Affect [ J.Emotion disorder ]190:264-71 (2016)).
5-HT2AReceptors play an important role in the regulation of sleep (Vanover KE, Davis RE. role of 5-HT2A receptor antagonists in the treatment of insomnia [5-HT2A receptor antagonists]Nat Sci Sleep [ essence and science of Sleep]2:139-50(2010)). In clinical trials evaluating the safety and efficacy of the 5-HT2A receptor inverse agonist Pimavanserin in patients with moderate to severe Parkinson's disease, participants reported that Pimavanserin improved night sleep and daytime alertness compared to placebo (Cummings J et al, Pimavanseries for patients with Parkinson's disease psychology: a randomised, placebo-controlled phase 3trial [ Pimavanserin for Parkinson's mental patients: randomised, placebo-controlled phase 3trial ]]Lancet [ Lancet]383:533-40(2014)). Another 5-HT2AThe receptor inverse agonist, eleterin, has demonstrated clinical efficacy in insomnia patients (European drug management)Bureau (European Medicines Agency) Withdrawal Association Report for the Assessment of Withdrawal of Sliwens (Eplivanselin) [ Sliwens (Elliselin) ]]18/3/2010, london EMA/CHMP/90435/2010).
A combinatorial analysis of a randomized controlled study of another non-selective NMDA receptor channel blocker, memantine, in Alzheimer's patients indicates that memantine contributes to a significant improvement in nocturnal interference/circadian rhythm disturbances (Kishi T et al, the effects of memantine on biochemical disorders in patients with Alzheimer's disease. meta-analysis. [ effect of memantine on behavioral disorders in Alzheimer's patients: meta-analysis ] neuropsychiator disorder Treatment [ neuropsychiatric diseases and treatments ]13: 1909-. In AD patients, Memantine is effective in reducing fragmented sleep, and polysomnography indicates prolonged sleep time, increased sleep efficiency and phase II occupancy, and decreased nocturnal arousal, periodic limb movement index, and phase I occupancy (Ishikawa I et al, The effect of memantine on sleep architecture and psychomotor characteristics with Alzheimer's disease, [ effect of Memantine on sleep architecture and mental symptoms in Alzheimer's patients ] Acta neuropsythatr [ Proc. Natl. Neuropathitr ]28(3):157-64 (2016)).
The incidence of appetite and eating disorders is low in the general Population, in the normal Cognitive Aging Population (5.3%), but increased in subjects with MCI (10.4% -10.7%) and dementia (19.6% -34%) (Geda YE et al, the prediction of Neuropsychiatric Symptoms in Mild Cognitive improvement and Cognitive Aging: A Point-Based Study [ Prevalence of Mild Cognitive Impairment and Neuropsychiatric Symptoms in normal Cognitive Aging: Population Based Study ] Arch Genzhiath [ general psychiatric profile ]65(10): 3. sup. 1198 (2008); Lykeos et al, prediction of Neuropsychiatric Symptoms in diabetes and mental disorder [ health ] Study of cardiovascular disease: Mild Cognitive Impairment: dementia [ 12 ] cardiovascular dementia in Japanese Cognitive Impairment: Mild Cognitive Impairment: 5. J. Study of cardiovascular disease: Mild Cognitive Impairment: dementia 2002 and dementia [ 1. J. Zuricular Study of cardiovascular disease ]288 in cardiovascular disease, the prevalence of neuropsychiatric systems in Alzheimer's disease: Systematic review and meta-analysis [ prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic evaluation and meta-analysis J Affect [ J.Emotion disorder ]190:264-71 (2016)).
Serotonin plays a major role in the presentation and maintenance of various eating disorders (Steiger H, Eatingdisorders and the serotonin connections: state, trait and developmental effects) [ eating disorders and serotonin relationships: state, characteristics and developmental impact ] J Psychiatry Neurosci [ psychiatric and neuroscience ]29(1):20-9 (2004)). The gene encoding the 5-HT2A receptor (HTR2A) has been identified as a functional candidate for a number of neuropsychiatric phenotypes, including eating disorders (Norton N, Owen MJ. HTR2A: association and expression studies in neuropsychiatric genetics) [ HTR2A: Ann Med [ Ann annual seal ]37 (121-9 (2005)). Eating behavior and appetite are also regulated by a serotonin transporter, one of The receptor targets of dextromethorphan, which is affected in eating-impaired patients (Spies M et al, The serotonin transporter in psychiatric disorders: insight from PET imaging. [ Lancet Psychiatry ]2(8):743-55 (2015)).
Thus, current evidence suggests that the pathophysiology of neurodegenerative diseases (such as alzheimer's disease) is complex, involving multiple neuroanatomical substrates, neurochemistry, and neuropharmacological mechanisms, leading to the following outcomes: i) one Therapeutic Mode of Action (TMA) may be used to treat more than one clinically diagnosable item of BPSD (e.g., a symptom or group of symptoms of NPI); ii) is as
Figure GDA0002354989720000621
As shown by the emerging efficacy curves, one TMA may be used to treat the symptoms of two or more clinically distinct neurodegenerative diseases (e.g., AD, PD, DLB, FTLD, etc.); iii) a single TMA cannot cover the full spectrum of BPSD symptoms; iv) a single TMA may not even produce the greatest possible therapeutic benefit for a single symptom or group of symptoms of BPSD.
Thus, in contrast to the limited clinical efficacy exerted by single MTA therapy with pimavanserin (r) ((r))Ballard C et al, Evaluation of the safety, tolerability and efficacy of the safety, efficacy, tolerability, and efficacy of pimavanserin plants in tissues with Alzheimer's disease processes aphase 2, randomised, placebo-controlled, double-blue study [ Evaluation of safety, tolerability and efficacy of Alzheimer's disease psychotic patients with pimavanserin in combination with placebo: phase 2, randomized, placebo-controlled, double-blind study]Lancet Neurology[Lancet Neurology](2018)17: 213-22), combination therapy comprising several MTAs represented by the compound of formula I and the compound of formula II provides a broader and stronger efficacy profile.
One embodiment is a method of treating behavioral and psychiatric 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: 5-HT2A receptor antagonists, 5-HT2A receptor inverse agonists, and CYP2D6 inhibitors. In another embodiment, the agent is a Dual Agent (DA) having both 5-HT2A receptor antagonist and CYP2D6 inhibitor properties. In another embodiment, the agent is a DA that has both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor properties. In another embodiment, DA is a compound of formula I.
In another embodiment, The composition comprises NMDA receptor Antagonists such as clonoxyphen, cathodolone and dextromethorphan (Jamero et al, The Emerging Role of NMDA Antagonists in pain management), US Pharm [ U.S. Pharmacopeia ]36(5), HS4-HS8 (Sang, NMDA Antagonists in neuropathic pain management: perimethoprene, or a combination of compounds having The general formula < 1 > and < 5 > as a combined test for The formation of a covalent bond with a compound of formula < 2 > or a compound of formula < 5 > in a combined manner of a combined test for The formation of a covalent bond with a dextromethorphan, a prodrug, a compound, a prodrug.
In another embodiment, the pharmaceutical composition comprises a compound of formula I and a compound of formula II (e.g., SARPODEX)TM、DERADEXTMOr DERAPHANTM). Another embodiment is a method of treating a patient in need thereof, the method comprising the steps of: administration of a composition comprising SARPODEXTM、DERADEXTMOr DERAPHANTMThe pharmaceutical composition of (1).
The psychological symptoms of dementia involve a disturbance of the glutamatergic, cholinergic, serotonergic and noradrenergic neurotransmitter systems. Thus, one embodiment is a method of treating behavioral and psychiatric symptoms of dementia. Another embodiment is a method of treating a person in need thereof comprising administering a composition comprising a compound of formula I and a compound of formula II to improve EEG abnormalities, behavior, cognition, and reduce seizures, as well as improve respiratory abnormalities, motor ability, bone density, and GI dysfunction. Another embodiment is a method of treating a person in need thereof, the method comprising administering a pharmaceutical composition comprising DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo improve EEG abnormalities, behaviour, cognition, and reduce seizures, and to improve respiratory abnormalities, motor ability, bone density, and GI dysfunction. Another embodiment is a method of treating a person in need thereof, the method comprising administering a pharmaceutical composition comprising DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo treat other diseases anddisorders including involuntary affective expression disorder (IEED) or pseudobulbar effect (PBA), neurodegenerative diseases, neuropathic pain, and brain injury.
Another embodiment is a composition comprising: DERATINE alone or in combination with other drugsTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMThe other drugs are, for example, analgesics (e.g., acetaminophen), antihistamines (e.g., chlorpheniramine), decongestants (e.g., pseudoephedrine) and/or expectorants (e.g., guaifenesin).
Dextromethorphan starts with O-and N-demethylation in the liver and metabolizes into active metabolites to form the main metabolite DO, 3-methoxy-morphinan which is further demethylated into 3-hydroxy-morphinan by N-and O-respectively. The main metabolic catalyst is the cytochrome P450 enzyme 2D6(CYP2D6), which is responsible for the O-demethylation reaction of dextromethorphan and 3-methoxy morphinan. N-demethylation of dextromethorphan and DO is catalyzed by enzymes in the related CYP3A family. Conjugates of DO and 3-hydroxymorphinans are detectable in human plasma and urine within hours of ingestion. DO is the most attractive substance for psychotropic effects.
SGL is a 5-HT2A receptor inverse agonist and a CYP2D6 inhibitor. SGL inhibits responses to 5-HT mediated by the 5-HT2A receptor, such as platelet aggregation, vasoconstriction and vascular smooth muscle proliferation. SGL (MCI-9042) was shown to have the same affinity for the 5-HT2A receptor as ritanserin (ritanserin) (Nishio et al, Binding affinity of compounds of formula I or sarpogrelate, a new antiplatelet agent, and itsmetolite for serotonin receptor subtypes [ novel antiplatelet agent formula I compounds or sarpogrelate and their metabolites for the Binding affinity of serotonin receptor subtypes]Arch Int Pharmacodyn Ther [ International Pharmacology and therapy archive]331(2) 189-; incorporated by reference in its entirety). Blockade of the 5-HT2A receptor inhibits thrombosis, inhibits platelet aggregation, and inhibits vascular smooth muscle cell proliferation (Pertz et al, In-viropharmacology of a compound offormula I, and the enantiomers of the enantiomers of formula I and major metabolites thereof: modulation of 5-HT2A receptor specificity, stereoselectivity, and ritanserin-induced inhibition of 5-HT constriction in rat tail arteries]J Pharm Pharmacol [ J Pharmacol]47(4):310-6 (4 months 1995); incorporated by reference in its entirety). Thus, one embodiment is a method of treating a patient in need thereof, the method comprising administering a pharmaceutical composition comprising a compound of formula I and a compound of formula II, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMThe composition of (1).
Another embodiment is a method of treatment, wherein the patient is suffering from a disease or disorder, including peripheral artery disease, such as Raynaud's disease and intermittent claudication; pulmonary arterial hypertension (Saini et al, 2004; incorporated by reference in its entirety), angina (Kinugawa et al, 2002; incorporated by reference in its entirety), and/or diabetes (Piettaszek et al, 1993; Ogawa et al, 1999; incorporated by reference in its entirety). In another embodiment, a method of treating a patient after coronary stenting comprises a compound of formula I and may be used for restenosis (Doggrell, sarpogrelate: cardiac and renal clinical potential. [ sarpogrelate: cardiovascular and renal clinical potential ], Expert Opinion on Investigational Drugs [ Expert Opinion on Investigational Drugs ] Vol.13, No. 7 (2004); the entire contents of which are incorporated by reference).
DO is the substance most attractive for its possible psychotropic effects due to NMDA receptor blockade. For the NMDA receptor, DO has substantially higher affinity compared to DEX. The undesirable psychotropic effects of DEX are related to its metabolism into DO (Taylor et al, Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine
Figure GDA0002354989720000651
clinical use [ pharmacology of dextromethorphan: with dextromethorphan/quinidine
Figure GDA0002354989720000652
Correlation of clinical use]Pharmacol Ther. [ Pharmacol and therapeutics ]]164:170-82(2016 month 8); incorporated 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, the method comprising the step of administering a pharmaceutical composition comprising DEX and one or more agents selected from the group comprising: 5-HT2A receptor antagonist/inverse agonist, and CYP2D6 inhibitor. In another embodiment, the agent is an agent that has both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor properties. In another embodiment, the agent is an agent that has both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor properties. In another embodiment, the agent is a compound of formula I and a compound of formula II, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
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; the entire content of which is incorporated by reference), a 5-HT2A receptor inverse agonist and a CYP2D6 inhibitor.
Genetic polymorphisms cytochrome CYP2D6 have been implicated in the metabolism of many antipsychotic agents, including thioridazine, perphenazine, chlorpromazine, fluphenazine, haloperidol, clopenthixol, risperidone, and sertindole (Michalets, 1998). This enzyme is also important in the metabolism of other drugs commonly prescribed to patients with mental disorders, for example tricyclic antidepressants (nortriptyline, desipramine, amitriptyline, imipramine, and clomipramine) and selective serotonin reuptake inhibitors, including fluoxetine and paroxetine (Taylor and Lader, 1996; Sproule et al, 1997; the entire contents of which are incorporated by reference). It is expected that drugs that inhibit these enzymes will cause an increase in the plasma concentration of the co-administered antipsychotic (Goff, 1993; Ereshefsky, 1996; Michalets, 1998; the entire contents of which are incorporated by reference). These increases, in turn, may lead to the development and exacerbation of antipsychotic-induced side effects, including cardiotoxicity, anticholinergic side effects, or the development or worsening of orthostatic hypotension (Ereshefsky, 1996; Desta et al, 1999; incorporated by reference in its entirety).
Many antipsychotic drugs inhibit the DEX O-demethylation catalyzed by CYP2D 6. Of the antipsychotics tested, thioridazine and perphenazine were the most potent inhibitors, reducing DO formation to 26.5% and 19.7% of control activity at 10 μ M and 11.4% and 10.7% of control activity at 25 μ M, respectively. The inhibitory potency of these drugs in DEX O-demethylation is comparable to that of 10 to 25 μ M quinidine. The estimated mean IC50 values for thioridazine and perphenazine were 2.7. + -. 0.5 and 1.5. mu.M, respectively. Under these conditions, the IC50 of the potent CYP2D6 inhibitor quinidine is estimated to be 0.52 ± 0.2 μ M. The estimated IC50 for chlorpromazine, flufenazine, and haloperidol (haloperidol) were 9.7, 16.3, and 14.4 μ M, respectively. Thiothixene (cisthiothrix), clozapine, and risperidone exhibit weaker inhibitory effects than the other Drugs tested, with average IC50 estimated as 136.6, 92.2, and 39.1 μ M, respectively (Shin et al, Effect of antibiotic Drugs on Human Liver cell P-450(Cyp) isof orms in Vitro.
In one embodiment, the pharmaceutical composition of the invention comprises one or more of CYP2D6 inhibitors, such as, but not limited to, amiodaline, amiodarone, amitriptyline, aprepidine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, erythromycin, fluoxetine, flufenazine, fluvastatin, fluvoxamine, haloperidol, imipramine, indinavir, lansoprazole, levomepromazine, lopinavir, loratadine, mequinatadine, mesalamine, metoclopramide, mibexadil, moclobemide, nelfinavir, nevirapine, nicardipine, norfluoxetine, paroxetine, phenacetin, pizimod, tifloratadine, thioridazine, cimetidine, quinidine, cisapride, citalopram, clomipramine, clozapine, tiprezine, tiprex, tipepinasil, lopanadine, doxine, meclizine, and a, Saquinavir, sertraline, terbinafine, ticlopidine, trifluperidol, venlafaxine, and yohimbine.
In one embodiment, the present invention is a combination of a 5HT2A receptor antagonist and a CYP2D6 inhibitor that provides the therapeutic advantage of concurrent 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 that provides the therapeutic advantage of concurrent 5HT2A receptor inverse agonism and 2D6 inhibition. By combining both CYP2D6 inhibition and 5HT2A receptor inverse agonism, a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMProvides unique therapeutic advantages to improve the magnitude of response to DEX treatments. Thus, compounds of formula I and formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMPotential health risks associated with the use of the antiarrhythmic drugs quinidine and DEX together are avoided. Thus, one embodiment is a pharmaceutical composition comprising a compound of formula I and formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMThe composition of (1).
Some embodiments include methods of reducing the number of doses and/or total daily dose of dextromethorphan, metabolites, derivatives or prodrugs thereof (DEX) that can be administered while increasing potency and ensuring tolerability and safety, comprising orally administering an effective amount of a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
Some embodiments include reduction and treatmentA method of treating an adverse event of interest, the method comprising co-administering a compound of formula I and a compound of formula II; or, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo DEX and/or a compound of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTreating a subject in need thereof, wherein the subject is undergoing treatment with DEX and/or a compound of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMRisk of adverse events resulting from treatment.
Some embodiments include methods of reducing DO plasma levels comprising co-administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need of treatment with DEX, wherein the compound of formula I and the compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMIs administered on the first day of treatment with DEX for at least two days, wherein a decrease in DO plasma levels occurs upon administration of a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMOn the first day, this is compared to administration of the same amount of DEX without the compound of formula I.
Another embodiment is a method of reducing DO plasma levels comprising co-administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need of treatment with DEX for at least eight consecutive days, wherein on day eight the DO plasma level is lower than the DO plasma level that would be reached by administration of the same amount of DEX for eight consecutive days without the compound of formula I.
5-HT2A receptor antagonists/inverse agonists, such as compounds of formula I and compounds of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMCan be used to improve DEX, for example in the treatment of neurological disorders. Compounds of formula I and compounds of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM-stereochemistry-independent-effective in inhibiting or reducing DEX metabolism in some subjects by co-administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMThis is achieved.
Another embodiment is a method of treating a neurological disorder comprising administering a 5-HT2A receptor antagonist/inverse agonist and DEX to a subject in need thereof, wherein the subject is a rapidly metabolizing species of DEX.
Another embodiment is a method of treating a neurological disorder comprising administering a 5-HT2A receptor inverse agonist, an antagonist, and DEX to a subject in need thereof, wherein the subject is a rapidly metabolizing species of DEX.
Another embodiment is a method of increasing plasma levels of DEX in a subject in need of treatment with DEX, wherein the subject is a rapidly metabolizing species of DEX, the method comprising co-administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo the subject.
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 DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject, wherein the subject is a rapid metabolizer of DEX, and wherein DEX and the compound of formula I are present simultaneously in the body of the subject.
Another embodiment is a method of increasing the metabolic life of DEX, the method comprising administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need of treatment with DEX, wherein the subject is a rapidly metabolizing species of DEX, and wherein DEX and the compound of formula I are present in the body of the subject simultaneously.
Another embodiment is a method of correcting for the extensive metabolism of DEX, the method comprising administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need thereof.
Another embodiment is a method of improving the antitussive properties of DEX, the method comprising administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMIn conjunction with administration of DEX to a subject in need of cough treatment.
Another embodiment is a method of treating cough comprising administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need thereof.
Another embodiment is a method of treating a neurological disorder comprising administering a compound of formula I and a compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need thereof, wherein the compound of formula I and the compound of formula II; or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMIs administered at least once daily for at least eight days.
Another embodiment is a method of treating a neurological disorder comprising administering about 5 mg/day to about 600 mg/day, about 5 mg/day to about 300 mg/day, about 5 mg/day to about 400 mg/day, about 5 mg/day to about 500 mg/day, about 5 mg/day to about 600 mg/day, about 5 mg/day to about 1,000 mg/day, about 50 mg/day to about 1000 mg/day, about 100 mg/day to about 1000 mg/day, about 150 mg/day to about 5000 mg/day, about 150 mg/day to about 300 mg/day, or about 150 mg/day to about 100 mg/day, or a desired amount of a compound of formula I, and about 0.1 mg/day to about 1 mg/day, about 0.5 mg/day to about 15 mg/day, or a combination thereof, 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 a desired amount of DEX to a subject in need thereof.
Another embodiment is a method of increasing a plasma level of DEX in a subject in need of treatment with DEX, wherein the subject is a rapidly metabolizing species of DEX, the method comprising co-administering to the subject a compound of formula I and DEX.
Another embodiment is a method of inhibiting the metabolism of DEX, the method comprising administering a compound of formula I to a subject, wherein the subject is a rapidly metabolizing species of DEX, and wherein DEX and the compound of formula I are present simultaneously in the body of the subject.
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 treatment with DEX, wherein the subject is a rapidly metabolizing species of DEX, wherein DEX and the compound of formula I are both present in the body of the subject.
Another embodiment is a method of increasing a plasma level of DEX, comprising co-administering to a subject in need of treatment with DEX a compound of formula I, wherein the compound of formula I is administered on a first day of at least two days of co-administration of the compound of formula I, and DEX, wherein an increase in the plasma level of DEX occurs on the first day that the compound of formula I, and DEX have been co-administered, compared to administration of the same amount of DEX without the compound of formula I.
Another embodiment is a method of increasing a plasma level of DEX, the method comprising co-administering to a subject in need of treatment with DEX a compound of formula I, and DEX for at least five consecutive days, wherein on day five the plasma level of DEX is higher than the plasma level of DEX that would be achieved by administration of the same amount of DEX on five consecutive days without the compound of formula I.
Another embodiment is a method of increasing a plasma level of DEX, the method comprising co-administering to a subject in need of treatment with DEX a compound of formula I, and DEX for at least six consecutive days, wherein on day six the plasma level of DEX is higher than the plasma level of DEX that would be achieved by administration of the same amount of DEX for six consecutive days without the compound of formula I.
Another embodiment is a method of reducing the trough effect of DEX, comprising co-administering a compound of formula I and DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administration of the compound of formula I and DEX that is at least twice the plasma level that would be achieved by administration of the same amount of DEX without the compound of formula I.
Another embodiment is a method of reducing the trough effect of DEX, comprising co-administering a compound of formula I and DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administration of the compound of formula I and DEX that is at least twice the plasma level that would be achieved by administration of the same amount of DEX without the compound of formula I.
Another embodiment is a method of reducing the trough effect of DEX, comprising co-administering a compound of formula I and DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administration of the compound of formula I and DEX that is at least twice the plasma level that would be achieved by administration of the same amount of DEX without the compound of formula I.
Another embodiment is a method of reducing adverse events or other undesirable consequences associated with DEX treatment, such as addiction, the method comprising co-administering a compound of formula I and DEX to a subject in need of DEX treatment, wherein the subject is at risk of experiencing an adverse event caused by treatment with DEX.
Another embodiment is a method of reducing adverse events associated with treatment with a compound of formula I, the method 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 experiencing an adverse event caused by treatment with a compound of formula I.
Another embodiment is a method of improving the antitussive properties of DEX, the method comprising administering a compound of formula I, in conjunction with DEX to a subject in need of treatment for cough.
Another embodiment is a method of treating cough comprising administering a combination of a compound of formula I and DEX to a subject in need thereof.
Another embodiment is a method of treating a neurological disorder comprising administering to a subject in need thereof a compound of formula I and DEX, wherein the compound of formula I and DEX are administered once on at least one day for at least 8 days.
Another embodiment is a method of treating a neurological disorder comprising administering a pharmaceutical composition comprising DEX of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need thereof, wherein the DEX is of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMIs administered at least once daily for at least 8 days.
Another embodiment is a method of treating a neurological disorder comprising administering DEX, formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need thereof, wherein the compound of formula I and DEX are administered at least once daily for at least 8 days.
Another embodiment is an oral sustained release delivery system for DEX, the system comprising a composition comprising DEX, formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMAnd a carrier.
Another embodiment is a method of reducing the number of doses of DEX that can be administered without loss of efficacy, the method comprising orally administering an effective amount of a composition comprising DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMTo a subject in need of treatment with DEX.
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.
In one aspect, provided are methods of increasing the metabolic lifespan of DEX, comprising administering a 5-HT2A receptor antagonist/inverse agonist to a subject in need of treatment with DEXWherein the 5-HT2A receptor antagonist/inverse agonist is an inhibitor of the CYP2D6 enzyme and wherein the DEX and the CYP2D6 inhibitor are both present in the subject. In another embodiment, the composition comprises DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
In another aspect, provided is a method of preventing an adverse event associated with DEX treatment, the method comprising co-administering a 5-HT2A receptor antagonist/inverse agonist or, for example, a compound of formula I, to a subject in need of treatment with DEX, wherein the subject is at risk of experiencing an adverse event caused by treatment with DEX.
In another aspect, provided are methods of using 5HT2A receptor antagonists, such as compounds of formula I, to improve the therapeutic properties of DEX for the treatment of neurological disorders.
In another aspect, provided is a method of treating a disorder or disease, the method comprising administering to a subject in need thereof a composition comprising a 5HT2A receptor antagonist and DEX. In another embodiment, the composition comprises DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
In another aspect, provided are methods of selecting a 5-HT2A receptor antagonist/inverse agonist for use in combination with DEX in a subject in need thereof.
Another example, NMDA receptor antagonists decrease the physical aspects of morphine-dependent expression as measured by the withdrawal of naloxone (naloxone) precipitate (Bristow et al, comparative and glycine: NMDA receptor antagonists with dry-induced muscles and increased cognitive acetylcholine efflux in rats Competitive and glycine: NMDA receptor antagonists decrease morphine-dependent rat withdrawal induced behavior and increase hippocampal acetylcholine efflux [ Neuropharmacology ].36:241-, inhibition of morphine and naloxone precipitated opioid withdrawal by novel glycine site and non-competitive NMDA receptor antagonists enhancement [ Neuropharmacology ].37: 1033-fold (1998); not only the physical but also the emotional and motivational components, which are incorporated by reference in their entirety) and which can attenuate the abstinence state, and craving (Cornish et al, a random, double-blind, placbo-controlled safety study in methadone-main efficacy initiatives [ random, double blind, placebo-controlled safety study of high-dose dextromethorphan in male hospitalized patients maintained in meisha winter ]. Drug & Alcohol Dependence [ Drug and Alcohol Dependence ].67(2):177-83 (2002); incorporated by reference in its entirety). Such medications should benefit patients during the acute detoxification phase of opioid Dependence by reducing withdrawal symptoms (Cornish et al, a random, double-blind, placenta-controlled safety study of high-dose dextromethorphan in male hospitalized patients maintained in mexadong, randomized, double-blind, placebo-controlled safety study ] Drug & Alcohol Dependence [ Drug and Alcohol Dependence ]67(2):177-83 (2002); the entire contents are incorporated by reference).
Thus, embodiments are methods of treating a subject in need of treatment for a disorder or disease associated with addiction and substance abuse, the method comprising administering DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
Chronic exposure to morphine is responsible for many of the biochemistries of the glutamatergic receptors of the limbic systemAdaptation (Fitzgerald et al, Drugs of use and stress in the expression of GluR and NMDAR glutamate receptor subunits in the rat ventral tegmental area: common Adaptation of amino-presenting genes [ Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: Co-adaptation between cross sensitizers]Neurosci [ journal of neuroscience ]]16:274-282 (1996); incorporated by reference in its entirety). Excitatory amino acids are involved in the mediation of many neurochemical and behavioral effects resulting from chronic exposure to drugs of abuse, several of which may be prevented or reversed using glutamatergic antagonists (Inturrisi, Preclinical evidence for the role of the glutamatergic system in opioid tolerance and dependence]Nemin. neurosci. [ seminal symposium for neuroscience]9:110-119 (1997); incorporated by reference in its entirety). Sustained self-administration of drugs of abuse, including opioids, results in dopamine overstimulation of the reward center of the brain and increased release of excitatory amino acids, including glutamate, leading to the development of tolerance and dependence, which may be blocked by glutamate antagonists (Herman et al, Clinical medical maintenance for oral administration: focus on nopipenics and opioid antagonists for the evaluation of opioid with dry eyes systems and relax expression) [ Clinical drug development for opioid addiction: concentration on non-opioids and opioid antagonists to improve opioid withdrawal symptoms and relapse prevention]Nemin. neurosci. [ seminal symposium for neuroscience]9:158-172 (1997); incorporated by reference in its entirety). Thus, an embodiment is a method of treating a subject in need of treatment for a disorder or disease associated with addiction and substance abuse due to opioid tolerance and dependence by alleviating opioid withdrawal symptoms and preventing relapse, the method comprising administering DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
DEX provides neuroprotective effects on dopamine neurons in several inflammation-based animal models of Parkinson's disease (Li et alProtective effect of dextromethorphan on mouse endotoxic shock]Biochemical Pharmacology [ Biochemical Pharmacology ]]69(2) 233-40 (2005); liu et al, Dextromethorphan protects dopaminergic neuron α in inflammation-mediated degeneration inhibition of microlialization, [ Dextromethorphan protects dopaminergic neurons from inflammation-mediated degeneration by inhibiting microglial activation]Journal of pharmacological Experimental Therapeutics [ Journal of pharmacological and Experimental Therapeutics ]]305(1) 212-8 (2003); zhang et al, Neuroprotective effect of dextran inter MPTP Parkinson's disease model role of NADPH oxidase [ Neuroprotective effect of dextromethorphan in MPTP Parkinson's disease model: action of NADPH oxidase]FASEB Journal [ J.Association of American society for laboratory and biology ]]18(3) 589-91 (2004); zhang et al, 3-hydroxymorphinan is neurotrophic additive LPS-induced neurooxydics [ [ 3-hydroxymorphinan has neurotrophic effects on dopaminergic neurons and also neuroprotective effects on LPS-induced neurotoxicity]FASEB Journal [ J.Association of American society for laboratory and biology ]]19(3) 395-7 (2005); incorporated by reference in its entirety). In rat primary mixed mesencephalic neuron-glial cell cultures, 1-10 μ M DEX protected dopamine neurons from Lipopolysaccharide (LPS) -induced decreases in dopamine uptake. Morphologically, in LPS-treated cultures, the dendrites of the remaining dopamine neurons were significantly less fine than the control, except for the decrease in enrichment of dopamine neurons. In cultures pre-treated with DEX (10 μ M) prior to LPS stimulation, dopamine neurons were significantly more and dendrites were less affected. In cultures supplemented with DEX up to 60 minutes after LPS addition, a significant neuroprotective effect was observed. Thus, DEX significantly protected monoamine neurons not only with pretreatment, but also with post-treatment (Zhang et al, neuroprotectant effect of dextromethorphan in the MPTP parkinsonism's model: role of NADPH oxidase. [ Neuroprotective effect of dextromethorphan in MPTP Parkinson's disease model: effect of NADPH oxidase ]]FASEB Journal. [ journal of the American society for laboratory and biology Union]18(3) 589-91 (2004); incorporated by reference in its entirety). Animal studies using both LPS and MPTP PD models also showed a potent protective effect of DEX (Zhang et al, neuroprotectant effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. [ Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: effect of NADPH oxidase ]]FASEB Journal [ J.Association of American society for laboratory and biology ]]18(3) 589-91 (2004); incorporated by reference in its entirety). Thus, embodiments are methods of treating a subject in need of treatment for parkinson's disease, the method comprising administering DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
The neuroprotective effect of DEX is related to the inhibition of microglial over-activation by inhibition of superoxide anion produced by NADPH oxidase, and this neuroprotective effect of DEX is not related to its NMDA receptor antagonist properties. A correlation was observed between anti-inflammatory efficacy and neuroprotection with NMDA receptor antagonists (e.g., MK801, AP5, and memantine), and at the same time this suggests that the dopamine neuroprotection provided by DEX in inflammation-related neurodegenerative models is not mediated through NMDA receptors. This conclusion is in no conflict with previous reports, indicating that NMDA receptor blockade is associated with a neuroprotective effect of DEX in an acute glutamate-induced excitotoxicity model. Thus, one embodiment is a method of treating a subject in need of treatment for a disorder or disease, the method thus comprising administering DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMWherein the disorder or disease is an inflammation-related neurodegenerative disorder.
The GC-dependent effect of morphine activates the hypothalamic-pituitary-adrenal (HPA) axis. Activation of the HPA axis increases GC production as potent immunomodulatory hormones (Freeer et al, A mechanism of action for hormone-induced immunological delivery: [ morphine-induced delivery of natural killer cell activity ]The mechanism of action of immunosuppression of (a): corticosterone-mediated inhibition of morphine-induced natural killer cell activity]J Pharmacol Exp Ther [ journal of pharmacology and Experimental therapeutics ]]270(3), 1127-33 (1994); mellon et al, Role of central opioid receptors in morphine-induced alterations in peripheral lymphocyte activity]Brain research]789(1) 56-67 (1998); incorporated by reference in its entirety). Thus, one embodiment is a method of treating a subject in need of treatment for a disorder or disease, the method thus comprising administering DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMWherein the disorder or disease is opioid dependence. For heroin addicts undergoing withdrawal, doses of DEX up to about 500 mg/day are recommended, including DEX doses of 120, 240, and 480 mg/day. High doses of DEX cause slight elevation in heart rate, blood pressure, body temperature, and plasma bromide (Cornish et al, Arandomized, double-blind, placenta-controlled safety study of high-dose dextromethorphan in methadone-main patients Indian outpatients) [ randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in Male hospitalized patients maintained in Meishadong]Drug&Alcoholdependence [ drug and alcohol dependence ]]67(2) 177-83 (2002); incorporated by reference in its entirety). Particularly in Taiwan, DEX has been reported to have a completely different "dextromethorphan metabolizing enzyme CYP2D 6" (Yeh et al, Analysis of pharmacological parameters for assessment of dextromethorphan metabolic phenotypes) [ Analysis of pharmacokinetic parameters for assessing dextromethorphan metabolic phenotype ] from the Western population]J.biomed.sci. [ biomedical science]10: 552-; incorporated by reference in its entirety).
Significantly higher levels of interleukin-6, interleukin-8, and TNF- α -are expressed during manic and Depressive events in bipolar disorder (BP) Patients than in normal controls (Kim et al, aleximia and Stress responses patterns in Korean Depressive disorder Patients.) psychiatric investing [ psychiatric survey ]6(1):13-8(2009), O' Brien et al, Cytokinase bipolar in bipolar disorder Patients: focus on acute Patients ] manic disorder [ magazine of cytokines in bipolar disorder ]90(2-3): Bri-7; British approach 263 for acute Patients ] see acute Patients ] mania disorder [ 13-8 ] see [ 13-3 ] see [ 13-7 ] see [1 ] see-11 ] see [1 ] see-12, 3, rd [1 ] see [ see-1 ] see, 2-3, rd, 2009, et al, see [ see ] see, et al, see [1 ] see, 2, 3, 1,2, 3, et al.
In the postmortem frontal cortex from BP patients significantly higher protein and mRNA levels of IL-1 β receptor and neuroinflammatory marker Inducible Nitric Oxide Synthase (iNOS) and c-fos were found (Rao et al, incorporated exciting toxicity and neuroinflammatory markers in postmortem from bipolar disorder patients and increased neuroinflammatory markers) mol. psychotherapeutic [ molecular psychiatry ]15(4) 384-92(2010), incorporated in reference fashion the entire contents, together with an imbalance of the immune system that leads to an inflammatory response of neurons, possibly associated with brain atrophy and an aggravation of BP symptoms,. BP treatment with targeted immunotherapy shows an anti-depressive effect, when fluoxetine is added, the open response to salicylic acid in a clinical trial [ 18: the total success of salicylic acid in a clinical trial ] the non-onset trial [ 31. major stress of depression,. 1. see no effect of salicylic acid in a clinical trial [ 227 ] use of an immediate reaction of salicylic acid alone.
Thus, the use of an anti-inflammatory agent incorporating a mood stabilizer improves the therapeutic effect on BP. Mood stabilizers have been shown to beIs the activation of interconnected intracellular signaling pathways that promote neurogenesis and synaptic plasticity. It was found that the reduction of brain volume in BP patients is largely prevented by long-term treatment with Implantation (VPA), resulting in neuroprotective effects, since VPA renders neurons less susceptible to various insults (Chen et al, Valproate protects subparagraphical nerves in neuronal/glia cultures by stimulating the release of neuronal enzymes from dopaminergic neurons in mesobrain neuron/glial cell cultures]Mol Psychiatry [ molecular Psychiatry]1116-1125(2006, 12 months); incorporated by reference in its entirety) and even stimulate neurogenesis in the adult rodent brain. VPA induces cytoprotective proteins like Bc1-2, glucose regulatory protein 78(Grp78), brain-derived neurotrophic factor (BDNF) and heat shock protein 70. Furthermore, VPA promotes neurite outgrowth, while therapeutic levels of VPA reportedly inhibit Histone Deacetylase (HDAC), an enzyme that catalyzes the removal of acetyl groups from lysine residues of histones, thereby promoting local, neuronal BDNF biosynthesis. Thus, one embodiment is a method of treating a subject in need of treatment for a disorder or disease, the method thus comprising administering DEX and a compound of formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMWherein the disorder or disease is BP.
Another embodiment is a method of reducing a DEX adverse event in a subject in need thereof, comprising:
a. administering DEX; and
b. administering a compound of formula I to the subject.
Some embodiments include methods 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.
Some embodiments include methods of enhancing the therapeutic properties of DEX in the treatment of neuropsychiatric disorders comprising co-administering DEX and a compound of formula I.
Some embodiments include increasing a plasma level of DEX in a subject who is a rapidly metabolizing species of DEX, the method comprising co-administering to the subject a 5-HT2A receptor antagonist/inverse agonist, e.g., a compound of formula I and DEX.
Some embodiments include a method of inhibiting DEX metabolism comprising administering a 5-HT2A receptor antagonist/inverse agonist, e.g., a compound of formula I, to the subject, wherein the subject is a rapid metabolizer of DEX, and wherein DEX and the 5-HT2A receptor antagonist/inverse agonist are both present in the body of the subject.
Some embodiments include methods of increasing the metabolic life of DEX, comprising increasing the elimination half-life (T) of DEX1/2). These embodiments may comprise administering a 5-HT2A receptor antagonist/inverse agonist, e.g., a compound of formula I, to the subject, wherein the subject is a rapid metabolizer of DEX, and wherein DEX and the 5-HT2A receptor antagonist/inverse agonist are present concurrently in the body of the subject.
Some embodiments include methods of correcting rapid metabolism of DEX comprising administering a 5-HT2A receptor antagonist/inverse agonist, e.g., a compound of formula I, to a subject in need thereof, e.g., a subject in need of treatment for pain.
Some embodiments include methods of improving the therapeutic properties of DEX for the treatment of a neuropsychiatric disorder, comprising administering a 5-HT2A receptor antagonist/inverse agonist, e.g., a compound of formula I, in conjunction with the administration of DEX to a subject in need of treatment of a neuropsychiatric disorder.
Some embodiments include methods of treating a neuropsychiatric disorder comprising administering a combination of a 5-HT2A receptor antagonist/inverse agonist, e.g., a compound of formula I and DEX, to a subject in need thereof.
DEX is used as an antitussive. According to the DEX product labeling requirements of the FDA in OTC monograph [21CFR341.74], DEX should be administered 6 times per day (every 4 hours), 4 times per day (every 6 hours), or 3 times per day (every 8 hours).
DEX is rapidly metabolized in the human liver. Such rapid hepatic metabolism may limit systemic drug exposure in rapidly metabolizing individuals. The subject may be: 1) rapid metabolizers of DEX-those who rapidly metabolize DEX; 2) poor metabolizers of DEX-those who do not metabolize DEX; or 3) moderate metabolizers of DEX-those whose DEX metabolism is somewhere between rapid metabolizers and poor metabolizers. The rapid metabolizer may also be a super rapid metabolizer. Rapid metabolizers of DEX comprise a large part of the population. DEX can, for example, be metabolized to DO.
Plasma levels of DEX are significantly higher in poor or moderate metabolizers when given the same oral dose of DEX as compared to rapid metabolizers of DEX. Low plasma concentrations of DEX can limit its clinical applicability as a single agent for rapid and possibly moderate metabolizers of DEX. Some antidepressants, such as compounds of formula I, can inhibit the metabolism of DEX and thus can improve its therapeutic efficacy. Similarly, antidepressants may allow DEX to be administered less often without loss of therapeutic efficacy, e.g., once a day rather than twice a day, once a day rather than three times a day, once a day rather than four times a day, twice a day rather than three times a day, or twice a day rather than four times a day.
Pain or other neuropsychiatric disorders may 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, e.g., a compound of formula I, to a person in need thereof.
Examples of neuropsychiatric disorders that may be treated or may be treated with increased potency by a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist (compound of formula I) include, but are not limited to: affective disorders, psychotic disorders, brain dysfunction, movement disorders, dementia, traumatic brain injury, chronic traumatic encephalopathy, PTSD, motor neuron disease, neurodegenerative disorders, seizure disorders, and headache.
Affective disorders that can be treated by DEX and a 5-HT2A receptor antagonist/inverse agonist (combination of compounds of formula I) include, but are not limited to, depression, major depressive disorder, refractory depression and refractory bipolar depression, BPs including cyclothymia, seasonal affective disorder, mania, anxiety, Attention Deficit Disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit/hyperactivity disorder (AD/HD), bipolar and manic conditions, obsessive compulsive disorder, bulimia, anorexia, obesity or weight gain, lethargy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychogenic-sexual dysfunction, pseudobulbar effect, and mood swings.
Depression may be manifested as mood changes, intense sadness, despair, mental retardation, sleep disturbance, loss of attention, pessimistic apprehension, agitation, and self-depreciation. Physical symptoms of depression may include insomnia, anorexia, weight loss, decreased energy and libido, apathy, and abnormal hormonal circadian rhythms.
Psychiatric disorders which may be treated by 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 depression, hypomania, unipolar depression, stress, psychosomatic, personality disorders, psychotic disorders, schizophrenia, delusional disorders, schizoaffective disorders, schizophreniform disorders, aggressivity to alzheimer's disease, agitation, and apathy to alzheimer's disease.
Apathy, or loss of motivation, is the most common behavioral change in Alzheimer's Disease (AD). It is common within the spectrum of cognitive decline ranging from mild cognitive impairment to severe Alzheimer's Disease (AD) and in a variety of other neuropsychiatric disorders. Apathy represents a form of executive cognitive dysfunction. Apathy patients suffer from decreased daily functioning and specific cognitive deficits and rely on the home to provide more care, resulting in increased family stress. Apathy is one of the major syndromes associated with frontal and subcortical pathology, while apathy of AD appears to have multiple neuroanatomical associations involving components of the frontal subcortical network. Although this common syndrome has profound effects, only a few instruments are designed to specifically assess apathy, and these instruments are not directly compared. Apathy assessment of AD requires clinicians to differentiate between loss of motivation and loss of competence due to cognitive decline. While apathy may be misdiagnosed as depression due to symptom overlap, current studies have shown that apathy is a separate symptom cluster. Distinguishing apathy from depression is of great therapeutic interest, as these disorders respond to different interventions.
Apathy scale (IA) -scoring table for overall assessment of apathy and separate assessment of affective dullness, lack of aggressiveness, and lack of interest-is a reliable method for assessing several dimensions of apathy syndrome in mentally and non-mentally elderly subjects, and also the subject's perception of these symptoms. IA is The effective assessment of Apathy as in The Apathy paragraph of The neuropsychiatric Scale (Robert et al, The Apath invasion: assessment of Apathy and aware in Alzheimer's Disease, Parkinson's Disease and fine cognitive impairment, [ cryo-desert investigation: assessment of Apathy, Parkinson's Disease and mild cognitive impairment ] The Journal of Geriathic Psychiatry [ J. senile-desert ], Vol. 17, Vol. 12, p. 1099-1105 (12.2002), Landes et al, Apathy in Alzheimer's Disease [ Apathy. of Alzheimer's Disease ], The Journal of American ginseng Society [ J. American Society of Sowth ], The Treatment of Alzheimer's Disease [ J. 49, p. 17012, P. 51, and other diseases [ see. 12, J. alpi et al ] and The Treatment of Alzheimer's Disease, Olymphadenity [ D. 12, J. 51, D. 51, and other diseases [ see D. 12, D. 1, D. 20. D. patients, D. Vol XXII, stage 13 (11/1/2005); incorporated by reference in its entirety). Apathy may be the result of damage to one or more regions of the brain, such as the frontal cortex, thalamus, striatum, and amygdala. In most cases, direct damage to the frontal lobe or the subcortical nucleus associated with the frontal lobe results in apathy. Apathy associated with alzheimer's disease is difficult to treat. Antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors, etc. only alleviate apathy to some extent.
Thus, one embodiment of the present invention is DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMA combination of (1); and one or more antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors, dopaminergic agents. Another example is DEX and formula I, or DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMAnd combinations of one or more of the following: donepezil (donepezil), memantine, amantadine, bupropion (bupapion), ropinirole (ropiniole), methylphenidate (methylphenidate), amphetamine, modafinil (modafinil), metribuzin (metrifonate), tacrine (tacrine), galantamine (galantamine), rivastigmine (rivastigmine), nefiracetam (nefiracetam), ginkgo biloba extract, etc. (ruthirahan et al, pharmaceutical interventions for applying alzheimer's disease (Protocol) [ apathy ] pharmaceutical interventions in alzheimer's disease]Cochran database of systematic students]Article No. CD012197, article No. 2016, 5, from John Wiley, Inc. (John Wiley&Sons, Ltd.); pharmaceutical and immunopharmaceutical Treatment for Apathy in Alzheimer Disease A systematic review Across modifications [ Pharmacological and non-drug Treatment of Apathy of Alzheimer's Disease: cross-modal system evaluation]Journal of Geriatric Psychiatry and Neurology]Vol 30, No. 1, No. 2017; the references are incorporated by reference in their entirety).
Acetylcholinesterase is one of the most important components in the central cholinergic pathway. It terminates the synaptic effects of acetylcholine by hydrolysis and produces the choline moiety necessary for transmitter recycling. The pathogenesis of Alzheimer's Disease (AD) is associated with a deficiency in the brain neurotransmitter acetylcholine. The efficacy of acetylcholinesterase inhibitors (AChEI) is achieved by increasing acetylcholine-mediated neuron-to-neuron transmission. This is achieved by increasing the concentration of acetylcholine by reversibly inhibiting its hydrolysis by acetylcholinesterase. (USFDA reference ID: 3096907; guide on donepezil Hydrochloride [ guide for donepezil hydrochloride ], completed 8 months 2017, the entire contents of which are incorporated by reference).
Thus, in one embodiment, the composition comprises AChI, such aS 2- ((1-benzylpiperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydro-1H-inden-1-one (donepezil), (S) -3- (1- (dimethylamino) ethyl) phenylethyl (methyl) carbamate (rivastigmine), dimethyl (2, 2, 2-trichloro-1-hydroxyethyl) phosphonate (metrapfop-mate), (4aS, 6R, 8aS) -3-methoxy-11-methyl-4 a, 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-dimethylacetylthiophosphoramidate, O-dimethyl S- ((4-oxobenzo [ d ] [1, 2, 3] triazin-3 (4H) -yl) methyl) dithiophosphate, 2-dimethyl-2, 3-dihydrobenzofuran-7-ylmethyl carbamate, S- (((4-chlorophenyl) thio) methyl) O, O-diethyl dithiophosphate, 2-chloro-1- (2, 4-dichlorophenyl) ethenyldiethyl sulfate, O-diethyl O- (3, 5, 6-trichloropyridin-2-yl) thiophosphate, O- (3-chloro-4-methyl-2-oxo-2H-chroman-7-yl) O, O-diethylthiophosphate, 1-phenylethyl (E) -3- ((dimethoxyphosphoryl) oxy) but-2-enoate, 4- (tert-butyl) -2-chlorophenylmethylaminophosphate, O-diethyl O- (2- (ethylthio) ethyl) thiophosphate, O-diethyl S- (2- (ethylthio) ethyl) thiophosphate, O-diethyl O- (2-isopropyl-6-methylpyrimidin-4-yl) thiophosphate, salts of N, N-dimethyl-N-phosphono-, N-methyl-, N-and N-phosphono-amino acids, salts of N, N-dimethyl-amino acids, salts of N, 2, 2-dichlorovinyldimethyl sulfate, (E) -4- (dimethylamino) -4-oxobut-2-en-2-yldimethylsulfate, O, O-dimethyl S- (2- (methylamino) -2-oxoethyl) dithiophosphate, S '- (1, 4-dioxane-2, 3-diyl) O, O, O', O '-tetraethylbis (dithiophosphate), O, O-diethyl S- (2- (ethylthio) ethyl) dithiophosphate, O-ethyl O- (4-nitrophenyl) phenyl thiophosphonate, O, O, O', O '-tetraethyl S, S' -methylenebis (dithiophosphate), O-ethyl S, S-dipropyldithiophosphate, O- (4- (N, N-dimethylaminosulfonyl) phenyl) O, O-dimethylthiophosphate, ethyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate, O-dimethyl O- (3-methyl-4-nitrophenyl) thiophosphate, O-ethyl S-phenylethyldithiophosphate, isopropyl 2- ((ethoxy (isopropylamino) thiophosphoryl) oxy) benzonate, diethyl 2- ((dimethoxythiophosphoryl) thio) succinate, di-methyl-S, S-dipropyldithiophosphate, O- (4- (N, N-dimethylaminosulfonyl) phenyl) O, O-dimethylthiophosphate, O-dimethyl O- (3-methyl-4-nitrophenyl) thiophosphate, O, S-dimethylthiophosphoramide salt, S- ((5-methoxy-2-oxo-1, 3, 4-thiadiazol-3 (2H) -yl) methyl) O, O-dimethyldithiophosphate, methyl 3- ((dimethoxyphosphoryl) oxy) but-2-enoate, (E) -dimethyl (4- (methylamino) -4-oxobut-2-en-2-yl) sulfate, 1, 2-dibromo-2, 2-dichloroethyldimethyl sulfate, isopropyl (S) -methylfluorophosphonate, 3-dimethylbutan-2-yl (S) -methylfluorophosphonate, di-or tri-methyl-fluorophosphonate, O, O-diethylO- (4-nitrophenyl) thiophosphate, S- (2- (ethylsulfinyl) ethyl) O, O-dimethylthiophosphate, O-diethylS- ((ethylthio) methyl) dithiophosphate, S- ((6-chloro-2-oxobenzo [ d ] oxazol-3 (2H) -yl) methyl) O, O-diethyldithiophosphate, S- ((1, 3-dioxoisoindolin-2-yl) methyl) O, O-dimethyldithiophosphate, (E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yldimethylsulfate, and salts thereof, O, O '-tetramethylo, O' - (thiobis (4, 1-phenylene)) bis (thiophosphate), tetraethyl diphosphate, S- ((tert-butylthio) methyl) O, O-diethyldithiophosphate, 2-chloro-1- (2, 4, 5-trichlorophenyl) vinyldimethyl sulfate, and dimethyl (2, 2, 2-trichloro-1-hydroxyethyl) phosphonate, or a pharmaceutically acceptable derivative, metabolite, analog, or salt thereof.
Substance abuse and addiction that may be treated by the combination of DEX and a 5-HT2A receptor antagonist/inverse agonist (such as a compound of formula I) include, but are not limited to, drug dependence, addiction to Cocaine (Cocaine), psychostimulants (e.g., quick (crack), Cocaine, amphetamines (speed), metham (meth)), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (cannabis), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking, cigar and/or pipe, and chewing tobacco addiction.
Brain dysfunction that may be treated by a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist (such as a compound of formula I) includes, but is not limited to, disorders involving intellectual deficit such as vascular dementia, dementia of the alzheimer's type, dementia with lewy bodies, frontotemporal lobar degeneration, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, attention deficit, speech disorders, vocational spasms, parkinson's disease, eno-Gastaut syndrome, autism, hyperactivity syndrome, and schizophrenia. Brain dysfunction also includes disorders resulting from cerebrovascular disease, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, and the like, among which symptoms include disturbance of consciousness, dementia, coma, attentiveness reduction, apathy, and speech impairment.
Dyskinesias that can be treated by 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, akathisia, akinesia, associative motor, spasticity, ataxia, ballism, hemiballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, schwann's chorea, dyskinesia, tardive dyskinesia, muscular dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive muscular dystonia, parkinson's disease, Restless Leg Syndrome (RLS), tremor, essential tremor, tourette's syndrome, and Wilson's disease.
Dementia treatable by the combination of DEX and a 5-HT2A receptor antagonist/inverse agonist (such as a compound of formula I) includes, but is not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewybodes, dementia of mixed type, frontotemporal dementia, Cui's disease (Creutzfeldt-Jakob disease), normal pressure hydrocephalus, Huntington's disease, Wernike-high Saokov syndrome (Wernicke-Korsakoff syndrome), and frontotemporal degeneration (FTLD).
Motor neuron diseases that can be treated by 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 muscular atrophy, post-polio syndrome (PPS), Spinal Muscular Atrophy (SMA), spinal motor atrophy, Tay-sachs 'disease, Sandhoff's disease, and hereditary spastic paraplegia.
Neurodegenerative diseases that can be treated by 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-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), Spinal Muscular Atrophy (SMA), bulbar muscular atrophy, Fischer's ataxia, Huntington's disease, Louis's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lugal's disease, LouGehrig's disease), Multiple Sclerosis (MS), multiple systemic atrophy, summer-treeto syndrome (Shuy-Drynargrome), cerebral corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Mengkins disease (Menkens disease), adrenoleukopathy, cerebral arteriolar degeneration in vivo, and cerebral cortical cerebral infarction (CAIL), and cerebral white cerebral infarction (CAIL) Muscular dystrophy, Charcot-Marie-tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatal degeneration, Guillain-barre syndrome, and spastic paraplegia.
Seizure disorders that may be treated by 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; seizures in areas, including, but not limited to, simple seizures, Jackson seizures, complex seizures, and persistent epilepsy (epilepsia parkinia continua); generalized seizures, including, but not limited to, generalized tonic clonic seizures, absence seizures, atypical seizures, muscular pumping seizures, juvenile muscular pumping seizures, and infantile spasms; and status epilepticus.
Types of headaches that may be treated by the 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 headaches, tension, and cluster headaches, including the sympton-louton Syndrome (Bing-Horton-Syndrome).
Other neurological disorders that may be treated by a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist (such as a compound of formula I, a derivative, metabolite or prodrug of any of these compounds) include Rett Syndrome, autism, tinnitus, disturbance of consciousness, sexual dysfunction, refractory cough, lethargy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasm, including, but not limited to, abduction spastic dysphonia, adductor spastic dysphonia, muscle tone dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence, including, but not limited to, stress incontinence, urge incontinence, and fecal incontinence; and erectile dysfunction.
The pain relieving properties of DEX can be enhanced by a method comprising co-administering DEX and a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I, a metabolite, derivative, or prodrug of any of these compounds, and DEX.
The pain relieving properties of the compound of formula I may be enhanced by a method comprising co-administering DEX and the compound of formula I.
These methods may be used to treat or provide relief for any pain, including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain (nociceptive pain), and the like.
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, osteoarthropathy, axial spondyloarthritis, including ankylosing spondylitis, and the like.
In some embodiments, a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist, e.g., a compound of formula I, is used to treat chronic musculoskeletal pain.
Examples of neuropathic pain include idiopathic and diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, unilateral root neuropathy (monodauculoplathies), phantom limb pain, 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-related neuropathy, and radiation or chemotherapy-related neuropathy, and the like.
The term "treating" or "treatment" includes diagnosing, curing, alleviating, treating, or preventing a disease in a human or other animal, or any activity that otherwise affects the structure or any function of the human or other animal's body.
Any 5-HT2A receptor antagonist/inverse agonist can be used in combination with DEX to improve the therapeutic properties of DEX. The DEX and the 5-HT2A receptor antagonist/inverse agonist can be administered in separate compositions or dosage forms, or can be administered in a single composition or dosage form comprising both.
5-HT2A receptor antagonists/inverse agonists that may be co-administered with DEX include, but are not limited to, compounds of formula I, clomipramine, duloxetine, fluoxetine, mianserin, imipramine, 2-clomipramine, amitriptyline, amoxapine, desipramine, protiline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindane, benalazine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, bazedoxifene, siprine, and indole, Lofepramine, opipramol, norfluoxetine, dapoxetine, and the like, or a metabolite or prodrug of any of these compounds, or a pharmaceutically acceptable salt of any of these compounds.
Combining a compound of formula I and DEX may provide greater efficacy, e.g., better pain relief, than that achieved by administering either component alone. In rapidly metabolizers, DEX can be metabolized more rapidly and rapidly, resulting in low systemic exposure even at high doses. In addition to possessing antidepressant and analgesic properties, the compounds of formula I are inhibitors of DEX metabolism. Metabolites of compounds of formula I-including compounds, derivatives, metabolites of formula I-are also inhibitors of DEX metabolism. Thus, the compounds of formula I, including forms of the compounds of formula I that switch rapidly in vivo (e.g., salts, hydrates, solvates, polymorphs, and the like) are prodrugs of the compounds of formula I.
As explained above, this inhibition may enhance DEX plasma levels, resulting in additive or synergistic efficacy, e.g., relief of neurological disorders including pain, depression, smoking cessation, etc. Thus, while inhibiting DEX metabolism is only one of the many potential benefits of this combination, co-administration of DEX with a compound of formula I can therefore enhance the efficacy of a compound of formula I under a number of conditions. For many conditions, co-administration of DEX and a compound of formula I may potentiate the analgesic properties of the compound of formula I. Co-administration of DEX with the compound of formula I may also potentiate the antidepressant properties of the compound of formula I, including a more rapid onset of action, for many conditions.
Another potential benefit of co-administration of DEX and a compound of formula I is that it can be used to reduce the likelihood of adverse events associated with DEX treatment, such as lethargy or disturbance of consciousness. This may be useful, for example, for subjects at risk of experiencing adverse events caused by treatment with DEX.
Another potential benefit of co-administration of DEX with a compound of formula I is that it can be used to reduce the likelihood of adverse events, such as epilepsy, associated with the treatment of a compound of formula I. This may be useful, for example, for subjects at risk of experiencing adverse events resulting from treatment with a compound of formula I.
For DEX, a compound of formula I, co-administration can reduce central nervous system adverse events, gastrointestinal events, or another type of adverse event associated with any of these compounds. Central Nervous System (CNS) adverse events include, but are not limited to, tension, dizziness, insomnia, dizziness, tremor, hallucinations, tics, CNS depression, fear, anxiety, headache, irritability or agitation, tinnitus, lethargy, dizziness, sedation, somnolence, delirium, disorientation, weakness, incoordination, fatigue, euphoria, tension, insomnia, sleep disorders, seizure seizures, excitation, catatonic-like states, hysteria, hallucinations, delusions, paranoia, headache and/or migraine, and extrapyramidal symptoms such as oculomotor crisis, torticollis, hyperexcitability, increased muscle tone, ataxia, and tongue prominence.
Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia (dyspepsia), diarrhea, abdominal distension, flatulence, peptic ulcers with bleeding, loose stools, constipation, stomachache, heartburn, pneumatosis, anorexia, stomach satiety, dyspepsia (dyspepsia), gastrectasia, hyperacidity, dry mouth, gastrointestinal disorders, and stomachache.
Co-administration of DEX and a 5-HT2A receptor antagonist/inverse agonist (such as a compound of formula I) does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. Furthermore, the two compounds may be administered simultaneously, but this is not required. The compounds may be administered at different times, so long as both are present in the human body at the same time for at least a portion of the time of concurrent coadministration of the treatments.
In some embodiments, co-administration of a combination of a compound of formula I and DEX results in pain relief properties. For example, the combination may have improved pain relief properties, including potentially more rapid-acting treatment, compared to the compound of formula I alone or to DEX alone.
In some embodiments, the combination can have at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, 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 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or a range defined by any of these values, or an amount of pain relief between any of these values, compared to the compound of formula I alone.
In some embodiments, the combination can have at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, 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 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or a range defined by any of these values, or an amount of pain relief between any of these values, compared to DEX alone.
Whenever a compound of the present case is referred to by structure, name, or in any other way, such as DEX, a compound of formula I includes pharmaceutically acceptable salts, unless otherwise indicated; alternative solid forms, such as polymorphs, solvates, hydrates, and the like; tautomers; deuterium modified compounds, such as deuterium modified DEX and compounds of formula I; or any chemical species that can be rapidly converted to a compound described herein under the conditions in which the compound is used as described herein. Examples of deuterium modified DEX and compounds of formula I include, but are not limited to, those shown below.
A dosage form or composition can be a mixture or mixture of DEX and a compound that inhibits the metabolism of DEX, for example a compound of formula I alone or in combination with a carrier. For example, DEX and a compound of formula I can be dispersed among each other or together in a carrier. A dispersion may comprise a mixture of solid materials in which the small individual particles are essentially one compound, but the small particles are dispersed within each other, for example if two powders of two different drugs are admixed with a solid carrier material, the admixture being accomplished in a solid form. In some embodiments, the DEX and the compound of formula I can be substantially uniformly dispersed within a composition or dosage form. Alternatively, the DEX and the compound of formula I may be in separate blocks or phases of a composition or dosage form. For example, one drug may be in the coating and the other drug may be in the core inside the coating. For example, one drug may be formulated for sustained release and the other drug may be formulated for immediate release.
Some embodiments include administering a tablet containing a compound of formula I in a form that provides sustained release and DEX or vice versa in a form that provides immediate release. Although there are many ways to achieve sustained release of the compound of formula I, in some embodiments, the compound of formula I is combined with hydroxypropyl methylcellulose. For example, particles of the hydrochloride salt of the compound of formula I can be combined with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL)TM) Blending to form a blend (additure) of blended powders. This can then be combined with the immediate release DEX in a single tablet.
DEX and/or 5-HT2A receptor antagonist/inverse agonist (such as compounds of formula I) can be combined with a Pharmaceutical carrier selected based on the chosen route of administration and standard Pharmaceutical practice (e.g., as described in Remington's Pharmaceutical Sciences, 2005). The relative proportions of active ingredient and carrier can be determined, for example, by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice.
The therapeutic compound may be administered by any means that allows the active agent(s) to contact the desired site or sites of action in the patient's body. The compounds may be administered by any conventional means used in conjunction with pharmaceuticals, such as individual therapeutic agents or combinations of therapeutic agents. For example, they may be administered as the sole active agent of a pharmaceutical composition, or they may be used in combination with other therapeutically active ingredients.
The therapeutic compound may be administered to the subject in a variety of forms suitable for the chosen route of administration, e.g., oral or parenteral. Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial (including transdermal), ocular, sublingual, and buccal; topical includes ocular, dermal, ocular, rectal and systemic via insufflation, intranasal inhalation of aerosols, and rectal.
The ratio of DEX to the compound of formula I may vary. In some embodiments, the weight ratio of DEX to the compound of formula I can be about 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or a range defined by, or any ratio between, any of these values. A ratio of 0.1 indicates that the weight of DEX is 1/10 of the weight of the compound of formula I. A ratio of 10 indicates that the weight of DEX is 10 times the weight of the compound of formula I.
The amount of DEX in the therapeutic composition can vary. For example, some liquid compositions may comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 0.001% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 0.5% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v); and, About 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) DEX.
Some liquid dosage forms may contain from about 10mg to about 500mg, from about 30mg to about 350mg, from about 50mg to about 200mg, from about 50mg to about 70mg, from about 20mg to about 50mg, from about 30mg to about 60mg, from about 40mg to about 50mg, from about 40mg to about 42mg, from about 42mg to about 44mg, from about 44mg to about 46mg, from about 46mg to about 48mg, from about 48mg to about 50mg, from about 80mg to about 100mg, from about 110mg to about 130mg, from about 170mg to about 190mg, about 45mg, about 60mg, about 90mg, about 120mg, or about 180mg DEX, or a range defined by, or any amount between any of these values.
Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), About 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) DEX.
Some solid dosage forms may contain from about 10mg to about 500mg, from about 30mg to about 350mg, from about 20mg to about 50mg, from about 30mg to about 60mg, from about 40mg to about 50mg, from about 40mg to about 42mg, from about 42mg to about 44mg, from about 44mg to about 46mg, from about 46mg to about 48mg, from about 48mg to about 50mg, from about 50mg to about 200mg, from about 50mg to about 70mg, from about 80mg to about 100mg, from about 110mg to about 130mg, from about 170mg to about 190mg, about 60mg, about 90mg, about 120mg, or about 180mg of DEX, or a range defined by or any amount between any of these values.
The amount of the compound of formula I in the therapeutic composition can vary. If it is desired to increase the plasma level of DEX, the compound of formula I should be administered in an amount that increases the plasma level of DEX. For example, the compound of formula I can be administered in an amount such that, on day 8, the subject's plasma concentration of DEX is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 60-fold, at least about 70-fold, or at least about 80-fold greater than the plasma concentration when the same amount of DEX is administered without the compound of formula I.
In some embodimentsWherein the compound of formula I is such that, on day 8, the area under the curve (AUC) is 12 hours from the time of DEX administration0-12) Or the mean plasma concentration (C) of the subject 12 hours after administrationavg) An amount that is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 60-fold, at least about 70-fold, or at least about 80-fold greater than the plasma concentration of the same amount of DEX administered in the absence of the compound of formula I.
In some embodiments, the compound of formula I is such that, on day 8, the subject's maximum plasma concentration of DEX (C)max) An amount that is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 30-fold, or at least about 40-fold greater than the plasma concentration of the same amount of DEX administered in the absence of the compound of formula I.
For co-administration of the compound of formula I, an increase in plasma levels of DEX can occur on the first day that the compound of formula I has been administered, compared to administration of the same amount of DEX without the compound of formula I. For example, the first day that a compound of formula I has been administered may have a plasma level of DEX that is at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, or at least about 10-fold greater than the level that would be achieved if the same amount of DEX were administered without the compound of formula I.
In some embodiments, the AUC of DEX on the first day that a compound of formula I has been administered may be at least twice the AUC that would be achieved by administration of the same amount of DEX without the compound of formula I.
In some embodiments, the first day of DEX C to which a compound of formula I has been administeredmaxMay be such that the same amount of DEX is administered without the C that the compound of formula I would achievemaxAt least twice as large.
In some embodiments, the trough level of DEX on the first day (e.g., plasma level 12 hours after administration) for which a compound of formula I has been administered may be at least twice the trough level that would be reached by administration of the same amount of DEX without the compound of formula I.
In some embodiments, the compound of formula I is administered on the first day of treatment with DEX for at least two days, wherein a decrease in DO plasma levels occurs on the first day that the compound of formula I and DEX have been co-administered, as compared to administration of the same amount of DEX without the compound of formula I. For example, the DO plasma levels on the first day may be reduced by at least 5% compared to DO plasma levels that would be achieved by administering the same amount of DEX without the compound of formula I.
In some embodiments, the compound of formula I and DEX are co-administered to a subject in need of treatment with DEX for at least five consecutive days, wherein on the fifth day the DEX plasma level is higher than the DEX plasma level that would be achieved by administration of the same amount of DEX on the five consecutive days without the compound of formula I. For example, the plasma level of DEX on the fifth day (e.g., 0 hour, 1 hour, 3 hours, 6 hours, or 12 hours post-administration) can be at least 5-fold, at least 10-fold, at least 20-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 65-fold, or up to about 500-fold the level that would be achieved by administration of the compound of formula I on five consecutive days.
In some embodiments, the compound of formula I and DEX are co-administered to a subject in need of treatment with DEX for at least six consecutive days, wherein on day six the DEX plasma level is higher than the DEX plasma level that would be achieved by administration of the same amount of DEX for six consecutive days without the compound of formula I. For example, the plasma level of DEX on day six (e.g., 0 hour, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 75-fold, or up to about 500-fold the level that would be achieved by administration of the compound of formula I on consecutive days.
In some embodiments, the compound of formula I and DEX are co-administered to a subject in need of treatment with DEX for at least seven consecutive days, wherein on day seven the DEX plasma level is higher than the DEX plasma level that would be achieved by administration of the same amount of DEX for seven consecutive days without the compound of formula I. For example, the plasma level of DEX on day seven (e.g., 0 hour, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 70-fold, at least 80-fold, at least 90-fold, or up to about 500-fold the level that would be achieved by administration of the compound of formula I on consecutive days.
In some embodiments, the compound of formula I and DEX are co-administered for at least eight consecutive days, wherein on day eight the DEX is of a plasma level that is at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or up to about 1,000-fold greater than the plasma level that would be achieved by the compound of formula I given 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after the co-administration of the compound of formula I and DEX, by way of example, for eight consecutive days.
In some embodiments, the compound of formula I and DEX are co-administered to a subject in need of treatment with DEX for at least eight consecutive days, wherein on day eight the DO plasma level is lower than the DO plasma level that would be achieved by administration of the same amount of DEX for eight consecutive days without the compound of formula I. For example, the DO plasma level on day eight (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the DO plasma level that would be achieved by administering the same amount of DEX on eight consecutive days without the compound of formula I.
In some embodiments, the compound of formula I is such that, on day 8, the AUC of the compound of formula I in the subject0-12Is administered to a subject in an amount of at least about 100nghr/mL, at least about 200nghr/mL, at least about 500nghr/mL, at least about 600nghr/mL, at least about 700nghr/mL, at least about 800nghr/mL, at least about 900nghr/mL, at least about 1,000nghr/mL, at least about 1,200nghr/mL, at least 1,600nghr/mL, or up to about 15,000 nghr/mL.
In some embodiments, the compound of formula I is C of the compound of formula I such that, on day 8, the subjectavgIs at least about 10ng/mL, at least about 20ng/mL, at least about 40ng/mL, at least about 50ng/mL, at least about 60ng/mL, at least about 70ng/mL, at least about 80ng/mL, at least about 90ng/mL, at least about 100ng/mL, at least 120ng/mL, or up to about 1,500ng/mL to a subject.
Some liquid compositions may comprise from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) to about 20% (w/v), from about 0.01% to about 10% (w/v), from about 1% (w/v) to about 3% (w/v), from about 3% (w/v) to about 5% (w/v), from about 5% (w/v) to about 7% (w/v), from about 5% (w/v) to about 15% (w/v), from about 7% (w/v) to about 10% (w/v), from about 10% (w/v) to about 15% (w/v), from about 15% (w/v) to about 20% (w/v), from about 20% (w/v) to about 30% (w/v), from about 30% (w/v) to about 40% (w/v); and, Or about 40% (w/v) to about 50% (w/v) of a compound of formula I, or a range defined by any of these values, or any amount between any of these values.
Some liquid dosage forms may contain from about 10mg to about 1000mg, from about 50mg to about 1000mg, from about 10mg to about 50mg, from about 50mg to about 100mg, from about 40mg to about 90mg, from about 200mg to about 300mg, from about 70mg to about 95mg, from about 100mg to about 200mg, from about 105mg to about 200mg, from about 110mg to about 140mg, from about 180mg to about 220mg, from about 280mg to about 320mg, from about 200mg, about 150mg, or about 300mg of a compound of formula I, or a range defined by, or an amount ranging between, any of these values.
In some embodiments, the solid composition may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), About 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of the compound of formula I, or a range defined by, or any amount between, any of these values.
Some solid dosage forms may contain from about 10mg to about 1000mg, from about 50mg to about 1000mg, from about 10mg to about 50mg, from about 50mg to about 100mg, from about 40mg to about 90mg, from about 200mg to about 300mg, from about 70mg to about 95mg, from about 100mg to about 200mg, from about 105mg to about 200mg, from about 110mg to about 140mg, from about 50mg to about 150mg, from about 180mg to about 220mg, from about 280mg to about 320mg, from about 200mg, about 150mg, or about 300mg of a compound of formula I, or a range defined by, or any amount between, any of these values.
In some embodiments, the compound of formula I is administered at a dose that results in a plasma level of the compound of formula I of about 0.1 μ Μ to about 10 μ Μ, about 0.1 μ Μ to about 5 μ Μ, about 0.2 μ Μ to about 3 μ Μ, 0.1 μ Μ to about 1 μ Μ, about 0.2 μ Μ to about 2 μ Μ,1 μ Μ to about 10 μ Μ, about 1 μ Μ to about 5 μ Μ, about 2 μ Μ to about 3 μ Μ, or about 2.8 μ Μ to about 3 μ Μ, about 1.5 μ Μ to about 2 μ Μ, about 4.5 μ Μ to about 5 μ Μ, about 2.5 μ Μ to about 3 μ Μ, about 1.8 μ Μ, about 4.8 μ Μ, about 2.9 μ Μ, about 2.8 μ Μ, or a range defined by or any plasma level between any of these values.
In some embodiments, the compound of formula I is such that, on day 8, the AUC of the compound of formula I in the subject0-12Is administered to a subject in an amount of at least about 200nghr/mL, at least about 400nghr/mL, at least about 700nghr/mL, at least about 1,000nghr/mL, at least about 3,000nghr/mL, at least about 7,000nghr/mL, at least about 10,000nghr/mL, at least about 15,000nghr/mL, at least about 20,000nghr/mL, at least 30,000nghr/mL, up to about 50,000nghr/mL, up to about 150,000nghr/mL, or a range defined by, or any AUC between any of these values.
In some embodiments, the compound of formula I is C of the compound of formula I such that, on day 8, the subjectmaxIs at least about 20ng/mL, at least about 60ng/mL, at least about 90ng/mL, at least about 100ng/mL, at least about 150ng/mL, at least about 200ng/mL, at least about 300ng/mL, at least about 1,000ng/mL, at least about 4,000ng/mL, up to about 10,000ng/mL, up to about 50,000ng/mL, or a range defined by or between any of these values, or any C between any of these valuesmaxIs administered to a subject.
In some embodiments, the compound of formula I is C of the compound of formula I such that, on day 8, the subjectavgIs at least about 20ng/mL, at least about 30ng/mL, at least about 50ng/mL, at least about 80ng/mL, at least about 90ng/mLng/mL, at least about 100ng/mL, at least about 150ng/mL, at least about 200ng/mL, at least about 300ng/mL, up to about 1,000ng/mL, up to about 5,000ng/mL, up to about 30,000ng/mL, or a range defined by any of these values, or any C between any of these valuesavgIs administered to a subject.
For compositions comprising both DEX and a compound of formula I, some liquids may comprise from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) to about 20% (w/v), from about 0.01% to about 10% (w/v), from about 1% (w/v) to about 3% (w/v), from about 3% (w/v) to about 5% (w/v), from about 5% (w/v) to about 7% (w/v), from about 5% (w/v) to about 15% (w/v), from about 7% (w/v) to about 10% (w/v), from about 10% (w/v) to about 15% (w/v), from about 15% (w/v) to about 20% (w/v), from about 20% (w/v) to about 30% (w/v) About 30% (w/v) to about 40% (w/v), about 40% (w/v) to about 50% (w/v) of the combined DEX and compound of formula I, or a range defined by any of these values, or any amount between any of these values. Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), About 70% (w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) of the combined DEX and compound of formula I, or a range defined by any of these values, or any amount between any of these values. In some embodiments, the weight ratio of DEX to the compound of formula I in a single 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, from about 0.3 to about 0.5, from about 0.5 to about 0.7, from 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 a range defined by, or any ratio between, any of these values.
The therapeutically effective amount of the therapeutic compound may vary from case to case, by way of example, the daily dose of DEX may in some cases be in the range: from about 0.1mg to about 1000mg, from about 40mg to about 1000mg, from about 20mg to about 600mg, from about 60mg to about 700mg, from about 100mg to about 400mg, from about 15mg to about 20mg, from about 20mg to about 25mg, from about 25mg to about 30mg, from about 30mg to about 35mg, from about 35mg to about 40mg, from about 40mg to about 45mg, from about 45mg to about 50mg, from about 50mg to about 55mg, from about 55mg to about 60mg, from about 20mg to about 60mg, from about 60mg to about 100mg, from about 100mg to about 200mg, about 100mg to about 140mg, about 160mg to about 200mg, about 200mg to about 300mg, about 220mg to about 260mg, about 300mg to about 400mg, about 340mg to about 380mg, about 400mg to about 500mg, about 500mg to about 600mg, about 15mg, about 30mg, about 60mg, about 120mg, about 180mg, about 240mg, about 360mg, or a range defined by or between any of these values for any daily dose. DEX can be given 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 amounts that are about one-half, one-third, one-fourth, or one-sixth, respectively, of the daily dosage.
The daily dosage of a compound of formula I may in some cases be in the following ranges: about 10mg to about 1000mg, about 50mg to about 600mg, about 100mg to about 2000mg, about 50mg to about 100mg, about 70mg to about 95mg, about 100mg to about 200mg, about 105mg to about 200mg, about 100mg to about 150mg, about 150mg to about 300mg, about 150mg to about 200mg, about 200mg to about 250mg, about 250mg to about 300mg, about 200mg to about 300mg, about 300mg to about 400mg, about 400mg to about 500mg, about 400mg to about 600mg, about 360mg to about 440mg, about 560mg to about 640mg, or about 500mg to about 600mg, about 100mg, about 150mg, about 200mg, about 300mg, about 400mg, about 600mg, or any daily dosage between any of these values or any range defined by any of these values. The compound of formula I may be administered once a day; or twice daily or every 12 hours, or three times daily in an amount of about one-half or one-third of the daily dose, respectively.
In some embodiments: 1) about 50 mg/day to about 100 mg/day, about 100 mg/day to about 150 mg/day, about 150 mg/day to about 300 mg/day, about 150 mg/day to about 200 mg/day, about 200 mg/day to about 250 mg/day, about 250 mg/day to about 300 mg/day, or about 300 mg/day to about 500 mg/day of a compound of formula I; and/or 2) about 15 mg/day to about 60 mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45 mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100 mg/day, about 80 mg/day to about 110 mg/day, about 100 mg/day to about 150 mg/day, or about 100 mg/day to about 300 mg/day of DEX is administered to a subject in need thereof.
In some embodiments, about 150 mg/day of a compound of formula I and about 30 mg/day DEX, about 150 mg/day of a compound of formula I and about 60 mg/day 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 DEX, about 200 mg/day of a compound of formula I and about 30 mg/day 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 DEX, about 200 mg/day of a compound of formula I and about 120 mg/day 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 DEX, about 300 mg/day of a compound of formula I and about 90 mg/day DEX, Or about 300 mg/day of a compound of formula I and about 120 mg/day of DEX are administered to the subject.
In some embodiments, about 100 mg/day of a compound of formula I, and about 15 mg/day of DEX are administered to the subject 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, about 100 mg/day of a compound of formula I, and about 30 mg/day of DEX is administered to the subject 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.
In some embodiments, about 75 mg/day of a compound of formula I, and about 15 mg/day of DEX is administered to the subject 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, about 75 mg/day of a compound of formula I, and about 30 mg/day of DEX is administered to the subject 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.
5-HT2A receptor antagonists/inverse agonists, such as the compounds of formula I, may be administered as needed to treat neurological conditions such as pain, depression or cough. In some embodiments, the 5-HT2A receptor antagonist/inverse agonist, e.g., a compound of formula I and DEX, are administered at least once daily, e.g., once or twice daily, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or more.
The therapeutic compound may be formulated for oral administration, by way of example, with an inert diluent or with an edible carrier, or it may be enclosed within hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a meal. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
The tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, potato starch, alginic acid, and the like; lubricants, such as magnesium stearate; a sweetening agent, such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring agents. When the dosage unit form is a capsule, it may contain, in addition to materials of the type described above, a liquid carrier. Various other materials may be present as coatings, for example, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the amounts employed.
Some compositions or dosage forms may be liquid, or may comprise a solid phase dispersed in a liquid.
The therapeutic compound may be formulated for parenteral or oral administration. Solutions of the active compound as a free base or a pharmaceutically acceptable salt can be prepared in water mixed with a surfactant, such as hydroxypropyl cellulose. The dispersion can also have an oil dispersed within or in the glycerol, the liquid polyethylene glycol, and mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
Although dementia, such as Alzheimer's Disease (AD), is characterized by cognitive deficits, neuropsychiatric symptoms (behavioral and psychiatric symptoms of dementia, BPSD) are one of the major drivers of caregiver burden and hospitalization. The frequency of BPSD symptoms increases with disease progression (e.g., up to 60% in mild and moderate AD, and up to 90% in severe AD).
There is much room for improvement in current commercial dementia therapies for treating BPSD, but there are other non-cognitive concerns. This becomes increasingly important in the continuing lack of disease modifying therapies, as symptoms like hostility, aggressiveness, wandering, inappropriate behaviour or incontinence pose significant problems for caregivers and families and are a predictor of (expensive) nursing home placements.
It is a global practice to develop (typical or atypical) neuroleptics to aid in care and care. However, the FDA has determined that off-label prescriptions of neuroleptics pose a significant threat to the health of mentally disabled subjects and has issued black box warnings, citing serious cardiovascular adverse events and increased risk of death. The european union approved risperidone (risperidone) for short-term use in moderately severe AD patients only in cases of injury to himself or others. In parkinson's disease, the anticholinergic effects of neuroleptics are highly undesirable, as those inevitably worsen motor pathology and symptoms of the trophic nervous system. Among all dementias, lowering seizure threshold is another rare but highly undesirable potential adverse effect of neuroleptics. These concerns with the use of neuroleptic drugs in dementia have led to a reduction in the use of neuroleptic agents in such patients, with the symptoms of BPSD being essentially untreated in the vast majority of patients with mild to moderate AD.
Thus, several embodiments are novel compositions and methods useful for the symptomatic and disease modifying treatment of: neurodegenerative diseases and brain injury, including sequelae thereof, such as organic brain syndrome and chronic traumatic encephalopathy; chronic or intractable pain, ophthalmological indications associated with retinopathy, anxiety disorders, post-traumatic stress disorder, depression, diabetes and its complications, such as peripheral neuropathy with or without neuropathic pain, Burger's Disease, Raynaud's Disease, coronary artery Disease, angina, atherosclerosis, including the CNS, such as multi-infarct dementia, vascular cognitive dysfunction, vascular dementia or Binswanger's Disease, and nephropathy.
In a first aspect, provided is a method of increasing the metabolic lifespan of DEX, comprising administering to a subject in need of treatment with DEX a 5-HT2A receptor antagonist/inverse agonist of formula I, wherein the 5-HT2A receptor antagonist/inverse agonist is an inhibitor of the CYP2D6 enzyme and wherein DEX and M1 are present simultaneously in the body of the subject.
In a second aspect, provided is a method of preventing an adverse event associated with DEX treatment, the method comprising co-administering to a subject in need of treatment with DEX a 5-HT2A receptor antagonist/inverse agonist of formula I, wherein the subject is at risk of experiencing an adverse event caused by treatment with DEX.
In a third aspect, provided is a method of using a 5HT2A receptor antagonist of formula I to improve DEX therapeutic properties in the treatment of a neuropsychiatric disorder.
In a fourth aspect, provided is a method of treating a neuropsychiatric disorder, the method comprising administering a 5HT2A receptor antagonist of formula I and DEX to a subject in need thereof.
In one embodiment of the first, second, third and fourth aspects, the 5-HT2A receptor antagonist/inverse agonist is M1, e.g., a prodrug of a compound of formula I, or a pharmaceutically acceptable salt thereof.
In one embodiment of the first, second and third aspects, the 5-HT2A receptor antagonist/inverse agonist is an enantiomer of M1, 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 a pharmaceutically acceptable salt thereof.
In an embodiment of the third and fourth aspects, the neuropsychiatric disorder is alzheimer's disease.
In a fifth aspect, provided are methods of selecting a 5-HT2A receptor antagonist/inverse agonist for use in combination with DEX in a subject in need thereof.
In one embodiment of the fifth aspect, a specific enantiomer of a 5HT2A receptor antagonist having potent CYP2D6 inhibitory activity has a higher blood brain barrier penetration.
In one embodiment of the fifth aspect, the specific enantiomer of the 5HT2A receptor antagonist with potent CYP2D6 inhibitory activity has a preferred ratio of central to peripheral effects when administered in combination with DEX, wherein central effects are assessed by direct or indirect 5HT2A receptor binding methods and peripheral effects are assessed by methods based on blood glucose measurements.
In one embodiment of the fifth aspect, the DEX and the selected 5-HT2A antagonist are administered in a combined dose, wherein the amount of DEX administered comprises from about 20 mg/day to about 80 mg/day.
In an embodiment of the fifth aspect, the DEX is administered in a combined dose with a selected enantiomer of M1, wherein the amount of the M1 enantiomer administered comprises from about 0.1 mg/day to about 1000 mg/day.
One embodiment of the invention is a method of enhancing the therapeutic properties of DEX by administering DEX and a 5HT2A receptor antagonist with potent CYP2D6 inhibitory activity, as well as its own multiple therapeutic benefits.
Some embodiments include methods of treating a disease or disorder comprising administering about 5 mg/day to about 600 mg/day, about 5 mg/day to about 300 mg/day, about 5 mg/day to about 400 mg/day, about 5 mg/day to about 500 mg/day, about 5 mg/day to about 600 mg/day, about 5 mg/day to about 1,000 mg/day, about 50 mg/day to about 1000 mg/day, about 100 mg/day to about 1000 mg/day, about 150 mg/day to about 5000 mg/day, about 150 mg/day to about 300 mg/day, or about 150 mg/day to about 100 mg/day, or a compound of formula I in a required amount, and about 0.1 mg/day to about 1 mg/day, about 0.5 mg/day to about 15 mg/day, or a pharmaceutically acceptable salt thereof, 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 a range defined by any of these values, or any amount between any of these values, or in accordance with the required amount of DEX to a subject in need thereof.
Borodkin, Book changer Ion-exchange resin delivery system [ section: ion exchange resin Delivery system ], described in "Polymers for Controlled Drug Delivery" edited by Tarcha, P J, CRC Press (CRC Press), Boca Raton (Boca Raton), 1990; the entire contents of which are incorporated by reference. The compositions of the present invention may be formulated into any pharmaceutical dosage form for oral, topical, rectal, vaginal, intranasal, or ocular administration, and include syrups and suspensions, which may be used to formulate the compositions of the present invention using commonly known ingredients and procedures (US4,221,778, US4,762,709, US4,788,055, US4,959,219, US4,996,047, US5,071,646, and US5,186,930; Borodkin, Book: Ion-exchange resin Delivery system [ section in the Book ], Polymers for Controlled Drug Delivery [ Polymers ] ", compiled by Tarcha, P J, CRC Press (CRCPress), Bocaton Raton (Bocaton Rad 1990; the entire contents of which are incorporated by reference).
The present invention may be formulated into any pharmaceutical dosage form for oral, topical, rectal, vaginal, intranasal, or ocular administration, and includes syrups and suspensions, and the usual known ingredients and procedures for formulating pharmaceutical dosage forms are within the purview of those skilled in the art, including various known methods (US4,221,778, US4,762,709, US4,788,055, US4,959,219, US4,996,047, US5,071,646, US4,221,778, and US5,186,930; the entire contents of which are incorporated herein by reference) may be used to formulate the compositions of the present invention.
Oral formulations and tablet formulations include enteric-coated layered formulations comprising a separation layer to separate the acidic enteric coating material from the omeprazole (omeprazole) which is an acid sensitive substance. HPC or other suitable polymers disclosed herein may be used in the layer separating the core material and the enteric coating layer in the formulation.
Synthesis method
SGL hydrochloride (CAS number: 135159-51-2), its systematic name is succinic acid mono (2- (dimethylamino) -1- ((2- (2- (3-methoxyphenyl) ethyl) phenoxy) methyl) ethyl) ester hydrochloride, which can be manufactured by a number of synthetic methods (Chen et al, A practical synthesis of saline hydrochloride and in vitro platelet aggregation inhibitor activity of sarpogrelate hydrochloride and its analogs ], Chinese Chemical Letters [ Chinese Rapid Letters ], Vol.21, No.3, 3 months 2010, pp.287-28; J Med Chem [ pharmaceutical chemistry ]33(6) (1990); CN 103242179A; WO 2015008973; the entire contents of which are incorporated by reference).
The reaction of 2-hydroxy-3 ' -methoxybibenzyl with epichlorohydrin by means of alkali in a suitable solvent affords 2- (2, 3-epoxypropoxy) -3' -methoxybibenzyl, which is reacted with dimethylamine at reflux in a suitable solvent to give 2- [3- (dimethylamino) -2-hydroxypropoxy ] -3' -methoxybibenzyl. Finally, the compound is treated with succinic anhydride and refluxed with an acid in a suitable solvent.
Figure GDA0002354989720000931
The following scheme shows that the reaction of 2-hydroxy-3 ' -methoxybibenzyl with epichlorohydrin by means of NaH in DMF affords 2- (2, 3-epoxypropoxy) -3' -methoxybibenzyl, which reacts with dimethylamine in refluxing THF to give 2- [3- (dimethylamino) -2-hydroxypropoxy ] -3' -methoxybibenzyl. Finally, this compound was treated with succinic anhydride in refluxing THF and HCl in acetone (J Med Chem [ journal of pharmaceutical chemistry ]33(6) (1990), incorporated herein by reference).
SGL hydrochloride is synthesized from salicylaldehyde via benzyl protection, reduction, chlorination, abbozov reaction (Arbuzovreaction), Wittig-Horner reaction, catalytic hydrogenation to produce 2-2- (3-methoxyphenyl) ethylphenol, which is reacted with epichlorohydrin, amination, esterification, and salt formation, with an overall yield of about 46%.
The SGL hydrochloride drug substance used to prepare the SGL hydrochloride tablet needs to reach an acceptable purity, and the single heterogeneous content must meet the corresponding requirements. US 4485258 discloses the first synthesis of SGL hydrochloride and recrystallisation from acetone, but experiments have shown that SGL hydrochloride has poor solubility in acetone, hydrochloric acid and is not suitable as a solvent for the recrystallisation of SGL. CN 101239920 a discloses that acetonitrile, propionitrile, 1, 4-dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, sulfolane, dimethylsulfoxide, or a mixture of these more than two and methanol, ethanol, acetone, ethyl acetate, diethyl ether, isopropyl ether or the like can be used as a recrystallization solvent for SGL hydrochloride, and the purity of the product can reach 98%. And C2-10Alkane, C3-10Ketones, C2-10Carboxylic acid ester, C1-10Halogenated alkanes, aromatic hydrocarbons or aromatic derivatives cannot obtain a high purity product at room temperature to reflux temperature (in this temperature range, solubility of hydrochloric acid is small and SGL alone should not be used as a recrystallization solvent), SGL hydrochloride and water as a recrystallization solvent or an organic solvent, and water at 5% or more is contained. The prior literature does not address the problem of single impurity content control.
Enantiomerically pure forms of SGL can be made using chiral ligands to induce the formation of a selected single enantiomer as shown below:
Figure GDA0002354989720000941
chiral organic compounds play an important role in biologically active pharmaceuticals, agrochemicals and other materials having utility. Enzymes and other natural binding sites recognize substrates with specific chiralities to produce a wide variety of biological functions. The action of these enzyme or receptor sites is specific, and enantiomers may exhibit different properties due to chirality. Thus, in the case of biologically active compounds, only one of the enantiomers may be active and the other inactive, both enantiomers being active, but they have different potencies or both enantiomers having similar or equal activity. Thus, the manufacture of enantiomerically pure molecules of drugs is of interest and methodology has three basic strategies, 1) resolution (2) use of chiral building blocks and (3) asymmetric synthesis. To date, asymmetric synthesis offers the most efficient use of one chiral material to prepare the other.
The preparation of enantiomerically pure molecules of biological interest can be efficiently achieved by asymmetric synthesis. The method involves creating one or more chiral centers from a prochiral starting material under the influence of a chiral substrate. The preparation of enantiomerically pure compounds involves the use of chiral auxiliaries, chiral reagents or chiral catalysts, or a combination thereof.
In another embodiment, compounds of the disclosure can be prepared from (2R) -3- (dimethylamino) 2-propanediol and (2S) -3- (dimethylamino) -1, 2-propanediol (scheme VIII).
Various multifunctional and convenient Chiral carboxylic acid Ligands can be found In the literature, such As mandelic acid, 2-methylmandelic acid, 2-chloromandelic acid, 3-chloromandelic acid, 4-methoxymandelic acid, O-acetylmandelic acid, α -methoxyphenylacetic acid, malic acid, tartaric acid, etc. Chiral Ligands can be prepared from readily available building blocks (molecular Carbohydrate derivative), volume 7, volume 9, month 9, 2551. sup. 2562. U.S. Pat. No. 3B 2; Product: (S) -2-Amino-1, 2, 3, 4-tetrahydro-6-methoxy-naphthalene [ Product: (S) -2-Amino-1, 3, 4-dihydroxy-6-methyl-naphthalene [ Product, 2-Amino-1, 3-methoxy-6-methoxy-methyl-naphthalene [ Product, 2, 3, 4-methoxy-6-methyl-Hydroxy-naphthalene [ Product of synthetic methods, chemical engineering, 2, 5. sup. No. 7, 5. sup. No. 9, 1996, 9. th, 1996, 2551. sup. pp. 2562. No. 5. sup. No. 5. by chemical industries [ synthetic methods, 5. No. 7. see, 5. No. 5. by chemical industries, 5. No. 5. 2. No. 5. see, 2. No. 5. see, 2. No. 5. sup. No. 5. see, 2. by chemical industries, 2. by chemical industries, 5. 2. No. 7. 2. see, 5. 2. by 5. 2. by 5. Chiral ligand, 5. 2. by 5. 2. Chiral ligand, 5. by 5. Chiral ligand, 5. by 5. 2. Chiral ligand, 5. by 5. Chiral ligand, 2. by 5. 2. by 5. Chiral ligand, 2. Chiral ligand, 5. Chiral ligand, 6. by 5. Chiral ligand, 5. by 5. Chiral ligand, 2. Chiral ligand, 2. by 5. Chiral ligand, 2. by 5. Chiral ligand, 2. by 5. see, 2. Chiral ligand.
The formation of the diastereomeric compounds and salts is carried out in a suitable reaction medium. Suitable reaction media include water, methanol, ethanol, 1-propanol, 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetic acid, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, benzene, toluene and xylene, and/or mixtures thereof.
SARPODEXTERTMAnd SarpogexamideTM
Amidation/acylation (http:// www.organic-Chemistry. org/Synthesis/C1N/Amides. shtm; https:// Chemistry. library. org/Core/Organic _ Chemistry/Amides/Synthesis _ of _ Amides; http:// www.chemguide.co.uk/Organic prop/Amides/preparation. html; WO1998043961, incorporated by reference in its entirety).
In the above scheme, can be used for synthesizing SarpodexamideTMLinkers for derivatives include, but are not limited to, those described in: (Simplicio et al, Prodrugs for Amines [ Prodrugs of Amines)]Molecules [ Molecules ]]13, 519-; mahato et al, Prodrugs for Improving turbine targeting and Efficiency [ prodrugs for improving tumor targeting and efficiency]Adv Drug Deliv Rev [ advanced Drug delivery review ]]659 and 670(2011, 7, 18); jornada et al, The Prodrug Approach: Asuccesful Tool for Improving Drug Solubility [ Prodrug Approach: successful tool for increasing drug solubility]Molecules [ Molecules ]]21, 42 (2016); jain et al, Mutual precursors conjugating bio-reactive and drug releasable disulfide linkers [ Mutual prodrugs containing a biocleavable and drug releasable disulfide linker]Bioorganic Chemistry]49C:40-48 (7 months in 2013); US20130053301, WO 2011089216a 1; WO 2006136586 a 2; US 7932294; US 20060046967a 1; US 8357723; US 8349901; US 8354455; US 9550734; US 20160220694; US 20160002167; US 20150328323; US 9090563; US 20140058063; US 20130158271; US 8288557; US 20110274695; WO 1998043961; incorporated by reference in its entirety).
The esterified ester is derived from a carboxylic acid. The carboxylic acids contain a-COOH group, the hydrogen of which is replaced in the ester by a hydrocarbon radical R', such as alkyl, cycloalkyl, aryl, and heteroaryl. Esters are made when a carboxylic acid and an alcohol are heated in the presence of an acid catalyst. The catalyst is an acid, typically concentrated sulfuric acid. In some cases, anhydrous hydrogen chloride gas may be used. TsOH (p-toluenesulfonic acid) is also frequently used.
The esterification reaction is slow and reversible. The reaction equation between the acid RCOOH and the alcohol R 'OH (where R and R' may be the same or different) is:
Figure GDA0002354989720000961
the alcohol is generally used as a solvent and is therefore present in excess. (http:// www.chemguide.co.uk/Organic/alcohols/engineering. html; http:// www.organic-Chemistry. org/namedreams/fisher-engineering. shot.;// www.masterorganicchemistry.com/interaction-guide/conversion-of-Carboxylic-Acids-to-engineering-use-Acids-and-alcohols-fixer-engineering/; http:// video. org/. 3/AP% 20 Lab/AP% 20 Lab% 20. recording/engineering. pdf; http:// science. J. random. org/pages/73/engineering. html/acetic. html. express. TM. text. WO. org. WO. origin/simulation. 1998043961. in its entirety; Fischer _ org. text. org. 2525/engineering. g/equation).
SARPODEXTERTM
In another embodiment of preparing the compositions of the present application, the diastereomerically pure sarpogexeter can be prepared by combining racemic sarpogrelate and optically pure dextrorphan (DO-H)3Compound 151) under mild esterification conditions to obtain a mixture of diastereomeric esters, compound 165-166, which can be separated by the crystallization and chromatography techniques mentioned above and the techniques described in the present specification to obtain diastereomerically pure sarpdexeters 165 and 166.
Examples of the invention
SARPODEXAMIDETMPreparation of derivatives
A compound of formula I or SarpodexamidetmThe derivatives can be obtained by: dextromethorphan and 2, 2, 2-trichloroethylchloroformate as a single isomer or a mixture thereof are reacted in refluxing toluene to obtain the N-demethylated compound.
Figure GDA0002354989720000971
The above trichloroethoxycarbonyl group can be converted into N-desmethyl dextromethorphan by heating to reflux in glacial acetic acid in the presence of zinc powder.
N-desmethyldextromethorphan (CAS number: 125-71-3), obtained or purchased as described above, can be treated with triflic anhydride and pyridine at room temperature (as described in Liebigs Ann. chem. [ Anbian Chemicals ]1986, 336 and WO1998043961, the entire contents of which are incorporated herein).
Optically pure SARPODEXAMIDE
As shown in scheme XIII, the amide (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((4bS, 8aS, 9S) -3-methoxy-6, 7, 8, 8a, 9, 10-hexahydro-5H-9, 4b- (desmoethylene) phenanthren-11-yl) -4-oxobutanoate (Compound 167) and (R) -1- (dimethylamine) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((4bS, 8aS, 9S) -3-methoxy-6, 7, 8, 8a, 9, 10-hexahydro-5H-9, 4b- (desmoethylene) phenanthren-11-yl) -4-oxobutanoate (Compound 168) can be obtained from sargracile by using HBTU in combination with permissive base (H ü g' S base) to obtain N-desmethylmethadyl dextromethorphan under the list of NaHCO-2- (cyanoethoxy) -2-aminoethoxycarbonyl) phosphonate, such aS N-aminoethoxycarbonyl-2-oxobutanoate (Compound 167), N-hydroxyiminomethyl-2-aminoethoxycarbonyl-2-oxobutanoate (Compound 168), N-hydroxymethanesulfonate (N-hydroxymethanesulfonate) and N-hydroxymethanesulfonate (N-hydroxymethanesulfonate) can be obtained by using N-hydroxymethanesulfonate aS N-demethyl-N-3、B(OCH2CF3)3Trimethyl aluminum, lanthanum trifluoromethanesulfonate and ZrOCl2·8H2O, methanesulfonyl chloride and N-methylimidazole, N' -Carbonyldiimidazole (CDI), and the like.
Optically pure DEX of formula I, SARPODEXTM、DERADEXTMOr DERAPHANTMSALT
Figure GDA0002354989720000981
Formation of dextromethorphan (S) -4- ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) -4-oxobutanoate (S-SARPODEX) from compound 50 and compound 149 in chloroform or other suitable solvent, e.g., dichloromethane, DMF, and the likeTM) Salts and dextromethorphan (R) -4- ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) -4-oxobutyrate (R-SARPODEX)TM) Mixtures of diastereomeric salts of the salts, which can be separated by crystallization and recrystallization in a suitable solvent, such as DMF, and/or chromatographic techniques mentioned and described in this specification.
In one embodiment, provided is a method for separating diastereomers of a compound by increasing the separation efficiency through the use of an ionic liquid. When the diastereomers are separated, for example, by methods such as liquid-liquid extraction, one or more ionic liquids may be used as the extractant.
In one embodiment, the separation process may be carried out on a compound containing a mixture of at least one pair of diastereomers, the diastereomers may be separated by contacting the mixture with at least one ionic liquid, wherein one of the diastereomers is more soluble than the other diastereomer, and separating the less soluble diastereomer from the mixture. The invention disclosed herein then comprises a process for separating diastereomers, the use of such a process, and the products obtained and obtainable by such a process.
In another embodiment, the isolation method can be performed on a compound, such as DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMA mixture of diastereoisomers of a salt, wherein the diastereoisomers are separated by contacting the mixture with at least one ionic liquid, wherein one of the diastereoisomers is more soluble than the other diastereoisomer, and separating the less soluble diastereoisomer from the mixture.
In yet another embodiment, a method for separating DERATINE from a mixture comprising two diastereomers is providedTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMBy liquid-liquid extraction using at least one ionic liquid as extraction solvent.
Another embodiment is a method for performing an industrial operation selected from the group consisting of: calibration operation, cleaning operation, rinsing operation, drying operation, particle removing operation, solvent operation, dispersing operation, heat transfer operation, and insulating operationComprises reacting a compound containing DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMWherein one of the diastereomers is more soluble than the other diastereomer, separating the less soluble diastereomer from the mixture, and using the separated diastereomer in the process.
Another embodiment is a method for separating one diastereomer from another diastereomer of a compound. In such processes, ionic liquids are used to facilitate separation, the diastereomers can be separated by contacting the mixture with at least one ionic liquid, wherein one of the diastereomers is more soluble than the other diastereomer, and separating the less soluble diastereomer from the mixture.
The term "ionic liquid" is defined as an organic salt that is fluid at about 100 ℃ or below about 100 ℃.
"liquid-liquid extraction" is a process of separating components in a solution by partitioning between two immiscible liquid phases. Liquid-liquid extraction involves the transfer of a substance from one liquid phase to a second immiscible liquid phase and is carried out using an extractant or solvent.
The components in the liquid mixture can be separated by, for example, liquid-liquid extraction using a single equilibrium (or theoretical) stage, or using multiple stages. An equilibrium, or theoretical stage, is a device that allows the feed and immiscible liquids to mix sufficiently to bring the concentrations close to equilibrium, followed by physical separation of the two immiscible liquid phases. The single stage device can be a separatory funnel, or stirred vessel, which allows for thorough mixing of the feed and immiscible extractant. After thorough mixing, one or both of these liquids may be recovered by, for example, decantation.
The multi-stage device for liquid separation may be a cross-flow or counter-flow device. In a multi-stage apparatus, the feed enters a first equilibrium stage and contacts an extractant. Mixing two liquid phases, one phase of droplets suspended in a second phase, and subsequently separating the two phases to obtain the DERATINE from the first stageTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMAnd additional extractant, and the separation process is repeated. The following methods: (1) making DERATINETM、SARPOTINETM、DERADEXTM、DERAPHANTMOr SARPODEXTMContacting with an extractant, (2) allowing the equilibrium concentration to approach, and (3) repeatedly separating the liquid phase until the desired purity of the component of interest is achieved. The number of equilibration stages will depend on the desired purity, as well as the solubility of the components in the extractant and the flow rates of the feed and extractant.
In a cross-flow system (or apparatus), the feed is first contacted with the extractant in a first equilibrium stage. DEX from this stage, formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMAnd then cascaded through one or more additional stages. At various stages, the composition is contacted with fresh extractant and further purification of the desired component of the composition is achieved. An example of a cross-flow system wherein the threo isomer of the composition is 1-butyl-3-methylimidazolium tetrafluoroborate ([ BMIM ]) using an ionic liquid][BF4]) Used as an extractant for purification. In a counter-current system or apparatus, the extractant enters at the stage furthest from the feed and the two phases pass in two different (e.g., opposite) directions and through each other.
Devices for liquid-liquid extraction can be classified as "staged" or "continuous (differential) contact" devices. The staged equipment is also called "mixer-settler". Mixing of the liquids takes place by contacting the feed and the extractant, and as the two phases separate, the resulting dispersion settles. Mixing can occur using baffles or impellers and the separation process can be carried out batchwise or continuously. The settler may be a simple gravity settler, such as a decanter, or may be a cyclone or centrifuge, which enhances the speed of settling.
Continuous contacting devices are generally arranged for multi-stage countercurrent contacting of immiscible liquids without repeated separation of the liquids from one another between stages. Instead, the liquids are maintained in continuous contact throughout the process through the apparatus. The counter-current flow is maintained by differences in liquid density and gravity (vertical column) or centrifugal force (centrifugal extractor). Gravity operated extractors can be divided into spray, packed or perforated (sieve) columns. Gravity operated towers also include towers with rotating agitators and pulsating towers known in the art.
When the diastereomers of the compounds of the composition, and in particular the threo and erythro isomers of 2, 3-dihydrodecafluoropentane, are separated by a method such as liquid-liquid extraction, the separation can be performed using any of the equipment described above. In a preferred embodiment, the separation is performed using a vertical column with perforated plates. After separating the phase containing the less soluble diastereomer from the phase containing the extractant and the more soluble diastereomer, the more soluble diastereomer can be separated from the extractant by, for example, distillation.
The transfer of substances from one Liquid phase to the respective immiscible phase by means of Liquid-Liquid Extraction, and the Equipment used therein are further discussed in resources such as Robbins and Cusack, "Liquid-Liquid Extraction operations and Equipment," Perry's Chemical Engineers' Handbook of Chemical Engineers in Pele, 7 th edition, (McGraw-Hill, 1997, section 15) (incorporated by reference). The operating principles of known Liquid-Liquid Extraction processes that should be applied to the separations described herein, which are the same or similar, include the recovery of acetic acid from water using ether or ethyl acetate as an extractant (Brown, chem.engr.prog. [ chemical and biomolecular engineering ] (1963)59:65) and phenol from water using methyl isobutyl ketone as an extractant, as described by Scheibel in "Liquid-Liquid Extraction ]" (Perry and Weissburg (editors), separationon and Purification ], 3 rd edition (1978) chapter 3, John Wiley & Sons, Inc.
The dielectric constant of the solvent (if the solvent is used for resolution) alters crystal formation, composition and enantiomeric discrimination (Sakai et al Tetrahedron: Asymmetry 14, 3716(2003), the entire contents of which are incorporated by reference). The composition of the crystalline diastereomer is also affected by the pH of the reaction mixture (Fogassy et al, J.chem.Res. [ J.Chem.Res. ] [ J.Chem.S. 11, 346 (1981); Fogassy et al, J.chem.Soc. [ J.Chem.Soc. [ J.Chem.J. ] Perkin Trans. [ Perkin report ]2.(1988), the entire contents of which are incorporated by reference). The purity (de) of the diastereoisomers can be improved using a mixture of structurally related resolving agents. This is frequently referred to in the literature as "Dutch's analysis" (Kellogg et al Synthesis 1626(2003), incorporated by reference). If diastereomeric salts cannot be separated by fractional precipitation, their crystalline solvates can be obtained from solvate-forming solutions by fractional precipitation (schinder et al Chirality, 19, 239(2007), incorporated by reference). When solvents unsuitable for the Separation of diastereomers contain Compounds which are structurally partially similar to the solvate-forming solution (US 214720, chem. abs. [ chemical abstracts ]124, 117097 (1995); US 2133894; chem. abs. [ chemical abstracts ]139, 90595(2001), incorporated by reference), the Separation of enantiomers is made possible by fractional precipitation of diastereomeric salts (Palovics et al, Separation of the Mixtures of Chiral Compounds by crystallization, Advances in crystallization processes, pages 1-37 (2012), incorporated by reference).
In the crystallization of a melt forming an enantiomeric mixture of the racemate, the composition of the eutectic composition generally determines the composition of the crystalline mixture and the oily residue. The eutectic composition is known from the binary melting point phase diagram. Pure optical isomers can crystallize when the initial isomeric composition (ee0) is higher than the eutectic composition.
Ionic liquids, or mixtures of two or more thereof, may be used in the present invention to separate diastereomers of a compound. When, for example, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMWhen the diastereomers of (a) are separated by, for example, 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 ℃). They differ from most salts in that they have very low melting points and their liquids generally tend to be liquids over a wide temperature range. Those also tend to be insoluble in nonpolar hydrocarbons in general; water immiscible (depending on the anion); and is highly ionized (but of low dielectric strength). Ionic liquids have essentially no vapor pressure and are largely air and water stable, and they can be neutral, acidic or basic.
The cation or anion of the ionic liquid useful herein can in principle be any cation or anion such that the cation and anion together form an organic salt that is liquid at about 100 ℃ or below about 100 ℃. However, the properties of ionic liquids can be tailored by varying the identity of the cations and/or anions. For example, the acidity of the ionic liquid can be adjusted by varying the molar equivalents and types and combinations of lewis acids used.
Many ionic liquids are formed by: the nitrogen-containing heterocyclic ring, preferably a heteroaromatic ring, is reacted with an alkylating agent (e.g., an alkyl halide) to form a quaternary ammonium salt, and ion exchanged or otherwise suitably reacted with various lewis acids or conjugate bases thereof to form the ionic liquid. Examples of suitable heteroaromatic rings include substituted pyridines, imidazoles, substituted imidazoles, pyrroles and substituted pyrroles. These rings may be substituted with virtually any straight, branched or cyclic C1-20The alkyl group is alkylated, but preferably the alkyl group is C1-16Groups, as groups larger than this may yield low melting point solids rather than ionic liquids. Triarylphosphines of the various formulae, thioethers and cyclic and acyclic quaternary ammonium salts can also be used for this purpose. Counter ions which may be used include chloroaluminate, bromoaluminate, gallium chloride, tetrafluoroborate, tetrachloroborate, hexafluorophosphate, nitrate, triflate, methanesulfonate, p-methanesulfonateBenzenesulfonate, hexafluoroantimonate, hexafluoroarsenate, tetrachloroaluminate, tetrabromoaluminate, perchlorate, hydroxide anion, copper dichloride anion, ferric trichloride anion, zinc trichloride anion, and various lanthanum, potassium, lithium, nickel, cobalt, manganese, and other metal-containing anions.
Ionic liquids can also be synthesized by salt metathesis (salt metathesis), by acid-base neutralization, or by quaternary ammonification of selected nitrogen-containing compounds; or they are commercially available from several companies, such as Merck (Merck) (damschtatt, germany) or BASF (mantel olv, new jersey).
Representative examples of useful ionic liquids are described in sources such as J.chem.Tech.Biotechnol. [ J.Chem.Tech.Biotechnol. ], 68: 351-; ind. [ chemical industry ], 68: 249-; j. Phys. condensed Matter [ journal of physico-condensed materials ], 5 (supplement 34B): B99-B106 (1993); chemical and Engineering News, 3 months and 30 days, 1998, 32-37; J.Mater.chem. [ J.Chem. Material J. ], 8: 2627-; chem.rev. [ chemical review ], 99: 2071-; and US 2004/0133058; all of these documents are incorporated herein by reference.
In one embodiment, libraries of ionic liquids can be prepared, by way of example, by preparing various alkyl derivatives of a particular cation (e.g., a quaternary ammonium cation) and varying the associated anion (US20090131728 a1, incorporated by reference in its entirety). In another embodiment, diastereomers of the invention can be separated efficiently by cation exchange in a mixed mode adsorbent in a Solid Phase Extraction (SPE) procedure.
In one embodiment, the diastereomers can be separated by extractive distillation, wherein an adjuvant that changes the partial pressure of the various diastereomers to be separated to varying degrees allows the diastereomers to be readily separated by distillation in good yield. The separation can be accomplished using a fractionation column, preferably at about 10-3Low pressure of bar to about 1 bar (US 4874473A, US20070225505 a1, incorporated by reference in its entirety).
In one embodiment, reverse phase (RP-HPLC) and normal phase chromatographic (NP-HPLC) separations can be used to separate diastereomers of the invention. The columns that can be used for the Separation of enantiomers can be Primesep C, NUCLEOSIL, cellulose-based chiral HPLC columns, SHISEIDO chiral CD-Ph, etc. (Fekete et al, Comparative Study of diastereoisomers by HPLC Separation by high performance liquid chromatography ], chromatographhia [ chromatograms ], 57, No.3/4(2 months 2003), US 7119211B 2, the entire contents of which are incorporated by reference).
Adamantylamino-4-oxobutyrate derivatives
Using the amide and ester formation scheme described above, derivatives of compounds 50-52cn were prepared to obtain amide compounds 1001-1006 and ester compounds 1007-1009:
Figure GDA0002354989720001031
the 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;
the 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;
the 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 formulations
The compositions of the invention may be prepared by adding a compound of formula I, DERATINE, to a suitable solventTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMAnd dissolved therein. The solution thus obtained is added to a complex magnesium aluminum silicate to form a paste-like substance. Although the foregoing steps are performed at about room temperature, elevated temperatures may be used if desired. Then, sodium chloride and sodium saccharin were added and distributed evenly throughout the paste. Food coloring and flavoring materials may be incorporated into the system at any stage of the manufacturing process. In another embodiment, the soluble component is added to the compound of formula I, DERATINE, prepared in the first stepTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMAnd (3) solution. The paste thus obtained can be easily incorporated into conventional hard candy forming materials which in turn can be processed by conventional procedures into attractive, palatable buccal tablets each containing a uniformly distributed therapeutically effective amount of a compound of formula I, deravitineTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
Variations of the preparation methods presented in this case fall within the scope of the present invention. For example, in producing the compositions of the invention, racemic or enantiomerically pure compounds of formula I, DERATINE, may be preparedTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMAnd (2) compoundMagnesium aluminum silicate is mixed and then a suitable solvent is added thereto to form a paste. The sodium chloride and saccharin sodium may be added to the dextromethorphan-complex magnesium aluminum silicate mixture prior to forming the mixture into a paste. In the alternative, sodium chloride and sodium saccharin may be added to the paste. Again, suitable odorants and colorants may be added to the dry mixture or to the paste. In carrying out the present invention, any pharmaceutically acceptable organic solvent suitable for pharmaceutical use may be employed, and wherein the compound of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMIs soluble. Thus, for example, organic solvents such as propylene glycol, glycerol, 1, 3-butylene glycol, benzyl alcohol, and the like may be used. In an embodiment of the composition of the present invention, benzyl alcohol is used as saprodexTMThe solvent of (1).
Food coloring agents and food flavoring agents may be used to prepare the compositions of the present invention. Flavoring agents suitable for use include, for example, licorice, ginger, natural fruit extracts, and the like. As colorant we can use any color suitable for food and drugs. The amount of coloring agent and the amount of odorant used to formulate the compositions of the present invention can vary.
In one embodiment, the formulation contains about 0.3g to about 1.5g, about 1.0g of thickener; about 1g to about 10g, about 2.5g of 1, 2-propanediol as a co-solvent; about 0.12g to about 0.19g, or 0.15g of at least one paraben preservative, such as methyl paraben; about 0.05g to about 0.2g, or about 0.1g, of sorbic acid; about 30g to about 60g, or 40g of a sugar alcohol solution; about 0.05 to about 0.2g, or 0.1g, of artificial sweetener; an amount of the compound of formula I, DERATINE, yielding about 2.10g of the desired strengthTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMResin complex (to deliver equivalent to 60mg of compound of formula I, DERATINE in a 20ml adult 12-hour doseTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMThe amount of 1:6 complex required); and sufficient water to bring the volume to 100ml。
In another embodiment, suitable thickeners include: gum tragacanth; bentonite; gum arabic and lower alkyl ethers of cellulose (including hydroxy and carboxyloxy derivatives of cellulose ethers). Exemplary paraben preservatives are C1-C4 alkyl parabens, i.e., methyl, ethyl, propyl, and butyl parabens. In one embodiment, both methyl and propyl parabens are present in the formulation in a ratio of from about 2.5:1 to about 7.5:1 methyl paraben to propyl paraben. In another embodiment, the methyl and propyl paraben ratio is 4: 1.
In one embodiment, the artificial sweetener is a form of saccharin or aspartame. In one embodiment, the saccharin is sodium saccharin. In other embodiments, other known sweeteners may be substituted, such as the equivalent sweetening amounts of the sugar alcohol sorbitol.
In another embodiment, the formulation comprises a compound of formula I, DERATINE, in an amount sufficient to deliver an antitussive effective amount when administered in a dose every 12 hoursTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMSuch administration to a patient in need thereof of an amount of a resinate for a period of time of up to about 12 hours.
In one embodiment, the formulation comprises an adult dose of 20ml containing about 420mg of the resinate to deliver an equivalent of 60mg of the compound of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMWhen the drug to resin ratio is 1:6 and 2.10g of resinate is present per 100ml of formulation. The dose can be similarly modified to that known for administering dextromethorphan not complexed with resin, i.e. typically 15mg-30mg dextromethorphan hydrobromide per dose, 1 to 4 times a day, to S-20ml, one to two times a day.
In another embodiment, the formulation comprises a nontoxic NMDA receptor blocking substance according to the invention which is dextromethorphan ((+) -3-hydroxy-N-methylmorphinan), a compound of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMOr a derivative thereof, and saprodexterTMMixtures thereof and pharmaceutically acceptable salts thereof.
In another embodiment, the formulation contains a substance that blocks NMDA receptors, including dezocyclopine (5-methyl-10, 11-dihydro-5H-5, 10-methanone dibenz [ a, d ] [7] annulene), ketamine (2- (2-chlorophenyl) -2- (methylamino) cyclohex-1-one), magnesium, seofita ((2S, 4R) -4- (phosphonomethyl) piperidine-2-carboxylic acid), atifida ((E) -1- (3-ethylphenyl) -1-methyl-2- (naphthalen-1-yl) guanidine), felbamate (2-phenylpropane-1, 3-dimethyldicarbamate), phencyclidine (1- (1-phenylcyclohexyl) piperidine), Amantadine (1-aminoadamantane), memantine (3, 5 dimethylaminoadamantanone), 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-phosphonovaleric acid salt, (S) and (R)6- (1 Htetrazol-5-ylmethyl) decahydroisoquinoline-3-carboxylic acid, (S) -a-amino-5- (phosphonomethyl) [1, 19-diphenyl ] -3-propionic acid, and, (S) and (R) (6) -cis-4- (4-phenylbenzoyl) piperazine-2, 3-dicarboxylic acid, cis-4-phosphonomethyl-2-piperidinecarboxylic acid, 2R, 4R, 5S- (2-amino-4, 5- (1, 2-cyclohexyl) -7-phosphonoheptanoic acid), and cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, mixtures and pharmaceutically acceptable salts thereof. (US 5,891,885, Christie et al, Native N-Methyl-D-aspartate Receptors conjugation NR2A And NR2B Subunits havey pharmacological diagnosis comparative Antagonist Binding Sites [ N-Methyl-D-aspartate Receptors Containing NR2A And NR2B Subunits have pharmaceutically different Competitive Antagonist Binding Sites ], the journal Of pharmacological And Experimental Therapeutics, Vol.292, No.3, pp.1169-74 (2000), the entire contents Of which are incorporated by reference).
In another embodiment, the therapeutic composition comprises at least one additional pharmacologically active substance, for example, caffeine (stimulant), an antiemetic drug, such as metoclopramide, domperidone, belladonna alkaloids, and phenothiazines, such as chlorpromazine (chlorpromazine), prochlorperazine (prochlorperazine), and promethazine (promethazine), non-narcotic analgesics, such as acetaminophen (acetophen), or non-steroidal anti-inflammatory drugs, such as aspirin, diclofenac (diclofenac), difluorophenyl ether (diflusinal), etodolac (etodolac), fenbufen (fenbufen), fenoprofen (fenoprofen), flufenisal (flurbiprofen), ibuprofen (ibuprofen), indomethacin (indomethacin), ketotoloprofen (ketoprofen), ketoprofen (flufenamic acid), ketoprofen (ketoprofen), ketoprofen (fenamic acid), naproxen (meclofen), ketoprofen (fenamic acid), meclofenamic acid (fenamic acid), chlorpromazine (chlorpromazine), chlorpromazine (chlorpromazine), chlorp, Phenylbutazone (phenylbutazone), piroxicam (piroxicam), sulindac (sulindac), tolmetin (tolmetin), and zomepirac.
Synthesis of Compounds of the invention
All reactions were carried out under an argon atmosphere with anhydrous solvents unless otherwise indicated. Anhydrous Chloroform (CH)3Cl), dichloromethane (CH)2Cl2) Tetrahydrofuran (THF), ethyl acetate, DMF, DMSO, methanol, ethanol, and acetonitrile (CH)3CN) is purchased or prepared. All commercially available reagents were purchased and used without further purification. All commercially available reagents were purchased and used without further purification. The reaction was monitored by Thin Layer Chromatography (TLC) on a silica gel disk (Merck TLC silica gel 60F254) using UV light with PMA (ethanolic phosphomolybdic acid) or ANIS (ethanolic p-anisaldehyde) as a visual agent. Purification of the product was performed by column chromatography through silica gel 60 (0.060-0.200 mm). NMR spectra were obtained on Bruker AVANCE III 500MHz (Bruker Corporation, biler card, ma, usa) using residual undeuterized solvent or TMS (tetramethylsilane) as internal reference. High resolution mass spectrometry (HR-MS) was recorded using EI (Electron impact) on JEOL JMS-700(JEOL, Tokyo, Japan).
Example 1: dextromethorphan has been synthesized from benzylisoquinolines (with a planar structure) via a griwe's cyclization reaction (to give the corresponding morphinans, where the 1,2, 3, 4, 5, 6, 7, 8-octahydro-1- (4-methoxybenzyl) isoquinoline is converted to an N-formyl derivative, crystallized to an N-formyl morphinan, which formyl is reduced to an N-methyl group to give a 3-methoxy-17-methyl morphinan. Dextromethorphan is readily soluble in 96% ethanol and is substantially insoluble in water. Dextromethorphan can be a monochlorobromite monohydrate or bound to a polystyrene sulfonic acid based ion exchange resin. The specific optical rotation of dextromethorphan in water was +27.6 ° (20 ℃, sodium D-line).
Example 2: equimolar amounts of sarpogrelate (429.506g/mol) and dextromethorphan (271.40g/mol) were mixed in a suitable solvent, agitated and allowed to crystallize. The compound of formula I and dextromethorphan positive cation will form a hydrogen bond, form a complex and crystallize.
Example 3: to a solution of 54.28g dextromethorphan in one liter chloroform was added a solution of 85.9g sarpogrelate in chloroform at 70 ℃. The 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 yield d-3-methoxy-N-methylmorphinan 4- [ 1-dimethylamino-3- [2- [2- (3-methoxyphenyl) ethyl]Phenoxy radical]Propane-2-yl radical]Oxy-4-oxobutyrate and recrystallization from aqueous Dimethylformamide (DMF) to give 135g of the compound of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM。
Example 4: the components: 15g of the compound of formula I, DERATINETM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTM(ii) a 15g of glycerol tristearate; 100ml of carbon tetrachloride. Preparation: dissolving glycerol tristearate in warm carbon tetrachloride at 55-60 deg.C. Followed by the subsequent reaction of a compound of formula I, a derivative thereof, SARPODEXTMOr a derivative thereof is added to and suspended in the solution. The suspension was then spray dried using an inlet temperature of 90 ℃ and an outlet temperature of 40 ℃. Followed by subjecting the resulting coated compound of formula I, DERATINE, having an average particle size of about 10 to about 200 micronsTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMSuspended in the following aqueous carrier.
The components: 10.00g of gum tragacanth, USP; 1.20g methyl paraben, USP; 0.20g propyl paraben, USP; 0.30g sodium saccharin, USP; 3.00g sodium sulfonate, USP; 250.00mL sorbic acid; 1.00g methyl cellulose, 15 cps; 2.00mL of artificial blackcurrant; and 1000.00mL of distilled water.
The parabens, sodium saccharin, sodium sulfonate and sorbic acid are dissolved in a portion of distilled water that has been heated to 85 ℃. Then, tragacanth is added to this solution and uniformly dispersed. The dispersion was again heated and cooled, and then sorbitol solution, methyl cellulose in water solution and imitation blackcurrant were added with stirring to form the vehicle. The coated compound of formula I, DERATINE, is then driedTM、SARPOTINETM、SARPODEXTM、DERADEXTMOr DERAPHANTMAdd to the above carrier and mix until the particles are thoroughly wetted and uniformly dispersed.
The controlled drug release composition of the present invention is characterized by comprising 100 parts by weight of an organic polymeric material which is soluble in an organic solvent and insoluble in water; 5 to 60 parts by weight of a fat-soluble, low molecular weight release adjuvant; and 1 to 70 parts by weight of a drug.
In one embodiment, the polymeric material is biodegradable or biocompatible or both, by way of example, biodegradable aliphatic polyesters, or aliphatic poly (carbonates), poly (lactic acid), lactic acid-glycolic acid copolymers, poly (caprolactone), poly (hydroxybutyric acid), and the like.
In one embodiment, the release adjuvant is a carboxylic acid ester, monoester or diester of glycerol. In another embodiment, the release adjuvant is an ester of an organic acid selected from succinic acid, citric acid, tartaric acid, malic acid or the like, or is a mono-or diacetate of glycerol.
In one embodiment, the composition may further comprise a cell adhesion material or an endothelialization promoting agent on the surface of the therapeutic device.
In one embodiment, the present invention is a drug-releasable therapeutic device characterized by containing a composition of the present disclosure. The drug releasable medical device is disposed on a surfaceA layer of the composition is formed and contacted with a living body, or incorporated or left in a living body. The device comprises a stent, a catheter, a clip, an organ replacement medical device, a capsule sensor, or an artificial organ. The stent is in one embodiment used to treat a coronary stenosis and gradually release the composition from the surface. The release rate of the indwelling stent after 21 days is 1/103μg/mm2H to 1. mu.g/mm2H is used as the reference value. In addition, the stent of the present invention is characterized in that the drug to be gradually released is carried in the polymeric material coated on the surface of the metal forming the stent or in the porous stent base material.
The polymeric material coated on the surface of the stent is amorphous. The polymeric material coated on the surface of the stent is an amorphous biodegradable polymeric material. The polymeric material is poly (lactic acid) or lactic acid-glycolic acid copolymer, which is biodegradable. The polymeric material further comprises a release adjuvant that facilitates the release of the drug to be carried. The adjuvant for promoting drug release is tartrate or malate ester, or mono-or di-ester of glycerol. The surface of the metal forming the stent may be a porous body and the above-mentioned drug to be gradually released may be carried in the porous body. In one embodiment, the porous body has a pore size of 0.01nm to 300nm in diameter.
Example 5: optically pure saprophytic malate: malic acid is an integral part of many foods we eat daily. While it is found to be a naturally occurring organic compound in a variety of fruits, many people choose to take malic acid supplements to increase their overall health, as well as to treat various ailments. Nowadays, acids are the most commonly used food additives and preservatives. When used in appropriate amounts, it is a mild, relatively harmless acid. As a food supplement, it is generally considered beneficial for health and is present in large amounts in apple juice. However, just like taking any supplements, you should not exceed the recommended consumption.
(http:// www.newsmax.com/FastFeatures/metallic-acids-Benefits-Health-Supplements/2015/03/31/id/635519/, incorporated by reference). Natural organic compounds having asymmetric carbons generally exist as optically active materials and exhibit physiological activities significantly different from those of enantiomers.
Malic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or diastereomerically pure sapro malate (compounds 25-29), depending on the M1 and malic acid used, respectively. Racemic saprolac malate can be purified by crystallization and/or chiral chromatography to obtain diastereomerically pure saprolac malate.
Example 6: optically pure salt of salposmetinate: methionine (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5ml), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50ml) and saturated aqueous NaHCO3(30ml) dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexane: EtOAc) to yield racemic or diastereomerically pure salt of saprodontin (compounds 30-34), depending on the M1 and methionine used, respectively. Racemic saprotine may be purified by crystallization and/or chiral chromatography to obtain diastereomerically pure saprotine.
Example 7: optically pure saprophthalate: phthalic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol,1.0 equivalent) to CH2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield either racemic or optically pure saphthalate, depending on the M1 and phthalic acid used, respectively, to yield compounds 35-37. Racemic saprophthalate can be purified by crystallization and/or chiral chromatography to obtain diastereomerically pure saprophytic acid salt.
Example 8: optically pure saprodontic malonate: acetylsalicylic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sabo malonate, dependent on M1, to yield compounds 38-40, respectively. Racemic saprolegniate can be purified by crystallization and/or chiral chromatography to obtain optically pure saprolegniate.
Example 9: optically pure salpeter tyrosine salt: caseine salt (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5ml), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50ml) and saturated aqueous NaHCO3(30ml) dilution. The organic layer was separated and dried (Na)2SO4) Is filtered and mixed inConcentrating under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure saponarine salt, dependent on M1, to yield compounds 41-43, respectively. Racemic sartorine salt can be purified by crystallization and/or chiral chromatography to obtain optically pure sartorine salt.
Example 10: optically pure salt of salposon tryptophan: tryptophan (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine are added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5ml), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50ml) and saturated aqueous NaHCO3(30ml) dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure salt of safrole, dependent on M1, to yield compounds 44-46, respectively. Racemic saperchromate salt can be purified by crystallization and/or chiral chromatography to obtain optically pure saperchromate salt.
Example 11: optically pure sapelo maleate: maleic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sapelo maleate, dependent on M1, to yield compounds 47-49, respectively. Racemic sapelo maleate can be purified by crystallization and/or chiral chromatography to obtain optically pure sapelo maleate.
Example 12: optical systemSarpogrelate ester purified above: succinic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sarpogrelate, respectively, depending on M1, to yield compounds 50-52. Racemic sarpogrelate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpogrelate.
Example 13: optically pure sapropivalate: glutaric acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure saproleglutate, dependent on M1, to yield compounds 53-55, respectively. The racemic saproproleginate may be purified by crystallization and/or chiral chromatography to obtain optically pure saproproleginate.
Example 14: optically pure saproducic adipate: adipic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sapeaadipic acid salt, dependent on M1, to yield compounds 56-58, respectively. Racemic sapropolyadipate can be purified by crystallization and/or chiral chromatography to obtain optically pure sapropolyadipate.
Example 15: optically pure salt of saproprolegenin: pimelic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine are added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure saboheptanedioate, dependent on M1, to yield compounds 59-61, respectively. The racemic saproproleptate can be purified by crystallization and/or chiral chromatography to obtain optically pure saproproleptate.
Example 16: optically pure saproprodate salt: sebacic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sabo sebacate, dependent on M1, to yield compounds 62-64, respectively. Racemic saprophosporol acid salt can be prepared by crystallization andand/or chiral chromatographic purification to obtain the optically pure sapropargonate.
Example 17: optically pure sapropham formate: formic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sabofoate, dependent on M1, to yield compounds 65-67, respectively. The racemic sapropham formate can be purified by crystallization and/or chiral chromatography to obtain optically pure sapropham formate.
Example 18: optically pure saprophytic acetate salt: acetic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure saproacetate, dependent on M1, to yield compounds 68-70, respectively. The racemic saproprolac acetate can be purified by crystallization and/or chiral chromatography to obtain optically pure saproprolac acetate.
Example 19: optically pure sapropropionate: propionic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2Stirring in (5mL)Heating the solution to 25 deg.C for 30min, stirring the mixture at 25 deg.C for 18-24 h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sapropropionate, dependent on M1, to yield compounds 71-73, respectively. The racemic sapropropionate can be purified by crystallization and/or chiral chromatography to obtain optically pure sapropropionate.
Example 20: optically pure saprobutyrate: butyric acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sabobutyrate, dependent on M1, to yield compounds 74-76, respectively. The racemic saprodate can be purified by crystallization and/or chiral chromatography to obtain optically pure saprodate.
Example 21: optically pure sapropivalate: pentanoic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine are added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sapentanoate, each of which was taken separatelyDepending on M1, compounds 77-79 were generated. The racemic sapropivalate may be purified by crystallization and/or chiral chromatography to obtain optically pure sapropivalate.
Example 22: optically pure salt of saproproducic acid: hexanoic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure saproxacin salt, dependent on M1, yielding compounds 80-82, respectively. The racemic saproprodate can be purified by crystallization and/or chiral chromatography to obtain an optically pure saprodate.
Example 23: optically pure salt of saproproleptate: n-heptylic (heptanoic) acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sapro-heptanoate, dependent on M1, to yield compounds 62-64, respectively. The racemic saproleptate can be purified by crystallization and/or chiral chromatography to obtain optically pure saproleptate.
Example 24: optically pure salpospora octanoate: octanoic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to the racemate or para-isomer at 0 deg.CEnantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sabot octanoate, dependent on M1, yielding compounds 86-88, respectively. The racemic saprophytic acid salt can be purified by crystallization and/or chiral chromatography to obtain optically pure saprophytic acid salt.
Example 25: optically pure sapropargonate: nonanoic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine are added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sabonolate, dependent on M1, yielding compounds 89-91, respectively. The racemic sapropargonate salt can be purified by crystallization and/or chiral chromatography to obtain an optically pure sapropargonate salt.
Example 26: optically pure sapropargonate: decanoic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. Purifying by column chromatography (silica gel, hexane: EtOAc)The crude residue was purified to give racemic or optically pure salt of sapindocaprate, dependent on M1, to give compounds 92-94, respectively. The racemic saproridum decanoate can be purified by crystallization and/or chiral chromatography to obtain an optically pure salt of saproridum decanoate.
Example 27: optically pure saprophytic acid salt: oxalic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure saproleglate, dependent on M1, to yield compounds 95-97, respectively. Racemic saparate can be purified by crystallization and/or chiral chromatography to obtain optically pure saparate.
Example 28: optically pure saprophthalate: isophthalic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sabo-isophthalate, dependent on M1, yielding compounds 98-100, respectively. The racemic sapropoisophthalate may be purified by crystallization and/or chiral chromatography to obtain optically pure sapropoisophthalate.
Example 29: optically pure saprophthalate: at the temperature of 0 ℃ and under the temperature of 0 ℃,terephthalic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sapro-terephthalate, dependent on M1, yielding compound 101-103, respectively. The racemic saprophthalate can be purified by crystallization and/or chiral chromatography to obtain optically pure saprophthalate.
Example 30: optically pure saprophytic salicylate: salicylic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc) to yield racemic or optically pure sapercosan salt, dependent on M1, yielding compound 104-106, respectively. The racemic saligenin salts can be purified by crystallization and/or chiral chromatography to obtain optically pure saligenin salts.
Example 31: optically pure sapropargyl salicylate: acetylsalicylic acid (0.55mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55mmol, 1.1 equiv.) and 4-dimethylaminopyridine were added to racemic or enantiomerically pure M1(0.50mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(5mL), heating to 25 ℃ for 30min, stirring the mixture at 25 ℃ for 18 to 24h, and adding CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Purification of the crude residue by column chromatography (silica gel, hexane: EtOAc) to yield racemic or optically pure saproreacetylsalicylate, dependent on M1, to yield compound 107-acetyl salicylate, respectively racemic saproreacetate can be purified by crystallization and/or chiral chromatography to obtain optically pure saproreacetate (Park et al, inactivation of α -Aminoalcohol (Sarpoglate M1) [ α -amino alcohol (Sarpogrelate M1) ]aspirin]Molecules [ Molecules ]]21(9), 1126 (2016); incorporated by reference in its entirety).
Example 32: at 25 ℃ on M1(0.50mmol, 1.0 equiv.) in CH2Cl2(5mL) or CH3To a stirred solution in CN (5mL) was added aspirin (0.55mmol, 1.1 equiv.) and 1, 1' -carbonyldiimidazole (CDI, 0.60mmol, 1.2 equiv.). The mixture was stirred for 12h and CH was used2Cl2(40ml) and saturated aqueous NH4Cl (25 mL). The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexane: EtOAc) to obtain compound 107. Racemic saprorotalic salicylate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure saprorotalic salicylates 108 and 109.
Example 33: to a stirred solution of M1(0.50mmol, 1.0 equiv.) in THF (5mL) was added acetylsalicylic acid (0.75mmol, 1.5 equiv.), triphenylphosphine (0.75mmol, 1.5 equiv.) and diisopropyl azodicarboxylate (DIAD, 0.75mmol, 1.5 equiv.) at 0 deg.C. The mixture was stirred at the same temperature for 1h and the solvent was removed under reduced pressure. The residue was taken up in EtOAc (30mL) and saturated aqueous NH4Cl (15ml) dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexane: EtOAc) to obtain compound 107. Racemic saproproleglic salicylate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure compoundPure sapropargyl salicylate 108 and 109.
Example 34: at 0 deg.C, p-acetylsalicylate (1.00mmol, 2.0 equiv.) in CH2Cl2To a stirred solution (5mL) was added oxalyl chloride (2M in CH)2Cl20.60mL, 1.20mmol, 2.4 equiv.) and dimethylformamide (DMF, 8.0. mu.L, 0.10mmol, 0.2 equiv.). Subsequently, the temperature was gradually increased to 25 ℃. The mixture was stirred at the same temperature for 12 h. Subsequently, M13(0.50mmol, 1.0 equiv.) in CH2Cl2To another stirred solution in (5mL) was added pyridine (0.24mL, 3.0mmol, 6.0 equiv.) and the previously prepared aspirin chloride solution. The mixture was stirred for a further 12h and with CH2Cl2(50mL) and saturated aqueous NaHCO3(30mL) for dilution. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexane: EtOAc) to obtain compound 107. Racemic saprorotalic salicylate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure saprorotalic salicylates 108 and 109.
Example 35: ac was added to a stirred solution of salicylate (241mg, 0.536mmol, 1.0 equiv.) in pyridine (2ml) at 0 deg.C2O (76. mu.L, 0.81mmol, 1.5 equiv.). The temperature was increased to 25 ℃. The mixture was stirred at the same temperature for 12 h. Subsequently, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (30ml) and with H2O (10mL) wash. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes: EtOAc ═ 1:2) to afford compound 107(239mg, 90% yield). Racemic saprorotalic salicylate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure saprorotalic salicylates 108 and 109.
Example 36
1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propane-2-yl 2-acetoxybenzoate (compound 163): a colorless oil; rf0.25 (silica gel, hexanes: EtOAc1: 1);1H-NMR(500MHz，CDCl3):δ＝7.99(dd，J1＝1.6Hz，J2＝7.9Hz，1H)，7.53–7.50(m，1H)，7.18(ddd，J1＝1.1Hz，J2＝7.9Hz，J3＝7.9Hz，1H)，7.18–7.14(m，2H)，7.10–7.06(m，2H)，6.89–6.86(m，2H)，6.77(d，J＝7.7Hz，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；13C-NMR(125MHz，CDCl3) 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): with C29H33NO6Calculate [ M+]: 491.2308, found 491.2310.
Example 37
1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl acetate (compound 164): a colorless oil; rf0.19 (silica gel, hexanes: EtOAc1: 2);1H-NMR(500MHz，CDCl3):δ＝7.21(t，J＝7.8Hz，1H)，7.16(ddd，J1＝1.7Hz，J2＝7.8Hz，J3＝7.8Hz，1H)，7.11(dd，J1＝1.7Hz，J2＝7.4Hz，1H)，6.87(ddd，J1＝1.0Hz，J2＝7.4Hz，J3＝7.4Hz，1H)，6.84(t，J＝8.9Hz，2H)，6.78(t，J＝1.9Hz，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；13C-NMR(125MHz，CDCl3):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; hrms (ei): with C22H29NO4Calculate [ M+]: 371.2097, found 371.2095.
Example 38
Figure GDA0002354989720001161
1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl-2-hydroxybenzoate (compound 165) as a colorless oil; rf0.23 (silica gel, hexanes: EtOAc 2: 1);1H-NMR(500MHz，CDCl3):δ＝10.69(s，1H)，7.83(dd，J1＝1.7Hz，J2＝8.0Hz，1H)，7.44–7.41(m，1H)，7.20–7.16(m，2H)，7.11(dd，J1＝1.6Hz，J2＝7.4Hz，1H)，6.96(dd，J1＝0.9Hz，J2＝8.4Hz，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；13C-NMR(125MHz，CDCl3) 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): with C27H31NO5Calculate [ M+]: 449.2202, found 449.2200.
Example 39
Figure GDA0002354989720001162
2- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propyl 2-ethoxybenzoate (compound 166): a colorless oil; rf0.20 (silica gel, hexanes: EtOAc1: 1);1H-NMR(500MHz，CDCl3):δ＝7.98(dd，J1＝1.6Hz，J2＝7.8Hz，1H)，7.55(ddd，J1＝1.7Hz，J2＝7.8Hz，J3＝7.8Hz，1H)，7.28(ddd，J1＝1.1Hz，J2＝7.7Hz，J3＝7.7Hz，1H)，7.21–7.17(m，2H)，7.13(dd，J1＝1.5Hz，J2＝7.4Hz，1H)，7.11(dd，J1＝1.0Hz，J2＝8.1Hz，1H)，6.92–6.88(m，2H)，6.81(d，J＝7.7Hz，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(125MHz，CDCl3) Delta-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): with C29H33NO6Calculate [ M+]: 491.2308, found 491.2309.
Example 40: deuterating the H-compound to form the D-compound: h-compound (compound of the invention, about 1.25mmol) was dissolved in 3mL of 100mM pH 7 deuterated phosphate buffered saline (D-PBS) at 9.00mL D2O was diluted to a final concentration of 25 mM. 100mM D-PBS pH 7(pH paper) buffer was prepared by mixing 259.5mg K3PQ4Dissolved in D2O (12.00ml) and added dissolved in D2264 μ L of 20% DCl O. The reaction mixture was shaken at room temperature for 11 days while monitoring hydrogen/deuterium (HID) with LC/MS to complete the exchange.
A small scale post-treatment was performed to prepare the hydrochloride salt of the deuterated compound. Thus, 1.2ml aliquots of the reaction mixture (10% of the total volume) were treated with 5ml saturated NaHCO3Diluted and extracted with EtOAc (3 × 5 mL). The organic layer was dried over Na2SO4 and filtered. Evaporation of the solvent gave 20mg of a colorless oil which was converted to the HCl salt by addition of a few drops of 4M HCl (in dioxane). The salt was triturated with ether and the solvent was evaporated, giving the deuterated compound the HCl salt. A9.6 mL aliquot (80% of the total volume) was diluted with 40mL of saturated NaHCO3Diluted and extracted once with EtOAc (200 mL). The organic layer was washed with Na2SO4And (5) quickly drying. The solvent was evaporated to give the compound, which was stored in a freezer.
Example 41: preparing crude sarpogrelate hydrochloride: 250ml of 1-dimethylamino-3- [2- [2- (3-methoxyphenyl) ethyl ] phenoxy ] -2-propanoic acid hydrochloride 13.7g and 25ml of water were placed in a single-necked flask and dissolved with stirring. The solution was treated with 20% aqueous sodium hydroxide to a pH of about 9 to about 14 and extracted with 30mL of toluene, and the organic layer was concentrated at 50 ℃ under reduced pressure to give a brown oil which was dissolved in 30mL of tetrahydrofuran. Subsequently, 4.5g of butyric anhydride was added and heated to reflux while stirring for about 1 to about 4 hours, and concentrated to dryness under reduced pressure at 40 ℃. Ethyl acetate (25mL) was added to dissolve the residue, and saturated hydrogen chloride dissolved in ethyl acetate solution was added dropwise to adjust PH 1 or lower while stirring for about 50-60min to obtain a crude wet product of sarpogrelate hydrochloride, which was dried at 45-55 ℃ under reduced pressure (-0.08-0. l MPa) to give 14.7g of crude sarpogrelate hydrochloride in 86% yield with HPLC purity of 98.6%.
Example 42: purification of the crude sarpogrelate hydrochloride: dissolving 5g of crude sarpogrelate hydrochloride in butanone (20mL), heating while stirring until the crude sarpogrelate hydrochloride is dissolved, refluxing for 20-30 min, cooling to 25-35 ℃, continuing to stir for 40-60 min, filtering, rinsing a filter block with a small amount of methyl ethyl ketone, giving a white loose solid, drying at 55-65 ℃ under reduced pressure for 24h, giving 4.6g of sarpogrelate hydrochloride, the yield is 92%, and the HPLC purity is 99.9%.
Example 43: purification of the crude sarpogrelate hydrochloride: heating 5g of crude sarpogrelate hydrochloride placed in 30ml of butanone while stirring until dissolved and refluxing for 20-30 min, cooling to 25-35 ℃, incubating while stirring for 40-60 min, filtering, rinsing the filter cake with a small amount of methylethylketone, giving a white loose solid, drying at 55-65 ℃ under reduced pressure for 24h, giving 4.55 sarpogrelate hydrochloride in 91% yield and 99.7% HPLC purity.
Example 44: purification of the crude sarpogrelate hydrochloride: heating 5g of crude sarpogrelate hydrochloride placed in 40ml of butanone while stirring until dissolving and refluxing for 20-30 min, cooling to 25-35 ℃, incubating while stirring for 40-60 min, filtering, rinsing the filter cake with a small amount of methylethylketone, giving a white solid, drying at 55-65 ℃ under reduced pressure for 24h, giving 4.5g of sarpogrelate hydrochloride, the yield is 90%, and the HPLC purity is 99.8%.
Example 45: purification of the crude sarpogrelate hydrochloride: the crude product is sarpogrelate hydrochloride 5g, butanone 20ml is added, stirring is carried out while heating until the crude product is dissolved and reflows for 20-30 min, the mixture is slowly cooled to room temperature while stirring, the mixture is kept stand at-10 ℃ for crystallization, filtering is carried out, a filter block is rinsed by a small amount of methyl ethyl ketone, a white fluffy solid is given, drying is carried out for 24h under reduced pressure at 55-65 ℃, sarpogrelate hydrochloride 4.62g is given, the yield is 92.4%, the HPLC purity is 99.2%, and the maximum single substance content is 0.09%.
Sarpogrelate ester enantiomers: enantiomers of the compounds described herein can be separated using chromatographic techniques. The preparation of isolated enantiomers by Chromatography on Chiral Stationary Phases (CSP) is well established as an alternative to more traditional methods, such as the mirror-selective synthesis and enzymatic conversion (Francotte, Enantioselective Chromatography a power functional alternative for the preparation of drug enantiomers), Journal of Chromatography A [ Journal of Chromatography A ], volume 906, stages 1-2, page 379-, journal of Chromatography A [ Journal of Chromatography A ], vol.906, pp.3-33, stages 1-2 (1/12/2001); miller et al, Chromatographic resolution of the enantiomers of the pharmaceutical intermediates from the milligram to the kilogram scale [ Chromatographic separation of enantiomers of pharmaceutical intermediates on a milligram to kilogram scale ], Journal of chromatography A [ Journal of chromatography A ], Vol.849, No. 2, p.309-317 (23.7.1999); andersson et al, Preparative, chiral chromatographic resolution of enantiomers in drug discovery, Journal of Biochemical and biophysical Methods, Vol.54, pp.1-3, pp.11-23 (12/31/2002); pirkle et al, chapter 6 Separation of Enantiomers by liquid chromatography, asymmetry Synthesis, pages 87-124, Vol.1: Analytical Methods of the major and organic Synthesis used to determine enantiomeric ratios, by Morrison (ed.), Elsevier (Elsevier), (12.2.2012); incorporated by reference in its entirety). The racemates of the present invention can be resolved by this technique from the analytical to preparative scale.
Simulated moving bed chromatography can be used to separate enantiomers of the compounds of the invention, on all production scales from laboratory to pilot plant (Juza et al, Simulated moving-bed chromatography and iterative to technology [ Simulated moving bed chromatography and its use in chiral technology ], trends Biotechnology [ Biotechnology trends ], Vol.18, No.3, p.108-118 (3.1.2000), the entire contents of which are incorporated by reference).
Example 46: separation of enantiomer of sarpogrelate hydrochloride ((-) -4- ((1- (dimethylamino) -3- (2- (3-ethoxyphenethyl) phenoxy) propan-2-yloxy) -4-oxobutanoic acid hydrochloride)
Figure GDA0002354989720001181
C183.5 μm, 2.1 × 50mm column separation, using mobile phase: gradient elution from 10% MeCN (with 0.01% TFA) to 95% MeCN (with 0.01% TFA) at a flow rate of 0.5ml/min gave 5.30mg of enantiomer (99% HPLC purity) at UV 254 nm. NMR 400MHz1H-NMR (C0300, ppm)7.20-7.14(m, 2H)7.11(dd, J ═ 7.4, 1.6Hz, 1H)6.94-6.87(m, 2H)6.79-6.71(m, 3H)5.70-5.62(m, 1H)4.18(dd, J ═ 10.6, 4.1Hz, 1H)4.15(dd, J ═ 10.6, 4.7Hz, 1H)3.75(S, 3H)3.70(dd, J ═ 13.8, 10.1Hz, ddh) 3.54(dd, J ═ 13.8, 2.3Hz, 1H)2.98(S, 6H)2.96-2.77(m, 4H) 2.76-2H (m, 4H) 2.53(m, 4H). ESI-MS, M/z) 429[ M + H]+. melting point (DEG C) 155-156 DEG optical rotation, α [ D ]]:-20.0(c 0.33，MeOH)。
Example 47: dextromethorphan malate: the free base dextromethorphan (0.05 mol) was dissolved in 20ml of acetone, the solution was added to a solution of malic acid (0.05 mol) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 48: dextromethorphan methionine salt: the free base dextromethorphan (0.05 mol) is dissolved in 20ml of acetone, the solution is added to a solution of methionine or N-acylmethionine (0.05 mol) in 60ml of hot water, and the reaction mixture is then cooled, the crystals are isolated by filtration and dried.
Example 49: dextromethorphan phthalate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of phthalic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 50: dextromethorphan malonate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of malonic acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 51: dextromethorphan caseinate: the free base dextromethorphan (0.05 mol) was dissolved in 20ml of acetone, the solution was added to a solution of tyrosine or N-acyltyrosine (0.05 mol) in 60ml of hot water, and then the reaction mixture was cooled, the crystals were isolated by filtration and dried.
Example 52: dextromethorphan tryptophan salt: the free base dextromethorphan (0.05 mol) was dissolved in 20ml of acetone, the solution was added to a solution of tryptophan or N-acyltryptophan (0.05 mol) in 60ml of hot water, and then the reaction mixture was cooled, the crystals were isolated by filtration and dried.
Example 53: dextromethorphan maleate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of maleic acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and the crystals were isolated by filtration and dried.
Example 54: dextromethorphan succinate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of succinic acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 55: dextromethorphan glutarate/glutamate: the free base dextromethorphan (0.05 mol) is dissolved in 20ml of acetone, the solution is added to a solution of glutaric acid, glutamic acid or N-acyl glutamic acid (0.05 mol) in 60ml of hot water, and the reaction mixture is then cooled, the crystals are isolated by filtration and dried.
Example 56: dextromethorphan adipate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of adipic acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 57: dextromethorphan pimelate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of pimelic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 58: dextromethorphan sebacate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of sebacic acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 59: dextromethorphan formate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of formic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 60: dextromethorphan acetate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml acetone, the solution was added to a solution of acetic acid (0.05 moles) in 60ml hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 61: dextromethorphan propionate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of propionic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, and the crystals were isolated by filtration and dried.
Example 62: dextromethorphan butyrate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of butyric acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 63: dextromethorphan valerate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of valeric acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 64: dextromethorphan caproate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of hexanoic acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 65: dextromethorphan heptanoate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of n-heptylic (heptylic) acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, the crystals were isolated by filtration and dried.
Example 66: dextromethorphan octanoate: the free base dextromethorphan (0.05 mol) was dissolved in 20ml of acetone, the solution was added to a solution of octanoic acid (0.05 mol) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 67: dextromethorphan nonanoate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of pelargonic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, the crystals were isolated by filtration and dried.
Example 68: dextromethorphan caprate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of decanoic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, and the crystals were isolated by filtration and dried.
Example 69: dextromethorphan oxalate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of oxalic acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 70: dextromethorphan isophthalate: the free base dextromethorphan (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of isophthalic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, and the crystals were isolated by filtration and dried.
Example 71: dextromethorphan terephthalate: the free base dextromethorphan (0.05 moles) was dissolved in 20ml of acetone, the solution was added to a solution of terephthalic acid (0.05 moles) in 60ml of hot water, and then the reaction mixture was cooled, and the crystals were isolated by filtration and dried.
Example 72: dextromethorphan salicylate: the free base (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of salicylic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, and crystals were isolated by filtration and dried.
Example 73: dextromethorphan acetylsalicylate: the free base (0.05 mole) was dissolved in 20ml of acetone, the solution was added to a solution of acetylsalicylic acid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, the crystals were isolated by filtration and dried.
Examples 74 to 96: diacid addition salts of dextromethorphan and a compound selected from the group consisting of compounds of formula I comprising FDic and FDId (compound 219-269): the free base (FDIc or FDId) (0.25 mole) and dextromethorphan (0.25 mole) were dissolved in 20ml of acetone, the solution was added to a solution of diacid or triacid (0.05 mole) in 60ml of hot water, and then the reaction mixture was cooled, the crystals were isolated by filtration and dried. Diacids and triacids include, but are not limited to, adipic acid, aspartic acid, N-acyl aspartic acid, citric acid, fumaric acid, galactonic acid, glutaric acid, glutamic acid, N-acyl glutamic acid, glucaric acid (sugar acid), malic acid, maleic acid, mannonic acid, mucic acid, oxalic acid, pimelic acid, phthalic acid, isophthalic acid, terephthalic acid, rhamnose acid, sebacic acid, succinic acid, and tartaric acid. Thus, addition salts are formed, for example:
example 74, (FDIc or FDId) and the adipic acid addition salt of dextromethorphan;
example 75, an aspartic acid addition salt of (FDIc or FDId) and dextromethorphan;
example 76, the N-acyl aspartic acid addition salt of (FDIc or FDId) and dextromethorphan;
example 77, (FDIc or FDId) and the citric acid addition salt of dextromethorphan;
example 78, a fumaric acid addition salt of (FDIc or FDId) and dextromethorphan;
example 79, the galacturonic acid addition salt of (FDIc or FDId) and dextromethorphan;
example 80, the glutaric acid addition salt of (FDIc or FDId) and dextromethorphan;
the glutamic acid addition salt of example 81, (FDIc or FDId) and dextromethorphan;
example 82, the N-acyl glutamic acid addition salt of (FDIc or FDId) and dextromethorphan;
example 83, a glucaric acid (sugar acid) addition salt of (FDIc or FDId) and dextromethorphan;
example 84, (FDIc or FDId) and the malic acid addition salt of dextromethorphan;
example 85, (FDIc or FDId) and the maleic acid addition salt of dextromethorphan;
example 86, (FDIc or FDId) and the mannonic acid addition salt of dextromethorphan;
example 87, a mucic acid addition salt of (FDIc or FDId) and dextromethorphan;
example 88, (FDIc or FDId) and the oxalic acid addition salt of dextromethorphan;
example 89, the pimelic acid addition salt of (FDIc or FDId) and dextromethorphan;
example 90, (FDIc or FDId) and the phthalic acid addition salt of dextromethorphan;
example 91, (FDIc or FDId) and the isophthalic acid addition salt of dextromethorphan;
example 92, (FDIc or FDId) and the terephthalic acid addition salt of dextromethorphan;
example 93, (FDIc or FDId) and the rhamnose acid addition salt of dextromethorphan;
sebacic acid addition salt of example 94, (FDIc or FDId) and dextromethorphan;
example 95, (FDIc or FDId) and the succinic acid addition salt of dextromethorphan;
example 96, (FDIc or FDId) and the tartaric acid addition salt of dextromethorphan;
example 97, compound 901, ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
example 98, compound 902, ((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
example 99, compound 903, (((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
example 100, compound 904, ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3, 3-dimethylbutan-2-yl) (R) -fluorophosphate;
example 101, compound 905, sec-butyl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
example 102, compound 906, sec-butyl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
example 102, compound 907, O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
example 103, compound 908, O- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
example 104, compound 909, O- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
example 105, compound 910, O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- ((1, 3-dioxoisoindol-2-yl) methyl) (dimethyl-l 3-oxyalkyl) dithiophosphinate;
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-l 3-oxyalkyl) dithiophosphinate;
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-l 3-oxyalkyl) dithiophosphinate;
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) methylphosphate;
example 109, compound 914, (E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenylethyl) phenoxy) propan-2-yl) oxy) methyl) methylphosphonate;
example 110, compound 915, (E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenylethyl) phenoxy) propan-2-yl) oxy) methyl) methylphosphonate;
example 111, compound 916, O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
example 112, compound 917, O- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
example 113, compound 918, O- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
example 114, compound 919, O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
example 115, compound 920, O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
example 116, compound 921, O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
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;
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;
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;
example 120, compound 925, S- ((tert-butylthio) methyl) O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
example 121, compound 926, S- ((tert-butylthio) methyl) O- (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
example 122, compound 927, S- ((tert-butylthio) methyl) O- (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
example 123, compound 928, O- (4- ((4- ((((((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
example 124, compound 929, O- (4- ((4- (((((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
example 125, compound 930, O- (4- ((4- (((((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
example 126, compound 931, ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
example 127, compound 932, ((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
example 128, compound 933, (((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
example 129, compound 934, ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl (2, 2, 2-trichloro-1-hydroxyethyl) phosphonate;
example 130, compound 935, (((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl (2, 2, 2-trichloro-1-hydroxyethyl) phosphonate;
example 131, compound 936, (((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl (2, 2, 2-trichloro-1-hydroxyethyl) phosphonate;
example 132, the compound 937, 2-chloro-1- (2, 4, 5-trichlorophenyl) ethenyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
example 133, compound 938, 2-chloro-1- (2, 4, 5-trichlorophenyl) ethenyl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
example 134, the compound 939, 2-chloro-1- (2, 4, 5-trichlorophenyl) vinyl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
example 135, compound 940, O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphoramide salt;
example 136, compound 941, O- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacethylthiophosphamide salt;
example 137, compound 942, O- (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphoramide salt;
example 138, compound 943, (O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthio-phosphorus) anhydride;
example 139, compound 944, (O- (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthio) anhydride;
example 140, compound 945, (O- (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthio) anhydride;
Example 141, compound 946, O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphoramide salt;
example 142, compound 947, O- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacethylthiophosphamide salt;
example 143, compound 948, O- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacethylthiophosphamide salt;
example 144, compound 949, 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, compound and methane (1: 1);
example 145, compound 950, 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 compound with methane (1: 1);
example 146, compound 951, 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 compound with methane (1: 1);
example 147, compound 952, 2-chloroethyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
example 148, compound 953, 2-chloroethyl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
example 149, compound 954, 2-chloroethyl ((((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
example 150, compound 955, 3-chlorobutan-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
example 151, compound 956, 3-chlorobutan-2-yl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
example 152, compound 957, 3-chlorobutan-2-yl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
example 153, compound 958, ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
example 154, compound 959, (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
example 156, compound 960, (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
example 157, compound 961, 2-chloroethyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
example 158, compound 962, 2-chloroethyl ((((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
example 159, compound 963, 2-chloroethyl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - ((((chlorofluoromethylene) amino) oxy) fluorophosphate;
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;
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;
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;
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;
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;
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.
Example 166, compound 970, ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate.
Example 167, compound 971, (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
example 168, compound 972, (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylmethyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate.
Example 169, the compound 973, 4- (tert-butyl) -2-chlorophenyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate, compound with methane (1: 1);
example 170, compound 974, 4- (tert-butyl) -2-chlorophenyl ((((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate compound with methane (1: 1).
Example 171, compound 975, 4- (tert-butyl) -2-chlorophenyl ((((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate compound with methane (1: 1).
Example 172, compound 976, ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate;
example 173, compound 977, (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate.
Example 174, compound 978, (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate.
Example 175, the fumarate salt of compound 829((2, (-) - [1R,2S,4R ] -2- (2-dimethylaminoethoxy) -2-phenyl-1, 7, 7-trimethylbicyclo [2.2.1] heptane) fumarate (US 4,342,762A; Lad a nyi L et al, Stereochemistry and anticancer reagent, deramciclane fumarates [ Stereochemistry and enantiomeric purity of the novel anxiolytic agent deramciclane fumarate ]. Chirality [ Chirality 11:689-93(1999) ] incorporation of compound 829 can be prepared by a three-step synthesis scheme using a readily available and low cost starting material (camphor) having a very high enantiomeric purity (> 99.9%), to 100ml anhydrous xylene, 3.9g (0.1g atom) of potassium metal, and the mixture was reacted with 23.04g (0.1 mole) (+) -2-phenyl-1, 7, 7-trimethyl-bicyclo (2,2, l) heptan-2-ol with vigorous stirring. When the formation of hydrogen stops, a solution of 10.3g (0.11 mole) of 1-dimethylamino-2-chloro-ethane in 30ml of anhydrous xylene is introduced with further stirring. The reaction mixture is kept at 100 ℃ for 6 hours and then washed three times with 50ml of water and extracted with a solution of 15g (0.1 mol) of tartaric acid in 80ml of water or with an aqueous solution of 0.11 mol of dilute hydrochloric acid. The aqueous phase was made basic to pH 10 with 20% aqueous potassium hydroxide solution under cooling (at 0 to 5 ℃). The base separated as an oil was extracted with diethyl ether. After distilling off the solvent, the residue is purified by fractional distillation in vacuo or is used for the formation of salts. Yield: 25.2g (D.6%) of a pale yellow oil, BP: 131 ℃ -135 ℃/26.7Pa, hydrogen fumarate, m.p.: 180-182 ℃. Chiral resolution was done by HPLC at room temperature with Chiralcel OD (250X 4.6 mm; 10 μm) and hexane-ethanol (99.5: 0.5) as the mobile phase. The chemical formula is as follows: c24h35no5. molecular weight: 417.55. elemental analysis: calculated values: c: 69.03%, H: 8.45%, N: 3.35%, found value: c: 69.05%, H: 8.59%, N: 3.44 percent;
compound 829 is a clinically relevant dose of bis-5-HT2A/5-HT2CInverse agonists of receptors and do not induce down-regulation of these receptors (EP et al, Deramciclane, a reactive antiviral drug, is aspertonin 5-HT2C receptor inhibitor but genes to inhibitor 5-HT2C receptor-regulation [ putative anxiolytic drug Deramciclane is a serotonin 5-HT2C receptor inverse agonist, but is not capable of inducing down-regulation of the 5-HT2C receptor]Psychopharmacology [ Psychopharmacology ]](1998)136:99-104). Deramciclane vs dopamine D2The Receptor selectivity is at least 10 times (Gacs-lyi et al, Receptor binding profile and antianxietic activity of Receptor binding-type activity of deramciclane (EGIS-3886) in animal models]Drug Dev Res [ Drug development research](1997)40:333-348). Extensive evaluation of compound 829 in the dopaminergic model did not reveal any functional significance of these receptor binding data. The compound 829 was not found to elevate prolactin-at least within a dose range encompassing therapeutically relevant exposures (Laine K et al, Effect of the novel anxiolytic drug deramciclane on the pharmacological kinetics and pharmacodynamics of the CYP3a4 probe drug buspirone [ Effect of novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of CYP3a4 probe drug buspirone ]]Eur JClin Pharmacol [ European journal of clinical pharmacology](2003)59:761-766)。
Compound 829 has been extensively characterized preclinically and there is a large body of evidence suggesting the pharmacokinetic activity of one or more CNS targets for deramciclane. Gacs-lyi and colleagues (Gacs-lyi et al, Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animalmodels]Drug Dev Res [ drug development research](1997)40:333-2A/5-HT2CReceptor reversalAn agonist. The N-demethyl derivative of compound 829 is a biologically active metabolite having similar characteristics to compound 829.
Targeting of Compound 829 to 5-HT in the CNS2AThe receptor capacity has been shown in two animals (EP et al, Deramciclane, a reactive antiviral drug, is a serotonin 5-HT2C receptor antagonist drugs to indicator 5-HT2C receptor down-regulation [ putative anxiolytic drug Deramciclane is a serotonin 5-HT2C receptor inverse agonist, but is not capable of inducing down-regulation of the 5-HT2C receptor]Psychopharmacology [ Psychopharmacology ]](1998)136:99-104) and humans (Kanerva H et al Brain 5-HT2A receptor occupancy of deramcrine in humans after a single oral administration-positron emission tomography study]Psychopharmacology [ Psychopharmacology ]](1999)145:76-81) was directly demonstrated.
Targeting of Compound 829 to 5-HT in the CNS2AThe receptor capacity has been exploited [3H](results of Meshuergot binding to choroid plexus in rats
Figure GDA0002354989720001272
EP et al, Deramciclane, a reactive antiviral drug, is aspertonin 5-HT2C receptor inhibitor but genes to inhibitor 5-HT2C receptor-regulation [ putative anxiolytic drug Deramciclane is a serotonin 5-HT2C receptor inverse agonist, but is not capable of inducing down-regulation of the 5-HT2C receptor]Psychopharmacology [ Psychopharmacology ]](1998)136:99-104). To produce [3H]The dose of compound 829 (0.5mg/kg) with near-maximal inhibition of mesulerge binding is effective at low dose ranges in animal models (Gacs a li I et al, Receptor binding profile and inhibitory-type activity of deramciclane (EGIS-3886) in animal models [ Receptor binding profile and anxiolytic activity of deramciclane (EGIS-3886) in animal models]Drug Dev Res [ Drug development research](1997)40:333-348). Thus, compound 829 is expectedProduce antidepressant, anxiolytic, appetite stimulating and other effects in humans, all of which are associated with the treatment of patients with dementia (Jensen NH et al, Therapeutic potential of 5-HT2C receptors) [ Therapeutic potential of 5-HT2C receptor ligands ]]Scientific world journal]9 month and 14 days 2010; 1870-85; meltzer HY et al, Serotonin receptors for drug delivery to treatment of diseases and cognitive impairment in schizophrenia [ Serotonin receptors as targets for drugs used to treat psychosis and cognitive disorders in schizophrenia ]]Curr pharm biotechnol [ contemporary drug biotechnology]6 months 2012; 13(8):1572-86).
For compound 829, there is evidence for a therapeutic effect in clinical studies in patients with generalized anxiety disorder (Naukkarien H et al, Deramciclane in the treatment of the patients with generalized anxiety disorder: a plant-controlled, double-blind, dose finding study of Deramciclane in the treatment of generalized anxiety disorder: placebo-controlled, double-blind, dose finding study. Eur Neuropsychharmacol [ European neuropsychopharmacology ] (1999)15:617-23), reinforcing the claim that compound 829 is a CNS active compound capable of binding to one or more of its targets. In the treatment population (n-208), deramciclane at 30 mg/day and 60 mg/day provided clinically relevant improvements in the total score after 8 weeks of HAM-a treatment on the hamilton anxiety rating scale, with statistical significance achieved in the 60 mg/day dose group (p-0.024, n-54), with a clear trend in the 30 mg/day group (p-0.059, n-53) but not in the 10 mg/day group (n-54) compared to placebo (n-51). Regarding HAM-A anxiety factor, a significant improvement was observed in patients of the deramciclane 30 mg/day and 60 mg/day treatment groups compared to the placebo group.
Compound 829 is also a CYP2D6 inhibitor based on human studies using deramciclane as substrate. In this randomized double-blind crossover study, 15 healthy subjects received 60 mg/day of compound 829 or placebo for a period of 8 days. On day 8 of each study period, subjects received a single dose of 100mg of deramciclane. Repeated administration of compound 829 increases the AUC of desipramine by one fold (Laine K et al, Effect of the novel anxiolytic drug, deramciclane on cytochromes P (450)2D6 activity as measured by desipramine pharmacokinetics, the Effect of deramciclane on cytochrome P (450)2D6 activity, Eur J Clin Pharmacol [ european journal of clinical pharmacology ] (2004)59: 893-.
Example 176, compound 1001, 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate: the chemical formula is as follows: C34H46N2O 5; accurate quality: 562.34, respectively; molecular weight: 562.75, respectively; m/z 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); elemental analysis: c, 72.57; h, 8.24; n, 4.98; o, 14.21; boiling point: 1300.87[ K ]; melting point: 890.75[ K ]; critical temperature: 1176.29[ K ]; critical pressure: 8.99[ Bar ]; critical volume: 1685.5[ cm3/mol ]; gibbs energy: 126.8[ kJ/mol ]; and Log P: 5.06; MR: 160.74[ cm3/mol ]; henry's law: 16.03; forming heat: -719.51[ kJ/mol ]; and (2) tPSA: 77.1; CLogP: 6.5154, respectively; CMR: 16.1393, respectively; and Logs: -6.845; pKa: 8.362.
example 177, compound 1002, (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate: the chemical formula is as follows: C34H46N2O 5; accurate quality: 562.34, respectively; molecular weight: 562.75, respectively; m/z 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); elemental analysis: c, 72.57; h, 8.24; n, 4.98; o, 14.21; boiling point: 1300.87[ K ]; melting point: 890.75[ K ]; critical temperature: 1176.29[ K ]; critical pressure: 8.99[ Bar ]; critical volume: 1685.5[ cm3/mol ]; gibbs energy: 126.8[ kJ/mol ]; and Log P: 5.06; MR: 160.74[ cm3/mol ]; henry's law: 16.03; forming heat: -719.51[ kJ/mol ] ltPSA: 77.1; CLogP: 6.5154, respectively; CMR: 16.1393, respectively; and Logs: -6.845; pKa: 8.362.
example 178, compound 1003, (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate: the chemical formula is as follows: C34H46N2O 5; accurate quality: 562.34, respectively; molecular weight: 562.75, respectively; m/z 562.34 (100.0%), 563.34 (36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); elemental analysis: c, 72.57; h, 8.24; n, 4.98; o, 14.21; boiling point: 1300.87[ K ]; melting point: 890.75[ K ]; critical temperature: 1176.29[ K ]; critical pressure: 8.99[ Bar ]; critical volume: 1685.5[ cm3/mol ]; gibbs energy: 126.8[ kJ/mol ]; and Log P: 5.06; MR: 160.74[ cm3/mol ]; henry's law: 16.03; forming heat: -719.51[ kJ/mol ] ltPSA: 77.1; CLogP: 6.5154, respectively; CMR: 16.1393, respectively; and Logs: -6.845; pKa: 8.362.
example 179, compound 1004, (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate: the chemical formula is as follows: C36H50N2O 5; accurate quality: 590.37, respectively; molecular weight: 590.81, respectively; m/z 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; o, 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[ cm3/mol ]; gibbs energy: 132.66[ kJ/mol ]; and Log P: 6; MR: 169.53[ cm3/mol ]; henry's law: 15.78; forming heat: -730.31[ kJ/mol ]; and (2) tPSA: 77.1; CLogP: 7.5534, respectively; CMR: 17.0669, respectively; and Logs: -7.773; pKa: 8.362.
example 180, compound 1005, 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate: the chemical formula is as follows: C36H50N2O 5; accurate quality: 590.37, respectively; molecular weight: 590.81, respectively; m/z 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; o, 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[ cm3/mol ]; gibbs energy: 132.66[ kJ/mol ]; and Log P: 6; MR: 169.53[ cm3/mol ]; henry's law: 15.78; forming heat: -730.31[ kJ/mol ]; and (2) tPSA: 77.1; CLogP: 7.5534, respectively; CMR: 17.0669, respectively; and Logs: -7.773; pKa: 8.362.
example 181, compound 1005, (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate: the chemical formula is as follows: C36H50N2O 5; accurate quality: 590.37, respectively; molecular weight: 590.81, respectively; m/z 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; o, 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[ cm3/mol ]; gibbs energy: 132.66[ kJ/mol ]; and Log P: 6; MR: 169.53[ cm3/mol ]; henry's law: 15.78; forming heat: -730.31[ kJ/mol ]; and (2) tPSA: 77.1; CLogP: 7.5534, respectively; CMR: 17.0669, respectively; and Logs: -7.773; pKa: 8.362.
example 182, compound 1007, 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate: the chemical formula is as follows: C28H37Cl3NO 9P; accurate quality: 667.13, respectively; molecular weight: 668.93, respectively; m/z 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; cl, 15.90; n, 2.09; o, 21.53; p, 4.63.
Example 183, compound 1008, (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate: the chemical formula is as follows: C28H37Cl3NO 9P; accurate quality: 667.13, respectively; molecular weight: 668.93, respectively; m/z 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; cl, 15.90; n, 2.09; o, 21.53; p, 4.63.
Example 184, compound 1009, (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate: the chemical formula is as follows: C28H37Cl3NO 9P; accurate quality: 667.13, respectively; molecular weight: 668.93, respectively; m/z 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; cl, 15.90; n, 2.09; o, 21.53; p, 4.63.
Biological research
Biological studies using compounds of formula I, such as 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);
Figure GDA0002354989720001301
n, N-dimethyl-2- [ [ (1R,3S,4R) -4,7, 7-trimethyl-3-phenyl-3-bicyclo [2.2.1] heptanyl ] oxy ] ethylamine 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 a compound of formula II, for example dextromethorphan, derivatives and metabolites thereof.
Example 185: central-effect antipsychotics of DEX metabolism and 5HT2A receptor blockade attenuate hyperactivity induced by psychostimulants and psychotropics in laboratory rodents. Although hyperactivity induced by dopaminergic agents, such as d-amphetamines, is reversed by typical and atypical antipsychotics currently in clinical use, 5HT2A receptor antagonists are more effective against hyperactivity induced by NMDA receptor antagonists, such as phencyclidine-like channel blockers (Carlsson et al, The 5-HT2A receptor antagonist M100907is mole effective administration of NMDA antagonist-this dopamine antagonist-induced reactivity inhibitor [5-HT2A receptor antagonist M100907is more effective against NMDA antagonist-induced mouse hyperactivity than dopamine agonists ], j. Pimavanserin (ACP-103) is an example of a 5HT2A receptor antagonist administered 15min before the test segment and 0.3mg/kg MK-801(i.p.) in combination (Vanover et al, pharmaceutical and biochemical profile of N- (4-fluorophenylmethyl) -N- (1-methylpiperidin-4-yl) -N '- (4- (2-methylprophyloxy) phenylmethyl) carbamide (2R, 3R) -dihydrobutanoate (2:1) (ACP-103), alpha no 5-dihydroxypropylamine (2A) receptor agonist [ N- (4-fluorophenylmethyl) -N- (1-methylpiperidin-4-yl) -N' - (4- (2-methylpropoxy) phenyl) carbodiamide (ACP-103) (ACP-2R-1), pharmacological and behavioral characteristics of novel5-hydroxytryptamine (2A) receptor inverse agonists, JPharmacol Exp Ther [ journal of pharmacological and experimental therapeutics ]317(2):910-8 (5 months 2006); incorporated by reference). Locomotor activity data was collected in the light room during the 15-min segment. Mice had not previously been exposed to the locomotion cage. Shortly before placing the mice in the exercise chamber, the effect on muscle relaxation/ataxia was measured by contacting the forepaws of each mouse with a horizontal wire while grasping the mouse by the bottom of the tail. Mice required at least one hind paw to contact the lead within 10s to be rated as "pass" and were not considered ataxia. Individual doses or dose combinations were tested in separate groups of mice. ACP-103 significantly attenuated MK-801 induced hyperactivity in mice dosed with 0.1 and 0.3mg/kg s.c. [ F (7, 63) ═ 6.010; p <0.0001], consistent with the effects of similar antipsychotics.
When administered in combination with quinidine in patients with neurological disorders (Schoedel et al, evaluation of the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar effect]Neuropsychiatric Disease and Treatment]2014 101161-1174; incorporated by reference in its entirety), dextromethorphan is used in a dose of 10mg and may be administered twice daily. The clinical dose of sarpogrelate currently known is 100mg, usually given three times a day (Doggrell (2004) sarpogrelate: cardio and renal cl)inorganic potential [ sarpogrelate: cardiovascular and renal clinical potential]Expert opinions on Investigational Drugs [ Expert opinions on study of Drugs]13:7, 865-; incorporated by reference in its entirety). Thus, the clinical dose of sarpogrelate currently significantly exceeds that of dextromethorphan. Given that the molecular weight of sarpogrelate is about 429 and that of dextromethorphan is about 271, the combined use of dextromethorphan and sarpogrelate does not result in a 1:1 molar ratio at the present clinical dose. However, such a molar ratio of 1:1 is a prerequisite for the preparation and use of the sarpogrelate salt of dextromethorphan. Since the current clinical use of sarpogrelate is for peripheral (non-CNS) indications (Doggrell (2004) clinical diagnosis: cardiovascular and renal clinical potential of sarpogrelate: cardiovascular and renal]Expert Opinion on investigational drugs [ Expert Opinion on study of drugs]13:7, 865-; incorporated by reference in its entirety), lower doses may be required for the use of sarpogrelate for CNS indications and can therefore be co-administered with dextromethorphan as the sarpogrelate salt of dextromethorphan or as a mixture in a 1:1 molar ratio. In experimental animals, sarpogrelate is usually administered at a dose of 25mg/kg and above to induce peripheral effects (Ma et al, Effective treatment with combination of experimental 5-hydroxytryptamine synthesis and 5-hydroxytryptamine2receptor antagonist on glucose-induced bovine-insulin resistance with hyperglycemia [ peripheral blood 5-hydroxytryptamine synthesis inhibitor and 5-hydroxytryptamine2receptor antagonist in combination with Effective treatment of glucocorticoid-induced systemic insulin resistance and hyperglycemia]J Diabetes Investig [ Diabetes investigation Magazine ]]7(6) 833-844 (2016); incorporated by reference in its entirety). Examples of higher CNS activity of sarpogrelate are provided by the following examples: the Sprague-Dorael rats (Sprague-Dawley rats) were given 0.3, 1 and 3mg/kg doses of sarpogrelate 30min before the centrally acting 5-HT2A agonist DOI (3 mg/kg; (1(2, 5-dimethoxy-4-iodophenyl) -2-aminopropane) hydrochloride by co-administration of the compound of formula I, SARPODEXTM、DERADEXTMOr DERAPHANTMDOI induced shaking headThe frequency of (2) is reduced.
Both enantiomers of the compound of formula I and its major metabolite M1 are 5HT2A receptor antagonists (Pertz et al, In-vitro pharmacology of a compound of formula I, and the enantiomers of its major metabolite 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserine-induced depression of 5-htconnectionin tissue area [ In vitro pharmacology of the enantiomers of the compound of formula I and its major metabolites: 5-HT2A receptor specificity, stereoselectivity, and regulation of ritanserin-induced inhibition of 5-HT contraction ], Pharmacol [ pharmacology and pharmacology ]47(4):310-6 (1995-4 months) incorporated In their entirety). To confirm the ability of M1S and R-enantiomers to reach the 5HT2A receptor of the CNS, rats were pretreated with 0.1mg/kg MK801 and monitored for a range of doses of both compounds of formula I using a conventional locomotor activity monitor over a 120-min test interval for attenuation of MK 801-stimulated hyperactivity.
DEX acts on numerous receptors, one of its targets being the NMDA receptor (Taylor et al, Pharmacology of dextran: Relevance to dextran/quinidine)
Figure GDA0002354989720001321
clinicalose [ pharmacology of dextromethorphan: with dextromethorphan/quinidineCorrelation of clinical use]Pharmacol Tuer. [ pharmacology and therapeutics]164:170-82(2016 August); incorporated by reference in its entirety). However, DEX is a weaker NMDA receptor antagonist than its metabolite DO. Thus, DEX is less likely to induce phencyclidine-like locomotor activity than DO. The behavioral effects of DEX, DO and phencyclidine (PCP) were compared in rats. DO (15-120mg/kg) was similar to PCP (1.25-20mg/kg) in inducing dose-dependent hyperkinesia, stereotypy and ataxia. DEX (15-120mg/kg) induced moderate hyperactivity only about 45min after higher dose treatment. DEX and DO in opposite directions modify 10mg/kg PCP-induced locomotionPromoting effect. Pre-treatment with DO is intended to promote, while DEX dose-dependently inhibits PCP-induced hyperactivity (Szekey et al, Induction of phenyl-lipid metabolism by DO but not DEX [ induce phencyclidine-like behaviour in rats by DO but not by DEX]Pharmacol biochem Behav [ pharmacological biochemistry and behaviourology]381-6(1991, 10 months); incorporated by reference in its entirety).
Example 186: the two enantiomers of the compound of formula I, as well as its major metabolite, are CYP2D6 inhibitors. DEX is a commonly used substrate in vitro metabolic studies to reveal 2D6 inhibitory activity of biologically active substances and drugs. In a dedicated set of studies, the compound of formula I was administered before DEX and the locomotor activity of rats was monitored for 120min to demonstrate that the compound of formula I prevents overactivity in subjects treated with DEX. These studies were paralleled by measuring plasma DEX levels. The combination of pharmacokinetic (plasma DEX concentrations) and pharmacodynamic (MK-801 and DEX induced hyperactivity) studies was used to identify the M1 enantiomer and dose level(s) that produced the optimal ratio of anti-hyperactivity and DEX metabolism-suppressing effects.
Example 187: blood glucose and insulin sensitivity: in contrast to sulfonylurea drugs, which result in significantly higher basal insulin secretion compared to vehicle treatment, DO and its prodrug DEX DO not significantly alter basal insulin secretion from mouse or human islets or in vivo (Marquard et al, Characterization of pancreatic NMDA receptors as potential drug targets for diabetes treatment. Nat Med [ Nature medicine ]21(4):363-72 2015(s); incorporated by reference in its entirety). More specifically, administration of DEX (4mg/ml) overnight via drinking water did not alter basal plasma insulin and fasting plasma glucose concentrations in mice, but resulted in significantly higher glucose-induced plasma insulin concentrations and glucose tolerance (given intraperitoneally at 1.5mg/kg body weight) than seen in the non-DEX-treated control group.
Marguard et al (2015) suggested that the effects of DEX are mediated via NMDA receptor channel blockers and specifically that DEX is rapidly metabolized to DO, a potent inhibitor of NMDA receptors. To demonstrate the involvement of the NMDA receptor, Marguard et al demonstrated that glucose stimulated insulin secretion and glucose tolerance were not observed in mice deficient in NMDA receptor function.
To test whether DEX can cause higher serum insulin concentrations and lower blood glucose concentrations in people with type 2 diabetes (T2DM), a phase 2a, double-blind, placebo-controlled, randomized, crossover, single dose proof concept study (Marquard et al, Characterization of pancreatic NMDA receptors as potential drug targets for diabetes treatment. Nat Med [ Nature medicine ]21(4):363-72 (2015); incorporated by reference in its entirety) was conducted. Twenty men with T2DM treated with metformin (metformin) monotherapy (age 59(46-66) years, (mean (range)); mean Body Mass Index (BMI)29.2(25.2-34.1) kg m-2; glycated hemoglobin (HbA1c)6.9 (6.5-7.4)%) were enrolled. Each person received a single oral dose of 60mg DEX, 270mg DEX, 100mg amantadine or placebo, followed by an Oral Glucose Tolerance Test (OGTT) 1h after drug intake on four treatment days, 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 and lower fasting plasma glucose concentrations compared to placebo, and did not cause any serious hypoglycemic events at doses up to 270 mg. In contrast, both 60 and 270mg DEX doses resulted in significantly (P <0.05) higher maximum serum insulin concentrations after oral glucose ingestion compared to placebo.
In addition, the primary endpoint was reached at 270mg DEX; that is, the area under the blood glucose concentration curve within 2h prior to the OGTT (glucose AUC1-3 h) was significantly (P <0.05) smaller in subjects receiving a 270mg dose of DEX than in the same subjects receiving placebo on different treatment days.
Blood glucose levels are also under the control of peripheral 5HT2A receptors (Yamada et al, hyperglycemic by the 5-HT receptor agonist, 5-methoxytryptamine, inrates: the peripheral 5-HT2A receptor. [5-HT receptor agonist 5-methoxytryptamine-induced hyperglycemia in rats: involvement of the peripheral 5-HT2A receptor ] Eur J Pharmacol. [ European J.Pharmacol ]323(2-3):235-40 (1997); incorporated by reference in its entirety). More specifically, hyperglycemia induced by administration of a non-selective 5HT receptor agonist, such as 5-methoxytryptamine, is prevented by administering the 5-HT2A receptor antagonist, ketosertraline (ketanserin), and the peripherally acting 5-HT 2receptor antagonist, tolemidine (xylaminidine). These results indicate that 5-methoxytryptamine-induced hyperglycemia is mediated by the peripheral 5-HT2A receptor.
Certain 5HT2A receptor antagonists, such as, for example, ketanserin, are impaired in insulin sensitivity (Gilles et al, Antagonism of the serotonin (5-HT) -2receptor and insulin sensitivity: influence of atypical antipsychotics) certain 5HT2A receptor antagonists for example, insulin resistance [ Antagonism of the serotonin (5-HT) -2receptor and insulin sensitivity: influence of atypical antipsychotics ] Psychosom Med [ psychology ]67(5): 51 (2005)); incorporated by reference in its entirety) are shown to reduce insulin sensitivity in Gilles et al studies, ten healthy men were included in placebo studies at doses of 40 mg-5 mg-insulin receptor and placebo treatment of placebo-7. insulin receptor treatment was shown to reduce insulin sensitivity in placebo-7. placebo-8 g.7. placebo-9. placebo treatment of insulin receptor treatment.
Thus, combining DEX and a 5-HT2A receptor antagonist may result in a synergistic effect of blood glucose and insulin sensitivity, which may not be desirable in the case of chronic treatment, as it may have undesirable metabolic side effects similar in nature to those observed in patients treated with antipsychotic drugs. These effects may limit the dose of DEX and 5-HT2A receptor antagonists that can be safely administered as a combination.
There are two ways, these are part of the present invention and these enable the use of a combination of DEX and a 5HT2A receptor antagonist therapeutically while reducing the risk of peripheral metabolic adverse effects.
One approach is based on the use of 5HT2A receptor inverse agonists or antagonists that inhibit CYP2D6 and thereby reduce the conversion of DEX to DO. Both DEX and DO are NMDA receptor channel blockers, and NMDA receptor inhibition in the islets of langerhans is thought to be responsible for glucose-stimulated insulin secretion, and DEX and DO enhance glucose intolerance (Marquard et al, Characterization of pancreatic NMDA receptors as potential drug targets for diabetes treatment. Nat. Nat. Med. 21(4):363-72 (2015); incorporated by reference in its entirety). Since DO is a more potent NMDA receptor channel blocker than DEX (Pechnick et al, Comparison Of The Effects Of DEX, DO and levorphanol on The hypothalamus-Pituitary-Adrenal Axis ], The Journal Of Pharmacology and Experimental therapeutics 309:515-522 (2004); incorporated by reference in its entirety), inhibition Of DEX metabolism via CYP2D6 may reduce The expression Of The Effects Of DEX on glucose-stimulated insulin secretion and glucose tolerance, and thus reduce The risk Of metabolic side Effects.
The second approach is to select a 5HT2A receptor inverse agonist or antagonist with the most preferred ratio of central to peripheral 5HT2A receptor occupancy. Thus, a 5HT2A receptor inverse agonist or antagonist is selected to produce a therapeutically relevant central 5HT2A receptor occupancy at a dose that produces the least risk of undesirable metabolic effects, such as, but not limited to, glucose intolerance.
The compounds of formula I are 5HT2A receptor inverse agonists or antagonists with 2D6 inhibitory properties. Acute and chronic effects of compounds of formula I on glucose tolerance and insulin resistance have been examined (Takishita et al, effective of steroid hydrochloride, a 5-HT2 blocker, on insulin resistance in Otsuka Long-Evans Tokushima fat rats (OLETF rats), type 2 diabetes rate model [ sarpogrelate hydrochloride 5-HT2 blocker on insulin resistance in Otsuka Long-Evans Tokushima obese rats (OLETF rats), a type 2 diabetes rat model ] J Cardiovasc Pharmal [ J. Megaol ]43(2):266-70 (2004); incorporated by reference in its entirety). In these studies, the type 2 diabetes model tsukamuron-Evans fat rats (Otsuka Long-Evans Tokushima Fatty rates) were randomly divided into 2 groups; these were treated with 30mg/kgBW/d of the compound of formula I for 4 weeks (HTB group) and none (control group). The glucose infusion rate was significantly increased in the HTB group compared to the control group. The blood glucose levels and plasma insulin and blood lipid levels after oral glucose tolerance testing were significantly lower in the HTB group than in the control group. The compounds of formula I are shown to reverse insulin resistance induced by various means including glucocorticoid drug therapy (Ma et al, Effective treatment of glucocorticoid-induced systemic insulin resistance and hyperglycemia by the combination of an inhibitor of peripheral5-hydroxytryptamine synthesis and a 5-hydroxytryptamine2receptor antagonist on glucose-induced glucose-body insulin resistance with hypertension. J Diabetes research [ Diabetes research ]7:833 (2016); journal incorporated by reference in its entirety).
The synergistic effect of the compounds of formula I on blood glucose and insulin sensitivity has been shown in several drugs including carbidopa (carbidopa) (Ma et al, Effective therapeutic with a combination of experimental 5-hydroxyregulatory synthesis and 5-hydroxyregulatory-2 receptor antagonist on glucose-induced glucose-body inhibitor with hyperglycemia [ peripheral blood 5-hydroxytryptamine synthesis inhibitor and 5-hydroxytryptamine2receptor antagonist in combination with Effective treatment of glucocorticoid-induced systemic insulin resistance and hyperglycemia ] J antigens investigation [ Diabetes investigation ]7:833 (2016); incorporated by reference in its entirety) and pioglitazone (pigment hydrochloride) (Iii et al, carbohydrate hydrochloride of supplement of 5-glucose excipient of glucose-2 receptor of [ glucose-related protein hydrochloride of 5-glucose antagonist of ], a 5-HT2A receptor antagonist, beneficial effects on diabetic model mice ] Endocr Res [ endocrine research ]34(1-2):18-30 (2009); incorporated by reference in its entirety).
The insulin sensitizing effect of the compounds of formula I has been demonstrated in humans (Kokubu et al, Persistentin-sensing effectors of steroid hydrochlorides, a serotonin 2 Arecter antadonist, in Patients with peripheral arterial disease, [ continuous insulin sensitivity of Sarpogrelate hydrochloride, a serotonin 2A receptor antagonist, in patients with peripheral arterial disease ] Circ J [ J.CYCLE ]70(11), 1451-6(2006), the entire contents of which are incorporated by reference). The insulin resistance index (fasting immunoreactive insulin) was measured in 24 patients with peripheral artery disease (19 men, 76+/-9 years) before and after 2 weeks of administration of the compound of formula I (300 mg/day). Sixteen of 24 patients were also examined after 3 months of treatment. After 2 weeks of treatment, a significant decrease in fasting immunoreactive insulin was observed (p ═ 0.03). A significant reduction in fasting immunoreactive insulin (16.0+/-10.3vs 9.2+/-2.0 μ U/mL, p ═ 0.03) was maintained after 3 months of treatment.
The compounds of formula I are rapidly metabolized into metabolites which also have both 5HT2A receptor antagonist and 2D6 inhibitory properties. Both enantiomers of the metabolite are biologically active and share the ability to block the 5HT2A receptor and 2D 6. To establish which enantiomer and DEX combined is the optimal characteristics, the effect of these substances on oral glucose tolerance alone and in combination with DEX was evaluated (Taniguchi et al Diabetes [ Diabetes ], 55, 2371-2378 (2006); incorporated by reference in its entirety). This method is based on measuring whole blood glucose and plasma insulin. The test substance was administered to male Spirogrege-dory rats (group size: 8 per group). Animals were tested after not eating overnight and housed alone. The test substance was administered 60 minutes before the glucose challenge, i.e. after the baseline blood glucose measurement. Following blood glucose measurements, animals were challenged with an oral gavage of 2g/kg glucose at T0. At 8 time points: blood glucose was measured from a drop of blood collected from the tail cutting tip using a commercially available glucose meter at baseline (before treatment), T0 (before glucose), then 15, 30, 60, 90, 120 and 180 minutes after glucose challenge.
Example 188: the effect of formula 1 alone on AD pathophysiology: the Link between chronic diabetic metabolic status and the risk and emergence of AD pathophysiology has been suspected and proven in recent years (Goldwasser et al, Breakwown Soft liver cancer and Blood-Brain Barrier: A mechanical linkage between cerebrovascular and Alzheimer's Disease [ rupture of the cerebral vessels and Blood Brain Barrier: Mechanistic Link between diabetes and Alzheimer's Disease ] J Alzheimer's Disease [ J.Alzheimer's Disease ]54 (2016-1/8/2016); the entire contents of which are incorporated by reference). In several large autopsy series, more than one third of subjects clinically diagnosed with typical AD show evidence of cerebrovascular disease and have to be reclassified as mixed dementia (Grandal Leiros et al, Prevalence and concordance between the clinical and post mortem diagnosis of dementia in psychiatric clinics, Neurology [ neurology ] S0213-4853(16)30070-6(2016), the entire contents of which are incorporated by reference). From a clinical perspective, it is desirable to extend AD therapy beyond currently approved drugs and mechanisms and address cognitive impairment by optimizing underlying diabetic metabolic states or fairly frequent type 2 diabetes in elderly subjects. Indeed, glycemic control is believed to have an effect on the severity of Cognitive Impairment (Zilliox et al Diabetes and Cognitive Impairment [ Diabetes and Cognitive Impairment ] Curr Diabetes report [ 16(9):87 (2016); incorporated by reference in its entirety).
Due to the specific anti-diabetic effect of the compounds of formula I as described above, additional benefits intended for the symptoms and disease progression of AD, as well as cognitive disorders of predominantly vascular origin (multi-infarct dementia, vascular cognitive dysfunction, etc.) can be envisaged.
Based on the regulatory guidelines in japan, the incidence of adverse events for compound therapy of formula I at medicine is considerably lower compared to placebo, and the nature of the reported AEs is considered acceptable; thus, the benefit-risk ratio of adding a compound of formula I therapy also in elderly, frequently occurring people appears to be safeguardable.
Example 189: compounds stereoselectively reverse psychostimulant-induced hyperactivity in vivo: locomotor activity data was collected in the light room during the 15-min segment. Mice had not previously been exposed to the locomotion cage. Shortly before placing the mice in the exercise chamber, the effect on muscle relaxation/ataxia was measured by contacting the forepaws of each mouse with a horizontal wire while grasping the mouse by the bottom of the tail. Mice required at least one hind paw to contact the lead within 10s to be rated as "pass" and were not considered ataxia. Individual doses or dose combinations were tested in separate groups of mice. ACP-103 significantly attenuated MK-801 induced hyperactivity in mice dosed with 0.1 and 0.3mg/kg s.c. [ F (7, 63) ═ 6.010; p <0.0001], consistent with the effects of similar antipsychotics.
HEK-293 cells expressing human recombinant 5HT2A receptor were used for antagonist radioligand binding studies. The compound of formula I, e.g., compound 50 racemate and both enantiomers are administered at concentrations ranging from 3.0E-11M to 1.0E-07M. The M1 enantiomer was administered at a concentration ranging from 1.0E-11M to 3.0E-08M. IC50 values (the concentration responsible for half-maximal inhibition of control-specific binding) and hill number (nH) were determined by non-linear regression analysis of competition curves generated by mean-repeat values, using hill equation curve fitting. The inhibition constant (Ki) was calculated using the Zheng Prusoff equation. Both sarpogrelate enantiomers are potent inhibitors of [3H ] ketosertraline binding (table 1). The M1 enantiomer also bound strongly to the 5HT2A receptor with Ki values about one order of magnitude higher than those of the sarpogrelate enantiomer (table 1). There were no meaningful differences between the enantiomers with respect to the binding of sarpogrelate to the 5-HT2A receptor or its major metabolites.
TABLE 3 inhibitory Effect of sarpogrelate (racemates and enantiomers) and M-1 enantiomer on the binding of 5-HT2A receptor
Figure GDA0002354989720001371
To confirm the ability of M1 enantiomer to induce effects associated with CNS disorders and known to be effective with 5-HT2A receptor agonists and inverse agonists, a separate group of female wister rats (n-6-9) was housed 4-5 per cage, food and water were freely taken, pre-treated intraperitoneally with different doses of one of the two M1 enantiomers (0, 3 or 10mg/kg) under standard colony-chamber conditions, followed by 15 minutes later by 0.1mg/kg of MK801 or its vector, immediately thereafter, the exercise activity recording room (25x 35.5x 34cm, L x W x H; clear plexiglas walls and opaque plastic floor; enclosed in a sound-reducing ventilation compartment) was placed under computer control for 60 minutes, during which the infrared photocell interruptions (5 cm and 14 cm from the ground) were recorded as a measure of exercise activity. MK-801 is a phencyclidine-like NMDA receptor channel blocker, often used in psychopharmacology studies for novel therapies including novel antipsychotics. Analysis of variance (ANOVA) has revealed that the major effect of the M1 dose and the interaction between the M1 dose and MK-801 therapeutic factor are for the (-) M1 enantiomer [ F (2, 39) ═ 6.154; p is 0.0048, F (2, 39) is 4.613; p-0.0159 ] instead of for the (+) M1 enantiomer [ F (2, 42) ═ 0.5211, respectively; p-0.5977, F (2, 42) -0.5229; p-0.5966. As shown in FIG. 7, two doses of the (-) M1 enantiomer, as well as the 3mg/kg prototype 5-HT2A receptor antagonist M-100, 907 reduced MK-801 induced hyperactivity (Dunnett's multiple alignment test). Thus, although there were no significant differences between the M1 enantiomers in binding to the 5-HT2A receptor, it was unexpected that only one of these enantiomers would be effective in a preclinical model of psychomotor activation known to be sensitive to 5-HT2A receptor blockade.
Example 190: reversal of hypermotility induced by olfactory bulb resection in rats: in a specialized group of studies, adult male sparger-dorey rats (Charles River, Germany) were subjected to bilateral olfactory bulb resection under ketamine/xylazine anesthesia. Animals were allowed to recover for 14 days after surgery with daily management to eliminate any aggressiveness that might occur. Sham operated animals were managed in the same way, but the olfactory bulb remained intact. 4 administrations and motor activity tests were performed per rat, with 72 hours between successive test segments. Animals were treated with dextromethorphan (0, 15, 30 or 60mg/kg, oral) prior to each test session, placed in Opto-Varimex cages 15min later with sarpogrelate (1,3 and 10mg/kg, i.p.) and 15min later to record locomotor activity for more than 30 min. Hypermobility of rats after olfactory bulb resection was mostly observed in the early part of the test segment. Figure 8 presents the average activity counted 15 minutes prior to testing, when the activity of the excised animals was significantly higher than that of the sham control group. ANOVA revealed significant major effects of both surgery and sarpogrelate dose factors [ F (1, 88) ═ 5.04, p ═ 0.0273; f (3, 88) ═ 5.02, p ═ 0.0029 ]. Post hoc pairwise comparisons (multiple comparison test by Sidak) confirmed that significant differences between resected and sham operated subjects were only observed in rats pre-treated with vehicle, not sarpogrelate. Excised rats pretreated with 3 or 10mg/kg sarpogrelate spent less time walking than individual controls receiving vehicle instead of sarpogrelate. These anti-overactive effects of sarpogrelate were observed at doses that did not affect the activity of sham operated rats and therefore did not reflect a generalized non-specific impairment of motor capacity. Thus, unexpectedly, it was observed that sarpogrelate-rat sniffing after saccectotomy-often used to study models of CNS drugs such as antidepressants-exerts behavioral-specific anti-hyperactivity effects, despite what was previously referred to as a 5-HT2A receptor antagonist (Obata H et al Antinociception in a by sorpogrelate, asective 5-HT (2A) receptor antagonist, is peripheral, [ the antinociceptive effect on rats by sarpogrelate, a selective 5-HT (2A) receptor antagonist ] Eur J Pharmacol [ european pharmacology ]404(1-2):95-102 (2000)).
Example 191: inhibition of dextromethorphan metabolism in vitro and in vivo: dextromethorphan O-demethylase activity was measured in human liver microsomes. Sarpogrelate (1.0E-8M to 3.0E-5M) or M-1 (concentration: 3.0E-9M to 1.0E-5M) and dextromethorphan were dissolved in acetonitrile and serially diluted with acetonitrile to the desired concentration to give a final organic solvent concentration of 1.0% in the incubation mixture. The incubation mixture contained pooled human liver microsomes (final concentration: 0.25mg/ml), dextromethorphan, and an NADPH producing system (1.3mM NADP +, 3.3mM glucose 6-phosphate, 3.3mM MgCl2, and 0.4U/ml glucose-6-phosphate dehydrogenase). After incubation and centrifugation, the supernatant was diluted 100-fold with acetonitrile and subsequently injected into the LC-MS/MS system. All incubations were performed in triplicate and the average was used for analysis. IC50 values (the concentration responsible for half-maximal inhibition of control-specific binding) and hill number (nH) were determined by non-linear regression analysis of competition curves generated by mean-repeat values, using hill equation curve fitting. Both sarpogrelate enantiomers inhibited CYP2D 6-mediated O-demethylation of dextromethorphan (table 4).
TABLE 4 inhibitory effect of sarpogrelate (racemates and enantiomers) and M-1 enantiomer on CYP2D6 activity.
Figure GDA0002354989720001391
Although both enantiomers of M1 significantly inhibited 2D6 activity, with IC50 values of 0.038-0.096 μ M, the potency of the sarpogrelate enantiomer was about 10-15 times less (table 4). Based on previous in vivo studies, sarpogrelate was classified as a weak 2D6 inhibitor. This classification is based on a 2-fold increase in the substrate UC (i.e., according to the guidelines provided by the U.S. food and drug administration for industry: drug interaction students-study design, data analysis, drug administration and labeling recommendations for significance) Center for drug evaluation and Research [ drug evaluation and Research Center ], U.S. food and drug administration (2012), http:// www.fda.gov/downloads/Drugs/guide compatibility regulation/guidance/292362. pdf).
Pharmacokinetic studies were performed in male winster rats fitted with jugular vein cannulae. Sarpogrelate hydrochloride was formulated in a Pharmasolv PBS buffer (5:95) mixture and administered intravenously at a dose of 2 mg/kg. Blood samples were collected from the jugular vein at predetermined time points using heparin as an anticoagulant: 5min, 15min, 30min, 1h, 1.5h, 2h, 4h, and 6 h. The LC-MS/MS bioassay method was used to simultaneously quantify sarpogrelate and M1 in plasma samples. The plasma level curve shows small inter-individual variability after 2mg/kg i.v. bolus administration (fig. 9). The terminal elimination half-life was estimated to be 1.21. + -. 0.159 h. Because the highest M1 concentration was measured at the first sampling time point, the formation of the M1 metabolite of sarpogrelate was rapid. Despite the rapid formation, the concentration of the free M1 metabolite was several orders of magnitude lower in the circulation than the concentration of the parent compound (M1/sarpogrelate ratio 2.98 ± 0.597%). Thus, while the M1 enantiomer was a significantly more potent 2D6 inhibitor than the parent compound, the potential effect of M1 was reduced by the low relative exposure of M1 as indicated by the plasma AUC ratio of M1 and sarpogrelate.
Example 191: in another set of studies, the ability of sarpogrelate to inhibit dextromethorphan metabolism in vivo in rats was studied. Adult male Sdougredore rats (RjHan: SD) purchased from Janvier laboratories (Janvier Labs) (France) were housed in a climate controlled room with a 12h light/12 h dark cycle, with food and water ad libitum. Two to three days before blood collection, a catheter was placed in the jugular vein of the rat, and then the rat was treated with Carprofen (5mg/kg) directly after the operation once, and the catheter was rinsed with heparin (500IE/ml) (20. mu.l/rat/day) every day. On the day of the experiment, dextromethorphan (50mg/kg) was given by oral gavage, followed immediately by intravenous bolus injection of sarpogrelate (1,3 or 10 mg/kg; one of the racemates or enantiomers) or the carrier via vascular access at t ═ 0 h. Blood samples were collected at four time points until 6 hours after dextromethorphan administration. The sample size was 80. mu.l Li-heparin whole blood/time point, i.e. 40. mu.l Li-heparin plasma/time point. Whole blood samples were stored on ice until centrifugation (10min at 3000g, 4 ℃). Plasma was prepared within 45min after collection, frozen at-20 ℃ and stored at this temperature until processed for LC-MS analysis.
As shown in fig. 10, in rats treated with sarpogrelate (racemate or enantiomer), the plasma level of dextromethorphan was high even at later time points, while in rats treated with carrier, the dextromethorphan level declined towards the 6-h time point.
Unexpectedly, the AUC quantification of dextromethorphan indicates that sarpogrelate increased dextromethorphan AUC by 5.3-6.9-fold at the highest tested dose of 10 mg/kg. Even at lower doses of 3mg/kg, the dextromethorphan AUC increased from 2.7 (for the (-) enantiomer) to 3.3-fold (for the (+) enantiomer).
TABLE 5 area under the curve (0-6h) analysis of dextromethorphan plasma concentrations in rats treated with sarpogrelate (racemate and enantiomer)
Figure GDA0002354989720001401
Example 192: inhibition of phencyclidine-induced hyperactivity in rats treated with a combination of sarpogrelate and dextromethorphan: the behavioral effects of DEX, DO and phencyclidine (PCP) were compared in rats. DO (15-120mg/kg) was similar to PCP (1.25-20mg/kg) in inducing dose-dependent hyperkinesia, stereotypy and ataxia. DEX (15-120mg/kg) induced moderate hyperactivity only about 45min after higher dose treatment. DEX and DO modify the 10mg/kg PCP-induced motor promotion in opposite directions.
In a dedicated set of studies, compound 50 racemate and enantiomer were co-administered with DEX to demonstrate the ability of such drug combination(s) to counteract psychomotor activation and hyperactivity. Male sprague-dorey rats were administered compound 50 (sarpogrelate racemate), (-) sarpogrelate, (+) sarpogrelate or vehicle intraperitoneally with either subcutaneous (racemate experiment) or oral (enantiomer experiment) dextromethorphan or vehicle (water) and placed individually in the Opto-Varimex-4 autoorbital. Fifteen minutes later, the rats were removed from the box, injected with phencyclidine (PCP; 5mg/kg, subcutaneous) and returned to the auto-orbit for an additional 105min (i.e. until the total recorded time was 120 min). Data analysis was focused on the second half of the test (60-120 min). ANOVA has revealed a significant interaction between the dose of sarpogrelate and the dose of dextromethorphan (fig. 11, top; F (9, 120) ═ 2.38, and P ═ 0.015).
A statistically significant interaction similar to the dextromethorphan dose was observed in (-) sarpogrelate (fig. 11, middle panel; F (9, 141) ═ 3.07, P ═ 0.002), but (+) sarpogrelate was not (fig. 11, lower panel; F (9, 120) ═ 1.65, P ═ 0.1). Post hoc analysis indicated that in the presence of right methamphetamine, 3mg/kg of sarpogrelate racemate as well as 1mg/kg or 3mg/kg (-) sarpogrelate inhibited hyperactivity in PCP-treated rats (Dunnett's multiple comparative test). This mode of results was unexpected in view of the poorer potency of the (-) enantiomer of sarpogrelate compared to the (+) enantiomer in terms of inhibition of dextromethorphan metabolism in vitro (table 4) and in vivo (table 5).
Neither the sarpogrelate racemate nor the sarpogrelate enantiomer reduced activity in PCP-treated rats when not administered dextromethorphan. When co-administered with dextromethorphan, the inhibitory effect of sarpogrelate was observed whether dextromethorphan itself reduced (subcutaneous administration, as in the sarpogrelate racemate test) or enhanced (oral administration, as in the sarpogrelate enantiomer test) the locomotor activity of PCP-treated rats. Thus, in psychomotor-activated subjects, such as hyperactive rats with exposure to the psychotropic drug PCP, the presence of dextromethorphan may be necessary for sarpogrelate to exert an inhibitory effect. Such a super-additive interaction pattern between dextromethorphan and sarpogrelate is unexpected.
Example 193: methods for assessing blood glucose levels and oral glucose tolerance: test substances were administered to male Wensted (Han) rats housed in a herd and with free access to food and water(at the start of the experiment, 180-; 280 g; Janvier laboratories). After a night without food, the tip of the tail was excised and each rat was weighed, housed individually, and placed in a quiet room without pressure. After about 1 hour, a drop of blood collected from the tip of the tail was used to measure baseline blood glucose using a commercially available glucose meter (
Figure GDA0002354989720001411
Lifescan), then the rats received an intraperitoneal injection of sarpogrelate and/or dextromethorphan, 30min later the blood glucose was measured again and immediately challenged with 2g/kg glucose by oral gavage. Subsequently, blood glucose was measured at 6 time points until 180 minutes after the glucose challenge. As shown in fig. 12, there is a major effect of drug treatment (F (4, 59 ═ 12.0, p)<0.0001). Post-hoc compositional group comparisons indicate that dextromethorphan has significantly reduced blood glucose levels when administered alone, and that this effect of dextromethorphan is reversed when administered in combination with either of the racemic or enantiomeric forms of sarpogrelate.
Example 194: 52-week chronic toxicity test and 5-week recovery test using beagle dogs (Suzuki et al, Pharmacology & Therapeutics [ Pharmacology ] Vol. 19' 91 supplement): compound 50 hydrochloride was orally administered to beagle dogs at dosage levels of 5, 20, 80 and 320 mg/kg/day for 52 consecutive weeks. No animals died or were sacrificed in extreme cases, regardless of sex. In general terms, vomiting of males and females receiving 320 mg/kg/day and males receiving 80 mg/kg/day and salivation of females receiving 320 mg/kg/day were noted. Weight gain was inhibited in both male and female animals receiving 320 mg/kg/day. In females receiving 80 mg/kg/day and above, food intake was inhibited. Females receiving 320 mg/kg/day also showed drinking inhibition. During recovery, the observed gross condition showed no difference between the control and treatment groups. There were no treatment-related changes in the electrocardiogram or ophthalmic examination. In the urine analysis, it was revealed that the protein of the female receiving 320 mg/kg/day was increased, in the hematological examination, the platelet count of the male receiving 320 mg/kg/day was increased, and in the biochemical examination, the potassium of the male receiving 80 mg/kg/day or more and the female receiving 320 mg/kg/day was increased. These changes were recovered after withdrawal. Males receiving 80 mg/kg/day and above had increased relative weights of thyroid and liver, but no treatment-related changes were seen in histopathological examination. In histopathological examination, steatosis occurred in the renal cortical medullary border region of males receiving 320 mg/kg/day. However, during recovery, this change was not found. In the 52 week study, the dose level of compound 50 hydrochloride had no effect and was estimated to be 20 mg/kg.
While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as set forth in the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed within the scope of the claims. Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be apparent that the invention as described herein may be varied and that various modifications, additions, substitutions, and changes to the illustrative examples set forth herein may be made without departing from the spirit of the invention and are therefore considered to be within the scope of the invention. All documents cited above, including, but not limited to, printed publications, and provisional and frequent patent applications, are hereby incorporated by reference in their entirety.
Example 195: reversal of hyperactivity induced by NMDA receptor blockade in rats: to confirm the ability of the present invention (compound of formula I) to induce antipsychotic-like effects associated with efficacy against behavioral and psychiatric symptoms of dementia and known for 5-HT2A receptor agonists and inverse agonists, separate groups of rats were housed under standard habitat conditions, were freely taken with food and water, pretreated with different doses of deramciclane (up to 30mg/kg), followed by pretreatment with NMDA receptor channel blockers or their vehicle, and immediately placed in a computer controlled locomotor activity recording room. NMDA receptor channel blockers are frequently used in psychopharmacological studies of novel therapies, including novel antipsychotics. Analysis of variance (ANOVA) was used to reveal the major effects of deramciclane dose and the interaction between deramciclane dose and NMDA receptor therapeutic factors.
Example 196: reversal of hypermotility induced by olfactory bulb resection in rats: in a specialized group of studies, adult male rats undergo bilateral olfactory bulb resection, a model commonly used for studying CNS drugs (e.g., antidepressants). Animals were allowed to recover for at least 14 days after surgery. Sham operated animals were managed in the same way, but the olfactory bulb remained intact. Prior to each test session, animals were treated with dextromethorphan (up to 60mg/kg, oral) in combination with a compound of formula I (up to 30mg/kg, oral) and then placed in an activity monitor for motor activity recordings. Hypermobility of rats after olfactory bulb resection was mostly observed in the early part of the test segment. The results present the average activity calculated in the early part of the test section when the activity of the excised animals was significantly higher than the average activity in the sham-control group. ANOVA was used to reveal significant major effects of both surgical and therapeutic dose factors. The anti-overactive effect of deramciclane was observed at doses that did not affect the activity of the sham-operated rats and therefore did not reflect the generalized non-specific impairment of motor capacity.
Example 197: inhibition of dextromethorphan metabolism: dextromethorphan O-demethylase activity was measured in human liver microsomes. The compound of formula I (concentration: up to 3.0E-5M) and dextromethorphan were dissolved in acetonitrile and serially diluted with acetonitrile to the desired concentration to give a final organic solvent concentration of about 1.0% in the incubation mixture. The incubation mixture contained pooled human liver microsomes, dextromethorphan, and NADPH generating system. After incubation and centrifugation, the supernatant was diluted 100-fold with acetonitrile and then subsequently injected into the LC-MS/MS system. All incubations were performed in triplicate and the average was used for analysis. IC50 values (the concentration that causes half-maximal inhibition of control-specific binding) and hill coefficients (nH) were determined using hill equation curve fitting using, for example, a non-linear regression analysis of competition curves generated using mean-repeat values. Deramciclane was observed to inhibit CYP2D6 mediated O-demethylation of dextromethorphan.
Based on previous human studies with desipramine as a substrate, the compounds of formula I can be classified as weak 2D6 inhibitors (Laine K et al, (2004)59: 893-898, Effect of the novel anxiolytic drug, despramicicle on cytochromes P4502D 6 activity as measured by desipramine pharmacokinetics, the Effect of the novel anxiolytic drug, deramciclane, on cytochrome P4502D 6 activity, Eur J Clin Pharmacol [ European journal of pharmacology ] (2004)59: 893-898). This classification is based on an approximately 2-fold increase in substrate AUC (i.e., according to the guidelines provided by the U.S. food and Drug administration for industry: Drug interaction students-study design, data analysis, and labeling recommendations) [ draft of industry guidelines: Drug interaction study-study design, data analysis, Drug administration and labeling recommendations ] Center for Drug Evaluation and research [ Drug Evaluation and research Center ], U.S. food and Drug administration (2012), http:// www.fda.gov/downloads/Drugs/guide compatibility regulation Information/guidelines/ucm 292362. pdf).
The ability of the compounds of formula I to inhibit dextromethorphan metabolism was studied in vivo in pharmacokinetic studies in rats. Adult rats were housed in a climate controlled chamber with a 12h light/12 h dark cycle, with food and water ad libitum. On the day of the experiment, dextromethorphan (50mg/kg) was given by oral gavage followed immediately by deramciclane (up to 30mg/kg) or vehicle (t ═ 0 h). Blood samples were collected at various time points until 24 hours after dextromethorphan administration. The sample size was about 80 μ l Li-heparin whole blood/time point, i.e. 40 μ l Li-heparin plasma/time point. Whole blood samples were stored on ice until centrifugation (10min at 3000g, 4 ℃). Plasma was prepared within 45min after collection, frozen at-20 ℃ and stored at this temperature until processed for LC-MS analysis. In rats treated with the compound of formula I, the plasma levels of dextromethorphan were high even at later time points, whereas in vehicle-treated rats, the dextromethorphan levels declined more rapidly.
Example 199: the effect of compounds of formula I on the discriminatory stimulatory effect of dextromethorphan and memantine: drug discrimination is commonly used to assess the control of the inter-sensory stimuli produced by psychoactive drugs (Sukhotina IA et al, Effects of calcium channel blockers on behaviour induced by antibodies in rats [ effect of calcium channel blockers on N-methyl-D-aspartate receptor antagonists, dezocyclopine ]. Pharmacol Biochem Behav [ pharmacological biochemistry and behaviourology ] (1999)63: 569-80). These methods are used to address the ability of certain classes of CNS active drugs (e.g., NMDA receptor channel blockers) to produce adverse reactions (Nicholson KL et al, Evaluation of thermal and cognitive stimulation properties of the low-affinity N-methyl-D-aspartate channel blocker memantine [ Evaluation of enhancement and discrimination stimulation properties of low-affinity N-methyl-D-aspartate channel blocker memantine ] Behav Pharmacol [ behavioral pharmacology ] (1998)9: 231-43).
Adult male Wistar rats were individually housed and water was available ad libitum. Food consumption was limited to 14-16 grams/day after behavioral testing to maintain a constant body weight (300- & ltSUB & gt 330 g). Behavioral training and testing was performed using a standard two-lever operated conditioning chamber interfaced to a microcomputer and controlled by MED-PC software. Each chamber was equipped with a food dispenser that could dispense 45mg of food particles. At the beginning of each drug discrimination training session, rats were injected intraperitoneally with 0.056mg/kg dezocyclopine or saline, returned to their home cages, and then placed in the operating room 15min later for a total of 15 min. During the test section, 10 consecutive reactions on either lever produced particle transport. Two injections were performed before the test section; one intraperitoneal injection of deramciclane (3mg/kg) or its carrier (60 min injection time) and one injection of dezocyclopine (0.056mg/kg), memantine (10mg/kg), dextromethorphan (30mg/kg) or physiological saline (15 min injection time). The percent response and response rate (response/sec) on the Designated Lever (DLR) of dezocyclopine for each test segment was calculated to determine the intensity of deramciclane that significantly reduced the discriminating stimulatory effect of NMDA receptor channel blockers at doses that did not significantly impair performance (fig. 14B) (fig. 14A). The reduced magnitude of the discriminatory stimulatory effect of memantine in the presence of deramciclane (FIG. 1 above) indicates that deramciclane can control the adverse effects of NMDA receptor channel blockers (such as dextromethorphan) (Nicholson KL et al, Evaluation of the potentiating properties and benzene ring discriminatory stimulatory effects of dextromethorphan and dextrorphan in rats and rhesus monkeys [ Psychology [ Psychopharmacology ] (1999)146:49-59), this can be controlled not only by inhibiting the metabolic control of dextromethorphan (Zawertailo LA et al, Effect of metabolic block on the psychoactive effects of dextromethorphan. [ Effect of metabolic blockade on psychotropic effects of dextromethorphan ]. HumPsychopharmacol [ human psychopharmacology ] (2010)25:71-9), but also by pharmacokinetic mechanisms. Thus, given the 2D6 inhibitory properties of deramciclane, deramciclane most effectively controls the subjective effects of NMDA receptor channel blockers (such as dextromethorphan) metabolized via CYP2D 6.
Example 200: similar antidepressant effects of the compounds of formula I administered in combination with NMDA receptor channel blockers: tail suspension is one of the classical tests for studying antidepressant drugs and is also used to evaluate similar antidepressant effects of NMDA receptor channel blockers (Kos T et al, Effect of 5-HT3 receptor antagonist MDL 72222on behavionized by ketamine in rates and mice. [ Effect of 5-HT3 receptor antagonist MDL 72222on vitamin induced behavior in rats and mice ]. European Neuropsychopharmacology [ European neuropsychology ] (2006)16: 297-. Mice were transferred from the housing room to the test area in their home cage and allowed to acclimate to the new environment for at least 1 hour prior to drug treatment. Immobility was induced by tail suspension, so that mice were individually attached to a paper tape 65cm above the table. The tape was placed about 1cm from the tip of the tail. Animals were suspended for 6min and duration of immobility was recorded. Mice were considered immobile only when they were completely stationary. Two injections were performed before the test section; one intraperitoneal injection of deramciclane (3mg/kg) or its carrier (injection time 60min) and one injection of memantine (3mg/kg), dextromethorphan (10mg/kg) or physiological saline (injection time 30 min). Although none of the treatments given these dose levels alone had a statistically significant effect, the administration of deramciclane in combination with dextromethorphan significantly reduced the immobility time, indicating that the combination has a similar antidepressant potential (fig. 15A). The combination of deramciclane and memantine also reduced immobility time by 57% (P ═ 0.1). Surprisingly, when a sub-effective dose of memantine (3mg/kg) was administered in combination with another 5-HT2A/2C receptor antagonist, ritanserin (1mg/kg), no reduction in immobility time was observed (FIG. 15B). In contrast, ritanserin was able to reverse the similar antidepressant effect of an effective dose of memantine (10 mg/kg). These results indicate that deramciclane is capable of producing a pharmacodynamic effect when administered in combination with NMDA receptor channel blockers, which distinguishes it from at least some other representatives of the 5-HT2A/2C receptor antagonist and inverse agonist classes.
Example 201: anxiolytic effects of compounds of formula I administered in combination with NMDA receptor channel blockers: conflict tests (such as the geller-schiff test) are commonly used to study the Anxiolytic effect of drugs and are also used to assess the Anxiolytic effect of glutamate receptor antagonists (Pietraszek M et al, anallytic-lipid effects of mGlu1 and mGlu5receptor antagonists in rats [ similar Anxiolytic effect of mGlu1 and mGlu5receptor antagonists in rats ]. Eur J Pharmacol [ european journal of pharmacology ] (2005)514: 25-34).
Rats were trained to lever press under multiple Fixed Ratio (FR)20 (food only), FR 20 (food and shock) schedules with three 7-min non-penalized portions alternating with three 3-min penalized portions using a standard operating conditioning chamber interfaced to a computer and controlled by MED-PC software, with a total segment length of 30 min. The amperage and duration of the shock was adjusted for each individual rat. In the penalized and non-penalized portions of each zone, the data is analyzed as the response rate (responses per second). For analytical purposes, response rate data obtained during drug trials were expressed as response rate changes from a 5 day baseline. Two injections were performed before the test section; one intraperitoneal injection of deramciclane (1mg/kg) or its vehicle (injection time 60min) and one injection of memantine (3mg/kg) or physiological saline (injection time 30 min). The dose levels of both deramciclane and memantine had a significant effect on either punished or unpurified responses (fig. 16A and 16B). However, when sub-effective doses of memantine and deramciclane were given in combination, significantly more punitive responses were observed in rats, indicating that the synergistic interaction between deramciclane and memantine resulted in a reduction in anxiety.
Example 202: the anti-challenge effect of a compound of formula I administered in combination with an NMDA receptor channel blocker: male mice housed in isolation develop easily and show an aggression to an intruder. Such paradigms have been used to evaluate the resistance of NMDA receptor channel blockers to attack (Belozertseva IV, Bespalov AY, Effects of NMDA receptor channel on aggregation in isolated male mice [ influence of NMDA receptor channel blocking on Aggressive Behavior in isolated male mice ], Aggressive Behavior [ Aggressive Behavior ] (1999)25: 381-396). In these experiments, mice were housed individually and challenge-group housed challenge-challenged invasive mice were repeated (twice a week) for 4 minutes starting two weeks after the first two weeks of isolation. Only resident mice that consistently exhibited aggressive behavior to intruders were used for drug testing. Drug testing was initiated when the resident mice showed an attack on the intruder in at least three consecutive tests and lived in isolation for at least 35 days. The invader mice were housed in 5 mice per group. Thirty minutes prior to testing, mice were treated with memantine (10mg/kg) in combination with deramciclane (3mg/kg) or ritanserin (1 mg/kg). None of the selected doses of the compounds, when used alone, exerts any significant effect on the agonistic behaviour (aggression, bites, threats, tail rattle, upright and rolling posture, pushing and backing). However, when memantine was combined with deramciclane (but not ritanserin), the probability of mouse challenge was significantly reduced without any visible ataxia (figure 17). Thus, while deramciclane or NMDA receptor antagonists may be ineffective when administered alone, they may produce potent anti-challenge properties when administered in combination.
Example 203: the activity of O-demethylation of dextromethorphan (Yu et al, synthetic connective method by cytochromes P450 isoforms in vitro: a used as a dual probe for both CTP2D6 and CYP3A in vitro contribution of cytochrome P450 subtype to dextromethorphan metabolism. Recombinant CYP2D6(0.25pmol) and HLM (12.5. mu.g protein) were used as enzyme sources. The incubation mixture consisted of the enzyme source, dextromethorphan, NADPH generating system (500. mu.M NADP, 10mM glucose-6-phosphate, 10mM magnesium chloride, and 1 unit/ml 6-glucose-phosphate dehydrogenase), and 100mM potassium phosphate buffer (pH 7.4) in a final volume of 200. mu.l. The incubation was performed at 37 ℃ for 10min and then stopped by adding 10. mu.l of 70% (w/v) perchloric acid. After removal of the proteins by centrifugation, 50. mu.l of the supernatant was subjected to high performance liquid chromatography (D7500 integrator, L-7100 pump, L-7200 autosampler, L-7300 column oven and L-7485 fluorescence detector) equipped with a Mightysil RP-18GP column (4.6. mu.250 mm, 5 μm). The mobile phase was a mixture of acetonitrile/methanol: 10mM potassium phosphate buffer (pH adjusted to 3.5 with phosphoric acid) (200:160: 630). Elution was performed at a flow rate of 1.0 ml/min. The formation of dextrorphan was monitored at excitation at 280nm and emission at 310 nm.
The pre-incubation mixture contained recombinant CYP2D6(2pmol), each major cannabinoid (2.5-50. mu.M), NADPH-producing system (8.2. mu.M NADP, 0.41mM glucose-6-phosphate, 0.41mM magnesium chloride and 1 unit/ml glucose-6-phosphate dehydrogenase), and 100mM potassium phosphate buffer (pH 7.4) in a final volume of 180. mu.l. After 5 minutes of preheating at 37 ℃, the reaction was initiated by adding the NADPH generating system. After a pre-incubation of 20min, 20 μ l of AMMC solution was added to the pre-incubation mixture (final substrate concentration of 0.6 μ M). Incubation was performed in the same manner as described in the AMMC O-demethylase activity enzyme assay. Prediction of drug interactions in CYP2D 6. An estimate of in vivo inhibitory potency was determined by the method of Obach et al (2006). The maximum unbound liver input concentration Cmax, u, inlet was determined using the following formula:
Cmax，u，inlet＝fu·(Cmax+D·Fa·ka/Qh)
cmax is defined as the maximum systemic concentration, fu is the fraction unbound in the blood, D is the oral dose, Fa is the fraction of the absorbed oral dose, ka is the first order absorption constant, and Qh is the hepatic blood flow. In the case of the inhalation of hemp, the patient is,
absorption from the gastrointestinal tract is not considered. Thus, Cmax, u, let of inhaled cannabinoids is equal to fu Cmax. The fu value of cannabinoids is at most 0.05, as 95% to 99% of plasma THC binds to plasma proteins (mainly lipoproteins) (Grotenhermen, 2003). The ratio of the area under the curve (AUC) with inhibitor to the control AUC can be estimated using the following formula:
AUCsuppression of/AUCControl＝1/{[fm(CYP2D6)/(1+[I]In vivo/Ki)]+(1-fm(CYP2D6)}
In the above equation, the AUC inhibited is the area under the curve for a given substrate probe in the presence of the inhibitor, and AUCControlIs the area under the curve of the same probe substrate without inhibitor. The fraction of probe substrate metabolized by CYP2D6 and the magnitude of inhibitor potency are expressed as fm (CYP2D6) and Ki, respectively. A uniform value was used for fm (CYP2D6) for the dextromethorphan/dextromethorphan urine ratio (Obach et al, 2006). Thus, AUC for dextromethorphanSuppression ofAnd AUCControlIs equal to 1+ [ I ]]In vivo/Ki。
Example 204: the time-dependent distribution and pharmacokinetics of the dual-labeled compound 829 (compounds 829-phenyl-C-14 and-ethyl-H-3) in plasma, pituitary and 14 brain regions, including the rat spinal cord, were studied after a single oral treatment (acute experiment) and repeated administration of one dose per day for six days (subacute experiment). Tissue levels of compound 829 were calculated from concurrently determined dpm values and the specific activities of the two radiosomes present in the administered dose. EGIS-3885 is rapidly absorbed from the gastrointestinal tract (t (max) ═ 1.0 h). The concentration-time curve in tissue can be described with a two-compartment open model. H-3 activity can be measured throughout the acute experimental period (95H), while C-14 radioactivity is below the limit of detection within 24H. The AUC (0.96) value f of H-3 was 10 to 15 times higher than C-14.I, and a peak characteristic of the liver-intestine circulation was observed in 12H on the concentration time curve in all samples examined. Studies have shown that intact molecules enter brain tissue from the circulation. The results of the subacute experiments indicated that C-14 labeled compound 829 or one or more tracer-carrying metabolites reaches equilibrium as early as the second to third days, while the H-3 radioactivity levels continued to increase over the six days of repeated administration. In subacute experiments, peak concentrations were reached 0.5h after final treatment. However, the 3H value was higher than in the acute experiment. No final trend was observed in the case of the C-14 tracer. AUC values determined for the H-3 marker compound 829 in subacute experiments are advantageously higher than for C-14; the proportion of all brain areas is 50 to 60. Enterohepatic circulation observed after a single administration was also performed after repeated administrations. The time-related concentration of compound 829 in the pituitary is at least two-fold higher than the concentration in plasma and brain tissue. No significant difference was observed In the concentration Of compound 829 In the symmetric (left and right) regions Of the brain (Magyar et al, Distribution Of Deramciclane In Rat brain region, European journal Of drug metabolism and pharmacokinetics, 23(2), pp.125-131 (1998), incorporated by reference In its entirety.
Example 205: 5HT2a assay: evaluation of the affinity of compounds determined in the radioligand binding assay for the human 5-HT2A receptor in transfected HEK-293 cells. Cell membrane homogenates (30-50 μ g protein) were incubated with 0.5nM [3H ] ketanserin at 37 ℃ for 15min in a buffer containing 50mM Tris-HCl (pH 7.4) in the absence or presence of test compounds. Nonspecific binding was determined in the presence of 1 μ M ketanserin. After incubation, the samples were rapidly filtered under vacuum through a glass fiber filter pre-soaked with 0.3% PEI and rinsed several times with ice-cold 50mm tris-HCl using a 96-sample cell harvester. The filter is dried and the radioactivity is then counted in a scintillation counter using a scintillation cocktail (WO2005013952a1, EP1500391a1, the entire contents of which are incorporated by reference).
Example 206: male NMRI mice (20-25 g in weight) were placed on a hot plate (56. + -. 0.5 ℃) and the latency time elapsed before licking the forepaw was measured. The reaction time was tested twice before treatment. Animals were discarded if the first basal latency was >5 seconds, or the difference between the two control measurements was greater than 3 seconds. Mice were treated subcutaneously with saline or 1mg/kg morphine HCl and were concurrently treated intraperitoneally with 30mg/kg vehicle or deramciclane or buspirone HCl, respectively. After the treatment (15, 30, 45 and 60min) the reaction times were measured again. Animals are considered positive if they produce a 2.5-fold increase in reaction time at least 2 times greater than their first control value. The combined administration of morphine and compound 129 showed a statistically significant analgesic effect compared to either compound administered alone (EP1734940B1, incorporated by reference in its entirety).
Example 207: CNS efficacy of compounds of formula I may be mediated by biologically active metabolites: compound 50 is a peripherally acting 5-HT2A receptor antagonist (Obata H et al, Antinociception in the by saline, active 5-HT (2A) receptor antagonist, is peripheral [ the antinociceptive effect on Rats by sarpogrelate (a selective 5-HT (2A) receptor antagonist) is peripheral ]. Eu J Pharmacol [ European Pharmacol ] (2000)404:95-102), direct evidence generated using [14C ] labeled compound 50 suggests that sarpogrelate may not cross the blood brain barrier of Rats (Komatsu T et al, students on the Metabolic Fate of (+) -2 (diamido) -1-CCo (m-metaxyphenyl) phenoxy ] ethylene hydrochloride (MCmethoxy-ethyl) ligand of Rats [ (MCgraphoxyphenyl) 2- (dimethyl-phenoxy) -1-methoxy-ethyl ] (MCgraphoxyphenyl-ethyl-2-ethyl) Metabolism-3-ethyl acetate (I, methyl-phenoxy) -2- (dimethyl-ethyl) acetate (I, dimethyl-phenoxy) -2- (dimethyl-ethyl) succinate) Metabolic fate study of acid salt hydrochloride (MCI-9042) (II): absorption, distribution, metabolism, and excretion of rats after a single administration)).
Adult male SD rats (10mg/kg intraperitoneally) were pretreated with compound 146 or M1 and brain and plasma were collected at 30, 60, 120 and 240min after M1 administration. The amount of compound in the brain tissue extract was measured using UPLC/MS analysis. As shown in the XYZ panel, the total brain concentration of M1 significantly exceeded the blood concentration. Thus, unlike compound 50, M1 readily penetrates into the brain and can be responsible for the surprising CNS effects of compound 50.
The claims (modification according to treaty clause 19)
1. A composition comprising an NMDA receptor antagonist, 5-HT2AReceptor antagonists, 5-HT2AReceptor inverse agonists, 5-HT2CA receptor antagonist, and/or an inhibitor of the CYP2D6 enzyme, the composition comprising:
a) a compound of formula I:
b) a compound of formula II:
wherein R is6、R7And R8Independently is H, D, C1-10Alkyl, halo C1-10-alkyl, wherein halogen is F, Cl, or Br; r9And R10Independently is H; c1-10-an alkyl group; halogen substituted C1-10-alkyl, wherein halogen is F, Cl, or Br; OH; or R9And R10Together form a 5-membered heterocyclic ring, wherein the heteroatom is O, S, or N; an enantiomer, metabolite, derivative, prodrug, salt, diastereomer, pharmaceutically acceptable salt, or N-oxide thereof, or a combination thereof; or an enantiomer thereof, a metabolite thereof, a derivative thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or an acid addition salt thereof, or a combination thereof.
2. The composition of claim 1, further comprising 5-methyl-10, 11-dihydro-5H-5, 10-methanone dibenzo [ a, d ] [7] annulene; 2- (2-chlorophenyl) -2- (methylamino) cyclohex-1-one; magnesium; (2S,4R) -4- (phosphonomethyl) piperidine-2-carboxylic acid; (E) -1- (3-ethylphenyl) -1-methyl-2- (naphthalen-1-yl) guanidine; 2-phenylpropane-1, 3-dimethyldicarbamate; 1- (1-phenylcyclohexyl) piperidine; 1-aminoadamantane; 3,5 dimethylaminoadamantanone; 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-phosphonovaleric acid salts; (S) and (R)6- (1 httetrazol-5-ylmethyl) decahydroisoquinoline-3-carboxylic acid; (S) -a-amino-5- (phosphonomethyl) [1, 19-diphenyl ] -3-propionic acid; (S) - (6) -cis-4- (4-phenylbenzoyl) piperazine-2, 3-dicarboxylic acid; (R) - (6) -cis-4- (4-phenylbenzoyl) piperazine-2, 3-dicarboxylic acid; cis-4-phosphonomethyl-2-piperidinecarboxylic acid; 2R,4R,5S- (2-amino-4, 5- (1, 2-cyclohexyl) -7-phosphonoheptanoic acid); or cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid; or an enantiomer thereof, a metabolite thereof, a derivative thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or an acid addition salt thereof; or a combination thereof.
3. The composition of claim 1, wherein the compound of formula I is a dual agent having CYP2D6 inhibitor activity, and 5-HT2A receptor inverse agonist or 5-HT2A receptor antagonist/inverse agonist activity, selected from the group consisting of:
4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid;
(S) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid;
(R) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid;
4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid;
(S) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid;
(R) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid;
4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,2, 3-trifluoro-4-oxobutanoic acid;
(S) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,2, 3-trifluoro-4-oxobutanoic acid;
(R) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,2, 3-trifluoro-4-oxobutanoic acid;
4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,3, 3-trifluoro-4-oxobutanoic acid;
(S) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,3, 3-trifluoro-4-oxobutanoic acid;
(R) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,3, 3-trifluoro-4-oxobutanoic acid;
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-trimethyl-bicyclo [2,2,1] heptane;
2-benzyl-2- (2-diisopropylaminoethoxy) -1,7, 7-trimethyl-bicyclo [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-trimethyl-bicyclo [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 ] ethylamine; ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3, 3-dimethylbutan-2-yl) (R) -fluorophosphate;
sec-butyl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
sec-butyl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
compound 908O- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- ((1, 3-dioxoisoindolin-2-yl) methyl) (dimethyl-l 3-oxyalkyl) dithiophosphinate;
o- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- ((1, 3-dioxoisoindolin-2-yl) methyl) (dimethyl-l 3-oxyalkyl) dithiophosphinate;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- ((1, 3-dioxoisoindolin-2-yl) methyl) (dimethyl-l 3-oxyalkyl) dithiophosphinate;
(E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl phosphate;
(E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylphosphonate;
(E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl phosphate
O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
o- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
(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;
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;
(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;
(S- ((tert-butylthio) methyl) O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
(ii) S- ((tert-butylthio) methyl) O- (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
(S- ((tert-butylthio) methyl) O- (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
o- (4- ((4- ((((((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
o- (4- ((4- (((((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
o- (4- ((4- (((((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
2-chloro-1- (2,4, 5-trichlorophenyl) ethenyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
2-chloro-1- (2,4, 5-trichlorophenyl) ethenyl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
2-chloro-1- (2,4, 5-trichlorophenyl) ethenyl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphoramide salt;
o- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphamide salt;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphamide salt;
(O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthiophosphorus) anhydride;
(O- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthiophosphorus) anhydride;
(O- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthiophosphorus) anhydride;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphoramide salt;
o- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphamide salt;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphamide salt;
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 compound with methane (1: 1);
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 compound with methane (1: 1);
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 compound with methane (1: 1);
2-chloroethyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
2-chloroethyl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
2-chloroethyl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
3-chlorobutan-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
3-chlorobutan-2-yl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
3-chlorobutan-2-yl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
2-chloroethyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
2-chloroethyl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
2-chloroethyl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
1-chloropropan-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
1-chloropropan-2-yl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
1-chloropropan-2-yl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
3-chlorobutan-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
3-chlorobutan-2-yl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
3-chlorobutan-2-yl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
4- (tert-butyl) -2-chlorophenyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate compound with methane (1: 1);
4- (tert-butyl) -2-chlorophenyl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate compound with methane (1: 1);
4- (tert-butyl) -2-chlorophenyl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate compound with methane (1: 1);
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate;
((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate;
((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate;
((2(-) - [1R,2S,4R ] -2- (2-dimethylaminoethoxy) -2-phenyl-1, 7, 7-trimethylbicyclo [2.2.1] heptane) fumarate;
and wherein the compound of formula II is an NMDA receptor antagonist selected from the group consisting of: ketamine; meishadong; memantine; amantadine; dextro-propoxyphene; a Ketomitone; dextromethorphan; (4bS,8aS,9S) -11-methyl-3- (trifluoromethoxy) -6,7,8,8a,9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene;
(4bS,8aS,9S) -3- (trifluoromethoxy) -11- (trifluoromethyl) -6,7,8,8a,9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene; or
(4bS,8aS,9S) -3-methoxy-11- (trifluoromethyl) -6,7,8,8a,9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene;
or an acid addition salt selected from: acetate, acetylsalicylate, acetate,
Adipate, aspartate, butyrate, caprate, hexanoate, octanoate, heptanoate, formate, fumarate, glutamate, glutarate, hydrobromide, hydrochloride, isophthalate, maleate, malonate, methionate, oxalate, azelate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, hemi-lactobionate, glucaric acid (sugar acid), mannonate, mucate, rhamnosate, and tartrate; or a combination thereof.
4. The pharmaceutical composition of claim 3, wherein the agent is directed against CYP2D6, 5-HT2AAnd 5HT2CA triple agent of a receptor.
5. The pharmaceutical composition of claim 4, wherein the composition further comprises: a. a polymer, b an emulsifier, c a binder, d a disintegrant, and/or e a lubricant.
6. A pharmaceutical composition comprising a combination selected from the group consisting of:
or an acid addition salt thereof, selected from the group consisting of acetate, acetylsalicylate, adipate, aspartate, butyrate, caprate, hexanoate, octanoate, heptanoate, formate, fumarate, glutamate, glutarate, hydrobromide, hydrochloride, isophthalate, maleate, malonate, methionine, oxalate, nonanoate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, hemi-lactobionate, glucaric acid (sugar acid), Mannonate, mucate, rhamnonate, and tartrate; or a combination thereof.
7. The pharmaceutical composition of claim 6, wherein the composition is a fumarate and/or a hydrobromide salt of a combination of
8. The pharmaceutical composition of claim 6, wherein the composition further comprises: a. a polymer, b an emulsifier, c a binder, d a disintegrant, and/or e a lubricant.
9. The composition of claim 3, further comprising ajmaline, amiodarone, amitriptyline, amoxapine, aprepidine, azelastine, amphetamine, aryloxyaminoindane, benazene, baofensine, bupropion, butiline, celecoxib, 2-chloropropamicin, chlorpheniramine, chlorpromazine, cimetidine, cisapride, citalopram, clomipramine, clozapine, cocaine, dapoxetine, desipramine, desvenlafaxine, diphenylcetin, diphenhydramine, donepezil, dultiazepine, doxorubicin, duloxetine, escitalopram, fluoxetine, flufenazine, fluvastatin, fluvoxamine, galantamine, haloperidol, imipramine, indinavir, iprinin, ipramine, procarbazine, sorafen, levomeprazole, cloquinazine, clovir, cloquinazine, clorac, cloquinazine, and clomipramine, Loratadine, lurasidone, maprotiline, mequitazine, mesaprepin, methylphenidate, metoclopramide, mianserin, mibedil, milnacipran, mirtazapine, moclobemide, modafinil, nefazodone, nelfinavir, nevirapine, nialamide, nicardipine, norfluoxetine, nortriptyline, opipramine, perphenazine, phenelzine, pimozide, protriptyline, quinidine, rasagiline, risperidone, ritonavir, carbalartine, saquinavir, selegiline, sertindole, sertraline, sibutramine, tacrine, terbinafine, terfenadine, tesofensine, thioridazine, ticlopidine, tolterone, tranylcypromine, trazodone, trifluperidol, trimipramine, venlafaxine, yoclinol, or tiazaine; or a combination thereof.
10. The composition of claim 1, wherein the composition comprises 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate; (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate; (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate; (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate; 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate; (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate; 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate; (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate; (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate; 3, 5-dimethyladamantan-1-amine; or dimethyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate.
11. Use of a therapeutically effective composition of claim 4 in a method of increasing the plasma level of DEX in a subject in need thereof, wherein the subject is a rapidly metabolizing species of DEX, the method comprising administering the composition.
12. The method of claim 11, wherein the composition is administered once or twice daily, wherein the daily dose of DEX is from about 0.1mg to about 1000mg, such that AUC of DEX0-12Is greater than the AUC of DEX that would be achieved by administration of the same amount of DEX without the compound of formula I0-12。
13. The method of claim 11, wherein AUC for the compound of formula I0-12Is at least about 10ng/hr/mL, about 100ng/hr/mL, 200ng/hr/mL, about 300ng/hr/mL, or about 400ng/hr/mL, or about 500ng/hr/mL, or about 600ng/hr/mL, or about 700ng/hr/mL, or about 800ng/hr/mL, or about 900ng/hr/mL, or about 1000 ng/hr/mL.
14. The method of claim 11, wherein the administration is cutaneous, oral, intranasal, anal, rectal, vaginal, sublingual, buccal, sublabial, intramuscular, intravenous, peritoneal, epidural, intracerebral, intracerebroventricular, epidermal or topical, intraarticular, intracardiac, intracavernosal, intradermal, intralesional, intramuscular, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, or transmucosal.
15. Use of a therapeutically effective composition in a method of treatment comprising:
a) administering a therapeutically effective amount of the composition of claim 7;
b) targeting CYP2D6 enzyme, and NMDA, 5-HT2AAnd 5HT2CA receptor;
c) treating a neuropsychiatric or neurodegenerative disease or disorder, or brain injury, including Behavioral and Psychiatric Symptoms of Dementia (BPSD), in a patient in need thereof; and
d) resulting in remission and/or disease modification.

Claims (29)

1. A composition comprising one or more agents of the invention having at least one distinct Therapeutic Mode of Action (TMA), wherein the agent is an NMDA receptor antagonist, 5-HT2AReceptor antagonists, 5-HT2AReceptor inverse agonists, 5-HT2CA receptor antagonist, and/or an inhibitor of CYP2D6, wherein the agent is a compound of formula I:
Figure FDA0002304114410000011
wherein R is1And R2Independently is H, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C5-10Aryl, substituted or unsubstituted C3-10cycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10Bicycloalkyl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Heteroaryl, or substituted or unsubstituted C5-10Heteroaryl, or R1And R2Together with nitrogen to form a saturated or unsaturated heterocyclic ring having one or more heteroatoms selected from N, O, and S; r3Independently is H, substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C5-10Aryl, substituted or unsubstituted C5-10Heteroaryl, substituted or unsubstituted C3-10cycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10Bicycloalkyl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Aryl, substituted or unsubstituted C4-10bicycloalkyl-C5-10Heteroaryl or substituted or unsubstituted C5-10A heteroaryl group;
n is an integer from 0 to 5; r4Is H, NH-R5、S-R5、-OH、O-R5、–CO-R5、–O-CO-R5or-CO-O-R5Wherein R is5Is an acyl group; or R5And R2Forming a heterocyclic ring; or an enantiomer thereof, a metabolite thereof, a derivative thereof, a prodrug thereof, an acid addition salt thereof, a pharmaceutically acceptable salt thereof, or an N-oxide thereof; or a combination thereof.
2. The composition of claim 1, further comprising 5-methyl-10, 11-dihydro-5H-5, 10-methanone dibenzo [ a, d ] [7] annulene; 2- (2-chlorophenyl) -2- (methylamino) cyclohex-1-one; magnesium; (2S,4R) -4- (phosphonomethyl) piperidine-2-carboxylic acid; (E) -1- (3-ethylphenyl) -1-methyl-2- (naphthalen-1-yl) guanidine; 2-phenylpropane-1, 3-dimethyldicarbamate; 1- (1-phenylcyclohexyl) piperidine; 1-aminoadamantane; 3,5 dimethylaminoadamantanone; 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-phosphonovaleric acid salts; (S) and (R)6- (1 httetrazol-5-ylmethyl) decahydroisoquinoline-3-carboxylic acid; (S) -a-amino-5- (phosphonomethyl) [1, 19-diphenyl ] -3-propionic acid; (S) - (6) -cis-4- (4-phenylbenzoyl) piperazine-2, 3-dicarboxylic acid; (R) - (6) -cis-4- (4-phenylbenzoyl) piperazine-2, 3-dicarboxylic acid; cis-4-phosphonomethyl-2-piperidinecarboxylic acid; 2R,4R,5S- (2-amino-4, 5- (1, 2-cyclohexyl) -7-phosphonoheptanoic acid); cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid; or a compound of formula II, an enantiomer thereof, a metabolite thereof, a derivative thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or an acid addition salt thereof; or a combination thereof.
3. The composition of claim 1, wherein the compound of formula I is selected from the group consisting of:
4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid;
(S) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid;
(R) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -3, 3-difluoro-4-oxobutanoic acid;
4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid;
(S) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid;
(R) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2, 2-difluoro-4-oxobutanoic acid;
4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,2, 3-trifluoro-4-oxobutanoic acid;
(S) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,2, 3-trifluoro-4-oxobutanoic acid;
(R) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,2, 3-trifluoro-4-oxobutanoic acid;
4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,3, 3-trifluoro-4-oxobutanoic acid;
(S) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,3, 3-trifluoro-4-oxobutanoic acid;
(R) -4- ((4- (dimethylamino) -1- (2- (3-methoxyphenethyl) phenoxy) butan-2-yl) oxy) -2,3, 3-trifluoro-4-oxobutanoic acid;
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-trimethyl-bicyclo [2,2,1] heptane;
2-benzyl-2- (2-diisopropylaminoethoxy) -1,7, 7-trimethyl-bicyclo [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-trimethyl-bicyclo [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 ] ethylamine; ((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methylisopropyl (S) -fluorophosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3, 3-dimethylbutan-2-yl) (R) -fluorophosphate;
sec-butyl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
sec-butyl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
compound 908, O- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl O- (4-nitrophenyl) thiophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- ((1, 3-dioxoisoindolin-2-yl) methyl) (dimethyl-l 3-oxyalkyl) dithiophosphinate;
o- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- ((1, 3-dioxoisoindolin-2-yl) methyl) (dimethyl-l 3-oxyalkyl) dithiophosphinate;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- ((1, 3-dioxoisoindolin-2-yl) methyl) (dimethyl-l 3-oxyalkyl) dithiophosphinate;
(E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl phosphate;
(E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylphosphonate;
(E) -3-chloro-4- (diethylamino) -4-oxobut-2-en-2-yl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl phosphate
O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
o- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S- (2- (ethylsulfinyl) ethyl) O-methylthiophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyl S- ((ethylthio) methyl) dithiophosphate;
(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;
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;
(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;
(S- ((tert-butylthio) methyl) O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
(ii) S- ((tert-butylthio) methyl) O- (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
(S- ((tert-butylthio) methyl) O- (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-ethyldithiophosphate;
o- (4- ((4- ((((((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
o- (4- ((4- (((((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
o- (4- ((4- (((((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) thiophosphoryl) oxy) phenyl) thio) phenyl) O, O-dimethylthiophosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyltriethyldiphosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
2-chloro-1- (2,4, 5-trichlorophenyl) ethenyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
2-chloro-1- (2,4, 5-trichlorophenyl) ethenyl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
2-chloro-1- (2,4, 5-trichlorophenyl) ethenyl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphoramide salt;
o- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphamide salt;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphamide salt;
(O- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthiophosphorus) anhydride;
(O- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthiophosphorus) anhydride;
(O- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propylthiophosphorus) (O, O-dipropylthiophosphorus) anhydride;
o- (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphoramide salt;
o- ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphamide salt;
o- ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methylacetylthiophosphamide salt;
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 compound with methane (1: 1);
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 compound with methane (1: 1);
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 compound with methane (1: 1);
2-chloroethyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
2-chloroethyl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
2-chloroethyl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
3-chlorobutan-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
3-chlorobutan-2-yl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
3-chlorobutan-2-yl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (R) -fluorophosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (S) - (((((E) -chlorofluoromethylene) amino) oxy) fluorophosphonate;
2-chloroethyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
2-chloroethyl ((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
2-chloroethyl ((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
1-chloropropan-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
1-chloropropan-2-yl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
1-chloropropan-2-yl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
3-chlorobutan-2-yl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
3-chlorobutan-2-yl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
3-chlorobutan-2-yl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) (E) - (((chlorofluoromethylene) amino) oxy) fluorophosphate;
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate;
4- (tert-butyl) -2-chlorophenyl (((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate compound with methane (1: 1);
4- (tert-butyl) -2-chlorophenyl (((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate compound with methane (1: 1);
4- (tert-butyl) -2-chlorophenyl (((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) methylaminophosphate compound with methane (1: 1);
((1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate;
((((S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate;
(((((R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4- (methylthio) phenyl) isopropylaminophosphate and
((2, (-) - [1R,2S,4R ] -2- (2-dimethylaminoethoxy) -2-phenyl-1, 7, 7-trimethylbicyclo [2.2.1] heptane) fumarate.
4. The composition of claim 3, further comprising a compound of formula II, an enantiomer thereof, a metabolite thereof, a derivative thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or an acid addition salt thereof; or a combination thereof.
5. The composition of claim 4, wherein the compound of formula I is acetate, acetylsalicylate, adipate, butyrate, caprate, hexanoate, octanoate, heptanoate, formate, fumarate, glutarate, isophthalate, maleate, malonate, oxalate, nonanoate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, difluorosuccinate, trifluorosuccinate, tetrafluorosuccinate, difluoroglutarate, difluoroacetate, trifluoroacetate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-tyrosine, N-acyl-tryptophan, N-acyl-methionine, hexanoate, octanoate, heptanoate, octanoate, or octanoate, Citrate, hemi-lactobionate, glucaric acid, sugar acid, mannose acid salt, mucate, rhamnosate acid salt, tartrate, 3- (nitrooxy) propionate, 4-nitrooxybutyrate, and 3- (nitrooxy) butyrate.
6. The composition of claim 4 wherein the compound of formula I is N, N-dimethyl-2- [ [ (1R,3S,4R) -4,7, 7-trimethyl-3-phenyl-3-bicyclo [2.2.1] heptylalkyl ] oxy ] ethylamine or an acetate, acetylsalicylate, adipate, butyrate, caprate, hexanoate, octanoate, heptanoate, formate, fumarate, glutarate, isophthalate, maleate, malonate, oxalate, nonanoate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, difluorosuccinate, trifluorosuccinate, tetrafluorosuccinate, difluoroglutarate, difluoroacetate, trifluoroacetate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, hemi-lactobionate, glucaric acid, sugar acid, mannonate, mucate, rhamnosate, tartrate, 3- (nitrooxy) propionate, 4-nitrooxy butyrate, or 3- (nitrooxy) butyrate; or a combination thereof.
7. The composition of claim 1, wherein the compound of formula I is N, N-dimethyl-2- [ [ (1R,3S,4R) -4,7, 7-trimethyl-3-phenyl-3-bicyclo [2.2.1] heptylalkyl ] oxy ] ethylamine, or an acetate, acetylsalicylate, adipate, butyrate, caprate, hexanoate, octanoate, heptanoate, formate, fumarate, glutarate, isophthalate, maleate, malonate, oxalate, nonanoate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, difluorosuccinate, trifluorosuccinate, tetrafluorosuccinate, difluoroglutarate, difluoroacetate, trifluoroacetate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, hemi-lactobionate, glucaric acid, sugar acid, mannonate, mucate, rhamnosate, tartrate, 3- (nitrooxy) propionate, 4-nitrooxy butyrate, or 3- (nitrooxy) butyrate; or a combination thereof; the composition further comprises memantine.
8. The composition of claim 4, wherein the compound of formula II is (4bS,8aS,9S) -11-methyl-3- (trifluoromethoxy) -6,7,8,8a,9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene; (4bS,8aS,9S) -3- (trifluoromethoxy) -11- (trifluoromethyl) -6,7,8,8a,9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene; (4bS,8aS,9S) -3-methoxy-11- (trifluoromethyl) -6,7,8,8a,9, 10-hexahydro-5H-9, 4b- (epinoethanol) phenanthrene.
9. The composition of claim 4, wherein the compound of formula II is an acid addition salt selected from: acetate, acetylsalicylate, adipate, aspartate, butyrate, caprate, hexanoate, octanoate, heptanoate, formate, fumarate, glutamate, glutarate, isophthalate, maleate, malonate, methionate, oxalate, azelate, pimelate, propionate, phthalate, salicylate, sebacate, succinate, terephthalate, caseinate, tryptophan, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-caseinate, N-acyl-tryptophan, N-acyl-methionine, citrate, hemi-lactobionate, glucaric acid (sugar acid), mannonate, mucate, rhamnosate, and tartrate.
10. The composition of claim 1, further comprising dextromethorphan and one or more agents selected from the group consisting of: 5-HT2A receptor antagonist/inverse agonist, 5-HT2A receptor inverse agonist, and CYP2D6 inhibitor.
11. The pharmaceutical composition of claim 8, wherein the agent is a dual agent having CYP2D6 inhibitor and 5-HT2A receptor antagonist/inverse agonist activity.
12. The pharmaceutical composition of claim 8, wherein the agent is a triple agent that is CYP2D6, 5-HT2AAnd 5HT2CA ligand for a receptor.
13. The pharmaceutical composition of claim 12, wherein the agent is a compound of formula I.
14. The pharmaceutical composition of claim 14, wherein the composition further comprises: a. a polymer, b an emulsifier, c a binder, d a disintegrant, and/or e a lubricant.
15. A composition comprising an acid of formula I-formula II:
16. the composition of claim 1, wherein the compound of formula I is a pure enantiomer having formula Ic or formula Id:
Figure FDA0002304114410000092
17. the composition of claim 3, further comprising thioridazine, perphenazine, flufenazine, clopenthixol, risperidone, sertindole, nortriptyline, amitriptyline, imipramine, fluoxetine, ajmaline, amiodarone, amitriptyline, aprepidine, azelastine, celecoxib, chlorpromazine, diphenhydramine, erythromycin, flufenazine, fluvastatin, haloperidol, imipramine, indinavir, lansoprazole, levomepromazine, lopinavir, loratadine, mequinatadine, mesalamine, metolachlor, metoclopramide, mibedill, nefinavir, nevirapine, nicardipine, norfluoxetine, perphenazine, pimozide, terfenadine, thioridazine, cimetidine, quinethazine, cilazamide, cilazapine, citalopamide, citalopram, clozapine, and cocaine, Risperidone, ritonavir, saquinavir, sertraline, terbinafine, ticlopidine, trifluperidol, yohimbine, dolasepine, mianserin, imipramine, 2-clomipramine, amitriptyline, amoxapine, desipramine, protiline, trimipramine, meptyline, phenelzine, isocarboxazid, tranylcypromine, trazodone, citalopram, sertraline, aryloxyaminoindane, benazene, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, bazedoary, tiapridine, cilazapine, loperamide, indomethamphetamine, olamide, nifloratadine, iprodione, toloxanil, tollofenamipramine, sulpirtine, duloxetine, lopamide, loperamide, indomethamphetamine, doxoramide, thiralidine, perphenazine, fluphenazine, clopenthixol, risperidone, sertindole, nortriptyline, amitriptyline, imipramine, fluoxetine, paroxetine, amitriptyline, aprepidine, azelastine, celecoxib, chlorpheniramine, diphenhydramine, erythromycin, fluphenazine, fluvastatin, flupiridol, imipramine, indinavir, lansoprazole, levomeprobrazine, lopinavir, loratadine, mequinatadine, mesalamine, metoclopramide, mibedil, moclobemide, nelfinavir, nevirapine, nicardipine, norfluoxetine, perphenazine, pemetrexedine, thioridazine, cimetidine, quinidine, cisapride, citalopram, clomipramine, clozapine, nortriptyline, rivastigmine, ritinavir, loperazine, quinacrine, Ticlopidine, trifluperidol, yohimbine, dolasepine, mianserin, imipramine, 2-chlorimipramine, amitriptyline, amoxapine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, trazodone, citalopram, sertraline, aryloxyaminoindane, phenmediphazine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, baofensine, moclobemine, rasagiline, niazidine, ipratropium, toloxanil, buttiazepine, dibenzepine, ipine, iopenzazole, lofepramine, or dapoxetine; or a combination thereof.
18. Use of a therapeutically effective composition of claim 2 in a method of increasing a plasma level of DEX in a subject in need thereof, wherein the subject is a rapidly metabolizing species of DEX, the method comprising administering the composition.
19. The method of claim 18, wherein the composition is administered once or twice daily, wherein the daily dose of DEX is from about 0.1mg to about 1000mg, such that AUC of DEX0-12Is greater than the AUC of DEX that would be achieved by administration of the same amount of DEX without the compound of formula I0-12。
20. The method of claim 18, wherein the composition further comprises: a. a polymer, b an emulsifier, c a binder, d a disintegrant, and/or e a lubricant.
21. The method of claim 18, wherein AUC for the compound of formula I0-12Is at least about 10ng/hr/mL, about 100 ng-hr/mL, 200 ng-hr/mL, about 300 ng-hr/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-hr/mL, or about 1000 ng-hr/mL.
22. The method of claim 18, wherein the administration is cutaneous, oral, intranasal, anal, rectal, vaginal, sublingual, buccal, sublabial, intramuscular, intravenous, peritoneal, epidural, intracerebral, intracerebroventricular, epidermal or topical, intraarticular, intracardiac, intracavernosal, intradermal, intralesional, intramuscular, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, or transmucosal.
23. The composition of claim 16, wherein the compound is selected from the group consisting of:
Figure FDA0002304114410000111
24. the composition of claim 23, further comprising memantine.
25. The composition of claim 1, wherein the composition comprises 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate; (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate; (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- (adamantan-1-ylamino) -4-oxobutanoate; (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate; 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate; or (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl 4- ((3, 5-dimethyladamantan-1-yl) amino) -4-oxobutanoate.
26. The composition of claim 1, wherein the composition comprises 1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate; (S) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate; or (R) -1- (dimethylamino) -3- (2- (3-methoxyphenethyl) phenoxy) propan-2-yl (2,2, 2-trichloro-1- (dimethoxyphosphoryl) ethyl) succinate.
27. The composition of claim 3, wherein the composition further comprises 3, 5-dimethyladamantan-1-amine.
28. The composition of claim 3, wherein the composition further comprises dimethyl (2,2, 2-trichloro-1-hydroxyethyl) phosphonate.
29. The composition of claim 28, wherein the composition further comprises a compound of formula II.
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