EP3618819A1 - Targeted drug rescue avec de nouvelles compositions, associations et procédés correspondants - Google Patents

Targeted drug rescue avec de nouvelles compositions, associations et procédés correspondants

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Publication number
EP3618819A1
EP3618819A1 EP18794381.6A EP18794381A EP3618819A1 EP 3618819 A1 EP3618819 A1 EP 3618819A1 EP 18794381 A EP18794381 A EP 18794381A EP 3618819 A1 EP3618819 A1 EP 3618819A1
Authority
EP
European Patent Office
Prior art keywords
methyl
phenoxy
oxy
propan
dimethylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18794381.6A
Other languages
German (de)
English (en)
Other versions
EP3618819A4 (fr
Inventor
Sreenivasarao Vepachedu
Hans J. MOEBIUS
Anton Bespalov
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Exciva GmbH
Original Assignee
Exciva GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2017/048748 external-priority patent/WO2018039642A1/fr
Application filed by Exciva GmbH filed Critical Exciva GmbH
Publication of EP3618819A1 publication Critical patent/EP3618819A1/fr
Publication of EP3618819A4 publication Critical patent/EP3618819A4/fr
Pending legal-status Critical Current

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Classifications

    • 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

Definitions

  • TDR Targeted Drug Rescue
  • TDR Targeted Drug Rescue
  • the invention is a composition comprising a combination of one or more agents, each having a unique Therapeutic Mode of Action (TMA), wherein the agent is NMDA Receptor Antagonist, 5-HT2A Receptor Antagonist, 5-HT2A Receptor Inverse Agonist, 5- HT2C Receptor Antagonist, and/ or CYP2D6 Inhibitor.
  • TMA Therapeutic Mode of Action
  • ent of the invention is a composition comprising a compound of Formula I:
  • Ri and R2 are independently H, substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted Cs iocycloalkyl-Cs io aryl, substituted or unsubstituted Guo bicycloalkyl, substituted or unsubstituted C4-10 bicycloalkyl-Cs-io aryl, substituted or unsubstituted C4-10 bicycloalkyl-Cs io heteroaryl, substituted or unsubstituted C4-10 tricycloalkyl, substituted or unsubstituted C4-10 tricycloalkyl-Cs io aryl, substituted or unsubstituted O-io tricycloalkyl-Cs-io heteroaryl, or substituted or unsubstituted C5-10 heteroaryl, or Ri and R2 together with the nitrogen form a saturated or unsaturated
  • R3 is independently H, substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted C5-10 heteroaryl, substituted or unsubstituted C3-10 cycloalkyl-Cs- 10 aryl, substituted or unsubstituted C4-10 bicycloalkyl, substituted or unsubstituted C4-10 bicycloalkyl-Cs-io aryl, substituted or unsubstituted C4-10 bicycloalkyl-Cs-io heteroaryl, substituted or unsubstituted C4-10 bicycloalkyl-Ci-io-alkyl-Cs-io aryl, substituted or unsubstituted C4-10 bicycloalkyl-Ci-io-alkyl-Cs-io aryl, substituted or unsubstituted C4-10 bicycloalkyl-Ci-i
  • n is an integer from 0 to 5;
  • R 4 is H, NH-R5, S-R 5 , -OH, 0-R 5 , -CO-R5, -O-CO-R5, or -CO-O-R5, wherein R5 is an acyl radical; or R5 and R2 form a heterocycle; or enantiomers thereof, metabolites thereof, derivatives thereof, and/or prodrugs thereof, pharmaceutically acceptable salts thereof, N- oxides thereof, or a combination thereof.
  • compositions comprising an effective amount of: 1) a composition comprising a compound of Formula I, as defined above, enantiomers thereof, metabolites thereof, derivatives thereof, and/or prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or a combination thereof; or 2) a compound of Formula II
  • R 6 , R7, and R 8 are independently H, D, Ci-10-alkyl, halo Ci-10-alkyl wherein halogen is F, CI, or Br; R9 and Rio are independently H; Ci-10-alkyl; halo Ci-10-alkyl wherein halogen is F, CI, or Br; OH; or R9 and Rio together form a five-membered heterocycle wherein the hetero atom is O, S, or N; enantiomers, metabolites, derivatives, prodrugs, salts, diastereomers, pharmaceutically acceptable salts, or N-oxides thereof, or a combination thereof; or 3) a combination of 1 and 2; or a combinations thereof.
  • Some embodiments include a method of treating a disease or disorder in a subject in need thereof comprising an effective amount of: 1) a composition comprising a compound of Formula I, as defined above; enantiomers thereof, metabolites thereof, derivatives thereof, and/or prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or a combination thereof ; or 2) a compound of Formula II, as defined above, enantiomers, metabolites, derivatives, prodrugs, salts, diastereomers, pharmaceutically acceptable salts, or N-oxides thereof, or a combination thereof; or 3) a combination of 1 and 2.
  • Some embodiments include a method of treating a disease or disorder in a subject in need thereof comprising an effective amount of a composition comprising dextromethorphan, enantiomers, metabolites, derivatives, or prodrugs thereof, or a combination thereof; salts and diastereomers thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, processes and intermediates for preparation thereof, compositions thereof, and uses thereof.
  • the method is a method of decreasing the number of doses and/or total daily dose of the compound of Formula II that can be administered while increasing efficacy and safeguarding tolerability and safety; a method of reducing an adverse event associated with treatment by the compound of Formula II, wherein the subject is at risk of experiencing the adverse event as a result being treated with the compound of Formula II; a method of decreasing metabolites of the compound of Formula II plasma levels, a method of treating a neurological disorder, a method of increasing the compound of Formula II plasma levels in a subject in need of treatment with the compound of Formula II, wherein the subject is an extensive metabolizer of the compound of Formula II; a method of inhibiting the metabolism of the compound of Formula II; a method of increasing the metabolic lifetime of the compound of Formula II; a method of correcting extensive metabolism of the compound of Formula II; a method of improving the antitussive properties of the compound of Formula II; a method of treating cough.
  • Another embodiment is the method, wherein the disease or disorder is a neurological disorder, wherein the subject is at
  • Some embodiments include 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 1000 mg/day, about 150 mg/day to about 5000 mg/day, about 150 mg/day to about 300 mg/day, or about 150 mg/day to about 100 mg/day, or an amount as required of a compound of Formula I, and about 0.1 mg/day to about 1 mg/day, about 0.5 mg/day to about 15 mg/day, about 15 mg/day to about 60 mg/day, about 15 mg/day to about 120 mg/day, about 0.1 mg/day to about 200 mg/day, or an amount as required of the compound of Formula II
  • Another embodiment is a pharmaceutical composition comprising the compound of Formula II and one or more agents selected from the group comprising 5-HT2A receptor antagonist /inverse agonist, and CYP2D6 inhibitor.
  • the agent is an agent having properties of both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor.
  • the agent is a dual agent (DA) having properties of both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor.
  • the DA is a compound of Formula I.
  • FIGURES 1A, IB, and 1C represent Dixon plots to determine Ki values for CYP2D6 of compounds of Formula I exemplified by Sarpogrelate and M-l, and quinidine.
  • concentrations of dextromethorphan were determined 2.5 (filled circles), 5 (open circles), and 10 (triangles) mM, respectively.
  • V represents formation rate of dextrorphan (pmol/min/mg protein).
  • Data are the mean values of triplicate determinations.
  • FIGURES 2A, 2B, and 2C represent Mean Neuropsychiatric Inventory Agitation/ Aggression Domain Scores by Stage and Visit for Patients Included in the Sequential Parallel Comparison Design and 10-Week Analyses.
  • A Stage 1 (weeks 1-5);
  • B stage 2 (weeks 6-10) for placebo nonresponders rerandomized after stage 1;
  • C 10- week results (the 10-week secondary analysis includes only patients who continued the same treatment assignment throughout study participation; ie, were randomized to receive only dextromethorphan-quinidine or only placebo [excludes patients who were rerandomized from placebo to dextromethorphan-quinidine in stage 2], thus simulating a parallel-group design).
  • FIGURES 3A, 3B, and 3C show treatment effects on psychosis severity reduction in the 6 week study period in the full analysis set.
  • the full analysis set includes all patients who received
  • FIGURES 4A, 4B, and 4C represent Lineweaver-Burk plots for the inhibition of CYP2D6 and human liver microsomes (HLMs) by Compound 847 (canabiodiol, CBD).
  • Recombinant CYP2D6 was incubated with (A) 3-[2-(N,N-Diethyl-N-methylammonium) ethyl]-7- methoxy-4-methylcoumarin (AMMC) in the presence of CBD (FIGURE 4A), (B)
  • HLMs were incubated with dextromethorphan in the presence or absence of CBD. Each point is the mean of duplicate determinations.
  • FIGURES 4D, 4E, and 4F represent effects of the major phytocannabinoids ⁇ 9 - tetrahydro cannabinol (A 9 -THC), CBD, and cannabinol (CBN) on AMMC and the
  • dextromethorphan O-demethylase activities of CYP2D6 and HLMs Recombinant CYP2D6 was incubated with (D) 0.6 ⁇ AMMC (FIGURE 4D), (E) 0.6 ⁇ dextromethorphan (FIGURE 4E) in the presence of various amounts of A 9 -THC, CBD, and CBN; and (F) HLMs were incubated with 4 ⁇ dextromethorphan in the presence of various amounts of A 9 -THC, CBD, and CBN (FIGURE 4F). Each point is the mean of two determinations (Yamaori et al.,
  • Cannabidiol a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6, Drug Metabolism and Disposition, Vol. 39, No. 11 (2011) incorporated in entirety by reference).
  • FIGURE 9A, 9B, and 9C show effects of a combination of dextromethorphan with Compound 50 racemate (upper panel), (-) Compound 51 (middle panel) or (+) Compound 52 on PCP- induced hyperactivity in rats.
  • FIGURE 11A and 11B show the mean (SEM) concentrations of (a) buspirone and (b) 1- PP after administration of 20 mg buspirone after an 8-day pretreatment with either 60 mg
  • FIGURE 13 shows prodrug strategies for the most common functional groups on parent drug compounds of Formula I and II representd by R with general schemes representing various embodiments of prodrugs of compounds of Formulae I and II.
  • FIGURE 18 shows the total concentration of compound 146 (Ml) in plasma and brain tissue.
  • TDR Targeted Drug Rescue
  • inventive Targeted Drug Rescue (TDR)TM comprising novel compositions, and combinations, therapeutic formulations, symptomatic and disease-modifying treatments, therapies, kits thereof, and methods of making such compositions, combinations, therapeutic formulations, treatments, therapies, and kits comprising biologies, chemicals, nutritionals, pharmaceuticals, compositions, treatments, therapies, cures, prophylactics, supplements, and formulations, including the disclosures of patent applications US 62/501,693 filed 05/04/2017, PCT/US2017/048748 filed 08/25/2017 published WO 2018/039642 Al 03/01/2018, 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 filed 02/27/2018, and US 62/636,099 filed 02/27/2018, all of which are incorporated by reference.
  • An embodiment of the invention is a composition comprising a compound of formula I:
  • Formula I, w h ere m 5 Ri and R2 are independently H, substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted C3-10 cycloalkyl-Cs io aryl, substituted or unsubstituted O iobicycloalkyl, substituted or unsubstituted C4-10 bicycloalkyl-Cs-io aryl, substituted or unsubstituted Gt-iobicycloalkyl-Cs-ioheteroaryl, or substituted or unsubstituted Cs-ioheteroaryl, or Ri and R2 together with the nitrogen form a saturated or unsaturated heterocycle having one or more hetero atoms selected from N, O, and S;
  • R3 is independently H, substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted C5-10 heteroaryl, substituted or unsubstituted C3-10 cycloalkyl-Cs- 10 aryl, substituted or unsubstituted C4-10 bicycloalkyl, substituted or unsubstituted C4-10 bicycloalkyl-Cs io aryl, substituted or unsubstituted C4-10 bicycloalkyl-Cs io heteroaryl or substituted or unsubstituted C5-10 heteroaryl; n is an integer from 0 to 5; R4 is H, NH-R5, S-R5, - OH, O-R5, -CO-R5, -O-CO-R5, or -CO-O-R5, wherein R5 is an acyl radical; or R5 and R2 form a heterocycle; or en
  • An embodiment is a compound of Formula I, wherein the substituted or unsubstituted C4- 10 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl radical.
  • the cycloalkyl comprises one or more heteroatoms N, S, or O.
  • Another embodiment is a compound of Formula I, wherein the substituted or unsubstituted C3-10 bicycloalkyl is bicyclobutyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl, or bicyclodecyl radical.
  • the bicycloalkyl comprises one or more heteroatoms N, S, or O.
  • Another embodiment is a compound of Formula I, wherein the aryl is phenyl, naphtyl, anthracenyl, or phenanthrenyl.
  • the compound is a compound of Formula I wherein R5 is an acyl radical selected from the group consisting of mono, di, and tri carboxylic acid radicals.
  • the compound is a compound of Formula I wherein R5 is an acyl radical selected from the group consisting of acetate, acetyl salicylate, adipate, N-acyl-aspartate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, N-acyl-glutarate, glutarate, isophthallate, maleate, malonate, methionate, N-acyl-methionate oxalate, pelargonate, pimelate, propionate, phthallate, salicylate, sebacate, succinate, terephthallate, tyrosinate, N-acyl- tyrosinate, tryptophanate, N-acyl-tryptophanate, and valerate.
  • R5 is an acyl radical selected from the group consisting of acetate, acetyl salicylate, adipate, N-acyl-aspartate, aspartate,
  • Another embodiment is a compound of Formula II,
  • R 6 , R7, and Rs are independently H, D, Ci-10-alkyl, halo Ci
  • halogen is F, CI, or Br
  • R9 and Rio are independently H
  • OH is a five-membered heterocycle wherein the hetero atom is O, S, or N.
  • R5 and R2 form a heterocycle selected from the radicals such as morpholine, dihydrooxazine, oxazine, piperazine, dihydropiperzine, and tetrahydropirazine.
  • Compounds of this embodiment include, but not limited
  • Another embodiment is a pure enantiomer of Formula I selected from Formula la or lb.
  • composition comprising Formula I is sarpogrelate (SARPO), wherein Ri, R2, and R3 are methyl, X is ethyl, and R 4 is succinoyl radical, having the following compounds SGL, SGL-E1, and SGL-E2.
  • SARPO sarpogrelate
  • composition comprising formula I is sarpogrelate metabolite Ml, wherein Ri, R2, and R3 are methyl, X is ethyl, and R 4 is OH, having the following compounds M1, M1-E1, and Ml-E2.
  • composition comprising formula I is sarpogrelate metabolite
  • the heterocycle 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 the unsaturated heterocycle. In one embodiment the heterocycle has one hetero atom. In another, the heterocycle has two hetero atoms.
  • the compound of formula I, wherein the heterocycle formed from Ri and R2 together with the nitrogen is selected from the heterocycles listed below:
  • DEX represents a compound of Formula II, such as dextromethorphan, enantiomers thereof, metabolites thereof, derivatives thereof, and/or prodrugs thereof, or a combination thereof.
  • Derivatives include, but not limited to, deuterated derivatives, e.g., DEX- H3, DEX-D3, DO, and DO-D3.
  • SARPO represents one or more compounds selected from the group consisting of sarpogrelate (SGL), enantiomers thereof, a metabolite thereof, Ml, SGI, SG2, SMG1, SMG2,
  • SMG3, a derivative thereof, a prodrug thereof, and a combination thereof represents a combination of DEX and a compound of Formula I.
  • An embodiment of the invention is a composition comprising a compound of formula I and dextromethorphan.
  • An embodiment of the invention is a composition comprising a compound of formula I and DEX-H3, DEX-D3, DO, or DO-D3.
  • An embodiment of the invention is a composition comprising: Ml, Ml-El, M1-E2, SGL, SGL-E1, or SGL-E2; and DEX-H3, DEX-D3, DO, or DO-D3.
  • DERADEXTM or DERAPHANTM represents a combination of DEX and a compound of Formula I, wherein the compound is a derivative of bicyclo[2.2.1]heptanol having
  • Formula I Formula I, w h ere m R 3 is a bicyclic system and the rest of the Formula I
  • R 7 as shown in Formula If ' wherein, R 6 is H, substituted or unsubstituted -Ci-io alkyl, substituted or unsubstituted -C3-10 cycloalkyl, substituted or unsubstituted -C5-10 aryl, substituted or
  • R 7 is -Ci-ioalkyl-X-(Y) n , -C3-10 cycloalkyl-X-(Y) m , -C5-10 aryl-X-(Y)m, or -C5-10 heteroaryl-X-(Y) m ; wherein X is a bond, N, O, S, -Ci-10 alkyl, -C3-10 cycloalkyl, -C5-10 aryl, -CO- Ci-10 alkyl, -CO- C3-10 cycloalkyl, -COC5-10 aryl, -CO-C5-10 heteroaryl, -CO-NH-Ci-10 alkyl, -CO- NH-C3-10 cycloalkyl, -CO-NH- C5-10 aryl, or -CO-NH-C5-10 heteroaryl; Y is H, Ci-10 alkyl, C3-10 cycloalkyl, Cs io ary
  • DERATINETM represents a combination of an NMDA receptor antagonist and and a compound of Formula I, as defned above.
  • SARPOTINETM represents a combination of an NMDA receptor antagonist and and a compound of Formula I, as defned above.
  • An embodiment of the invention is a composition comprising a compound of Formula I and DEX-H3, DEX-D3, DO, or DO-D3.
  • An embodiment of the invention is a compound of formula I, wherein the compound is sarpomalate, wherein Ri, R 2 , and R 3 are 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 sarpomethionate, wherein Ri, R 2 , and R 3 are methyl, X is ethyl, and R4 is methionate; compounds 30-34.
  • An embodiment of the invention is a compound of formula I, wherein the compound is sarpophthallate, wherein Ri, R 2 , and R 3 are 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 sarpomalonate, wherein Ri, R 2 , and R 3 are methyl, X is ethyl, and R4 is malonate' compounds 38- 40.
  • An embodiment of the invention is a compound of formula I, wherein the compound is sarpotyrosinate, wherein Ri, R 2 , and R 3 are methyl, X is ethyl, and R4 is tyrosinate; compounds 41-43.
  • An embodiment of the invention is a compound of formula I, wherein the compound is sarpotryptophanate, wherein Ri, R 2 , and R 3 are methyl, X is ethyl, and R4 is tryptophanate; compounds 44-46.
  • the composition is a combination of DEX and at least one compound selected from compounds 10-46, SGL, SGL-E1, SGL-E2, Ml, Ml-El, M1-E2.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpogrelate, and dextromethorphan.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpogrelate, and dextromethorphan, wherein sarpogrelate and
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpogrelate, and dextromethorphan, wherein sarpogrelate and dextromethorphan form a salt, wherein the salt is a diastereomeric mixture.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpogrelate, and dextromethorphan, wherein sarpogrelate and dextromethorphan form a salt, wherein the salt is a pure diastereomer.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpogrelate metabolite Ml, and dextromethorphan.
  • An embodiment of the invention is a composition comprising dextromethorphan and a compound of formula I, wherein the compound is sarpomalate, forming a salt comprising diastereomeric mixture or a pure diastereomer thereof.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpomethionate, and dextromethorphan, forming a salt comprising diastereomeric mixture or a pure diastereomer thereof.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpophthallate, and dextromethorphan, forming a salt comprising diastereomeric mixture or a pure diastereomer thereof.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpomalonate, and dextromethorphan, forming a salt comprising diastereomeric mixture or a pure diastereomer thereof.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpotyrosinate, and dextromethorphan, forming a salt comprising diastereomeric mixture or a pure diastereomer thereof.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is sarpotryptophanate, and dextromethorphan, forming a salt comprising diastereomeric mixture or a pure diastereomer thereof.
  • An embodiment of the invention is a composition comprising a compound of formula I, wherein the compound is SGL, and dextromethorphan HC1, forming a salt comprising diastereomeric mixture or a pure diastereomer thereof.
  • An 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 diastereomeric mixture or a pure diastereomer thereof.
  • An embodiment of the invention is a composition comprising a compound selected from the group consisting of SGL, enantiomers thereof, a metabolite thereof, Ml, SGI, SG2, SMG1, SMG2, SMG3, a derivative thereof, a prodrug thereof, and a combination thereof.
  • An embodiment of the invention is a composition comprising a compound selected from the group consisting of SGL, enantiomers thereof, a metabolite thereof, Ml, SGI, SG2, SMG1, SMG2, SMG3, a derivative thereof, a prodrug thereof, and a combination thereof, and dextromethorphan.
  • Another embodiment is a compound of Formula 1, wherein the Ra and R2 form a five- or six-membered heterocyclic moiety, exemplary compounds are compounds 110-145.
  • An embodiment of the invention is a composition comprising a compound selected from the group consisting of SGL, enantiomers thereof, a metabolite thereof, Ml, SGI, SG2, SMG1, SMG2,
  • examples of the compound of formula I, wherein the heterocycle formed from Ri and R2 together with the nitrogen represented by the compounds having Formulae -Is comprising saturated (shown below) and unsaturated heterocycles:
  • the compound is a compound of Formulae Ic-Is, wherein the 5- membered heterocycle is unsaturated.
  • the composition comprises DEX and a compound of formula I and/or prehexiline, flecainide, quinidine, (R)-propaphenone, (S)-propaphenone, isoniazid, (R)fluoxetine, (S)fluoxetine, nefazodone, paroxetine, ketoconazole, chloroquine, oxamniquine, primaquine, quinine, acetbutolol, betaxolol, bufuralol, oxprenolol, pindolol, propranolol, budipine, simvastatin, fluvastatin, lovastatin, pravastatin, perazine, ajamlicine, corynanthine, lobeline, or derivatives thereof.
  • composition comprising formula I, wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is OH, represented by the following compounds Ml, Ml-El, and Ml- E2.
  • Sarpogrelate Enantiomer 1 (SGL-E1)
  • Sarpogrelate Enantiomer 2 (SGL-E2) 4 -(( 1 -(dimethylamino) -3 -(2 -(3 - (5 -4 -(( 1 -(dimethylamino) -3 -(2 -(3 - (R)- -(( 1 -(dimethylamino) -3 -(2 -(3 - methoxyphenethyl)phenoxy)propa methoxyphenethyl)phenoxy)propan- methoxyphenethyl)phenoxy)propan-2- n-2-yl)oxy)-4-oxobutanoic acid 2-yl)oxy)-4-oxobutanoic acid yl)oxy)-4-oxobutanoic acid
  • composition comprising formula I, wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is succinoyl radical, represented by the following compounds SGL, SGL-E1, and SGL-E2.
  • the composition comprises a formula I, wherein R5 is -0(CO)-CH2- CH2-(CO)0-Y, wherein an alkyl, cycloalkyl, aryl, heteroaryl, -akenyl-aryl, -aralkyl, alkyl-ONC , cycloalkyl-ON02, aryl-ONC , heteroaryl-ON02, -akenyl-aryl-ON02, and -aralkyl-ON02, as exemplified, but not limited to, the following: l-(dimethylamino)-3-(2-(3- methoxyphenethyl)phenoxy)propan-2-yl methyl succinate, l-(dimethylamino)-3-(2-(3- methoxyphenethyl)phenoxy)propan-2-yl ((nitrooxy)methyl) succinate, l-(dimethylamino)-3-(2- (3-meth
  • the composition comprises DEX-H3, DEX-D3, DO, DO-D3, levomethorphan, morphine, codeine, thebaine, benzocaine, ketamine, methadone, memantine (3,5- dimethyladamantan-1 -amine), amantadine, dextropropoxyphene ((2R)-4-(dimethylamino)-3- methyl- 1 ,2-diphenylbutan-2-yl propionate), ketobemidone (l-(4-(3-hydroxyphenyl)-l- methylpiperidin-4-yl)propan-l-one), tropane alkaloids such as cocaine, atropine, scopolamine, etc.
  • the composition comprises a combination of a compound of Formula I and a compound of Formula II comprising DEX-H3, DEX-D3, DO, DO-D3, levomethorphan, morphine, codeine, thebaine, or benzocaine; and /or ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone, cocaine, atropine, or scopolamine.
  • the composition comprises a combination of a compound of Formula I and ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone, cocaine, atropine, or scopolamine, wherein the compound of Formula I is racemic compound 50 (sarpogrelate), racemic compound 146 ( Ml), or compound 829 (deramciclane).
  • the composition comprises memantine.
  • the composition comprises sarpogrelate and memantine.
  • the composition comprises enatimerically pure S-compound 51 (S-sarpogrelate) and R-compound 52 ( R- sarpogrelate)) and memantine.
  • the composition comprises enatimerically pure S-compound 147 (S-Ml), R-compound 148 (R-Ml), and memantine. In another embodiment, the composition comprises enantiomeric ally pure deramciclane and memantine.
  • the compound of the invention is a compound Formula I, wherein, Rl, R2, and R3 are independently substituted with one, two or three halogens, wherein the halogen
  • a compound of Formula I or analogs can be made using the following carboxylic acids: difluorosuccinicacid, HO2C-CF2-CH2-CO2H (201-206), trifluorosuccinic acid, HO2C-CF2-CHF-CO2H (207-212), tetrafluorosuccinic acid, H0 2 C-(CF 2 ) 2 - CO2H, difluorosuccinicacid (213-215), HO2C-CHF-CHF-CO2H (216-219), difluoroglutaric acid, H0 2 C-(CH2)2-CF2-C0 2 H (219-221), difluoroglutaric acid, HO2C- CF 2 - (CH 2 ) 2 -C0 2 H (222-225),
  • a compound of Formula I is Formula Ic or Formula Id, as defined above, and derivatives thereof comprising acid addition salts selected from: acetate, acetyl salicylate, adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, glutamate glutarate, isophthallate, maleate, malonate, methionate, oxalate, pelargonate, pimelate, propionate, phthallate, salicylate , sebacate, succinate, terephthallate, tyrosinate, tryptophanate, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-tyrosinate, N-acyl-tryptophanate, N-acyl- methionate, citrate, galactonate, glucaric acid (saccharic acid), mannonate, mucate, rhamnon
  • a compound of Formula I is Formula Ic or Formula Id, as defined above, and derivatives thereof comprising acid addition salts formed from di and tri carboxylic 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 (saccharic acid), malic acid, maleic acid, mannonic acid, mucic acid, oxalic acid, pimelic acid, phthallic acid, isophthallic acid, terephthallic acid, rhamnonic acid, sebacic acid, succinic acid, and tartaric acid.
  • di and tri carboxylic 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 (saccharic acid), mal
  • 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 derivative of Formula Ic, Formula Id, and Formula II thereof is independently an acid addition salt: hydrogen acetate, hydrogen acetyl salicylate, hydrogen adipate, hydrogen aspartate, hydrogen butyrate, hydrogen caprate, hydrogen caproate, hydrogen caprylate, hydrogen enanthate, hydrogen formate, hydrogen fumarate, hydrogen glutamate, hydrogen glutarate, hydrogen isophthallate, hydrogen maleate, hydrogen malonate, hydrogen methionate, hydrogen oxalate, hydrogen pelargonate, hydrogen pimelate, hydrogen propionate, hydrogen phthallate, hydrogen salicylate , hydrogen sebacate, hydrogen succinate, hydrogen terephthallate, hydrogen tyrosinate, hydrogen tryptophanate, hydrogen valerate, hydrogen N-acyl-aspartate, hydrogen N-acyl-glutamate, hydrogen N-acyl- t
  • Another embodiment is a composition comprising an acid addition salt of dextromethorphan and Ml selected from: dextromethorphan and Ml dihydrogen adipate, dextromethorphan and Ml dihydrogen aspartate, dextromethorphan and Ml dihydrogen fumarate, dextromethorphan and Ml dihydrogen glutamate, dextromethorphan and Ml dihydrogen glutarate, dextromethorphan and Ml dihydrogen isophthallate, dextromethorphan and Ml dihydrogen maleate, dextromethorphan and Ml dihydrogen malonate, dextromethorphan and Ml dihydrogen oxalate, dextromethorphan and Ml dihydrogen pimelate, dextromethorphan and Ml dihydrogen phthallate, dextromethorphan and Ml dihydrogen sebacate, dextromethorphan and Ml dihydrogen succinate, dexxtrome
  • a compound of Formula I is Formula Ic or Formula Id, as defined above, and fluoro derivatives thereof.
  • a compound of Formula I is a compound of Formula Ic or Formula Id, wherein the compound is Fluoro Derivative (FD) of Formula Ic (FDIc) or Formula Id (FDId), selected from compounds 221 - 269, and dextromethorphan or a compound of Formula II as defined above.
  • Another embodiment is a composition comprising an acid addition salt of dextromethorphan and FDIc selected from: dextromethorphan and FDIc dihydrogen adipate, dextromethorphan and FDIc dihydrogen aspartate, dextromethorphan and FDIc dihydrogen fumarate, dextromethorphan and FDIc dihydrogen glutamate, dextromethorphan and FDIc dihydrogen glutarate, dextromethorphan and FDIc dihydrogen isophthallate, dextromethorphan and FDIc dihydrogen maleate, dextromethorphan and FDIc dihydrogen malonate, dextromethorphan and FDIc dihydrogen oxalate, dextromethorphan and FDIc dihydrogen pimelate, dextromethorphan and FDIc dihydrogen phthallate, dextromethorphan and FDIc selected from
  • Another embodiment is a composition comprising an acid addition salt of dextromethorphan and FDId selected from: dextromethorphan and FDId dihydrogen adipate, dextromethorphan and FDId dihydrogen aspartate, dextromethorphan and FDId dihydrogen fumarate, dextromethorphan and FDId dihydrogen glutamate, dextromethorphan and FDId dihydrogen glutarate, dextromethorphan and FDId dihydrogen isophthallate, dextromethorphan and FDId dihydrogen maleate, dextromethorphan and FDId dihydrogen malonate, dextromethorphan and FDId dihydrogen oxalate, dextromethorphan and FDId dihydrogen pimelate, dextromethorphan and FDId dihydrogen phthallate, dextromethorphan and FDId selected from
  • the compound of Formula I is Formula Ic or Formula Id: [0082] In some embodiments, the compound of Formula Ic or Formula Id is Ml, wherein, Y is CH3; 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.
  • composition comprising a compound having Formula I,
  • la I f , w h ere m 5 R 6 is H, substituted or unsubstituted -Ci-1 0 alkyl, substituted or unsubstituted -C3-10 cycloalkyl, substituted or unsubstituted -C5-10 aryl, substituted or
  • R 7 is -Ci-ioalkyl-X-(Y) n , -C3-10 cycloalkyl-X-(Y) m , -C5-10 aryl-X-(Y)m, or -C5-10 heteroaryl-X-(Y) m ; wherein X is a bond, N, O, S, -Ci-io alkyl, -C3-10 cycloalkyl, -C5-10 aryl, -CO- Ci-10 alkyl, -CO- C3-10 cycloalkyl, -COC5-10 aryl, -CO-C5-10 heteroaryl, -CO-NH-Ci-10 alkyl, -CO- NH-C3-10 cycloalkyl, -CO-NH- C5-10 aryl, or -CO-NH-C5-10 heteroaryl; Y is H, Ci-10 alkyl, C3-10 cycloalkyl, Cs io
  • the compound is a compound of Formula If wherein R 6 is an aryl, and R 7 is substituted or unsubstituted -Ci-10 alkyl-X-(Y) n .
  • R 6 is substituted or unsubstituted Ci-10 alkyl- C5-10 aryl, and R 7 is substituted or unsubstituted -Ci-10 alkyl-X-(Y) n .
  • R 6 is phenyl
  • R 7 is -Ci-10 alkyl-N-( Ci-10 alkyl)2.
  • the compound of Formula I includes, but not limited to, the following examples: RS4-((4-(dimethylamino)-l-(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)- l-(2-(3-methoxyphenethyl) phenoxy)butan-2-yl)oxy)-3,3-difluoro-4-oxobutanoic acid; RS4-((4-(dimethylamino)-l-(2-(3- methoxyphenethyl)phenoxy)
  • Another embodiment is a compound of Formula If, wherein R 6 and R 7 are independently substituted with one, two or three halogens, wherein the halogen is F, CI, or Br.
  • halogenated compounds of Formula I include, but not limited to:
  • composition comprising a compound of Formula If listed below:
  • Another embodiment is a composition comprising an acid addition salt of a compound of
  • Another embodiment is a composition comprising an acid addition salt of N,N-dimethyl- 2-[[(lR,3S,4R)-4,7,7-trimethyl-3-phenyl-3-bicyc]o[2.2.1]heptanyl]oxy]ethanamine
  • (deramciclane) comprising deramciclane hydrogen acetate, deramciclane hydrogen acetyl salicylate, deramciclane hydrogen adipate, deramciclane hydrogen aspartate, deramciclane hydrogen butyrate, deramciclane hydrogen caprate, deramciclane hydrogen caproate, deramciclane hydrogen caprylate, deramciclane hydrogen enanthate, deramciclane hydrogen formate, deramciclane hydrogen fumarate, deramciclane hydrogen glutarate, deramciclane hydrogen isophthallate, deramciclane hydrogen maleate, deramciclane hydrogen malonate, deramciclane hydrogen oxalate, deramciclane hydrogen pelargonate, deramciclane hydrogen pimelate, deramciclane hydrogen propionate, deramciclane hydrogen phthallate, deramciclane hydrogen salicylate , deramciclane hydrogen sebacate, deramciclane hydrogen succinate, deramciclane hydrogen terephthallate, deramciclane hydrogen tyrosinate, deramciclane hydrogen tryp
  • An embodiment of the invention is a composition comprising dextromethorphan or its acid addition salt and a compound of Formula I selected from the group consisting of:
  • An embodiment of the invention is a composition comprising dextromethorphan or its acid addition salt, and deramciclane, deramciclane acetate, deramciclane acetyl salicylate, deramciclane adipate, deramciclane butyrate, deramciclane caprate, deramciclane caproate, deramciclane caprylate, deramciclane enanthate, deramciclane formate, deramciclane fumarate, deramciclane glutarate, deramciclane isophthallate, deramciclane maleate, deramciclane malonate, deramciclane oxalate, deramciclane pelargonate, deramciclane pimelate, deramciclane propionate, deramciclane phthallate, deramciclane salicylate , deramciclane sebacate, deramciclane succinate, deramciclane terephthallate, deramciclane tyrosinate, deramciclane tryptophanate, or deramciclane
  • the compound of Formula II is a fluoro- derivative such as, but not limited to: (4bS,8aS,9S)-l l-methyl-3-(trifluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b- (epiminoethano)phenanthrene; (4bS,8aS,9S)-3-(trifluoromethoxy)-l l-(trifluoromethyl)- 6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene; (4bS,8aS,9S)-3-methoxy-l l- (trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene.
  • a fluoro- derivative such as, but not limited to: (4bS,8aS,9S)
  • the compound of Formula II is an acid addition salt selected from acetate, acetyl salicylate, adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate, fumarate, glutamate glutarate, isophthallate, maleate, malonate, methionate, oxalate, pelargonate, pimelate, propionate, phthallate, salicylate, sebacate, succinate, terephthallate, tyrosinate, tryptophanate, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-tyrosinate, N-acyl- tryptophanate, N-acyl-methionate, citrate, galactonate, glucaric acid (saccharic acid), mannonate, mucate, rhamnonate, and tartrate.
  • glucaric acid saccharide
  • mannonate mannonate
  • the compound of Formula II is an acid addition salt selected from N-acyl-aspartate, N-acyl-glutarate, N-acyl-tyrosinate, N-acyl-tryptophanate, and N-acyl- methionate.
  • Examples include addition salts of base of formula II represented by dextromethorphan, such as dextromethorphan hydrogen acetate, dextromethorphan hydrogen acetyl salicylate, dextromethorphan hydrogen adipate, dextromethorphan hydrogen aspartate, dextromethorphan hydrogen butyrate, dextromethorphan hydrogen caprate, dextromethorphan hydrogen caproate, dextromethorphan hydrogen caprylate, dextromethorphan hydrogen enanthate, dextromethorphan hydrogen formate, dextromethorphan hydrogen fumarate, dextromethorphan hydrogen glutarate, dextromethorphan hydrogen isophthallate, dextromethorphan hydrogen maleate, dextromethorphan hydrogen malonate, dextromethorphan hydrogen oxalate, dextromethorphan hydrogen pelargonate, dextromethorphan hydrogen pimelate, dexttrometh
  • Another embodiment of the invention is a composition comprising an acid addition salt of compound of Formula I and an acid addition salt of a compound of Formula II.
  • Another embodiment of the invention is a composition comprising an acid addition salt of deramciclane and an acid addition salt of dextromethorphan.
  • Another embodiment of the 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 the halogenated compound of Formula I is trifluoromethyl derivative of Ml.
  • An embodiment of the invention is an addition salt of Formula I, wherein with organic acid such as aspartic acid, benzenesulfonic acid, besylic acid, benzoic acid, bicarbonic acid, tartaric acid, bromide, camphor sulfonic acid, camsylic acid, chloride, citric acid, decanoic acid, edetate, lauryl sulfonic acid, estolic acid, ethanesulfonic acid, esylic acid, fumaric acid, gluceptic acid, gluconic acid, glutamic acid, glycolic acid, glycollylarsanilic acid, hexanoic acid, hexylresorcinol, hydroxynaphthoic acid, isethionic acid, iodide, lactic acide, galactopyranosyl-d-gluconic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid,
  • the compound of Formula I is a prodrug according to wherein the compound is an ester or an addition formed from the following acids: 3- (nitrooxy)propanoic acid (Vendors: AKos (AKOS006377427), and 1717 CheMall (OR235109)), 4-nitrooxybutanoic acid (Vendors: AKos (AKOS006378268) and iChemical
  • the compounds of Formula I form addition salts of 3-(nitrooxy)propanoic acid, 3-(nitrooxy)butanoic acid, and 4-(nitrooxy)butanoic acid.
  • the acid addition salt is of 3-(nitrooxy)propanoic acid, 3-(nitrooxy)butanoic acid, and 4-(nitrooxy)butanoic acid.
  • the pharmaceutically acceptable acid addition salts of the compounds of the Formula I can be formed with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid and nitric acid.
  • Another embodiment is a composition
  • a composition comprising a compound of Formula I, and at least one compound selected from thioridazine, perphenazine, fluphenazine, zuclopenthixol, risperidone, sertindole, nortriptyline, amitriptyline, imipramine, fluoxetine, paroxetine, ajmaline, amiodarone, amitriptyline, aprindine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, doxorubicin, fluphenazine, fluvastatin, haloperidol, imipramine, indinavir, lasoprazole, levomepromazine, lopinavir, loratadine, mequitazine, methadone, metoclopramide, mibefradil, moclobemide, nelfinavir, nevirapine, nicardipin
  • Another embodiment of the invention is a composition
  • a composition comprising a compound of Formula I, a compound of Formula II, and at least one compound selected from thioridazine, perphenazine, fluphenazine, zuclopenthixol, risperidone, sertindole, nortriptyline, amitriptyline, imipramine, fluoxetine, paroxetine, ajmaline, amiodarone, amitriptyline, aprindine, azelastine, celecoxib, chlorpheniramine, chlorpromazine, diphenhydramine, doxorubicin, fluphenazine, fluvastatin, haloperidol, imipramine, indinavir, lasoprazole, levomepromazine, lopinavir, loratadine, mequitazine, methadone, metoclopramide, mibefradil, moclobemide, nelfinavir,
  • the composition comprises a compound of Formula I, wherein the compound wherein R 3 is a conjugate or covalent compound formed either by etherification or esterification with derivatives of one or more of AChls such as 2-((l-Benzylpiperidin-4- yl)methyl)-5,6-dimethoxy-2,3-dihydro-lH-inden-l-one (Donepezil), (S)-3-(l-
  • HepDirect prodrugs cytochrome P(450) 3A-activated prodrugs
  • the prodrug compounds of of Formula I include, but not limited to:
  • the five most costly brain disorders were: dementia: €22,164; psychotic disorders: €16,717; mood disorders: €19,238; addiction: €11,719; anxiety disorders: €11,687.
  • these five disorders ranked amongst those with the lowest direct medical expenditure per subject ( ⁇ €3000) (Feinberg et al., The size, burden and cost of disorders of the brain in the UK, J Psychopharmacol. 27(9): 761-770 (2013 September); Projections of the Cost of Cancer Care in the United States: 2010-2020, J Natl Cancer Inst. 103(2): 117-128 (2011 Jan 19) incorporated in entirety by reference).
  • BP bipolar disorder
  • Glioblastoma multiform is the most common malignant primary brain tumor in adults, with an estimated incidence of 4.43 per 100,000 person-years in the United States and a median age at presentation of 64 years. Symptoms often include headaches; nausea and vomiting; and progressive memory, personality, or neurologic deficits. While Alzheimer and other dementias are projected to show a 66% increase from 2005 to 2030. In the United States, depression is the second highest source of disability among women, and antidepressant non-responders are among the heaviest users of health care resources.
  • Drug and alcohol dependence is a severe public health problem. It is estimated that between 26.4 million and 36 million people abuse opioids worldwide (UNODC, World Drug Report 2012), with an estimated 2.1 million people in the United States suffering from substance use disorders related to prescription opioid pain relievers in 2012 and an estimated 467,000 addicted to heroin (Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013; incorporated by reference in its entirety).
  • the present inventon provides benefit on both, symptoms and disease progression in AD, and in cognitive impairment of mainly vascular origin (multi-infarct dementia, vascular dementia, vascular cognitive impairment, etc.).
  • Parkinson's Disease the anticholinergic effects of neuroleptics are highly unwanted as they inevitably worsen, in addition the motor condition and symptoms of the vegetative nervous system. In all dementias, lowering the seizure threshold is another infrequent but highly unwanted potential adverse effect of neuroleptics. About 10 million people worldwide have Parkinson's disease. Parkinson's disease is a synucleinopathy resulting in progressive neurodegeneration marked by motor dysfunction and non-motor symptoms including psychosis. More than 50% of patients with Parkinson's disease have psychosis at some time. Psychosis affects up to 75% of patients with Parkinson's disease dementia, and symptoms are more intractable in this group.
  • the monoamine hypothesis has been the prevailing hypothesis of depression over the last several decades. It states that depression is associated with reduced monoamine function. Hence efforts to increase monoamine transmission by inhibiting serotonin (5-HT) and norepinephrine (NE) transporters has been a central theme in depression research since the 1960s.
  • the selective 5- HT reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) that have emerged from this line of research are currently first line treatment options for major depressive disorder (MDD).
  • MDD major depressive disorder
  • One of the recent trends in antidepressant research has been to refine monoaminergic mechanisms by targeting monoaminergic receptors and additional transporters (e.g.
  • BP frequently occurs together with other psychiatric disorders, especially anxiety disorders and substance abuse.
  • BP has been associated with a variety of general medical conditions, which further complicate management of the psychiatric disorder (Am J Manag Care, 11 : S85-S90 (2005); incorporated by reference in its entirety).
  • BP is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks.
  • BP is characterized by a dysregulation of mood, impulsivity, risky behavior and interpersonal problems.
  • BP is a recurrent and often chronic psychiatric illness, associated with functional impairment, elevated suicide rates and utilization of mental health systems.
  • BP is commonly under-recognized and as many as 40% of patients with BPs are initially misdiagnosed, resulting in increased risk for suicide, mania and chronic psychosocial suffering.
  • successful treatment is possible ⁇ 50% of diagnosed patients and as many as 10-15% of patients eventually die as a result of suicide (NIMH 2002).
  • volumetric neuroimaging now increasingly assessing potential involvement of different brain structures in mood regulation, could be applied to test neuroanatomical models of mood disorders. Imaging studies suggested that ongoing neuronal atrophy accompanies BP. For instance, PET images of the cerebral blood flow and the rate of glucose metabolism regarding as brain activity detected the reduced activity in the subgenual prefrontal cortex during the bipolar depression. This decrement in activity was, in part, at least explained by a corresponding reduction of cortical volume, as same as magnetic resonance imaging demonstration of the mean gray matter volume. In BP, abnormalities of the third ventricle, frontal lobe, cerebellum, and possibly the temporal lobe are also noted.
  • Brain tumors are formed by abnormal growths and can appear in different areas of the brain. Benign (not cancerous) tumors may grow and press on nearby areas of the brain, but rarely spread into other tissues. Malignant (cancerous) tumors are likely to grow quickly and spread into other brain tissue. A tumor that grows into or presses on an area of the brain may stop that part of the brain from working the way it should, whether the tumor itself is benign or malignant, and will then require treatment. The most common type of brain tumor seen does not originate from the brain tissue itself, but rather are metastases from extracranial cancers such as lung cancer and breast cancer.
  • Brain tumors include neurofibromatosis type 1 or 2, von Hippel-Lindau disease, tuberous sclerosis, Li-Fraumeni syndrome, Turcot syndrome type 1 and type 2, Klinefelter syndrome, and Nevoid basal cell carcinoma syndrome.
  • Neuroblastoma is cancer found in developing nerve cells, usually in children under 10 years of age. Almost 90% of cases are diagnosed by the age of 5. Different factors can affect the type of neuroblastoma a child has and their prognosis.
  • Treatment for neurological cancer is based on several factors including a patient's overall health and medical history; the type, location, and size of the tumor; the extent of the condition; and other individual factors.
  • treatment for patients with cancer of the brain or spinal cord includes surgery, chemotherapy, radiation therapy, and/or steroids to treat and prevent swelling, especially in the brain; anti-seizure medication to treat and prevent seizures associated with intracranial pressure; placement of a shunt (to help drain excess fluid in the brain); lumbar puncture/spinal tap (to measure pressure in the spinal cord and brain); bone marrow transplantation; rehabilitation (to regain lost motor skills and muscle strength); and/or antibiotics (to treat and prevent infections).
  • Chemotherapy is the use of anticancer drugs to treat cancerous cells. In most cases, chemotherapy works by interfering with the cancer cell's ability to grow or reproduce. These drugs may be given into a vein or by mouth, as a tablet.
  • Neuropsychiatric symptoms are a common burden in patients suffering from Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and many other neurodegenerative disorders, including but not limited to dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal lobar degeneration (FTLD) (Kazui H et al. Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016); Van der Schyf CJ. Psychotropic Drug Development Strategies that Target
  • BPSD Behavioral and psychological symptoms of dementia
  • AD neurodegenerative diseases and disease states including but not limited to AD
  • BPSD symptoms may appear as mutually exclusive but can nevertheless share the underlying mechanisms. This shared mechanism similarity can occur at the neurochemical and/or neuroanatomical levels and serves as a basis for developing targeted, but not mechanism- specific therapies addressing more than one BPSD symptom.
  • the dorsolateral prefrontal cortex projects to the dorsolateral caudate which in turn targets lateral dorsomedial parts of internal globus pallidus that sends projections to the principal part of the ventral anterior or mediodorsal thalamus which returns projections to the cortex.
  • the orbitofrontal cortex projects to the ventromedial caudate that projects to medial dorsomedial parts of internal globus pallidus that sends projections to the magnocellular part of ventral anterior or mediodorsal thalamus which returns projections to the cortex.
  • cortical networks operate (Aouizerate B et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol 72(3): 195-221 (2004)). Therefore, impairments in different circuits underlie the emergence of different BPSD symptoms. Heterogeneity of the clinical presentations of neurodegenerative disorders is determined by the predominant location of the pathology (i.e. by affected networks).
  • the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex are more affected in apathetic patients, and the medial orbital frontal cortex in disinhibited patients with bvFTLD (e.g., Massimo et al. Dement Geriatr Cogn Disord 27:96-104 (2009)).
  • 5-HT2A receptors that are targeted by compounds of Formula I, it is well established that serotonin via 5-HT2A receptors increases glutamatergic spontaneous excitatory postsynaptic currents in apical dendrites of layer V pyramidal cells of prefrontal cortex (Aghajanian GK, Marek GJ. Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825:161-71 (1999)).
  • Such excessive asynchronous transmission may be functionally expressed in a variety of forms dependent on which part of the cerebral cortex is affected - from auditory or visual hallucinations to disinhibition and apathy - but in most cases, will be sensitive to manipulations involving 5-HT2A receptors that are present across various cortical areas (van Dyck CH et al. PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin. J Nucl Med 41(2):234-41 (2000)).
  • [00128] Diseases like Alzheimer's disease are characterized by systematic, progressive, probably trans-synaptic spread of neurodegeneration. That does not only mean more cell loss in a certain area of the brain but also spreading of the pathology to other brain areas. As different brain areas have different functional roles, this explains why more advanced stages of the disease are accompanied by a wider spectrum of symptoms (Kazui et al. Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092 (2016)).
  • Behavioral and psychological symptoms of dementia also known as neuropsychiatric symptoms, are commonly studied in the clinic using research tools such as the Neuropsychiatric
  • NPI Neuropsychiatric Inventory: Assessing psychopathology in dementia patients. Neurology 48:S10-S16 (1997)).
  • the NPI scale recognizes 12 sub-domains of behavioral functioning: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, aberrant motor activity, night-time behavioral disturbances, and appetite and eating abnormalities.
  • NPI symptoms patients rarely display each and every of these NPI symptoms at once as there are NPI items like euphoria that are rare, even at a CDR score of 3. Conversely, clinical experience indicates that there is rarely a patient showing just one specific item, and none of the rest. Instead, BPSD symptoms occurs in various combinations or clusters. For example, a frequent AD cluster could e.g. be aggression, agitation, wandering, repetitiveness, while a frequent Vascular Dementia cluster could e.g. be confusion and restlessness, but the frequency and severity of NPI items is subject to change, e.g. from day to day, but especially during disease progression (Kazui et al.
  • 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 299(1) :268-76 (2001)).
  • 5-HT2A receptor antagonists and inverse agonists have been in development for neuropsychiatric indications and there were reports of beneficial antipsychotic effects obtained with compounds such as eplivanserin (Meltzer HY et al. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161: 975-84 (2004)).
  • HTR2A T102C polymorphism is a significant risk factor for psychosis with an allelic OR of 2.191 for C allele that increased to 5.143 for the homozygous CC genotype (Ramanathan S, Glatt SJ.
  • Dextromethorphan has NMDA receptor channel blocking properties and NMDA receptor channel blockers such as phencyclidine or ketamine are known to possess psychotomimetic rather than antipsychotic properties.
  • NMDA receptor channel blockers such as phencyclidine or ketamine are known to possess psychotomimetic rather than antipsychotic properties.
  • NMDA receptor channel blockers such as phencyclidine or ketamine are known to possess psychotomimetic rather than antipsychotic properties.
  • There are reports of psychosis induced by dextromethorphan in humans (Miller SC. Dextromethorphan psychosis, dependence and physical withdrawal. Addict Biol 10(4):325-7 (2005)).
  • These psychoactive properties of dextromethorphan may be a function of its metabolic degradation resulting in production of dextrorphan (Zawertailo LA et al.
  • Agitation and aggression are grouped together as one item on the NPI scale. Prevalence of agitation and aggression is low in general population, in people with normal cognitive aging (2.8- 2.9%) but is increased in subjects with MCI (9.1-11.3%) and dementia (30.3-40%) (Geda YE et al.
  • 5-HT2A receptor antagonism may counteract dysphoria induced by conventional neuroleptics such as haloperidol (Benaliouad F et al. Blockade of 5-HT2a receptors reduces haloperidol-induced attenuation of reward. Neuropsychopharmacology 32(3):551-61 (2007)).
  • 5-HT2A receptor antagonists exert antidepressant-like effects in preclinical models sensitive to clinically used antidepressant drugs (Marek GJ et al. The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine.
  • NMDA receptor channel blockers such as dextromethorphan have been shown to possess antidepressant-like properties in preclinical models (Sakhaee E et al. The role of NMDA receptor and nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effect of dextromethorphan in mice forced swimming test and tail suspension test.
  • ketamine is proven to have rapid and robust antidepressant activity in patients with treatment-resistant major depressive disorder (Singh JB et al. A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. Am J Psychiatry 173(8):816-26 (2016)). Dextromethorphan given in combination with quinidine also exerts antidepressant action in humans (Murrough JW et al. Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial.
  • Dextromethorphan is not a selective NMDA receptor channel blocker and is more potent at serotonin and norepinephrine transporters as well as sigma- 1 receptors that may contribute to therapeutic effects of dextromethorphan (Stahl SM. Mechanism of action of dextromethorphan/quinidine: comparison with ketamine. CNS Spectrums 18: 225-227 (2013)). While monoamine transporters are targeted by most currently used antidepressants, sigma-1 receptors have also been found to contribute to antidepressant-like effects of dextromethorphan in laboratory animals (Nguyen L et al. Involvement of sigma- 1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One 9(2):e89985 (2014)).
  • Apathy in AD was significantly associated with 5-HT2A receptor polymorphism such as T102C (Lam LC et al. 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 19(6):523-6 (2004)).
  • Apathy is a symptom frequently seen in patients with schizophrenia and belongs to the group of negative symptoms.
  • 5-HT2A receptor antagonists reduce the severity of negative symptoms in patients with schizophrenia (Davidson M et al.
  • NMDA receptor channel blockers such as memantine are reported to reduce apathy in certain patients with neurodegenerative diseases (Links KA et al. A case of apathy due to frontotemporal dementia responsive to memantine. Neurocase 19(3):256-61 (2013)) or with the negative symptoms in schizophrenia (Paraschakis A. Tackling negative symptoms of schizophrenia with memantine. Case Rep Psychiatry 2014:384783 (2014)).
  • 5-HT2A receptor antagonists exert anxiolytic in various preclinical models, particularly models of conditioned fear (Adamec R et al. Prophylactic and therapeutic effects of acute systemic injections of EMD 281014, a selective serotonin 2A receptor antagonist on anxiety induced by predator stress in rats. Eur J Pharmacol 504(l-2):79-96 (2004); Millan MJ. The neurobiology and control of anxious states. Progr Neurobiol 70: 83-244 (2003)).
  • 5-HT2A receptor blockade attenuates emotional processing in the orbitofrontal cortex involved in the evaluation of socially relevant stimuli (Hornboll B et al. Pharmacological blockade of 5-HT2A receptors reduces orbitofrontal activation during processing of fearful and angry faces in healthy subjects.
  • dextromethorphan was observed to induce anxiolytic-like effects in laboratory animals within a certain dose range (Dere E et al. NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL/6 mice. Behav Pharmacol 14(3):245-9 (2003)). Preclinical anxiolytic effects of dextromethorphan may be related not only to the inhibition of NMDA receptor function but also to interaction with the sigma- 1 receptors (Kamei H et al.
  • (+)-SKF- 10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated sigma 1 sites. Eur J Pharmacol 299(l-3):21-8 (1996)).
  • memantine significantly decreases in the scores of NPI subscale for anxiety (Ishikawa I et al. The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease. Acta Neuropsychiatr 28(3): 157-64 (2016)).
  • Alzheimer's disease Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
  • 5-HT2A receptors Vazquez-Borsetti P. et al. Pyramidal neurons in rat prefrontal cortex projecting to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors. Cereb Cortex 19: 1678-86 (2009)). Consequently, blockade of prefrontal 5-HT2A receptors may modulate pyramidal neurons projecting to the midbrain and thereby inhibit the dopaminergic system in the midbrain (Erbdrup BH et al. Serotonin 2A receptor antagonists for treatment of schizophrenia. Expert Opin Investig Drugs 20(9): 1211-1223 (2011)).
  • Dopaminergic midbrain system is also under control of cholinergic projections such as those originating in habenula and activity of these projections are modulated by a3 4-containing nicotinic acetylcholine receptors (McCallum SE et al. ⁇ 3 ⁇ 4 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo. Neuropharmacology 63(3):434-40 (2012)).
  • Antagonism at a3 4-containing nicotinic acetylcholine receptors is associated with various effects ascribed to reduced dopamine tone (Maisonneuve IM, Glick SD.
  • nicotinic acetylcholine receptors are one of the main targets of dextromethorphan (Taylor CP et al. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther 164: 170-82 (2016)).
  • neocortex is known to be rich in 5-HT2A receptors and behavioral disinhibition in neurodegenerative diseases such as behavioral variant frontotemporal dementia is correlated with the cortical thickness of the right parahippocampal gyrus, right orbitofrontal cortex and right insula (Santillo AF et al. Grey and White Matter Clinico-Anatomical Correlates of Disinhibition in Neurodegenerative Disease. PLoS One l l(10):e0164122 (2016)).
  • PBA pseudobulbar affect
  • PBA may occur in association with a variety of neurological diseases such as amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer's disease, stroke, and brain tumors.
  • PBA is a disinhibition syndrome, in which pathways involving serotonin and glutamate are disrupted (Ahmed A, Simmons Z. Pseudobulbar affect: prevalence and management. Ther Clin Risk Manag 9:483-9 (2013)).
  • Alzheimer's disease indicated that memantine induces significant improvement in disinhibition (Kishi T et al. The effects of memantine on behavioral disturbances in patients with Alzheimer' s disease: a meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).
  • Alzheimer's disease Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
  • 5-HT2A receptors play a major role in regulation of sleep (Vanover KE, Davis RE. Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nat Sci Sleep 2: 139-50 (2010)).
  • 5-HT2A receptor inverse agonist pimavanserin in patients with moderate to severe Parkinson's disease, participants reported improvements on nighttime sleep and daytime wakefulness for pimavanserin compared with placebo (Cummings J et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383: 533-40 (2014)).
  • Serotonin plays a major role in emergence and maintenance of various types of eating disorders (Steiger H. Eating disorders and the serotonin connection: state, trait and developmental effects. J Psychiatry Neurosci 29(l):20-9 (2004)).
  • the gene encoding 5-HT2A receptor (HTR2A) has been implicated as a functional candidate in many neuropsychiatric phenotypes including eating disorders (Norton N, Owen MJ. HTR2A: association and expression studies in neuropsychiatric genetics. Ann Med 37(2): 121-9 (2005)).
  • Eating behavior and appetite are also modulated by one of the receptor target's of dextromethorphan, serotonin transporter, that is affected in patients with eating disorders (Spies M et al. The serotonin transporter in psychiatric disorders: insights from PET imaging. Lancet Psychiatry 2(8):743-55 (2015)).
  • TMA may be used to treat more than one clinically diagnosable BPSD item (e.g. an NPI symptom or symptom cluster); ii) one TMA may be used to treat symptoms of two or more clinically distinct neurodegenerative diseases (e.g. AD, PD, DLB, FTLD, etc.) as illustrated by the emerging efficacy profile of Nuplazid®; iii) a single TMA is unlikely to ever cover the full spectrum of BPSD symptoms; iv) a single TMA may not produce a maximally possible therapeutic benefit against even a single BPSD symptom or symptom cluster.
  • a single TMA may be used to treat more than one clinically diagnosable BPSD item (e.g. an NPI symptom or symptom cluster); ii) one TMA may be used to treat symptoms of two or more clinically distinct neurodegenerative diseases (e.g. AD, PD, DLB, FTLD, etc.) as illustrated by the emerging efficacy profile of Nuplazid®; iii)
  • An embodiment is a method of treating behavioral and psychological 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 comprising 5-HT2A receptor antagonist, 5-HT2A receptor inverse agonist, and CYP2D6 inhibitor.
  • the agent is a Dual Agent (DA) having properties of both 5- HT2A receptor antagonist and CYP2D6 inhibitor.
  • the agent is a DA having properties of both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor.
  • the DA is a compound of Formula I.
  • DEX is an agonist of the ⁇ 2 receptor, an N-methyl-D-aspartate (NMDA) antagonist, and an ⁇ 3 ⁇ 4 nicotinic receptor antagonist. Uptake of norepinephrine and serotonin are also inhibited.
  • NMDA N-methyl-D-aspartate
  • NMDA N-methyl-D-aspartate
  • the composition comprises an NMDA receptor antagonist such as ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone and dextromethorphan (Jamero et al., The Emerging Role of NMDA Antagonists in Pain Management, US Pharm. 36(5):HS4-HS8 (2011); Sang, NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials, J Pain Symptom Manage. 19 (1 Suppl) S21-5 (2000); incorporated in entirety herein by reference).
  • an NMDA receptor antagonist such as ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone and dextromethorphan
  • the composition is a combination of a compound of Formula I, and ketamine, methadone, memantine, amantadine, dextropropoxyphene, ketobemidone, or dextromethorphan.
  • the compound of Formula I forms the combination as mixture, complex, conjugate, compound with covalent bond, or a salt.
  • the pharmaceutical composition comprises a compound of formula I and a compound of formula II (exemplified by SARPODEXTM, DERADEXTM, or DERAPHANTM).
  • a method of treatment of a patient in need thereof comprising the step of administering a pharmaceutical composition comprising comprises SARPODEXTM, DERADEXTM, or DERAPHANTM.
  • an embodiment is a method of treating behavioral and psychological symptoms of dementia.
  • Another embodiment is a treatment of 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 breathing abnormalities, motor capabilities, bone density, and GI dysfunction.
  • Another embodiment is the treatment of a person in need thereof comprising administering a composition comprising DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to improve EEG abnormalities, behavior, cognition, and reduce seizures, as well as improve breathing abnormalities, motor capabilities, bone density, and GI dysfunction.
  • Another embodiment is a treatment of a person in need thereof comprising administering a composition comprising DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM in the treatment of other diseases and conditions, including involuntary emotional expression disorder (IEED) or pseudobulbar affect (PBA), neurodegenerative diseases, neuropathic pain, and brain injuries.
  • IEED involuntary emotional expression disorder
  • PBA pseudobulbar affect
  • Another embodiment is a composition
  • a composition comprising a compound of DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM alone or in combination with other drugs such as analgesics (e.g. acetaminophen), antihistamines (e.g. chlorpheniramine), decongestants (e.g., pseudoephedrine) and/or expectorants (e.g., guaifenesin).
  • analgesics e.g. acetaminophen
  • antihistamines e.g. chlorpheniramine
  • decongestants e.g., pseudoephedrine
  • expectorants e.g., guaifenesin
  • Dextromethorphan is metabolized into active metabolites in the liver starting with O-and N-demethylation to form primary metabolites DO and 3-methoxy-morphinan are further N- and O- demethylated respectively to 3-hydroxy-morphinan.
  • a major metabolic catalyst is the cytochrome P450 enzyme 2D6 (CYP2D6), which is responsible for the O-demethylation reactions of dextromethorphan and 3-methoxymorphinan.
  • CYP2D6 cytochrome P450 enzyme
  • N-demethylation of dextromethorphan and DO are catalyzed by enzymes in the related CYP3A family. Conjugates of DO and 3- hydroxymorphinan can be detected in human plasma and urine within hours of its ingestion. DO is a substance most notable for its psychoactive effects.
  • SGL is a 5-HT2A receptor inverse agonist and CYP2D6 inhibitor. SGL inhibits responses to 5-HT mediated by 5-HT2A receptors such as platelet aggregation, vasoconstriction and vascular smooth muscle proliferation. SGL (MCI-9042) was shown to have the same affinity as ritanserin for 5-HT2A receptors (Nishio et al., Binding affinity of a compound of formula I or sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes. Arch Int Pharmacodyn Ther. 331(2): 189-202 (1996 March- April); incorporated by reference in entirety).
  • the blockade of 5-HT2A receptors can inhibit thrombus formation, suppresses platelet aggregation and inhibits vascular smooth muscle cell proliferation (Pertz et al., In-vitro pharmacology of a compound of Formula I and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery. / Pharm Pharmacol. 47(4):310-6 (1995 April); incorporated by reference in entirety).
  • an embodiment is a method of treatment of a patient in need thereof comprising administering a composition comprising a compound of Formula I and a compound of Formula II, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM.
  • Another embodiment is the method of treatment wherein the patient is suffering from a disease or disorder comprising peripheral arterial disease, e.g., Raynaud's Disease and claudicatio intermittens; pulmonary hypertension (Saini et al., 2004; incorporated by reference in entirety), angina pectoris (Kinugawa et al., 2002; incorporated by reference in entirety), and/or diabetes mellitus (Pietraszek et al., 1993; Ogawa et al., 1999; incorporated by reference in entirety).
  • a disease or disorder comprising peripheral arterial disease, e.g., Raynaud's Disease and claudicatio intermittens; pulmonary hypertension (Saini et al., 2004; incorporated by reference in entirety), angina pectoris (Kinugawa et al., 2002; incorporated by reference in entirety), and/or diabetes mellitus (Pietraszek et al., 1993; Ogawa
  • the method of treatment of a patient after coronary stenting comprising a compound of Formula I, to and is useful in restenosis (Doggrell, sarpogrelate: cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, Volume 13, Issue 7 (2004); incorporated by reference in entirety).
  • DO is a substance most notable for its psychoactive effects that likely arise from blockade of NMD A receptors. DO has a substantially higher affinity for NMDA receptors compared to that of DEX. Adverse psychoactive effects of DEX have been associated with its metabolism to DO (Taylor et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther. 164: 170-82 (2016 August); incorporated by reference in its entirety).
  • another embodiment is a method of reducing adverse effects of DEX during treatment of a patient in need thereof comprising the step of administering a pharmaceutical composition comprising DEX and one or more agents selected from the group comprising 5-HT2A receptor antagonist/inverse agonist, and CYP2D6 inhibitor.
  • the agent is an agent having properties of both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor.
  • the agent is an agent having properties of both 5-HT2A receptor inverse agonist and CYP2D6 inhibitor.
  • the agent is a compound of Formula I and a compound of Formula II, or DERATINETM, SARPOTINETM, SARPODEXTM,
  • Another embodiment is a composition
  • (6)-l- ⁇ 2-[2-(3-methoxyphenil) ethyl]- phenoxy ⁇ -3-(dimethylamino)-2-propanol (M-l) (Nagatomo et al., 2004; Saini et al., 2004; incorporated by reference in entirety), a 5-HT2A receptor inverse agonist and CYP2D6 inhibitor.
  • cytochrome CYP2D6 has been implicated in the metabolism of many antipsychotic agents, including thioridazine, perphenazine, chlorpromazine, fluphenazine, haloperidol, zuclopenthixol, risperidone, and sertindole (Michalets, 1998).
  • This enzyme is also important in the metabolism of other drugs that are commonly prescribed to patients with psychiatric disorders, e.g., tricyclic antidepressants (nortriptyline, desipramine, amitriptyline, imipramine, and clomipramine) and selective serotonin reuptake inhibitors, including fluoxetine and paroxetine (Taylor and Lader,1996; Sproule et al., 1997; incorporated by reference in entirety). Drugs that inhibit these enzymes would be expected to cause increases in the plasma concentration of co-administered antipsychotic drugs (Goff, 1993; Ereshefsky, 1996; Michalets, 1998; incorporated by reference in entirety).
  • the inhibitory potency of these drugs on DEX O-demethylation was comparable to the inhibitory effect of 10 to 25 microM quinidine.
  • the estimated mean IC50 values for thioridazine and perphenazine were 2.7 + 0.5 and 1.5j;0.3 micro M, respectively.
  • the IC50 of quinidine, a potent CYP2D6 inhibitor was estimated to be 0.52 + 0.2 micro M under these conditions.
  • the estimated IC50s of chlorpromazine, fluphenazine, and haloperidol were 9.7, 16.3, and 14.4 micro M, respectively.
  • Cisthiothixene, clozapine, and risperidone exhibited weaker inhibition than the other drugs tested, with mean IC50S estimated to be 136.6, 92.2, and 39.1 micro M, respectively (Shin et al., Effect Of Antipsychotic Drugs on Human Liver Cytochrome P-450 (Cyp) Isoforms in Vitro: Preferential Inhibition of CYP2D6,
  • the pharmaceutical composition of the invention comprise one or more of the CYP2D6 inhibitors such as, but are not limited to, Ajmaline, Amiodarone, Amitriptyline, Aprindine, Azelastine, Celecoxib, Chlorpheniramine, Chlorpromazine, Diphenhydramine, Doxorubicin, Fluoxetine, Fluphenazine, Fluvastatin, Fluvoxamine, Haloperidol, Imipramine,
  • the CYP2D6 inhibitors such as, but are not limited to, Ajmaline, Amiodarone, Amitriptyline, Aprindine, Azelastine, Celecoxib, Chlorpheniramine, Chlorpromazine, Diphenhydramine, Doxorubicin, Fluoxetine, Fluphenazine, Fluvastatin, Fluvoxamine, Haloperidol, Imipramine,
  • the invention is a combination of a 5HT2A receptor antagonist and a CYP2D6 inhibitor providing a therapeutic advantage of the simultaneous 5HT2A receptor antagonism and 2D6 inhibition.
  • the invention is a combination of a 5HT2A receptor inverse agonist and a CYP2D6 inhibitor providing a therapeutic advantage of the simultaneous 5HT2A receptor inverse agonism and 2D6 inhibition.
  • a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM provides a unique therapeutic advantage by combining both CYP2D6 inhibition and 5HT2A receptor inverse agonism to improve the magnitude of the therapeutic response to DEX.
  • Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM avoids potential health risks associated with the concomitant use of an anti- arrhythmic drug quinidine with DEX.
  • an embodiment is a composition comprising Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM.
  • Some embodiments include a method of decreasing the number of doses and/or total daily dose of dextromethorphan, a metabolite, a derivative or a prodrug thereof (DEX) that can be administered while increasing efficacy and safeguarding 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, DERADEXTM, or DERAPHANTM.
  • Some embodiments include a method of reducing an adverse event associated with treatment comprising co-administering a compound of Formula I and a compound of Formula II; or, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to a subject in need of DEX and/or a compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM treatment, wherein the subject is at risk of experiencing the adverse event as a result being treated with DEX and/or a compound of Formula
  • Some embodiments include a method of decreasing DO plasma levels comprising coadministering a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to a subject in need of treatment with DEX, wherein the compound of Formula I and a compound of Formula II; or
  • DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM is administered on the first day of at least two days of treatment with DEX, wherein a decrease in the DO plasma level occurs on the first day that a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM are administered, as compared to the same amount of DEX administered without a compound of
  • Another embodiment is a method of decreasing DO plasma levels comprising coadministering a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM, for at least eight consecutive days, to a subject in need of treatment with DEX, wherein, on the eighth day, the DO plasma level is lower than the DO plasma level that would have been achieved by administering the same amount of DEX administered without a compound of Formula I for eight consecutive days.
  • 5-HT2A receptor antagonist/inverse agonists such as a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or
  • DERAPHANTM can be used to improve the therapeutic properties of DEX, such as in the treatment of neurological disorders.
  • a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM regardless of stereochemistry, can be effective in inhibiting or reducing the metabolism of DEX in some subjects, accomplished by co-administering a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM regardless of stereochemistry, can be effective in inhibiting or reducing the metabolism of DEX in some subjects, accomplished by co-administering a compound of Formula I and a compound of Formula
  • DERATINETM SARPOTINETM
  • SARPODEXTM SARPODEXTM
  • DERADEXTM DERAPHANTM
  • 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 an extensive metabolizer of DEX.
  • Another embodiment is a method of treating a neurological disorder comprising administering a 5-HT2A receptor inverse agonist, antagonist, and DEX to a subject in need thereof, wherein the subject is an extensive metabolizer of DEX.
  • Another embodiment is a method of increasing DEX plasma levels in a subject in need of treatment with DEX, wherein the subject is an extensive metabolizer of DEX, comprising coadministering a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to the subject.
  • Another embodiment is a method of inhibiting the metabolism of DEX, comprising administering a compound of formula I, or a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM, to a subject, wherein the subject is an extensive metabolizer of DEX, and wherein DEX is present in the body of the subject at the same time as a compound of Formula I.
  • Another embodiment is a method of increasing the metabolic lifetime of DEX, comprising administering a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to a subject in need of treatment with DEX, wherein the subject is an extensive metabolizer of DEX, and wherein DEX is present in the body of the subject at the same time as a compound of Formula I.
  • Another embodiment is a method of correcting extensive metabolism of DEX, comprising administering a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM, to a subject in need thereof.
  • Another embodiment is a method of improving the antitussive properties of DEX comprising administering a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM in conjunction with administration of DEX to a subject in need of treatment for a cough.
  • Another embodiment is a method of treating cough comprising administering a combination of a compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to 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, DERADEXTM, or DERAPHANTM to a subject in need thereof, wherein the compound of Formula I and a compound of Formula II; or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM are administered at least once a day 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 1000 mg/day, about 150 mg/day to about 5000 mg/day, about 150 mg/day to about 300 mg/day, or about 150 mg/day to about 100 mg/day, or an amount as required of a compound of Formula I and about 0.1 mg/day to about 1 mg/day, about 0.5 mg/day to about 15 mg/day, about 15 mg/day to about 60 mg/day, about 15 mg/day to about 120 mg/day, about 0.1 mg/day to about 200 mg/day, or an amount as required of DEX to a subject in
  • Another embodiment is a method of increasing DEX plasma levels in a subject in need of treatment with DEX, wherein the subject is an extensive metabolizer of DEX, comprising coadministering a compound of Formula I with DEX to the subject.
  • Another embodiment is a method of inhibiting the metabolism of DEX, comprising administering a compound of Formula I, to a subject, wherein the subject is an extensive metabolizer of DEX, and wherein DEX is present in the body of the subject at the same time as a compound of Formula I.
  • Another embodiment is a method of increasing the metabolic lifetime of DEX, comprising administering a compound of formula I, to a subject in need of treatment with DEX, wherein the subject is an extensive metabolizer of DEX, and wherein DEX is present in the body of the subject at the same time as a compound of formula I.
  • Another embodiment is a method of increasing DEX plasma levels comprising coadministering a compound of formula I and DEX to a subject in need of treatment with DEX, wherein the compound of formula I is administered on the first day of at least two days of coadministration of a compound of formula I, with DEX, wherein an increase in the DEX plasma level occurs on the first day that a compound of formula I and DEX are co- administered, as compared to the same amount of DEX administered without a compound of formula I.
  • Another embodiment is a method of increasing DEX plasma levels comprising coadministering a compound of formula I and DEX for at least five consecutive days, to a subject in need of treatment with DEX, wherein, on the fifth day, the DEX plasma level is higher than the DEX plasma level that would have been achieved by administering the same amount of DEX administered without a compound of formula I, for five consecutive days.
  • Another embodiment is a method of increasing DEX plasma levels comprising coadministering a compound of formula I and DEX for at least six consecutive days, to a subject in need of treatment with DEX, wherein, on the sixth day, the DEX plasma level is higher than the DEX plasma level that would have been achieved by administering the same amount of DEX administered without a compound of formula I, for six consecutive days.
  • Another embodiment is a method of reducing a trough effect of DEX comprising, coadministering a compound of formula I, with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering a compound of formula I, with
  • DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without a compound of formula I.
  • Another embodiment is a method of reducing a trough effect of DEX comprising, coadministering a compound of formula I, with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering a compound of formula I, with
  • DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without a compound of Formula I.
  • Another embodiment is a method of reducing a trough effect of DEX comprising, coadministering a compound of formula I, with DEX to a subject in need of treatment with DEX, wherein DEX has a plasma level 12 hours after co-administering a compound of formula I, with
  • DEX that is at least twice the plasma level that would be achieved by administering the same amount of DEX without a compound of Formula I.
  • Another embodiment is a method of reducing an adverse event or other unwanted consequences such as addiction associated with treatment by DEX, 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 the adverse event as a result of being treated with DEX.
  • Another embodiment is a method of reducing an adverse event associated with treatment by a compound of formula I, comprising co-administering DEX and a compound of formula I, to a subject in need of a compound of Formula I, treatment, wherein the subject is at risk of experiencing the adverse event as a result of being treated with a compound of formula I.
  • Another embodiment is a method of improving antitussive properties of DEX comprising administering a compound of formula I, in conjunction with administration of 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 a compound of formula I and DEX to a subject in need thereof, wherein the compound of formula I and DEX are administered at least once a day for at least 8 days.
  • Another embodiment is a method of treating a neurological disorder comprising administering a composition comprising DEX, Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to a subject in need thereof, wherein the DEX, Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM is administered at least once a day for at least 8 days.
  • Another embodiment is a method of treating a neurological disorder comprising administering a composition comprising DEX, Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to a subject in need thereof, wherein the compound of formula I and DEX are administered at least once a day for at least 8 days.
  • Another embodiment is an oral sustained release delivery system for DEX, comprising a composition comprising DEX, Formula I, DERATINETM, SARPOTINETM, SARPODEXTM,
  • Another embodiment is a method of decreasing the number of doses of DEX that can be administered without loss of efficacy, comprising orally administering an effective amount of a composition comprising DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM to 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.
  • a method of increasing the metabolic lifetime of DEX comprising administering 5-HT2A receptor antagonist/inverse agonist to a subject in need of treatment with
  • the composition comprises DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM.
  • a method of preventing adverse events associated with treatment by DEX comprising co-administering 5-HT2A receptor antagonist/inverse agonist or such as a compound of formula I, to a subject in need of treatment with DEX, wherein the subject is at risk of experiencing the adverse event as a result of being treated with DEX.
  • a method for using 5HT2A receptor antagonists such as a compound of formula I, to improve the therapeutic properties of DEX in the treatment of neurological disorders.
  • composition comprising 5HT2A receptor antagonist and DEX to a subject in need thereof.
  • the composition comprises DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM.
  • a method for selecting a 5-HT2A receptor antagonist/inverse agonist for the use in combination with DEX in a subject in need thereof is provided.
  • NMDA receptor antagonists reduce the physical aspects of the expression of morphine dependence as measured by naloxone-precipitated withdrawal (Bristow et al., Competitive and glycine: NMDA receptor antagonists attenuate withdrawal-induced behaviors and increased hippocampal acetylcholine efflux in morphine-dependent rats. Neuropharmacology. 36: 241-250 (1997); Popik et al., Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine. /. Pharmacol. Exp. Ther.
  • an embodiment is a method of treating a subject in need of treatment for disorders or diseases associated with addiction and substance abuse comprising administration of DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM.
  • an embodiment is a method of treating a subject in need of treatment for disorders or diseases associated with addiction and substance abuse resulting from opioid tolerance and dependence by amelioration of opiate withdrawal symptoms and relapse prevention comprising administration of DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or
  • DEX affords neuroprotection on dopamine neurons in several inflammation-based animal Parkinson's disease models (Li et al., Protective effect of dextromethorphan against endotoxic shock in mice. Biochemical Pharmacology. 69(2): 233-40 (2005); Liu et al., Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. Journal of Pharmacology & Experimental Therapeutics. 305(1 ):212-8
  • an embodiment is a method of treating a subject in need of a treatment for Parkinson's disease comprising administration of DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM.
  • the neuroprotective effect of DEX is associated with the inhibition of microglia over- activation by inhibition of superoxide anion production from NADPH-oxidase, and this neuroprotective effect of DEX is not associated with its NMDA receptor antagonist property.
  • NMDA receptor antagonists such as MK801, AP5, and memantine.
  • an embodiment is a method of treating a subject in need of treatment for a disorder or disease thereof comprising administration of DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM wherein the disorder or disease is an inflammation-related neurodegenerative disorder.
  • GC-dependent effects of morphine activate the hypothalamic-pituitary-adrenal (HP A) axis.
  • HPA hypothalamic-pituitary-adrenal
  • the activation of the HPA axis increases the products of GC as potent immunomodulatory hormones (Freier et al., A mechanism of action for morphine-induced immunosuppression: corticosterone mediates morphine-induced suppression of natural killer cell activity. / Pharmacol
  • an embodiment is a method of treating a subject in need of treatment for a disorder or disease thereof comprising administration of DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or
  • DEX wherein the disorder or disease is opioid dependence.
  • the dosage of up to about 500 mg/day DEX is suggested, including doses of 120, 240, and 480 mg/day of DEX for heroin addicts undergoing withdrawal.
  • DEX at high doses caused mild elevations of heart rate, blood pressure, temperature, and plasma bromide (Cornish et al., A randomized, double-blind, placebo- controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients.
  • BP blood pressure
  • VP A Valproate
  • an embodiment is a method of treating a subject in need of treatment for a disorder or disease thereof comprising administration of DEX and a compound of Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM, wherein the disorder or disease is BP.
  • Another embodiment is a method of reducing adverse events of DEX in a subject in need thereof comprising:
  • Some embodiments include a method of treating neuropsychiatric disorders comprising administering a therapeutically effective amount of DEX and a therapeutically effective amount of a compound of formula I, to a person in need thereof.
  • Some embodiments include a method of enhancing the therapeutic properties of DEX in treating neuropsychiatric disorders, comprising co-administering DEX and a compound of formula I.
  • Some embodiments include a method of increasing DEX plasma levels in a subject that is an extensive metabolizer of DEX, comprising co- administering a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I and DEX to the subject.
  • Some embodiments include a method of inhibiting the metabolism of DEX, comprising administering a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I to a subject, wherein the subject is an extensive metabolizer of DEX, and wherein DEX is present in the body of the subject at the same time as the 5-HT2A receptor antagonist/inverse agonist.
  • a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I
  • Some embodiments include a method of increasing the metabolic lifetime of DEX, including increasing the elimination half-life (T1/2) of DEX. These embodiments may comprise administering a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I to a subject, wherein the subject is an extensive metabolizer of DEX, and wherein DEX is present in the body of the subject at the same time as the 5-HT2A receptor antagonist/inverse agonist.
  • Some embodiments include a method of correcting extensive metabolism of DEX, comprising administering a 5-HT2A receptor antagonist/ inverse agonist, such as a compound of formula I to a subject in need thereof, such as a subject in need of treatment for pain.
  • Some embodiments include a method of improving the therapeutic properties of DEX in treating neuropsychiatric disorders comprising administering a 5-HT2A receptor antagonist/ inverse agonist, such as a compound of formula I in conjunction with administration of DEX to a subject in need of treatment for a neuropsychiatric disorder.
  • Some embodiments include a method of treating neuropsychiatric disorders comprising administering a combination of a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I and DEX to a subject in need thereof.
  • a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I and DEX
  • DEX is used as a cough suppressant. According to the FDA's DEX product labeling requirement under the OTC Monograph [21CFR341.74], DEX should be dosed 6 times a day (every 4 hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours).
  • DEX is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are extensive metabolizers. Subjects can be: 1) extensive metabolizers of DEX-those who rapidly metabolize DEX; 2) poor metabolizers of DEX- -those who only poorly metabolize DEX; or 3) intermediate metabolizers of DEX-those whose metabolism of DEX is somewhere between that of an extensive metabolizer and a poor metabolizer. Extensive metabolizers can also be ultra-rapid metabolizers. Extensive metabolizers of DEX are a significant portion of the human population. DEX can, for example, be metabolized to DO.
  • DEX When given the same oral dose of DEX, plasma levels of DEX are significantly higher in poor metabolizers or intermediate metabolizers as compared to extensive metabolizers of DEX.
  • the low plasma concentrations of DEX can limit its clinical utility as a single agent for extensive metabolizers, and possibly intermediate metabolizers, of DEX.
  • Some antidepressants, such as a compound of Formula I inhibit the metabolism of DEX, and can thus improve its therapeutic efficacy.
  • antidepressants may allow DEX to be given less often, such as once a day instead of twice a day, once a day instead of three times a day, once a day instead of four times a day, twice a day instead of three times a day, or twice a day instead of four times a day, without loss of therapeutic efficacy.
  • 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, such as a compound of formula I to a person in need thereof.
  • Examples of neuropsychiatric disorders that may be treated, or that may be treated with increased efficacy, by a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist a compound of formula I include, but are not limited to: affective disorders, psychiatric disorders, cerebral function disorders, movement disorders, dementias, traumatic brain injury, chronic traumatic encephalopathy, PTSD, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.
  • Affective disorders that may be treated by a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist a compound of formula I include, but are not limited to, depression, major depression, treatment-resistant depression and treatment-resistant bipolar depression, BPs including cyclothymia, seasonal affective disorder, mania, anxiety disorders, 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, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.
  • BPs including cyclothymia, seasonal affective disorder, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit/hyperactivity disorder (AD/HD)
  • bipolar and manic conditions obses
  • Depression may be manifested by changes in mood, feelings of intense sadness, despair, mental slowing, sleep disturbances, loss of concentration, pessimistic worry, 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 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, anxiety disorders, including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and apathy in Alzheimer's disease.
  • anxiety disorders including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform
  • Apathy or loss of motivation, is the most common change in behavior in Alzheimer's disease (AD). It is common throughout the spectrum of cognitive decline from mild cognitive impairment to severe Alzheimer's disease (AD), as well as in a variety of other neuropsychiatric disorders. Apathy represents a form of executive cognitive dysfunction. Patients with apathy suffer from decreased daily function and specific cognitive deficits and rely on families to provide more care, which results in increased stress for families. Apathy is one of the primary syndromes associated with frontal and subcortical pathology, and apathy in AD appears to have multiple neuroanatomical correlates that implicate components of frontal subcortical networks.
  • apathy may be misdiagnosed as depression because of an overlap in symptoms, current research has shown apathy to be a discrete syndrome. Distinguishing apathy from depression has important treatment implications because these disorders respond to different interventions.
  • the Apathy Inventory (IA), a rating scale for global assessment of apathy and separate assessment of emotional blunting, lack of initiative, and lack of interest, is a reliable method for assessing in demented and non-demented elderly subjects several dimensions of the apathetic syndrome, and also the subject's awareness of these symptoms.
  • the IA assesses apathy as effectively as the Neuro Psychiatric Inventory apathy domain (Robert et al., The Apathy Inventory: assessment of apathy and awareness in Alzheimer's disease, Parkinson's disease and mild cognitive impairment, the Journal of Geriatric Psychiatry, Volume 17, Issue 12, Pages 1099-1105 (December 2002); Austin et al., Apathy in Alzheimer's Disease, the Journal of American Geriatric Society, Volume 49, Issue 12, Pages 1700-1707 (December 2001); Malloy et al., Apathy and Its Treatment in Alzheimer's Disease and Other Dementias, Psychiatric Times, Vol. XXII, Issue 13 (November 01, 2005); incorporated by reference in entirety).
  • Apathy can be the result of damage to one or more areas of the brain such as the frontal cortex, the thalamus, striatum and the amygdala. In most cases direct damage to the frontal lobes or the subcortical nuclei that have connections to the frontal lobes, cause apathy. Apathy associated with Alzheimer's disease is very difficult to treat. Antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors etc. alleviated apathy only to some degree.
  • an embodiment of the invention is a combination of DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM ; and one or more of antidepressants, SSRIs, psychostimulants, acetylcholinesterase inhibitors, dopaminergic agents.
  • Another embodiment is a combination of DEX and Formula I, or DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM and one or more of donepezil, memantine, amantanidine, bupropion, ropinirole, methylphenidate, amphetamine, modafinil, metrifonate, tacrine, galantamine, rivastigmine, nefiracetam, ginkgo biloba extract, etc.
  • donepezil memantine, amantanidine, bupropion, ropinirole, methylphenidate, amphetamine, modafinil, metrifonate, tacrine, galantamine, rivastigmine, nefiracetam, ginkgo biloba extract, etc.
  • Alzheimer Disease A Systematic Review Across Modalities, Journal of Geriatric Psychiatry and Neurology, Vol 30, Issue 1, 2017; references are incorporated by reference in entirety).
  • Acetylcholinesterase is one of the most prominent constituents of central cholinergic pathways. It terminates the synaptic action of acetylcholine through hydrolysis and yields the choline moiety that is necessary for transmitter recycling. The pathogenesis of Alzheimer' s disease
  • AD has been linked to a deficiency in the brain neurotransmitter acetylcholine.
  • the efficacy of acetylcholinesterase inhibitors (AChEIs) is attained through their augmentation of acetylcholine - medicated neuron to neuron transmission. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase.
  • the composition comprises AChls such as 2-((l- Benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-lH-inden-l-one (Donepezil), (S)-3-(l- (dimethylamino)ethyl)phenyl ethyl(methyl) carbamate (Rivastigmine), dimethyl (2,2,2-trichloro-
  • AChls such as 2-((l- Benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-lH-inden-l-one (Donepezil), (S)-3-(l- (dimethylamino)ethyl)phenyl ethyl(methyl) carbamate (Rivastigmine), dimethyl (2,2,2-trichloro-
  • Substance abuse and addiction 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, drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.
  • psychostimulants e.g., crack, cocaine, speed, meth
  • nicotine e.g., alcohol, opioids, anxiolytic and hypnotic drugs
  • cannabis marijuana
  • amphetamines e.g., hallucinogens
  • phencyclidine e.g., phencyclidine
  • volatile solvents e.g.,
  • Cerebral function 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, disorders involving intellectual deficits such as vascular dementia, Alzheimer's type dementia, Lewy Body Dementia, Fronto-Temporal Lobar Degeneration, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia.
  • disorders involving intellectual deficits such as vascular dementia, Alzheimer's type dementia, Lewy Body Dementia, Fronto-Temporal Lobar Degeneration, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia.
  • Cerebral function disorders also include disorders caused by cerebrovascular diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, dementia, coma, lowering of attention, apathy, and speech disorders.
  • Movement 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, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine - responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor,
  • Dementias 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, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia, Creutzfeldt- Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff Syndrome, and Fronto-Temporal Lobar Degeneration (FTLD).
  • FTLD Fronto-Temporal Lobar Degeneration
  • Motor neuron diseases 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, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sach's disease, Sandhoff disease, and hereditary spastic paraplegia.
  • ALS amyotrophic lateral sclerosis
  • PPS primary lateral sclerosis
  • PPS primary lateral sclerosis
  • SMA spinal muscular atrophy
  • spinal motor atrophies Tay-Sach's disease
  • Sandhoff disease Sandhoff disease
  • hereditary spastic paraplegia hereditary spastic paraplegia.
  • Neurodegenerative diseases 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 Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis,
  • SCA
  • 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, nonepileptic seizures, epilepsy, febrile seizures; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsia partialis continua; generalized seizures including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.
  • Types of headaches 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, migraine, trigeminal cephalgia, tension, and cluster headaches including 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, a metabolite or prodrug of any of these compounds include, Rett Syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.
  • Pain relieving properties of DEX may be enhanced by a method comprising coadministering DEX and a 5-HT2A receptor antagonist/inverse agonist, such as a compound of formula I, a metabolite, a derivative, or prodrug of any of these compounds, with DEX.
  • a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I, a metabolite, a derivative, or prodrug of any of these compounds
  • Pain relieving properties of a compound of formula I may be enhanced by a method comprising co-administering DEX with a compound of formula I.
  • These methods may be used to treat or provide relief to, any pain including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, etc.
  • Examples of musculoskeletal pain include low back pain (i.e. lumbosacral pain), primary dysmenorrhea, and arthritic pain, such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoarthosis, axial spondyloarthritis including ankylosing spondylitis, etc.
  • low back pain i.e. lumbosacral pain
  • primary dysmenorrhea i.e. lumbosacral pain
  • arthritic pain such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoarthosis, axial spondyloarthritis including ankylosing spondylitis, etc.
  • a combination of DEX and a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I, is used for treating chronic musculoskeletal pain.
  • neuropathic pain examples include idiopathic and diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, etc.
  • Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio- or chemo-therapy associated neuropathy, etc.
  • treating includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.
  • Any 5-HT2A receptor antagonist/inverse agonist may be used in combination with DEX to improve the therapeutic properties of DEX.
  • DEX and the 5-HT2A receptor antagonist/inverse agonist may be administered in separate compositions or dosage forms, or may be administered in a single composition or dosage form comprising both.
  • 5-HT2A receptor antagonist/inverse agonists that can be co-administered with DEX include, but are not limited to, a compound of formula I, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide,
  • Combining a compound of formula I, with DEX may provide greater efficacy, such as greater pain relief, than would otherwise be achieved by administering either component alone.
  • DEX can be rapidly and extensively metabolized, yielding low systemic exposure even at high doses.
  • a compound of formula I, besides possessing antidepressant and analgesic properties, is an inhibitor of DEX metabolism.
  • Metabolites of a compound of formula I, which include a compound of formula I, a derivative, a metabolite are also inhibitors of DEX metabolism.
  • a compound of formula I, including a form of a compound of formula I, that is rapidly converted in the body is a prodrug of a compound of formula I.
  • this inhibition may augment DEX plasma levels, resulting in additive or synergistic efficacy such as relief of neurological disorders including pain, depression, smoking cessation, etc.
  • co-administration of DEX with a compound of formula I may thereby enhance the efficacy of a compound of formula I, for many conditions.
  • Co-administration of DEX with a compound of formula I may enhance the analgesic properties of a compound of formula I for many conditions.
  • Co-administration of DEX with a compound of formula I may also enhance the antidepressant properties of a compound of formula I for many conditions, including faster onset of action.
  • Another potential benefit of co- administration of DEX and a compound of formula I is that it may be useful to reduce the potential for an adverse event, such as drowsiness or confusion, associated with treatment by DEX. This may be useful, for example, in subjects at risk of experiencing an adverse event as a result being treated with DEX.
  • an adverse event such as drowsiness or confusion
  • Another potential benefit of co-administration of DEX and a compound of formula I is that it may be useful to reduce the potential for an adverse event, such as seizure, associated with treatment by a compound of Formula I. This may be useful, for example, in subjects at risk of experiencing the adverse event as a result being treated with a compound of formula I.
  • a compound of formula I co-administration may reduce a central nervous system adverse event, a gastrointestinal event, or another type of adverse event associated with any of these compounds.
  • Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, sleeplessness, light-headedness, tremor, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or excitement, tinnitus, drowsiness, dizziness, sedation, somnolence, confusion, disorientation, lassitude, incoordination, fatigue, euphoria, nervousness, insomnia, sleeping disturbances, convulsive seizures, excitation, catatonic-like states, hysteria, hallucinations, delusions, paranoia, headaches and/or migraine, and extrapyramidal symptoms such as oculogyric crisis, torticollis, hyperexcitability, increased muscle tone, ataxia, and tongue protru
  • CNS adverse events include, but
  • Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic ulcers with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, feeling of fullness in stomach, indigestion, bloating, hyperacidity, dry mouth, gastrointestinal disturbances, and gastric pain.
  • Co-administering DEX and a 5-HT2A receptor antagonist/inverse agonist does not necessarily require that the two compounds be administered in the same dosage form.
  • the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. Additionally, the two compounds may be administered at the same time, but this is not required.
  • the compounds can be given at different times as long as both are in a human body at the same time for at least a portion of the time that treatment by co-administration is being carried out.
  • co-administration of a combination of a compound of formula I and DEX results in pain relieving properties.
  • the combination may have improved pain- relieving properties as compared to a compound of formula I alone or compared to DEX alone, including potentially faster onset of action.
  • the combination may have improved pain relieving properties of 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 any amount of pain relief in a range bounded by, or between, any of these values, as compared to a compound of formula I alone.
  • the combination may have improved pain relieving properties of 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 any amount of pain relief in a range bounded by, or between, any of these values, as compared to as compared to DEX alone.
  • any reference to a compound herein, such as DEX, a compound of Formula I by structure, name, or any other means includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; deuterium-modified compounds, such as deuterium-modified DEX and a compound of formula I; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • Examples of deuterium modified DEX and a compound of formula I include, but are not limited to, those shown below.
  • a dosage form or a composition may be a blend or mixture of DEX and a compound that inhibits the metabolism of DEX, such as a compound of formula I, either alone or within a vehicle.
  • DEX and a compound of formula I may be dispersed within each other or dispersed together within a vehicle.
  • a dispersion may include a mixture of solid materials wherein small individual particles are substantially one compound, but the small particles are dispersed within one another, such as might occur if two powders of two different drugs are blended with a solid vehicle material, and the blending is done in the solid form.
  • DEX and a compound of formula I may be substantially uniformly dispersed within a composition or dosage form.
  • DEX and a compound of formula I may be in separate domains or phases in a composition or dosage form.
  • one drug may be in a coating, and another drug may be in a core within the coating.
  • one drug may be formulated for sustained release and another drug may be formulated for immediate release.
  • Some embodiments include administration of a tablet that contains a compound of formula I in a form that provides sustained release and DEX in a form that provides immediate release or vice versa. While there are many ways that sustained release of a compound of formula I, may be achieved, in some embodiments, a compound of formula I is combined with hydroxypropyl methylcellulose. For example, particles of a compound of formula I hydrochloride could be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCELTM) to form an admixture of blended powders. This could then be combined with immediate release DEX in a single tablet.
  • METHOCELTM hydroxypropyl methylcellulose
  • DEX and/or a 5-HT2A receptor antagonist/inverse agonist such as a compound of formula I may be combined with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's
  • Therapeutic compounds may be administered by any means that may result in the contact of the active agent(s) with the desired site or site(s) of action in the body of a patient.
  • the compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents.
  • they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.
  • Therapeutic compounds may be administered to a subject in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally.
  • Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial, including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol and rectal systemic.
  • the ratio of DEX to a compound of formula I may vary.
  • the weight ratio of DEX to a compound of formula I may be about 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, or between, any of these values.
  • a ratio of 0.1 indicates that the weight of DEX is 1/10 that of a compound of formula I.
  • a ratio of 10 indicates that the weight of DEX is 10 times that of a compound of formula I.
  • the amount of DEX in a therapeutic composition may vary.
  • 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%
  • Some liquid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about
  • Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of DEX.
  • Some solid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about
  • DEX in a range bounded by, or between, any of these values.
  • the amount of a compound of formula I, in a therapeutic composition may vary. If increasing the plasma level of DEX is desired, a compound of formula I should be administered in an amount that increases the plasma level of DEX. For example, a compound of formula I, may be administered in an amount that results in a plasma concentration of DEX in the subject, on day
  • a compound of formula I may administered to a subject in an amount that results in a 12 hour area under the curve from the time of dosing (AUCo-12), or average plasma concentration in the subject for the 12 hours following dosing (C avg ) of DEX, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of DEX administered without a compound of formula I.
  • AUCo-12 time of dosing
  • C avg average plasma concentration in the subject for the 12 hours following dosing
  • a compound of formula I may administered to a subject in an amount that results in a maximum plasma concentration (Cmax) of DEX in the subject, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, or at least about 40 times the plasma concentration of the same amount of DEX administered without a compound of formula I.
  • Cmax maximum plasma concentration
  • an increase in the DEX plasma level can occur on the first day that a compound of formula I is administered, as compared to the same amount of DEX administered without a compound of formula I.
  • the DEX plasma level on the first day that a compound of formula I is administered may be at least about 1.5 times, at least about at least 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times the level that would be achieved by administering the same amount of DEX without a compound of formula I.
  • the DEX AUC on the first day that a compound of formula I is administered may be at least twice the AUC that would be achieved by administering the same amount of DEX without a compound of formula I.
  • the DEX Cmax on the first day that a compound of formula I is administered may be at least twice the Cmax that would be achieved by administering the same amount of DEX without a compound of formula I.
  • the DEX trough level (e.g., plasma level 12 hours after administration) on the first day that a compound of formula I is administered may be at least twice the trough level that would be achieved by administering the same amount of DEX without a compound of formula I.
  • a compound of formula I is administered on the first day of at least two days of treatment with DEX, wherein a decrease in the DO plasma level occurs on the first day that a compound of formula I and DEX are co-administered, as compared to the same amount of DEX administered without a compound of formula I.
  • the DO plasma level on the first day may be reduced by at least 5 % as compared to the DO plasma level that would be achieved by administering the same amount of DEX without a compound of formula I.
  • a compound of formula I and DEX are co-administered for at least five consecutive days, to a subject in need of treatment with DEX, wherein, on the fifth day, the DEX plasma level is higher than the DEX plasma level that would have been achieved by administering the same amount of DEX administered without a compound of formula I, for five consecutive days.
  • the DEX plasma level on the fifth day may be at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times, the level that would be achieved by administering the same amount of DEX without a compound of formula I, for five consecutive days.
  • a compound of formula I and DEX are co-administered for at least six consecutive days, to a subject in need of treatment with DEX, wherein, on the sixth day, the DEX plasma level is higher than the DEX plasma level that would have been achieved by administering the same amount of DEX administered without a compound of formula I, for six consecutive days.
  • the DEX plasma level on the sixth day may be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 75 times, or up to about 500 times, the level that would be achieved by administering the same amount of DEX without a compound of formula I, for six consecutive days.
  • a compound of formula I and DEX are co-administered for at least seven consecutive days, to a subject in need of treatment with DEX, wherein, on the seventh day, the DEX plasma level is higher than the DEX plasma level that would have been achieved by administering the same amount of DEX administered without a compound of formula I, for seven consecutive days.
  • the DEX plasma level on the seventh day may be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 70 times, at least 80 times, at least 90 times, or up to about 500 times, the level that would be achieved by administering the same amount of DEX without a compound of formula I, for seven consecutive days.
  • a compound of formula I and DEX are co-administered for at least eight consecutive days, wherein, on the eighth day, DEX has a plasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours, after co-administering a compound of formula I with DEX that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1,000 times, the plasma level that would be achieved by administering the same amount of DEX without a compound of formula I for eight consecutive days.
  • a compound of formula I and DEX are co-administered for at least eight consecutive days, to a subject in need of treatment with DEX, wherein, on the eighth day, the DO plasma level is lower than the DO plasma level that would have been achieved by administering the same amount of DEX administered without a compound of Formula I for eight consecutive days.
  • the DO plasma level on the eighth day may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, as compared to the DO plasma level that would be achieved by administering the same amount of DEX without a compound of formula I for eight consecutive days.
  • a compound of formula I may be administered to a subject in an amount that results in an AUCo-12 of a compound of formula I in the subject, on day 8, that is at least about 100 nghr/mL, at least about 200 nghr/mL, at least about 500 nghr/mL, at least about 600 nghr/mL, at least about 700 nghr/mL, at least about 800 nghr/mL, at least about 900 nghr/mL, at least about 1,000 nghr/mL, at least about 1,200 nghr/mL, at least 1,600 nghr/mL, or up to about 15,000 nghr/mL.
  • a compound of formula I may be administered to a subject in an amount that results in a C avg of a compound of formula I in the subject, on day 8, that is at least about 10 ng/niL, at least about 20 ng/niL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least 120 ng/mL, or up to about 1,500 ng/mL.
  • 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 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 5% (w/v) to about 15% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) of a compound of Formula I or any amount of a compound of Formula I, in a range bounded by, or between, any of these values.
  • Some liquid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 110 mg to about 140 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of a compound of Formula I, or any amount of a compound of Formula I, in a range bounded by, or 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) of a compound of Formula I, or any amount of a compound of Formula I, in a range bounded by, or between, any of these values.
  • Some solid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 110 mg to about 140 mg, about 50 mg to about 150 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of a compound of Formula I, or any amount of a compound of Formula I, in a range bounded by, or between, any of these values.
  • a compound of Formula I is administered at a dose that results in a a compound of Formula I, plasma level of about 0.1 ⁇ to about 10 ⁇ , about 0.1 ⁇ to about 5 ⁇ , about 0.2 ⁇ to about 3 ⁇ , 0.1 ⁇ to about 1 ⁇ , about 0.2 ⁇ to about 2 ⁇ , 1 ⁇ to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , about 2 ⁇ to about 3 ⁇ , or about 2.8 ⁇ to about 3 ⁇ , about 1.5 ⁇ to about 2 ⁇ , about 4.5 ⁇ to about 5 ⁇ , about 2.5 ⁇ to about 3 ⁇ , about 1.8 ⁇ , about 4.8 ⁇ , about 2.9 ⁇ , about 2.8 ⁇ , or any plasma level in a range bounded by, or between, any of these values.
  • a compound of Formula I may be administered to a subject in an amount that results in an AUCo-12 of a compound of Formula I in the subject, on day 8, that is at least about 200 nghr/mL, at least about 400 nghr/mL, at least about 700 nghr/mL, at least about 1,000 nghr/mL, at least about 3,000 nghr/mL, at least about 7,000 nghr/mL, at least about 10,000 nghr/mL, at least about 15,000 nghr/mL, at least about 20,000 nghr/mL, at least about 30,000 nghr/mL, up to about 50,000 nghr/mL, up to about 150,000 nghr/mL, or any AUC in a range bounded by, or between, any of these values.
  • a compound of Formula I is administered to a subject in an amount that results in a Cmax of a compound of Formula I in the subject, on day 8, that is at least about 20 ng/mL, at least about 60 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up to about 1,000 ng/mL, at least about 4,000 ng/mL, up to about 10,000 ng/mL, up to about 50,000 ng/mL, or any Cmax in a range bounded by, or between, any of these values.
  • a compound of Formula I is administered to a subject in an amount that results in a C avg of a compound of Formula I in the subject, on day 8, that is at least about 20 ng/niL, at least about 30 ng/niL, at least about 50 ng/niL, at least about 80 ng/niL, at least about 90 ng/niL, at least about 100 ng/niL, at least about 150 ng/niL, at least about 200 ng/niL, at least about 300 ng/niL, up to about 1,000 ng/niL, up to about 5,000 ng/niL, up to about 30,000 ng/niL, or any Cavg in a range bounded by, or between, any of these values.
  • compositions comprising both DEX and a compound of Formula I 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 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 5% (w/v) to about 15% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), about 40% (w/v), about 40% (w/v), about 40% (w/v) to about 50%
  • 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%
  • the weight ratio of DEX to a compound of Formula I in a single composition or dosage form may be about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, or between, any of these values.
  • a therapeutically effective amount of a therapeutic compound may vary depending upon the circumstances.
  • a daily dose of DEX may in some instances range from about 0.1 mg to about 1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg, about 60 mg to about 700 mg, about 100 mg to about 400 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 20 mg to about 60 mg, about 60 mg to about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140 mg, about 160 mg to about 200 mg, about 200 mg to about 300 mg, about 220 mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg to about 380 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 15 mg, about 30 mg, about 60 mg,
  • a daily dose of a compound of Formula I may in some instances range from about 10 mg to about 1000 mg, about 50 mg to about 600 mg, about 100 mg to about 2000 mg, about 50 mg to about 100 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 100 mg to about 150 mg, about 150 mg to about 300 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 200 mg about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg, about 560 mg to about 640 mg, or about 500 mg to about 600 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or any daily dose in a range bounded by, or between, any of these values, a compound of Formula I may be administered once daily; or twice daily or every 12 hours, or three times daily in an amount that is about half or one
  • about 150 mg/day of a compound of Formula I and about 30 mg/day of DEX about 150 mg/day of a compound of Formula I and about 60 mg/day of DEX, about 150 mg/day of a compound of Formula I and about 90 mg/day of DEX, about 150 mg/day of a compound of Formula I and about 120 mg/day of DEX, about 200 mg/day of a compound of Formula I and about 30 mg/day of DEX, about 200 mg/day of a compound of Formula I and about 60 mg/day of DEX, about 200 mg/day of a compound of Formula I and about 90 mg/day of DEX, about 200 mg/day of a compound of Formula I and about 120 mg/day of DEX, about 300 mg/day of a compound of Formula I and about 30 mg/day of DEX, about 300 mg/day of a compound of Formula I and about 30 mg/day of DEX, about 300 mg/day of a compound of Formula of a compound of Formula I and about 30 mg/day of DEX, about 300 mg/day of
  • Formula I and about 60 mg/day of DEX, about 300 mg/day of a compound of Formula I and about 90 mg/day of DEX, or about 300 mg/day of a compound of Formula I and about 120 mg/day of DEX is administered to the subject.
  • about 100 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 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.
  • 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.
  • a 5-HT2A receptor antagonist/inverse agonist such as a compound of Formula I may be administered for as long as needed to treat a neurological condition, such as pain, depression or cough.
  • a 5-HT2A receptor antagonist/inverse agonist such as a compound of Formula I and DEX are administered at least once a day, such as once daily or twice daily, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14 days, at least
  • Therapeutic compounds may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the food of the diet.
  • the active compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Tablets, troches, pills, capsules and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, cornstarch, or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid, and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially nontoxic in the amounts employed.
  • compositions or dosage forms may be a liquid or may comprise a solid phase dispersed in a liquid.
  • Therapeutic compounds may be formulated for parenteral or oral administration. Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. A dispersion can also have an oil dispersed within, or dispersed in, glycerol, liquid polyethylene glycols, and mixtures thereof.
  • a surfactant such as hydroxypropylcellulose.
  • a dispersion can also have an oil dispersed within, or dispersed in, glycerol, liquid polyethylene glycols, and mixtures thereof.
  • these preparations may contain a preservative to prevent the growth of microorganisms.
  • AD Alzheimer's disease
  • BPSD neuropsychiatric symptoms
  • BPSD symptoms are among the main drivers for caregiver burden and hospitalization.
  • Frequency of BPSD symptoms increases with the disease progression (e.g. up to 60% in mild and moderate AD and up to 90% in severe AD).
  • compositions and methods useful in the symptomatic and disease-modifying treatment of neurodegenerative diseases and brain injuries including sequelae thereof like organic brain syndrome and chronic traumatic encephalopathies; chronic or intractable pain, ophthalmologic indications associated with retinopathies, anxiety disorders, post-traumatic stress disorder, depression, diabetes mellitus and it's complications like peripheral neuropathies with or without neuropathic pain, Buerger' s disease, Raynaud' s disease, coronary artery disease, angina pectoris, atherosclerosis including CNS like multi-infarct dementia, Vascular Cognitive Impairment, Vascular Dementia or Binswanger's Disease, and nephropathies.
  • a method of increasing the metabolic lifetime of DEX comprising administering 5-HT2A receptor antagonist/inverse agonist of Formula I to a subject in need of treatment with DEX, wherein 5-HT2A receptor antagonist/inverse agonist is an inhibitor of a CYP2D6 enzyme and wherein DEX is present in the body of the subject at the same time as Ml.
  • a method of preventing adverse events associated with treatment by DEX comprising co-administering 5-HT2A receptor antagonist/inverse agonist of
  • Formula I to a subject in need of treatment with DEX, wherein the subject is at risk of experiencing the adverse event as a result of being treated with DEX.
  • a method for using 5HT2A receptor antagonists of Formula I to improve the therapeutic properties of DEX in the treatment of neuropsychiatric disorders is provided.
  • a method of treating a neuropsychiatric disorder comprising administering a 5HT2A receptor antagonist of Formula I and DEX to a subject in need thereof.
  • 5-HT2A receptor antagonist/inverse agonist is a prodrug of Ml such as a compound of Formula I or pharmaceutically acceptable salts thereof.
  • 5-HT2A receptor antagonist/inverse agonist is an enantiomer of Ml such as (R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-ol) or (S)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2- ol), or pharmaceutically acceptable salts thereof.
  • the neuropsychiatric disorder is Alzheimer's disease.
  • a method for selecting a 5-HT2A receptor antagonist/inverse agonist for the use in combination with DEX in subjects in need thereof is provided.
  • a specific enantiomer of a 5HT2A receptor antagonist with potent CYP2D6 inhibitory activity has higher blood-brain barrier penetration.
  • a specific enantiomer of an 5HT2A receptor antagonist with potent CYP2D6 inhibitory activity has a better ratio of central vs peripheral effects when administered in combination with DEX, wherein central effects are assessed by direct or indirect 5HT2A receptor engagement methods while peripheral effects are assessed by methods based on blood glucose measurement.
  • DEX and the selected 5-HT2A antagonist are administered in a combined dose, and wherein the amount of DEX administered comprises from about 20 mg/day to about 80 mg/day.
  • DEX is administered in a combined dose with a selected enantiomer of Ml, wherein the amount of the Ml enantiomer administered comprises from about 0.1 mg/day to about 1000 mg/day.
  • An embodiment of the invention is a method to augment therapeutic properties of DEX by administering it with a 5HT2A receptor antagonist that has potent CYP2D6 inhibitory activity, and multiple therapeutic benefits of its own.
  • Some embodiments include a method 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 1000 mg/day, about 150 mg/day to about 5000 mg/day, about 150 mg/day to about 300 mg/day, or about 150 mg/day to about 100 mg/day, or an amount as required of a compound of Formula I and about 0.1 mg/day to about 1 mg/day, about 0.5 mg/day to about 15 mg/day, about 15 mg/day to about 60 mg/day, about 15 mg/day to about 120 mg/day, about 0.1 mg/day to about 200 mg/day, or any amount of a compound of Formula I in
  • composition of the present invention can be formulated into any pharmaceutical dosage forms for oral, topical, rectal, vaginal, nasal, or ophthalmic administration, and include . syrups and suspensions, usingcommonly known ingredients and procedures and methods
  • the present invention can be formulated into any pharmaceutical dosage forms for oral, topical, rectal, vaginal, nasal, or ophthalmic administration, and include . syrups and suspensions, and ommonly known ingredients and procedures to formulate pharmaceutical composition are within the purview of a person 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; incorporated herein in their entirety by reference) can be used to formulate the composition of the invention.
  • the oral formulations and the tablet formulations include enteric coating layered formulations that comprise a separating layer to separate the acidic enteric coating material from omeprazole being an acid susceptible substance.
  • HPC or other suitable polymers disclosed herein may be used in a layer that separates the core material from the enteric coating layer in the described formulations.
  • SGL hydrochloride (CAS NO.: 135159-51-2), with its systematic name of Butanedioic acid, mono(2-(dimethylamino)-l-((2-(2-(3-methoxyphenyl) ethyl) phenoxy) methyl) ethyl) ester, hydrochloride, could be produced through many synthetic methods (Chen et al., A practical synthesis of sarpogrelate hydrochloride and in vitro platelet aggregation inhibitory activities of its analogues, Chinese Chemical Letters, Volume 21, Issue 3, March 2010, Pages 287-28; J Med Chem 33(6) (1990); CN103242179 A; WO2015008973; incorporated by reference in entirety).
  • SGL hydrochloride was synthesized with about 46% overall yield from salicylicaldehyde via benzyl protection, reduction, chlorination, Arbuzov reaction, Wittig-Horner reaction, catalytic hydrogenation to give 2-2-(3-methoxyphenyl)ethyl phenol, which was subjected to react with epichlorohydrin, amination, esterification and salt formation.
  • US4485258 discloses a synthesis method of the first SGL hydrochloride, and recrystallized from acetone to obtain, but the experiments show that SGL hydrochloride poor solubility in acetone, acetone, hydrochloric acid is not suitable as a recrystallization solvent SGL.
  • CN101239920A disclosed as acetonitrile, propionitrile, 1,4-dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, sulfolane, dimethyl sulfoxide or a mixture of more than two kinds thereof with methanol, ethanol, acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be used as the recrystallization solvent SGL hydrochloride, the purity of the product can reach 98%.
  • Enantiomerically pure form of SGL can be produced using chiral ligands to induce formation of a single enantiomer of choice as shown below:
  • Chiral organic compounds play an important role in pharmaceuticals, agrochemicals and other materials which possess useful biological activity.
  • Enzymes and other natural binding sites recognize substrates with particular chirality to generate a variety of biological functions. These enzymes or receptor sites are specific in their action, because the enantiomers may exhibit different properties due to the chirality.
  • biologically active compounds it is possible that only one of the enantiomer is active and the other is devoid of activity, both enantiomers are active but they have different potencies or both the enantiomers have similar or equal activities. Therefore, the production of enantiomerically pure molecules of drugs is of interest and the methodology has three basic strategies, 1) resolution (2) use of chiral building blocks and (3) asymmetric synthesis. Asymmetric synthesis provides by far the most efficient use of one chiral material to prepare another.
  • the preparation of enantiomerically pure molecules of biological interest can be effectively achieved by asymmetric synthesis. This method involves the creation of one or more chiral centers from prochiral starting materials under the influence of chiral substrates.
  • the preparation of enantiomerically pure compounds involves use of chiral auxiliaries, chiral reagents or chiral catalysts, or a combination thereof.
  • the compounds of the disclosure can be prepared from (2R)-3- (dimethylamino)-l,2-propanediol and (2S)-3-(dimethylamino)-l,2-propanediol (Scheme VIII).
  • reaction media include water, methanol, ethanol, 1-propanol, 2-propanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetic acid, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methylene chloride, chloroform, 1 ,2-dichloroethane, benzene, toluene and xylenes, and /or mixtures thereof.
  • Linkers that can be used in the synthesis of SARPODEXAMIDETM Derivatives in the above scheme include, but not limited to, linkers (described in Simplicio et al., Prodrugs for Amines, Molecules 13, 519-547 (2008); Mahato et al., Prodrugs for Improving Tumor Targetability and Efficiency, Adv Drug Deliv Rev.
  • Estenfication Esters are derived from carboxylic acids.
  • a carboxylic acid contains the - COOH group, and in an ester the hydrogen in this group is replaced by a hydrocarbon group R' such as an alkyl, cycloalkyl, an aryl, and a hetero-aryl group.
  • Esters are produced when carboxylic acids are heated with alcohols in the presence of an acid catalyst.
  • the catalyst is an acid, usually concentrated sulfuric acid. Dry hydrogen chloride gas can be used in some cases. TsOH (tosic acid) is also often used.
  • the alcohol is generally used as solvent so is present in large excess.
  • the diastereomerically pure SARPODEXTER can be obtained by reacting the racemic sarpogrelate with optically pure dextrorphan (DO-H3, compound 151) under mild esterification conditions to obtain a mixture of diastereomeric esters, compounds 165-166, which can be separated by crystallization and chromatographic techniques mentioned above and the techniques described in this specification to obtain diastereomerically pure SARPODEXTERs 165 and 166.
  • a compound of Formula I or Sarpodexamide tm derivatives can be obtained by reacting dextromethorphan either as a single isomer or a mixture thereof with 2,2,2-trichloroethyl chloroformate in refluxing toluene thus obtaining the N-demethylated compound.
  • Reagents such as uronium salt (l-cyano-2-ethoxy-2- oxoethylidenaminooxy) dimethylamino morpholino carbenium hexafluorophosphate (COMU), ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino) acetate (o-NosylOXY), EDCI and NaHCCb, B(OCH2CF3)3 , trimethylaluminium, Lanthanum trifluoromethanesulfonate, ZrOCh ⁇ 8 3 ⁇ 40, methanesulfonyl chloride and N-methylimidazole, ⁇ , ⁇ '-carbonyldiimidazole (CDI), etc. can be used.
  • uronium salt l-cyano-2-ethoxy-2- oxoethylidenaminooxy
  • o-NosylOXY ethyl 2-cyano-2-
  • a process for separating the diastereomers of a compound by using an ionic liquid to increase separation efficiency is provided.
  • an ionic liquid may be used as the extractant.
  • this separation process may be performed on a compound containing a mixture of at least one pair of diastereomers, and the diastereomers may be separated by contacting the mixture with at least one ionic liquid in which one of the diastereomers is soluble to a greater extent than the other diastereomer, and separating the lower- solubility diastereomer from the mixture.
  • the inventions disclosed herein thus include processes for the separation of diastereomers, the use of such processes, and the products obtained and obtainable by such processes.
  • this separation process may be performed on a compound such as a diastereomeric mixture of DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or
  • the diastereomers are separated by contacting the mixture with at least one ionic liquid in which one of the diastereomers is soluble to a greater extent than the other diastereomer, and separating the lower- solubility diastereomer from the mixture.
  • DERAPHANTM from a mixture comprising both diastereomers by liquid-liquid extraction using at least one ionic liquid as an extractive solvent.
  • Another embodiment is a process for performing an industrial operation selected from the group consisting of a calibration operation, a cleaning operation, a rinsing operation, a drying operation, a particulate removal operation, a solvent operation, a dispersion operation, a heat transfer operation, and an insulating operation, comprising contacting a mixture comprising a pair of diastereomers of DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM with at least one ionic liquid in which one of the diastereomers is soluble to a greater extent than the other diastereomer, separating the lower-solubility diastereomer from the mixture, and employing the separated diastereomer in the operation.
  • a calibration operation selected from the group consisting of a calibration operation, a cleaning operation, a rinsing operation, a drying operation, a particulate removal operation, a solvent operation, a dispersion operation, a heat transfer operation,
  • Another embodiment is a process for separating one diastereomer from another diastereomer in a pair of diastereomers in a compound.
  • an ionic liquid is used to facilitate the separation, and the diastereomers may be separated by contacting the mixture with at least one ionic liquid in which one of the diastereomers is soluble to a greater extent than the other diastereomer, and separating the lower- solubility diastereomer from the mixture.
  • ionic liquid is defined as an organic salt that is fluid at or below about 100 °C.
  • Liquid-liquid extraction is a process for separating components in solution by their distribution between two immiscible liquid phases. Liquid-liquid extraction involves the transfer of mass from one liquid phase into a second immiscible liquid phase, and is carried out using an extractant or solvent.
  • Components in a liquid mixture can be separated by a process such as liquid-liquid extraction using a single equilibrium (or theoretical) stage, or using multiple stages.
  • An equilibrium, or theoretical, stage is a device that allows intimate mixing of a feed with an immiscible liquid such that concentrations approach equilibrium, followed by physical separation of the two immiscible liquid phases.
  • a single stage device can be a separatory funnel, or an agitated vessel, which allows for intimate mixing of the feed with the immiscible extractant.
  • one or both of the liquid phases can be recovered, for example, by decantation.
  • Multiple stage devices for liquid separation can be crosscurrent or countercurrent devices.
  • the feed enters a first equilibrium stage and is contacted with an extractant.
  • the two liquid phases are mixed, with droplets of one phase suspended in the second phase, and then the two phases are separated, and DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM from the first stage is contacted with additional extractant, and the separation process is repeated.
  • a crosscurrent system the feed is initially contacted with extractant in a first equilibrium stage.
  • DEX, Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM from this stage then cascades down through one or more additional stages.
  • the composition is contacted with fresh extractant, and further purification of the desired component in the composition is achieved.
  • An example of a crosscurrent system where the threo isomer of the composition is purified using the ionic liquid l-butyl-3- methylimidazolium tetrafluoroborate ([BMIM][BF 4 ] as the extractant.
  • BMIM ionic liquid l-butyl-3- methylimidazolium tetrafluoroborate
  • the extractant enters at the stage farthest from the feed, and the two phases are passed through and across each other, coming from the two different (e.g. opposite) directions.
  • Equipment used for liquid-liquid extraction can be classified as “stagewise” or “continuous (differential) contact” equipment. Stagewise equipment is also referred to as “mixer- settlers”.
  • Mixing the liquids occurs by contacting the feed with the extractant, and the resultant dispersion is settled as the two phases separate. Mixing can occur with the use of baffles or impellers, and the separation process may be carried out in batch fashion or with continuous flow.
  • Settlers can be simple gravity settlers, such as decanters, or can be cyclones or centrifuges, which enhance the rate of settling.
  • Continuous contact equipment is typically arranged for multistage countercurrent contact of the immiscible liquids, without repeated separation of the liquids from each other between stages. Instead, the liquids remain in continuous contact throughout their passage through the equipment. Countercurrent flow is maintained by the difference in densities of the liquids and either the force of gravity (vertical towers) or centrifugal force (centrifugal extractors). Gravity- operated extractors can be classified as spray towers, packed towers or perforated-plate (sieve- plate) towers. Gravity-operated towers also include towers with rotating stirrers and pulsed towers as is known in the art.
  • the diastereomers of a compound of the composition and in particular the threo and erythro isomers of 2,3-dihydrodecafluoropentane, are separated by a process such as liquid-liquid extraction, any of the equipment described above can be used to perform the separation.
  • the separation is carried out using a vertical tower with perforated plates.
  • the higher solubility diastereomer may be separated from the extractant by a process such as distillation.
  • the dielectrical constant of the solvent changes the formation, composition and enantiomer recognition of the crystalls (Sakai et al., Tetrahedron: Asymmetry, 14, 3716 (2003); incorporated by reference in entirety).
  • the composition of crystalline diastereoisomers is also influenced by the pH of the reaction mixture (Fogassy et al., J. Chem. Res., S 11, 346 (1981); Fogassy et al., J. Chem. Soc. Perkin Trans. 2. (1988), incorporated by reference in entirety).
  • the purity (de) of the diastereoisomer can be improved using a mixture of structurally related resolving agents.
  • the eutectic composition usually determinates the composition of the crystallized mixture and the oily residue. That eutectic composition can be known from the binary melting point phase diagram.
  • the initial isomeric composition (eeO) is higher than the eutectic composition, the pure optical isomer cam be crystallized.
  • An ionic liquid, or a mixture of two or more thereof, may be used in a process hereof to separate the diastereomers of a compound.
  • the extractant used may be an ionic liquid or a mixture of two or more ionic liquids.
  • Ionic liquids are organic compounds that are liquid at room temperature (approximately 25 °C). They differ from most salts in that they have very low melting points, and they generally tend to be liquid over a wide temperature range.
  • Ionic liquids have essentially no vapor pressure, most are air and water stable, and they can either be neutral, acidic or basic.
  • a cation or anion of an ionic liquid useful herein can in principle be any cation or anion such that the cation and anion together form an organic salt that is liquid at or below about 100 °C.
  • the properties of an ionic liquid can, however, be tailored by varying the identity of the cation and/or anion.
  • the acidity of an ionic liquid can be adjusted by varying the molar equivalents and type and combinations of Lewis acids used.
  • ionic liquids are formed by reacting a nitrogen-containing heterocyclic ring, preferably a heteroaromatic ring, with an alkylating agent (for example, an alkyl halide) to form a quaternary ammonium salt, and performing ion exchange or other suitable reactions with various Lewis acids or their conjugate bases to form the ionic liquid.
  • alkylating agent for example, an alkyl halide
  • suitable heteroaromatic rings include substituted pyridines, imidazole, substituted imidazole, pyrrole and substituted pyrroles.
  • These rings can be alkylated with virtually any straight, branched or cyclic Ci-20 alkyl group, but preferably, the alkyl groups are C1-16 groups, since groups larger than this may produce low melting solids rather than ionic liquids.
  • Various triarylphosphines, thioethers and cyclic and non-cyclic quaternary ammonium salts may also been used for this purpose.
  • Counter ions that may be used include chloroaluminate, bromoaluminate, gallium chloride, tetrafluoroborate, tetrachloroborate, hexafluorophosphate, nitrate, trifluoromethane sulfonate, methylsulfonate, p- toluenesulfonate, hexafluoroantimonate, hexafluoroarsenate, tetrachloroaluminate, tetrabromoaluminate, perchlorate, hydroxide anion, copper dichloride anion, iron trichloride anion, zinc trichloride anion, as well as various lanthanum, potassium, lithium, nickel, cobalt, manganese, and other metal-containing anions.
  • Ionic liquids may also be synthesized by salt metathesis, by an acid-base neutralization reaction or by quaternizing a selected nitrogen-containing compound; or they may be obtained commercially from several companies such as Merck (Darmstadt, Germany) or BASF (Mount Olive, NJ).
  • a library of ionic liquids may be prepared, for example, by preparing various alkyl derivatives of a particular cation (such as the quaternary ammonium cation), and varying the associated anions (US 20090131728A1, incorporated in entirety by reference).
  • the diastereomers of the invention can be separated efficiently by cation exchange with mixed-mode sorbent in the solid phase extraction (SPE) procedure.
  • diastereomers can be separated by extractive distillation, wherein an auxiliary which changes the partial pressure of the various diastereomers to be separated to a different degree allowing easier separation of the diastereomers by distillation in a good yield. Separation can be accomplished using fractionating columns, and preferably under reduced pressure of about 10 "3 bar to about 1 bar (US 4874473 A, US 20070225505 Al, incorporated in entirety by reference).
  • RP-HPLC and normal phase chromatographic (NP-HPLC) separations can be used to separate the diastereomers of the invention
  • Columns that can be used in the separation of enantiomers can be Primesep C, NUCLEOSIL, cellulose based chiral HPLC columns, SHISEIDO Chiral CD-Ph, etc. (Fekete et al., Compative Study Separation of Diastereomers by HPLC, Chromatographia, 57, No. 3 ⁇ 4 (2003 February), US 7119211 B2, incorporated in entireity by reference).
  • compositions of this invention can be prepared by adding a compound of Formula I,
  • compositions of the invention in producing the compositions of the invention, one can mix racemate or enatiomerically pure compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM and the complex magnesium aluminum silicate and subsequently add a suitable solvent thereto to form a paste therewith.
  • Sodium chloride and sodium saccharin can be added to the dextromethorphan-complex magnesium aluminum silicate mixture prior to forming the mixture into a paste.
  • sodium chloride and sodium saccharin can be added to the paste.
  • suitable flavoring agents and coloring agents can be added either to the dry mixture or to the paste.
  • any medicinally acceptable organic solvent which is suitable for pharmaceutical use and in which a compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM is soluble can be employed.
  • organic solvents such as propylene glycol, glycerine, 1,3- butylene glycol, benzyl alcohol, etc., can be used.
  • benzyl alcohol is employed as the solvent for the saprodexTM.
  • Edible coloring agents and edible flavoring agents can be used in preparing the present compositions.
  • Flavoring agents which are suitable for use include, for example, licorice, ginger, natural fruit extracts, etc.
  • the coloring agent one can use any color which is suitable for use in foods and drugs.
  • the quantity of coloring and the quantity of flavoring agents used in formulating the composition of this invention is variable.
  • the formulation contains about 0.3 g to about 1.5 g, about 1.0 g, of thickener; about 1 g to about 10 g, about 2.5 g, of 1,2-propylen glycol as a dissolving agent; about 0.12 g to about 0.19 g, or 0.15 g, of at least one paraben preservative such as methyl paraben; about 0.05 g to about 0.2 g, or about 0.1 g, of sorbic acid; about 30 g to about 60 g, or 40 g of a sugar alcohol solution; about 0.05 to about 0.2 g, or 0.1 g of an artificial sweetener; a compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM - resin complex in an amount to yield a desired strength of about 2.10 g (the amount of a 1:6 complex needed to deliver equivalent to 60 mg of a compound of Formula I, DERATINETM
  • suitable thickeners include: tragacanth; bentonite; acacia and lower alkyl ethers of cellulose (including the hydroxy and carboxy derivatives of the cellulose ethers).
  • Exemplary paraben preservatives are Cl-C4alkyl parabens namely methyl, ethyl, propyl, and butyl parabens.
  • both methyl and propyl paraben are present in the formulation in a ratio of methyl paraben to propyl paraben of from about 2.5:1 to about 7.5:1.
  • the methyl and propyl paraben ratio is 4: 1.
  • the artificial sweetener is a form of saccharin or aspartame.
  • saccharin is sacharin sodium.
  • equivalent sweetening amounts of other known sweetening agents such as the sugar alcohol sorbitol may be substituted therefor.
  • the formulation comprises an amount of resinate sufficient to deliver, when administered at one dose every 12 hours, an antitussive effective amount of a compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM over a period of approximately 12 hours to a patient in need of such administration.
  • the formulation comprises an adult dose of 20 ml contains approximately 420 mg of resinate, to deliver equivalent to 60 mg of a compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM when the drug to resin ratio is 1 :6 and 2.10 g of resinate are present per 100 ml of formulation.
  • the dosage can be altered analogously to that known for the administration of dextromethorphan which has not been complexed with resin, i.e. the typical 15 mg-30 mg/dose of dextromethorphan hydrobromide 1 to 4 times daily, becomes S-20 ml once to twice daily.
  • the formulation comprises the nontoxic substances that block the NMDA receptor in accordance with this invention are dextromethorphan (( + )-3-hydroxy- Nmethylmorphinan), a compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM,
  • the formulation comprises substances that block the NMDA receptor include dizocilpine (5-melhyl-10,l l-dihydro-5H-540-epiminodibenzo[a,d][7]annulene), ketamine (2-(2-chlorophenyl)-2-(methylamino)cyclohexan-l -one), magnesium, selfotel ((2S,4R)- 4-(phosphonomethyl)piperidme-2-carboxylic acid), aptiganel ((E)-l-(3-ethylphenyl)- l-methyl-2- (naphi alen-l-yl)guanidine), felbam.ate (2-phenylpropane-l,3-diyl diearbamate), phencyclidine (l-(l-phenylcyclohexyl)piperidine), amantadine (1-aminoadamantine), memantine (3,5 di
  • the therapeutic composition comprises at least one other pharmacologically active substance e.g., caffeine (a stimulant), an antiemetic drug such as metoclopramide, domperidone, belladonna alkaloids and phenothiazines such as chlorpromazine, prochlorperazine, and promethazine, a nonnarcotic analgesic, e.g., acetaminophen or a nonsteroidal anti-inflammatory drug such as aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac,
  • an antiemetic drug
  • EXAMPLE 1 Dextromethorphan has been synthesized from a benzylisoquinoline (with a planar structure) by Grewe's cyclization to give the corresponding morphinan, wherein the 1,2,3,4, 5, 6,7, 8-octahydro-l-(4-methoxybenzyl)isoquinoline is converted into the N-formyl derivative, cyclized to the N- formyl normorphinan, and the formyl group reduced to an N-methyl group, to give 3-methoxy-17-methylmorphinan.
  • Dextromethorphan is freely soluble in ethanol 96% and essentially insoluble in water.
  • Dextromethorphan can be monohydrated hydrobromide salt or bound to an ion exchange resin based on polystyrene sulfonic acid. Dextrometorphan's specific rotation in water is + 27.6° (20°C, Sodium D-line).
  • EXAMPLE 2 Equimolar sarpogrelate (429.506 g/mol) and dextromethorphan (271.40 g/mol) were mixed in a suitable solvent, agitated and let crystallize. The compound of Formula I and dextromethorphan positive cation would form hydrogen bond to form a complex and crystallize.
  • EXAMPLE 3 To a solution of 54.28 g of dextromethorphan in one liter of chloroform is added a solution of 85.9 g of sarpogrelate in chloroform at 70° C. The salt is precipitated from the hot solution by the addition of ethyl acetate.
  • DERATINETM SARPOTINETM
  • SARPODEXTM SARPODEXTM
  • DERADEXTM DERAPHANTM
  • EXAMPLE 4 Ingredients: 15 g of a compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM; 15 g Glyceryl tristearate; 100 ml Carbon tetrachloride. Preparation: Glyceryl tristearate is dissolved in the warm carbon tetrachloride at 55-60 °C. A compound of formula I, derivative thereof, SARPODEXTM or derivative thereof is then added and suspended in the solution. The suspension is then spray dried using an inlet temperature of 90° C and an outlet temperature of 40° C.
  • the resulting coated a compound of Formula I, DERATINETM, SARPOTINETM, SARPODEXTM, DERADEXTM, or DERAPHANTM having an average particle size of from about 10 to about 200 microns is then suspended in the following aqueous vehicle.
  • the dispersion is again heated, cooled and the sorbitol solution, a solution of the methyl cellulose in water and the imitation black currant are then added with mixing to form the vehicle.
  • SARPODEXTM, DERADEXTM, or DERAPHANTM is then added to the above vehicle and mixed 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 lipid-soluble, low molecular weight release auxiliary agent; and 1 to 70 parts by weight of a drug.
  • the polymeric material is biodegradable or biocompatible, or both, for example, biodegradable aliphatic polyester, or an aliphatic poly(carbonate), poly(lactic acid), lactic acid-glycolic acid copolymer, poly(caprolactone), poly(hydroxybutyric acid) and the like.
  • the release auxiliary agent is a carboxylic acid ester, a monoester or diester of glycerin.
  • the release auxiliary agent is an ester of an organic acid selected from succinic acid, citric acid, tartaric acid, malic acid or the like, or monoacetate ester or diacetate ester of glycerin.
  • the composition may further comprise a cell adhesion material or an endothelialization promoting agent on a surface of a medical device.
  • in invention is a drug-releasable medical device characterized by containing the compositions of the present disclosure.
  • the drug-releasable medical device forms a layer of the composition on the surface, and contacts with a living body, or is incorporated or indwelled in a living body.
  • the device includes a stent, a catheter, a clip, an organ replacement medical device, a capsule sensor or an artificial organ.
  • the stent in one embodiment is used for treating coronary artery stenosis and gradually releasing the composition from the surface. The release rate is 1/10 3 mu g/mm 2 /h to 1 mu g/mm 2 /h on 21 days after indwelling the stent.
  • the stent of the present invention is characterized in that the drug to be gradually released is carried in a polymeric material coated on the surface of a metal forming the stent or in a porous stent substrate.
  • the polymeric material coated on the surface of the stent is amorphous.
  • the polymeric material coated on the surface of the stent is an amorphous biodegradable polymeric material.
  • the polymeric material is a poly(lactic acid) or a lactic acid-glycolic acid copolymer, which is biodegradable.
  • the polymeric material further comprises a release auxiliary agent that promotes the release of a drug to be carried.
  • the auxiliary agent that promotes the release of a drug is a tartrate ester or a malate ester, or a monoester or diester of glycerin.
  • the surface of the metal forming the stent may be a porous body and the above-mentioned drug to be gradually released may be carried in the porous body.
  • the porous body has a pore size of 0.01 nm to 300 nm in diameter.
  • EXAMPLE 5 OPTICALLY PURE SARPOMALATE: Malic acid is a component of many of the foods that we eat daily. Although it is found as a naturally occurring organic compound in various fruits, many choose to take malic acid supplements to increase their overall health, as well as treat various maladies. Today, the acid is most commonly used as a food additive and preservative. It is a mild and relatively harmless acid when used in appropriate amounts. As a food supplement, it is generally considered beneficial for health and is present in large amounts in apple juices. As when taking any supplement, however, you should not exceed the recommended amounts for consumption.
  • Natural organic compounds having asymmetric carbon usually exist as an optically active material and exhibit physiological activity markedly different from that of enantiomers.
  • Racemic sarpomalate can be purified by crystallization and/or chiral chromatography to obtain diasteriomerically pure sarpomalate.
  • EXAMPLE 6 OPTICALLY PURE SARPOMETHIONATE: Methionine (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq. NaHCOs (30 mL).
  • the organic layer is separated, dried (Na2S0 4 ), filtered, and concentrated under reduced pressure.
  • the crude residue is purified by column chromatography (silica gel, hexanes:EtOAc) to yield racemic or diasteriomerically pure sarpomethionate, respectively depending upon the Ml and methionine used (compounds 30-34).
  • Racemic sarpomethionate can be purified by crystallization and/or chiral chromatography to obtain diasteriomerically pure sarpomethionate.
  • EXAMPLE 7 OPTICALLY PURE SARPOPHTHALLATE: Phthallic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure
  • EXAMPLE 8 OPTICALLY PURE SARPOMALONATE: Malonic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure
  • Racemic sarpomalonate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpomalonate.
  • EXAMPLE 9 OPTICALLY PURE SARPOTYROSINATE: Tyrosine (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq.
  • Racemic sarpotyrosinate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpotyrosinate.
  • EXAMPLE 10 OPTICALLY PURE SARPOTRYPTOPHANATE: Tryptophan (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH 2 C1 2 (50 mL) and sat. aq.
  • Racemic sarpotryptophanate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpotryptophanate.
  • EXAMPLE 11 OPTICALLY PURE SARPOMALEATE: Maleic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-dimethylaminopyridine at
  • EXAMPLE 12 OPTICALLY PURE SARPOGRELATE: Succinic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq. NaHCOs (30 mL).
  • Racemic sarpogrelate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpogrelate.
  • EXAMPLE 13 OPTICALLY PURE SARPOGLUTARATE: Glutaric acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq. NaHCOs (30 mL).
  • the organic layer is separated, dried (Na2S0 4 ), filtered, and concentrated under reduced pressure.
  • the crude residue is purified by column chromatography (silica gel, hexanes:EtOAc) to yield racemic or optically pure sarpoglutarate, respectively depending upon the Ml to yield compounds 53-55.
  • Racemic sarpoglutarate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoglutarate.
  • EXAMPLE 14 OPTICALLY PURE SARPOADIPATE: Adipic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq.
  • Racemic sarpoadipnate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoadipate.
  • EXAMPLE 15 OPTICALLY PURE SARPOPIMELATE: Pimelic acid (0.55 mmol,
  • Racemic sarpopimelate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpopimelate.
  • EXAMPLE 16 OPTICALLY PURE SARPOSEBACATE: Sebacic acid (0.55 mmol,
  • Racemic sarposebacate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarposebacate.
  • EXAMPLE 17 OPTICALLY PURE SARPOFORMATE: Formic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq. NaHCCb (30 mL).
  • the organic layer is separated, dried (Na2S0 4 ), filtered, and concentrated under reduced pressure.
  • the crude residue is purified by column chromatography (silica gel, hexanes:EtOAc) to yield racemic or optically pure sarpoformate, respectively depending upon the Ml to yield compounds 65-67.
  • Racemic sarpoformate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoformate.
  • EXAMPLE 18 OPTICALLY PURE SARPOACETATE: Acetic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq. NaHCCb (30 mL).
  • Racemic sarpoacetate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetate.
  • EXAMPLE 19 OPTICALLY PURE SARPOPROPIONATE: Propionic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq.
  • Racemic sarpopriopionate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpopropionate.
  • EXAMPLE 20 OPTICALLY PURE SARPOBUTYRATE: Butyric acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH 2 C1 2 (50 niL) and sat. aq.
  • Racemic sarpobutyrate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpobutyrate.
  • EXAMPLE 21 OPTICALLY PURE SARPO VALERATE: Valeric acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at
  • Racemic sarpovalerate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpovalerate.
  • EXAMPLE 22 OPTICALLY PURE SARPOCAPROATE: Caproic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at
  • Racemic sarpocaproate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpocaproate.
  • EXAMPLE 23 OPTICALLY PURE SARPOENANTHATE: Enanthoic (heptanoic) acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at
  • EXAMPLE 24 OPTICALLY PURE SARPOCAPRYLATE: Caprylic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure
  • Racemic sarpocaprylate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpocaprylate.
  • EXAMPLE 25 OPTICALLY PURE SARPOPELARGONATE: Pelargonic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure
  • Racemic sarpopelargonate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpopelargonate.
  • EXAMPLE 26 OPTICALLY PURE SARPOCAPRATE: Capric acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq. NaHC03 (30 mL).
  • Racemic sarpocaprate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpocaprate.
  • EXAMPLE 27 OPTICALLY PURE SARPOOXALATE: Oxalic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq.
  • Racemic sarpooxalate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpooxalate.
  • EXAMPLE 28 OPTICALLY PURE SARPOISOPHTHALLATE: Isophthallic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq.
  • Racemic sarpoisophthallate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoisophthallate.
  • EXAMPLE 29 OPTICALLY PURE SARPOTEREPHTHALLATE: Terephthallic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq.
  • Racemic sarpoterephthallate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoterephthallate.
  • EXAMPLE 30 OPTICALLY PURE SARPOSALICILATE: Salicilic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq.
  • Racemic sarposalicilate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarposalicilate.
  • EXAMPLE 31 OPTICALLY PURE SARPOACETYLSALICILATE: Acetylsalicilic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4- dimethylaminopyridine at 0 °C are added to a stirred solution of racemate or enantiomerically pure Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL), heated over 30 min to 25 °C, stirred the mixture at 25 °C for 18 to 24 h, and diluted with CH2CI2 (50 mL) and sat. aq.
  • Racemic sarpoacetylsalicilate can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetylsalicilate. (Park et al., Aspirination of a-Aminoalcohol (Sarpogrelate Ml), Molecules 21(9), 1126 (2016); incorporated in entirety by reference).
  • EXAMPLE 32 To a stirred solution of Ml (0.50 mmol, 1.0 equiv.) in CH2CI2 (5 mL) or CH3CN (5 mL) was added aspirin (0.55 mmol, 1.1 equiv.) and ⁇ , ⁇ -carbonyldiimidazole (CDI, 0.60 mmol, 1.2 equiv.) at 25 °C. The mixture was stirred for 12 h, and diluted with CH2CI2 (40 mL) and sat. aq. NH 4 C1 (25 mL). The organic layer was separated, dried (Na2S0 4 ), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography
  • Racemic sarpoacetylsalicilate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetylsalicilates 108 and 109.
  • EXAMPLE 33 To a stirred solution of Ml (0.50 mmol, 1.0 equiv.) in THF (5 mL) was added acetyls alicylic acid (0.75 mmol, 1.5 equiv.), triphenylphosphine (0.75 mmol, 1.5 equiv.) and diisopropyl azodicarboxylate (DIAD, 0.75 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at the same temperature for 1 h, and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (30 mL) and sat. aq. NH 4 C1 (15 mL).
  • Racemic sarpoacetylsalicilate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetylsalicilates 108 and 109.
  • EXAMPLE 34 To a stirred solution of acetyl salicylate (1.00 mmol, 2.0 equiv.) in CH2CI2 (5 mL) was added oxalyl chloride (2 M in CH2CI2, 0.60 mL, 1.20 mmol, 2.4 equiv.) and dimethylformamide (DMF, 8.0 ⁇ L ⁇ , 0.10 mmol, 0.2 equiv.) at 0 °C. Then, the temperature was gradually raised to 25 °C. The mixture was stirred at the same temperature for 12 h.
  • oxalyl chloride 2 M in CH2CI2, 0.60 mL, 1.20 mmol, 2.4 equiv.
  • DMF dimethylformamide
  • EXAMPLE 35 To a stirred solution of salicylate ester (241 mg, 0.536 mmol, 1.0 equiv.) in pyridine (2 mL) was added AC2O (76 ⁇ , 0.81 mmol, 1.5 equiv.) at 0 °C. The temperature was raised to 25 °C. The mixture was stirred at the same temperature for 12 h. Then, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 mL) and washed with H2O (10 mL). The organic layer was separated, dried (Na2S0 4 ), filtered, and concentrated under reduced pressure.
  • Racemic sarpoacetylsalicilate compound 107 can be purified by crystallization and/or chiral chromatography to obtain optically pure sarpoacetylsalicilates 108 and 109.
  • EXAMPLE 40 DEUTERATION of H-COMPOUND to form D-COMPOUND:
  • the reaction mixture is shaken at room temperature for 11 days while monitoring for completion of hydrogen/deuterium (HID) exchange by LC/MS.
  • HID hydrogen/deuterium
  • a small scale workup is performed to prepare the hydrochloride salt of the deuterated compound.
  • a 1.2 mL aliquot of the reaction mixture (10% of total volume) is diluted with 5 mL saturated NaHCC and extracted with EtOAc (3 x 5mL). The organic layer is dried over
  • EXAMPLE 41 PREPARATION OF CRUDE SARPOGRELATE HYDROCHLORIDE: l-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-2-propanol hydrochloride
  • a 250 ml 13.7 g and water 25 ml were taken in a single-neck flask and stirred to dissolve.
  • the solution is treated with 20% aqueous sodium hydroxide to a pH about 9 to about 14, and was extracted with 30 ml of toluene, and the organic layer was concentrated at 50 °C under reduced pressure to give a brown oil, which was dissolved in 30 mL of tetrahydrofuran.
  • butyryl anhydride 4.5 g was added and heated to reflux with stirring for about 1 to about 4 hours, and concentrated to dryness under reduced pressure at 40 °C.
  • Ethyl acetate 25 mL is added to dissolve the residue and saturated hydrogen chloride in ethyl acetate solution is added dropwise to adjust PH 1 or lower while stirring for about 50-60 min to obtain sarpogrelate hydrochloride crude wet product, and dried under reduced pressure (-0.08—0. IMPa) at 45 to 55 °C to yield crude sarpogrelate hydrochloride 14.7 g, yield 86%, HPLC purity 98.6 %.
  • EXAMPLE 42 PURIFICATION OF THE CRUDE HYDROCHLORIDE SARPOGRELATE: The crude sarpogrelate hydrochloride 5g was dissolved in butanone (20 mL), heated while stirring until dissolved, refluxed for 20-30 min, cooled to 25-35 °C, continued stirring 40-60 min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55-65 °C and dried under reduced pressure to 24 h, to give sarpogrelate hydrochloride 4.6g, yield 92%, HPLC purity of 99.9%.
  • EXAMPLE 43 PURIFICATION OF THE CRUDE HYDROCHLORIDE SARPOGRELATE: The crude sarpogrelate hydrochloride 5g in butanone 30ml was heated with stirring until dissolved and refluxed 20 ⁇ 30min, cooling to 25-35 °C, incubated with stirring 40-60 min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55-65 0 C and dried under reduced pressure to 24 h, to give 4.55 sarpogrelate hydrochloride, yield 91 %, HPLC purity 99.7%.
  • EXAMPLE 44 PURIFICATION OF THE CRUDE HYDROCHLORIDE SARPOGRELATE: The crude sarpogrelate hydrochloride 5 g in butanone 40ml is heated with stirring until dissolved and refluxed 20-30 min, cooling to 25-35 °C, incubated with stirring 40-60 min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white solid, 55-65 °C and dried under reduced pressure to 24 h, to give sarpogrelate hydrochloride 4.5 g, yield 90%, HPLC purity 99.8 %.
  • EXAMPLE 45 PURIFICATION OF THE CRUDE HYDROCHLORIDE SARPOGRELATE: The crude product was sarpogrelate hydrochloride 5 g, join butanone 20 ml, heated with stirring until dissolved and refluxed 20-30 min, cooled slowly with stirring to room temperature, at -10 °C stand for crystallization, filtration, The filter cake was rinsed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55-65 °C and dried under reduced pressure to 24 h, to give the hydrochloride sarpogrelate 4.62 g, yield 92.4%, HPLC purity 99.2%, largest single matter content of 0.09%.
  • SARPOGRELATE ENANTIOMERS Enantiomers of compounds described here can be separated using chromatographic techniques.
  • the preparative separation of enantiomers by chromatography on chiral stationary phases (CSPs) has been recognized as being a useful alternative to the more conventional approaches such as enantioselective synthesis and enzymatically catalyzed transformations (Francotte, Enantioselective chromatography as a powerful alternative for the preparation of drug enantiomers, Journal of Chromatography A, Volume 906, Issues 1-2, Pages 379-397 (12 January 2001); Rajendran, et al., Simulated moving bed chromatography for the separation of enantiomers, Journal of Chromatography A, Volume 1216, Issue 4, Pages 709-738 (23 January 2009);Maier et al., Separation of enantiomers: needs, challenges, perspectives, Journal of Chromatography A, Volume 906, Issues 1-2, Pages 3-33 (12
  • Simulated moving-bed chromatography can be used for the separation of the enantiomers of the compounds of the invention, feasible at all production scales, from laboratory to pilot to production plant (Juza et al., Simulated moving-bed chromatography and its application to chirotechnology, Trends in Biotechnology, Volume 18, Issue 3, Pages 108-118 (1 March 2000), incorporated in entirety by reference).
  • EXAMPLE 46 SEPARATION OF ENANTIOMERS OF SARPOGRELATE HYDROCHLORIDE ((-)-4-((l-(dimethylamino)-3-(2-(3-ethoxyphenethyl) phenoxy)propan- 2-yloxy) -4-oxobutanoic acid hydrochloride): Sarpogrelate hydrochloride was separated with the XBridge® C18 3.5 ⁇ , 2.1x50 mm column, using a mobile phase: gradient elution from 10% MeCN in 0.01% TFA to 95% MeCN in 0.01% TFA, with a flow rate of 0.5 ml/min, at UV 254 nm, to yield 5.30 mg of enantiomer (99% HPLC purity).
  • EXAMPLE 47 DEXTROMETHORPHAN MALATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the malic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 48 DEXTROMETHORPHAN METHIONATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the methionine or N-acyl methionine (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 49 DEXTROMETHORPHAN PHTHALLATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the phthallic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 50 DEXTROMETHORPHAN MALONATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the malonic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 51 DEXTROMETHORPHAN TYROSINATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the tyrosine or N-acyl tyrosine (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 52 DEXTROMETHORPHAN TRYPTOPHANATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the tryptophan or N-acyl tryptophan (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 53 DEXTROMETHORPHAN MALEATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the maleic acid
  • EXAMPLE 54 DEXTROMETHORPHAN SUCCINATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the succinic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 55 DEXTROMETHORPHAN GLUTARATE/GLUTAMATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the glutaric acid, glutamic acid or N-acyl glutamic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 56 DEXTROMETHORPHAN ADIPATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the adiptic acid
  • EXAMPLE 57 DEXTROMETHORPHAN PIMELATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the pimelic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 58 DEXTROMETHORPHAN SEBACATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the sebacic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 59 DEXTROMETHORPHAN FORMATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the formic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 60 DEXTROMETHORPHAN ACETATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the acetic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 61 DEXTROMETHORPHAN PROPIONATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the propionic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 62 DEXTROMETHORPHAN BUTYRATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the butyric acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 63 DEXTROMETHORPHAN VALERATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the valeric acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 64 DEXTROMETHORPHAN CAPROATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the caproic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 65 DEXTROMETHORPHAN ENANTHATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the enanthoic (heptanoic) acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 66 DEXTROMETHORPHAN CAPRYLATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of thecaprylic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 67 DEXTROMETHORPHAN PELARGONATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the pelargonic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 68 DEXTROMETHORPHAN CAPRATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the capric acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 69 DEXTROMETHORPHAN OXALATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the oxalic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 70 DEXTROMETHORPHAN ISOPHTHALLATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the isophthalic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 71 DEXTROMETHORPHAN TEREPHTHALLATE: Dissolve the free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a solution of the terephthalic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 72 DEXTROMETHORPHAN SALICYLATE : Dissolve the free base
  • EXAMPLE 73 DEXTROMETHORPHAN ACETYLSALICYLATE : Dissolve the free base (0.05 mole) in 20 ml of acetone, add the solution to a solution of the acetyl salicylic acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to separate crystals by filtration and dry.
  • EXAMPLE 74-96 DIACID ADDITION SALT OF DEXTROMETHORPHAN AND A COMPOUND SELECTED FROM FORMULA I COMPOUNDS COMPRISING FDIc AND FDId (COMPOUNDS 219-269): Dissolve the free base (FDIc or FDId) (0.25 mole) and dextromethorphan (0.25 mole) in 20 ml of acetone, add the solution to a solution of a di or tri acid
  • the di and tri acids include, but 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 (saccharic acid), malic acid, maleic acid, mannonic acid, mucic acid, oxalic acid, pimelic acid, phthallic acid, isophthallic acid, terephthallic acid, rhamnonic acid, sebacic acid, succinic acid, and tartaric acid.
  • adipic acid aspartic acid, N-acyl aspartic acid
  • citric acid fumaric acid, galactonic acid
  • glutaric acid glutamic acid
  • N-acyl glutamic acid glucaric acid (saccharic acid)
  • malic acid maleic acid, mannonic acid, mucic acid
  • oxalic acid pimelic acid
  • phthallic acid isophthallic acid,
  • EXAMPLE 74 Adipic acid addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 75 Aspartic acid addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 76 N-Acyl aspartic acid, addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 78 Fumaric acid addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 80 Glutaric acid addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 83 Glucaric acid (saccharic acid) addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 85 Maleic acid addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 89 Pimelic acid addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 92 Terephthallic acid addition salt of (FDIc or FDId) and dextromethorphan
  • EXAMPLE 100 Compound 904 ((l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl (3,3-dimethylbutan-2-yl) (R)-phosphorofluoridate;
  • EXAMPLE 101 Compound 905 sec-butyl ((((S)-l-(dimethylamino)-3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl)oxy)methyl) (R)-phosphorofluoridate; [00514] EXAMPLE 102 Compound 906 sec-butyl ((((R)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
  • EXAMPLE 102 Compound 907 0-(((l-(dimethylamino)-3-(2-(3-methoxyphenetliyl) phenoxy)propan-2-yl)oxy)methyl) O-ethyl 0-(4-nitrophenyl) phosphorothioate;
  • EXAMPLE 103 Compound 908 0-((((S)-l-(dimethylamino)-3-(2-(3-methoxyphenetliyl) phenoxy)propan-2-yl)oxy)methyl) O-ethyl 0-(4-nitrophenyl) phosphorothioate;
  • EXAMPLE 104 Compound 909 0-((((R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-ethyl 0-(4-nitrophenyl) phosphorothioate;
  • EXAMPLE 105 Compound 910 0-(((l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) S-((l ,3-dioxoisoindolin-2-yl)methyl) (dimethyl-13- oxidaneyl)phosphonodithioate;
  • EXAMPLE 107 Compound 912 0-((((R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) S-((l ,3-dioxoisoindolin-2-yl)methyl) (dimethyl-13- oxidaneyl)phosphonodithioate;
  • EXAMPLE 109 Compound 914 (E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yl ((((S)- l-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) methyl phosphate;
  • EXAMPLE 110 Compound 915 (E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-yl ((((R)- l-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) methyl phosphate
  • EXAMPLE 111 Compound 916 0-(((l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy) methyl) S-(2-(ethylsulfinyl)ethyl) O-methyl phosphorothioate;
  • EXAMPLE 112 Compound 917 0-((((S)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) S-(2-(ethylsulfinyl)ethyl) O-methyl phosphorothioate;
  • EXAMPLE 113 Compound 918 0-((((R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) S-(2-(ethylsulfinyl)ethyl) O-methyl phosphorothioate;
  • EXAMPLE 114 Compound 919 0-(((l-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl) O-ethyl S-((ethyl thio)methyl) phosphorodithioate; [00528] EXAMPLE 115 Compound 920 0-(((l-(dimethylamino)-3-(2-(3-methoxyphenetliyl) phenoxy)propan-2-yl) oxy) methyl) O-ethyl S-((ethylthio)methyl) phosphorodithioate;
  • EXAMPLE 116 Compound 921 0-(((l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) O-ethyl S-((ethylthio)methyl) phosphorodithioate;
  • EXAMPLE 118 Compound 923 S-((6-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl) O- ((((S)-l -(dimethylamino) -3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl) O-ethyl phosphorodithioate;
  • EXAMPLE 120 Compound 925 S-((tert-butylthio)methyl) 0-(((l-(dimethylamino)-3-(2-
  • EXAMPLE 123 Compound 928 0-(4-((4-((((((l-(dimethyl amino)-3-(2-(3- methoxyphenethyl) phenoxy) propan-2-yl) oxy) methoxy) (methoxy) phosphorothioyl) oxy) phenyl) thio) phenyl) 0,0-dimethyl phosphorothioate;
  • EXAMPLE 124 Compound 929 0-(4-((4-((((((S)-l- (dimethylamino) -3-(2-(3 -methoxy phenethyl) phenoxy) propan- 2-yl) oxy) methoxy) (methoxy) phosphorothioyl) oxy) phenyl) thio) phenyl) ⁇ , ⁇ -dimethyl phosphorothioate;
  • EXAMPLE 125 Compound 930 0-(4-((4-((((((R)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy)propan-2-yl)oxy) methoxy) (methoxy) phosphorothioyl) oxy) phenyl) thio) phenyl) ⁇ , ⁇ -dimethyl phosphorothioate;
  • EXAMPLE 128 Compound 933 (((R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl triethyl diphosphate; [00542] EXAMPLE 129 Compound 934 ((l-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl methyl (2,2,2-trichloro-l-hydroxyethyl)phosphonate;
  • EXAMPLE 130 Compound 935 (((S)-l-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro-l-hydroxyethyl)phosphonate;
  • EXAMPLE 133 Compound 938 2-chloro-l -(2,4,5-trichlorophenyl) vinyl ((((S)-l- (dimethyl amino) -3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
  • EXAMPLE 134 Compound 939 2-chloro-l-(2,4,5-trichlorophenyl) vinyl ((((R)-l- (dimethyl amino)-3-(2-(3-methoxy phene thyl) phenoxy) propan-2-yl) oxy) methyl) hydrogen phosphate;
  • EXAMPLE 135 Compound 940 0-(((l-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl) S-methyl acetylphosphoramidothioate;
  • EXAMPLE 136 Compound 941 0-((((S)-l-(dimethylamino) -3-(2- (3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl) S-methyl acetyl phosphoramidothioate;
  • EXAMPLE 137 Compound 942 0-((((R)-l- (dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl) S-methyl acetylphosphoramidothioate;
  • EXAMPLE 138 Compound 943 (0-(((l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-propyl phosphorothioic) (0,0-dipropyl phosphorothioic) anhydride;
  • EXAMPLE 139 Compound 944 (0-((((S)-l -(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) O-propyl phosphorothioic) ( ⁇ , ⁇ -dipropyl phosphorothioic) anhydride;
  • EXAMPLE 140 Compound 945 (0-((((R)-l -(dimethyl amino) -3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl) oxy) methyl) O-propyl phosphorothioic) ( ⁇ , ⁇ -dipropyl phosphorothioic) anhydride;
  • EXAMPLE 141 Compound 946 0-(((l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) S-methyl acetylphosphoramidothioate;
  • EXAMPLE 142 Compound 947 0-((((S)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl) oxy) methyl) S-methyl acetylphosphoramidothioate; [00556] EXAMPLE 143 Compound 948 0-((((R)-l-(dimethylamino)-3-(2-(3-methoxy phenethyl)phenoxy)propan-2-yl) oxy) methyl) S-methyl acetylphosphoramidothioate;
  • EXAMPLE 144 Compound 949 0-(((l-(dimethylamino)-3-(2-(3-methoxyphenetliyl) phenoxy)propan-2-yl)oxy)methyl) O-methyl S-((4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)methyl) phosphorodithioate compound with methane (1:1);
  • EXAMPLE 145 Compound 950 0-((((S)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-methyl S-((4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)methyl) phosphorodithioate compound with methane (1:1);
  • EXAMPLE 146 Compound 951 0-((((R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) O-methyl S-((4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)methyl) phosphorodithioate compound with methane (1:1);
  • EXAMPLE 147 Compound 952 2-chloroethyl (((l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
  • EXAMPLE 148 Compound 953 2-chloroethyl ((((S)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
  • EXAMPLE 149 Compound 954 2-chloroethyl ((((R)-l-(dimethylamino)-3-(2-(3-methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
  • EXAMPLE 150 Compound 955 3-chlorobutan-2-yl (((l-(dimethylamino)-3-(2-(3- methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
  • EXAMPLE 152 Compound 957 3-chlorobutan-2-yl ((((R)-l-(dimethylamino)-3-(2-(3- methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
  • EXAMPLE 154 Compound 959 ((((S)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl (S)-((((E)- chlorofluoromethylene)amino)oxy)phosphonofluoridate;
  • EXAMPLE 156 Compound 960 ((((R)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl (S)-((((E)- chlorofluoromethylene)amino)oxy)phosphonofluoridate;
  • EXAMPLE 157 Compound 961 2-chloroethyl (((l-(dimethylamino)-3-(2-(3- methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene) amino)oxy)phosphorofluoridate;
  • EXAMPLE 158 Compound 962 2-chloroethyl ((((S)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene)amino) oxy)phosphorofluoridate ;
  • EXAMPLE 159 Compound 963 2-chloroethyl ((((R)-l-(dimethylamino) -3-(2-(3- methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene)amino) oxy)phosphorofluoridate ;
  • EXAMPLE 160 Compound 964 l-chloropropan-2-yl (((l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy) propan-2-yl) oxy)methyl) (E)-(((chlorofluoromethylene)amino)oxy) phosphorofluoridate ;
  • EXAMPLE 161 Compound 965 l-chloropropan-2-yl ((((S)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene) amino)oxy) phosphoro fluoridate;
  • EXAMPLE 162 Compound 966 l-chloropropan-2-yl ((((R)-l-(dimethylamino) -3-(2-(3- methoxy phenethyl) phenoxy) propan-2-yl) oxy)methyl) (E)-(((chlorofluoro methylene) amino) oxy) phosphoro fluoridate;
  • EXAMPLE 163 Compound 967 3-chlorobutan-2-yl (((l-(dimethylamino)-3-(2-(3- methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene)amino) oxy)phosphorofluoridate ;
  • EXAMPLE 164 Compound 968 3-chlorobutan-2-yl ((((S)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene)amino) oxy)phosphoro fluoridate;
  • EXAMPLE 165 Compound 969 3-chlorobutan-2-yl ((((R)-l-(dimethylamino)-3-(2-(3- methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-(((chlorofluoromethylene) amino)oxy) phosphoro fluoridate.
  • EXAMPLE 166 Compound 970 ((l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro-l-hydroxyethyl)phosphonate.
  • EXAMPLE 168 Compound 972 ((((R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl methyl (2,2,2-trichloro-l-hydroxyethyl)phosphonate.
  • EXAMPLE 171 Compound 975 4-(tert-butyl)-2-chlorophenyl ((((R)-l-(dimethylamino)- 3-(2-(3-methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) methylphosphoramidate compound with methane (1 : 1).
  • EXAMPLE 172 Compound 976 ((l-(dimethylamino) -3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl) oxy) methyl (3-methyl-4-(methylthio) phenyl) isopropylphosphoramidate;
  • EXAMPLE 173 Compound 977 ((((S)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl (3-methyl-4-(methylthio)phenyl) isopropylphosphoramidate.
  • EXAMPLE 174 Compound 978 ((((R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl)oxy) methyl (3-methyl-4-(methylthio)phenyl) isopropylphosphoramidate.
  • EXAMPLE 175 Compound 829 ((2,(-)-[lR,2S,4R]-2- (2-dimethyi amino ethoxy) -2- pheny! -1,7,7- trimethyl bicyclo [2.2.1] heptane) fumarate ( US 4.342.762 A; Ladanyi L et al., Stereochemistry and enantiomeric purity of a novel anxiolytic agent, deramciclane fumarate.
  • Fumarate of compound 829 can be prepared by a three-step synthesis scheme using readily available and low-cost starting materials (camphor) with very high enantiomeric purity (>99.9%).
  • 3.9 g (0.1 g atom) of potassium metal are added to 100 ml of anhydrous xylene, and the mixture is reacted with 23.04 g (0.1 mole) of(+)-2- phenyl- 1 ,7,7-trimethyl-bicy- clo(2,2,l)heptan-2-ol under vigorous stirring.
  • a solution of 10.3 g (0.11 moles) of l-dimethylamino-2-chioro-ethaJie in 30 ml of anhydrous xylene is introduced, under further stirring.
  • the reaction mixture is kept at 100° C. for 6 hours, then washed thrice with 50 ml of water, and extracted with a solution of 15 g (0.1 mole) of tartaric acid in 80 nil of water or with 0. 1 1 mole of diluted aqueous hydrochloric acid.
  • the aqueous phase is made alkaline to pH 10 with an aqueous solution of potassium hydroxide of 20% under cooling (at 0 to 5 °C).
  • Compound 829 is a dual 5-HT2A/5-HT2C receptors inverse agonist at clinically relevant doses and does not induce down-regulation of these receptors (Palvimaki EP et al., Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5- HT2C receptor down-regulation. Psychopharmacology (1998) 136:99-104). Deramciclane is at least 10-fold selective against dopamine D2 receptors (Gacsalyi I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997) 40:333-348).
  • Compound 829 was not found to elevate prolactin - at least within the dose-range that covers therapeutically relevant exposures (Laine K et al., Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone. Eur J Clin Pharmacol (2003) 59: 761- 766).
  • Deramciclane a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation.
  • Psychopharmacology (1998) 136:99-104).
  • Doses of Compound 829 that produce near-maximal inhibition of [3H]mesulergine binding are at the lower range of doses producing efficacy in animal models (Gacsalyi I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models.
  • Drug Dev Res a putative anxiolytic drug
  • Compound 829 is expected to produce in humans antidepressant, anxiolytic, appetite-stimulating and other effects, all of which are therapeutically relevant in patients with dementia (Jensen NH et al., Therapeutic potential of 5-HT2C receptor ligands. Scientific WorldJournal. 2010 Sep 14; 10: 1870-85; Meltzer HY et al., Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia. Curr Pharm Biotechnol. 2012 Jun;13(8):1572-86).
  • Compound 829 there is evidence on therapeutic effects from clinical studies in patients with generalized anxiety disorder (Naukkarinen H et al., Deramciclane in the treatment of generalized anxiety disorder: a placebo-controlled, double-blind, dose-finding study. Eur Neuropsychopharmacol (1999) 15:617-23), strengthening the claim that Compound 829 is a CNS- active compound that is capable of engaging its target(s).
  • HAM-A psychic anxiety factor significant improvements were seen in patients in the deramciclane 30 mg/day and 60 mg/day treatment groups compared with those in the placebo group.
  • Compound 829 is also a CYP 2D6 inhibitor based on studies in humans using desipramine as a substrate. In this randomized double-blind, cross-over study, fifteen healthy subjects received either 60 mg/day Compound 829 or placebo for 8 days. On day 8 of each study phase, the subjects received a 100-mg single dose of desipramine. Repeated administration of Compound 829 doubled the AUC of desipramine (Laine K et al., Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol (2004) 59:893-898, incorporated by reference).
  • EXAMPLE 176 Compound 1001 l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl 4-(adamantan-l-ylamino)-4-oxobutanoate: Chemical Formula: C34H46N205; Exact Mass: 562.34; Molecular Weight: 562.75; 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 Temp: 1176.29 [K]; Critical Pres: 8.99 [Bar]; Critical Vol: 1685.5 [cm3/mol]; Gibbs Energy: 126.8 [kJ/mol]; Log P: 5.06;
  • EXAMPLE 177 Compound 1002 (S)-l-(dimethylamino)-3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl 4-(adamantan -1- ylamino) -4- oxobutanoate: Chemical Formula: C34H46N205; Exact Mass: 562.34; Molecular Weight: 562.75; 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 Temp: 1176.29 [K]; Critical Pres: 8.99 [Bar]; Critical Vol: 1685.5 [cm3/mol]; Gibbs Energy: 126.8 [kJ/mol];
  • EXAMPLE 178 Compound 1003 (R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl 4-(adamantan-l-ylamino)-4-oxobutanoate: Chemical Formula:
  • EXAMPLE 179 Compound 1004 (R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl 4-((3,5-dimethyl adamantan-l-yl) amino) -4- oxo butanoate: Chemical Formula: C36H50N2O5; Exact Mass: 590.37; Molecular Weight: 590.81; 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,
  • EXAMPLE 180 Compound 1005 l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl 4-((3,5- dimethyl adamantan-l-yl)amino) -4- oxobutanoate: Chemical Formula: C36H50N2O5; Exact Mass: 590.37; Molecular Weight: 590.81; 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 Temp: 1191.88 [K]; Critical Pres: 8.46 [Bar]; Critical Vol: 1793.5 [cm3/mol]; Gibbs Energy: 132.66 [kJ/mol];
  • EXAMPLE 181 Compound 1005 (S)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl 4-((3,5-dimethyl adamantan-l-yl) amino) -4- oxobutanoate: Chemical Formula: C36H50N2O5; Exact Mass: 590.37; Molecular Weight: 590.81; m/z: 590.37 (100.0%),
  • EXAMPLE 182 Compound 1007 l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-2-yl (2,2,2-trichloro-l-(dimethoxyphosphoryl)ethyl) succinate: Chemical Formula: C28H37C13N09P; Exact Mass: 667.13; Molecular Weight: 668.93; m/z: 667.13
  • EXAMPLE 184 Compound 1009 (R)-l-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy)propan-2-yl (2,2,2-trichloro-l-(dimethoxyphosphoryl)ethyl) succinate: Chemical Formula: C28H37C13N09P; Exact Mass: 667.13; Molecular Weight: 668.93; 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; CI, 15.90; N, 2.09; O, 21.53
  • Sarpogrelate Racemate SGL
  • Sarpogrelate Enantiomer 1 SGL-E1
  • Sarpogrelate Enantiomer 2 SGL-E2
  • EXAMPLE 185 DEX METABOLISM AND CENTRAL EFFECTS OF 5HT2A RECEPTOR BLOCKADE: Antipsychotic drugs attenuate locomotor hyperactivity induced by psychostimulant and psychotomimetic drugs in laboratory rodents.
  • 5HT2A receptor antagonists are more effective against hyperactivity induced by NMDA receptor antagonists such as phencyclidine-like channel blockers (Carlsson et al., The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice, /. Neural. Transm. 106(2): 123-9 (1999)).
  • Pimavanserin (ACP-103) is an example of a 5HT2A receptor antagonist that was administered in mice in combination with 0.3 mg/kg MK-801 (i.p.) 15 min before the test session (Vanover et al., Pharmacological and behavioral profile of N-(4- fluorophenylmethyl)-N- (l-methylpiperidin-4-yl) -N'- (4-(2- methylpropyloxy) phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2: 1) (ACP-103), a novel 5 -hydroxy tryptamine (2A) receptor inverse agonist, / Pharmacol Exp Ther. 317(2):910-8 (2006 May); incorporated by reference).
  • dextromethorphan When given in combination with quinidine in patients with neurological diseases (Schoedel et al., Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect. Neuropsychiatric Disease and Treatment 2014: 10 1161-1174; incorporated by reference in its entirety), dextromethorphan is used at the dose of 10 mg that may be administered twice a day.
  • Currently known clinical dose of Sarpogrelate is 100 mg that is typically given three times a day (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical potential,
  • sarpogrelate As the current clinical use of sarpogrelate is for peripheral (non-CNS) indications (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical potential, Expert Opinion on Investigational Drugs, 13:7, 865-874; incorporated by reference in its entirety), use of sarpogrelate for CNS indications may require lower doses and therefore enable co-administration with dextromethorphan as sarpogrelate salt of dextromethorphan or as a mixture in a molar ratio of 1 : 1.
  • sarpogrelate is typically given at doses of 25 mg/kg and above to induce peripheral effects (Ma et al., Effective treatment with combination of peripheral 5 -hydroxy tryptamine synthetic inhibitor and 5 -hydroxy tryptamine 2 receptor antagonist on glucocorticoid- induced whole -body insulin resistance with hyperglycemia. / Diabetes Investig 7(6):833-844 (2016); incorporated by reference in its entirety).
  • sarpogrelate is given to Sprague-Dawley rats at the doses of 0.3, 1 and 3 mg/kg 30 min prior to a centrally acting 5-HT2A agonist DOI (3 mg/kg; (l(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)hydrochloride) and frequency of DOI-induced head shakes is reduced by co-administration of a compound of Formula I, SARPODEXTM, DERADEXTM, or DERAPHANTM.
  • a compound of Formula I as well as both enantiomers of its primary metabolite Ml are 5HT2A receptor antagonists (Pertz et al., In- vitro pharmacology of a compound of Formula I and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery, J Pharm Pharmacol. 47(4):310-6 (1995 April); incorporated by reference in its entirety).
  • rats are pretreated with 0.1 mg/kg of MK801 and attenuation of MK801-stimulated locomotor hyperactivity is monitored across a range of doses of both a compound of Formula I during 120-min test session conducted using conventional motor activity monitors.
  • DEX acts at a number of receptors and one of its targets is the NMDA receptor (Taylor et al., Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther. 164:170-82 (2016 August); incorporated by reference in its entirety).
  • NMDA receptor NMDA receptor
  • DEX is a less potent NMDA receptor antagonist than its metabolite, DO. Accordingly, DEX is less likely to induce phencyclidine-like motor activity than DO.

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Abstract

L'invention concerne des composés de la formule I, des sels pharmaceutiquement acceptables de ces derniers, leurs énantiomères, leurs métabolites, leurs dérivés, leurs promédicaments, leurs sels pharmaceutiquement acceptables, leurs N-oxydes, ou une association de ces derniers, des procédés et des intermédiaires pour leur préparation, des compositions les contenant, et leurs utilisations. L'invention concerne des compositions pharmaceutiques comprenant un composé de la formule I, ou ses énantiomères, ses métabolites, ses dérivés, ses promédicaments, ses sels d'addition d'acide, ses sels pharmaceutiquement acceptables, ou ses N-oxydes, ou une association de ces derniers, le composé étant un agent ou un ligand double et/ou un triple pour les récepteurs CYP2D6, 5-HT2A et/ou 5 HT2C, et/ou l'acétylcholinestérase.
EP18794381.6A 2017-05-04 2018-05-03 Targeted drug rescue avec de nouvelles compositions, associations et procédés correspondants Pending EP3618819A4 (fr)

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US6207674B1 (en) * 1999-12-22 2001-03-27 Richard A. Smith Dextromethorphan and oxidase inhibitor for weaning patients from narcotics and anti-depressants
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