WO2023147423A1 - Composés anxiolytiques, compositions pharmaceutiques et méthodes de traitement de l'anxiété et d'autres troubles - Google Patents

Composés anxiolytiques, compositions pharmaceutiques et méthodes de traitement de l'anxiété et d'autres troubles Download PDF

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WO2023147423A1
WO2023147423A1 PCT/US2023/061381 US2023061381W WO2023147423A1 WO 2023147423 A1 WO2023147423 A1 WO 2023147423A1 US 2023061381 W US2023061381 W US 2023061381W WO 2023147423 A1 WO2023147423 A1 WO 2023147423A1
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alkyl
compound
ester
group
independently selected
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Jonnie R. WILLIAMS SR.
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Miralogx Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • Psychedelic agents such as psilocybin have been investigated for use in the treatment of anxiety, depression, obsessive-compulsive disorder, smoking addiction, alcohol addiction, cocaine addiction, headache, and cancer-related or other end-of-life psychological distress.
  • Psilocybin is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungus. As a prodrug, psilocybin is quickly converted by the body to psilocin, which has mind-altering effects which may include euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and perceived spiritual experiences. Possible adverse reactions from psilocybin include nausea and panic attacks.
  • N,N-Dimethyltryptamine is a chemical substance that occurs in many plants and animals and which is both a derivative and a structural analog of tryptamine. It can be consumed as a psychedelic drug and has historically been prepared by various cultures for ritual purposes as an entheogen. DMT has a rapid onset, intense effects, and a relatively short duration of action. DMT can be inhaled, ingested, or injected and its effects depend on the dose, as well as its mode of administration. When inhaled or injected, the effects last a short period of time, about 5-15 minutes.
  • Effects can last three hours or more when orally ingested along with a monoamine oxidase inhibitor (MAOI), such as the ayahuasca brew of many native Amazonian tribes.
  • MAOI monoamine oxidase inhibitor
  • DMT can produce vivid “projections” of mystical experiences involving euphoria and dynamic hallucinations of geometric forms.
  • 5 -MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is another psychedelic of the tryptamine class. It is found in a wide variety of plant species, and at least one toad species, the Sonoran Desert toad. Like its close relatives DMT and bufotenine (5-HO- DMT), it has been used as an entheogen in South America.
  • TBG Tabernanthalog
  • TBG also was reported to increased formation of new dendrites (branches) in rat nerve cells, and of new spines on those dendrites, similar to the effect of ketamine, LSD, MDMA and DMT (the active component in the plant extract ayahuasca) on connections between nerve cells.
  • ketamine LSD
  • MDMA the active component in the plant extract ayahuasca
  • the present disclosure relates to a compound having a structure of Formula (I):
  • Ri, R2, R3, R4, R5, Re, R7, and Rs are each independently selected from the group consisting of an electron pair, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, a carboxylate, a carboxyl, an ester, a hydroperoxy, a peroxy, an ether, a hemiacetal, a hemiketal, an acetal, a ketal, an orthoester, a methylenedioxy, an orthocarbonate ester, carboxamide, an amine, an imine, an amide, an azide, an azo, a cyanate, a nitrate, a nitrile, an isonitrile, a nitrosooxy, a nitro, a pyridyl, a thiol, a sulfide, sulf
  • At least one of Rs, Re, R7, or Rs is a phosphate. [11] In some embodiments, at least one of Rs, Re, R7, or Rs is OH.
  • At least one of Rs, Re, R7, and Rs is — O-alkyl.
  • Ri and/or R2 is/are alkyl.
  • Ri and/or R2 is/are H.
  • Ri and R3 together form a carbocyclic or heterocyclic ring, optionally wherein the carbocyclic or heterocyclic ring is selected from a group consisting of an cycloalkane, aryl, cycloalkyl, heteroaryl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, and heterocycle.
  • the compound has a structure of Formula (II): wherein R2, R4, Rs, Re, R7, and Rs are defined as above, and R9, Rio, R11, and R12 are each independently selected from the group consisting of an electron pair, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, a carboxylate, a carboxyl, an ester, a hydroperoxy, a peroxy, an ether, a hemiacetal, a hemiketal, an acetal, a ketal, an orthoester, a methylenedioxy, an orthocarbonate ester, carboxamide, an amine, an imine, an amide, an azide, an azo, a cyanate, a nitrate, a nitrile, an isonitrile, a nitrosooxy
  • R9 and Rio together form a carbocyclic or heterocyclic ring, optionally wherein the carbocyclic or heterocyclic ring is selected from a group consisting of an cycloalkane, aryl, cycloalkyl, heteroaryl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, and heterocycle.
  • the compound has a structure of Formula (III): wherein R4, Rs, Re, R7, and Rs are defined as above, and wherein R11, R12 , R13 , R14, and Ris are each independently selected from the group consisting of an electron pair, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, a carboxylate, a carboxyl, an ester, a hydroperoxy, a peroxy, an ether, a hemiacetal, a hemiketal, an acetal, a ketal, an orthoester, a methylenedioxy, an orthocarbonate ester, carboxamide, an amine, an imine, an amide, an azide, an azo, a cyanate, a nitrate, a nitrile, an isonitrile, a
  • the compound has a structure selected from the group consisting of: or a pharmaceutically acceptable salt, ester, or ether thereof.
  • a pharmaceutical compound has the structure: or a pharmaceutically acceptable salt, ester, or ether thereof.
  • a pharmaceutical compound has the structure: or a pharmaceutically acceptable salt, ester, or ether thereof.
  • the compound is selected from the group consisting of 8- methoxy-3-methyl-l,2,3,4,5,10b-hexahydroazepino[4,5-b]indole or (6R,7S,9S,l lS)-7- ethyl-2-methoxy-6,6a,7,9,10,12,13,13a-octahydro-8H-6,9- methanopyrido[l',2': l,2]azepino[4,5-b]indole, or a pharmaceutically acceptable salt, ester, or ether thereof.
  • the compound has a structure selected from the group consisting of:
  • the compound has the structure or a pharmaceutically acceptable salt, ester, or ether thereof.
  • the compound is selected from the group consisting of 3-(2- aminoethyl)-5-hydroxy-3H-indol-l-ium, 2-(3H-pyrrolo[3,2-c]pyri din-3 -yl)ethan-l- amine, 3-(2-(dimethylamino)ethyl)-3H-indol-4-yl dihydrogen phosphate, 3-(2- (dimethylamino)ethyl)-3H-indol-4-ol, 2-(6-methoxy-3H-indol-3-yl)-N,N- dimethylethan- 1 -amine, 2-(3H-indol-3 -yl)-N,N-dimethylethan- 1 -amine, 3 -(2- aminoethyl)-3H-indol-5-ol, 2-(5-methoxy-3H-indol-3-yl)-N,N-dimethylethan-l- amine,
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed herein, and a pharmaceutically acceptable vehicle therefor.
  • the present disclosure relates to a method of treating a disorder selected from the group consisting of anxiety, depression, obsessive-compulsive disorder, tobacco addiction, alcohol addiction, cocaine addiction, headache, and psychological distress, the method comprising administering to an individual in need thereof a pharmaceutical composition disclosed herein.
  • the present disclosure relates to a method of treating anxiety comprising administering to an individual in need thereof a pharmaceutical composition disclosed herein.
  • the present disclosure relates to a compound having a structure of Formula (I): wherein Ri, R2, R3, R4, R5, Re, R7, and Rs are each independently selected from the group consisting of an electron pair, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, a carboxylate, a carboxyl, an ester, a hydroperoxy, a peroxy, an ether, a hemiacetal, a hemiketal, an acetal, a ketal, an orthoester, a methylenedioxy, an orthocarbonate ester, carboxamide, an amine, an imine, an amide, an azide, an azo, a cyanate, a nitrate, a nitrile, an isonitrile, a nitrosooxy, a nitro, a
  • At least one of Rs, Re, R7, or Rs is a phosphate. In some embodiments, at least one of Rs, Re, R7, or Rs is OH. In some embodiments, at least one of Rs, Re, R7, and Rs is — O-alkyl. In some embodiments, Ri and/or R2 is/are alkyl. In some embodiments, Ri and/or R2 is/are H.
  • Ri and R3 together form a carbocyclic or heterocyclic ring, optionally wherein the carbocyclic or heterocyclic ring is selected from a group consisting of an cycloalkane, aryl, cycloalkyl, heteroaryl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, and heterocycle.
  • the compound has a structure of Formula (II): wherein R2, R4, Rs, Re, R7, and Rs are defined as above, and R9, Rio, R11, and R12 are each independently selected from the group consisting of an electron pair, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, a carboxylate, a carboxyl, an ester, a hydroperoxy, a peroxy, an ether, a hemiacetal, a hemiketal, an acetal, a ketal, an orthoester, a methylenedioxy, an orthocarbonate ester, carboxamide, an amine, an imine, an amide, an azide, an azo, a cyanate, a nitrate, a nitrile, an isonitrile, a nitrosooxy
  • R9 and Rio together form a carbocyclic or heterocyclic ring, optionally wherein the carbocyclic or heterocyclic ring is selected from a group consisting of an cycloalkane, aryl, cycloalkyl, heteroaryl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, and heterocycle.
  • the compound has a structure of Formula (III): wherein R4, Rs, Re, R7, and Rs are defined as above, and wherein R11, R12 , R13 , R14, and Ris are each independently selected from the group consisting of an electron pair, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, a carboxylate, a carboxyl, an ester, a hydroperoxy, a peroxy, an ether, a hemiacetal, a hemiketal, an acetal, a ketal, an orthoester, a methylenedioxy, an orthocarbonate ester, carboxamide, an amine, an imine, an amide, an azide, an azo, a cyanate, a nitrate, a nitrile, an isonitrile, a
  • the compound has the structure:
  • the compound is 8-methoxy-3-methyl-l,2,3,4,5,10b-hexahydroazepino[4,5-b]indole.
  • the compound has the structure:
  • the compound is (6R,7S,9S, 11 S)-7-ethyl- 2-methoxy-6, 6a, 7, 9, 10,12,13,13 a-octahydro-8H-6,9- methanopyrido[T,2': l,2]azepino[4,5-b]indole.
  • a pharmaceutical compound has a structure selected from the group consisting of: or a pharmaceutically acceptable salt, ester, or ether thereof.
  • the compound has the structure
  • the compound is selected from the group consisting of 3-(2- aminoethyl)-5-hydroxy-3H-indol-l-ium, 2-(3H-pyrrolo[3,2-c]pyri din-3 -yl)ethan-l- amine, 3-(2-(dimethylamino)ethyl)-3H-indol-4-yl dihydrogen phosphate, 3-(2- (dimethylamino)ethyl)-3H-indol-4-ol, 2-(6-methoxy-3H-indol-3-yl)-N,N- dimethylethan- 1 -amine, 2-(3H-indol-3 -yl)-N,N-dimethylethan- 1 -amine, 3 -(2- aminoethyl)-3H-indol-5-ol, 2-(5-methoxy-3H-indol-3-yl)-N,N-dimethylethan-l- amine,
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier that facilitates processing of an active ingredient into pharmaceutically acceptable compositions.
  • a pharmaceutically acceptable carrier is synonymous with “pharmacological carrier” and means any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as “pharmacologically acceptable vehicle,” “stabilizer,” “diluent,” “additive,” “auxiliary” or “excipient.”
  • Such a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent. It is understood that the active ingredients can be soluble or can be delivered as a suspension in the desired carrier or diluent.
  • aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like
  • solid carriers such as, e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like
  • solvents dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient.
  • Selection of a pharmacologically acceptable carrier can depend on the mode of administration.
  • any pharmacologically acceptable carrier is incompatible with the active ingredient, its use in pharmaceutically acceptable compositions is contemplated.
  • Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman’s The Pharmacological Basis of Therapeutics (Joel G.
  • Purity refers to the ratio of a compound’s mass to the total sample mass following any purification steps.
  • the level of purity is at least about 95%, more usually at least about 96%, about 97%, about 98%, or higher.
  • the level of purity may be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher.
  • enantiomer may be provided either as racemic mixture or by isolating one of the enantiomers, the latter case in which purity as described above may refer to enantiomeric purity.
  • the compounds may be prepared synthetically using techniques described, for example, in L.P. Cameron et al., “A non-hallucinogenic psychedelic analogue with therapeutic potential,” Nature 589, 474-479 (2021), doi.org/10.1038/s41586-020-3008-z, with appropriate modifications of reagents to obtain the structures described herein as will be apparent to persons skilled in the art.
  • the compounds described herein may be prepared synthetically using techniques described, for example, in O. Shirota et al., “Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal Hallucinogenic Constituents of ‘Magic Mushroom,’” J. Nat. Prod.
  • DMT derivatives may be synthesized through the reaction of indole with oxalyl chloride followed by reaction with dimethylamine and reduction of the carbonyl functionalities with lithium aluminum hydride. Another route is through the N,N-dimethylation of tryptamine using formaldehyde followed by reduction with sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the compounds may be converted into a pharmaceutically acceptable salts using techniques well known to persons skilled in the art.
  • salts such as sodium and potassium salts may be prepared by treating the compound with a suitable sodium or potassium base, such as sodium hydroxide or potassium hydroxide, respectively.
  • Esters and ethers of the compounds may be prepared as described, e.g., in Advanced Organic Chemistry, 1992, 4th Edition, J. March, John Wiley & Sons, or J. Med. Chemistry, 1992, 35, 145-151.
  • the compounds as described herein may be useful for treating anxiety, depression, obsessive-compulsive disorder, tobacco addiction (including smoking addiction and smokeless tobacco addiction), alcohol addiction, cocaine addiction, headache, and cancer-related or other end-of-life psychological distress.
  • compositions as described herein may be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other suitable modes of administration.
  • a pharmaceutical composition may optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.
  • buffers include, without limitation, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline and borate buffers.
  • antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxy anisole and butylated hydroxytoluene.
  • Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide.
  • Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor.
  • the pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition.
  • auxiliaries and/or excipients examples include cremophor, poloxamer, benzalkonium chloride, sodium lauryl sulfate, dextrose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, carboxymethylcellulose sodium, talc, agar-agar, mineral oil, animal oil, vegtetable oil, organic and mineral waxes, paraffin, gels, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyglycols, tween 80, solutol HS 15, and water. It is also possible to administer the active substances as such, without vehicles or diluents, in a suitable form, for example, in capsules.
  • a pharmaceutical composition may comprise a therapeutic compound in an amount sufficient to allow customary administration to an individual.
  • a unit dose form may have, e.g., at least 0.001 mg, at least 0.005 mg, at least 0.01 mg, at least 0.1 mg, at least 0.5 mg, at least 0.75 mg, at least 1 mg, at least 1.5 mg, at least 2 mg, at least 2.5 mg, at least 5 mg, at least 7.5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 40 mg, or at least 50 mg of a therapeutic compound.
  • a pharmaceutical composition disclosed herein may include, e.g., about 0.001 mg to about 500 mg, about 0.01 mg to about 250 mg, or about 0.05 mg to about 100 mg of a therapeutic compound.
  • compositions as described herein may include a pharmaceutically acceptable solvent.
  • a solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous (the solute), resulting in a solution.
  • Solvents useful in the pharmaceutical compositions include, without limitation, a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent and a pharmaceutically acceptable non-polar solvent.
  • a pharmaceutically acceptable polar aprotic solvent includes, without limitation, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO).
  • a pharmaceutically acceptable polar protic solvent includes, without limitation, acetic acid, formic acid, ethanol, n-butanol, 1 -butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2 propan-diol, methanol, glycerol, and water.
  • a pharmaceutically acceptable non-polar solvent includes, without limitation, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-di oxane, chloroform, n-methyl-pyrrilidone (NMP), and diethyl ether.
  • microdosing techniques may be used as described, e.g., in L.P. Cameron et al., “Chronic, Intermittent Microdoses of the Psychedelic N,N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents,” ACS Chem. Neurosci. 2019, 10, 3261-70.
  • the daily dose of an active compound may be about 0.0001 mg to about 10 mg per kg, or from about 0.0005 mg to about 5 mg per kg.
  • Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art.
  • treatment of anxiety may comprise a one-time administration of an effective dose of a pharmaceutical composition as disclosed herein.
  • treatment may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly.
  • the timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual’s symptoms.
  • an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy.
  • a person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.
  • compositions may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles.
  • pH of the formulation may be adjusted with acceptable pharmaceutical or food grade acids, bases or buffers to enhance the stability of the formulated composition or its delivery form.
  • Liquid dosage forms for oral administration include acceptable pharmaceutical or food grade emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylsulfoxide (DMSO) dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water
  • Solid dosage forms for oral administration include capsules, tablets, lozenges, pills, powders, and granules.
  • the active compound is mixed with at least one inert, acceptable pharmaceutical or food grade excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and gly
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract or, optionally, in a delayed or extended manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Tablet formulations for extended release are also described in U.S. Pat. No. 5,942,244.
  • compositions may contain a compound as disclosed herein, alone or with other therapeutic compound(s).
  • a therapeutic compound is a compound that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.
  • a therapeutic compound disclosed herein may be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt, e.g., a hydrochloride. Additionally, therapeutic compound disclosed herein may be provided as racemates, or as individual enantiomers, including the R- or S-enantiomer.
  • the therapeutic compound disclosed herein may comprise a R-enantiomer only, a S-enantiomer only, or a combination of both a R-enantiomer and a S-enantiomer of a therapeutic compound.
  • the therapeutic compound may have anti-inflammatory activity, such as a non-steroidal anti-inflammatory drug (NSAID).
  • NSAIDs are a large group of therapeutic compounds with analgesic, anti-inflammatory, and anti-pyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase.
  • NSAIDs include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac, lactyl phenet
  • NSAIDs may be classified based on their chemical structure or mechanism of action.
  • Non-limiting examples of NSAIDs include a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non- selective cyclooxygenase (COX) inhibitor, a selective cyclooxygenase- 1 (COX-1) inhibitor, and a selective cyclooxygenase-2 (COX-2) inhibitor.
  • An NSAID may be a profen.
  • Examples of a suitable salicylate derivative NSAID include, without limitation, acetylsalicylic acid (aspirin), diflunisal, and salsalate.
  • Examples of a suitable p-amino phenol derivative NSAID include, without limitation, paracetamol and phenacetin.
  • Examples of a suitable propionic acid derivative NSAID include, without limitation, alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen.
  • acetic acid derivative NSAID examples include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, and zomepirac.
  • a suitable enolic acid (oxicam) derivative NSAID examples include, without limitation, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam.
  • a suitable fenamic acid derivative NSAID examples include, without limitation, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid.
  • a suitable selective COX-2 inhibitors include, without limitation, celecoxib, etoricoxib, firocoxib, lumiracoxib, mel oxicam, parecoxib, rofecoxib, and valdecoxib.
  • the present disclosure relates to a method of treating a disorder selected from the group consisting of anxiety, depression, obsessive-compulsive disorder, tobacco addiction, alcohol addiction, cocaine addiction, headache, and psychological distress, the method comprising administering to an individual in need thereof a pharmaceutical composition disclosed herein.
  • the present disclosure relates to a method of treating anxiety comprising administering to an individual in need thereof a pharmaceutical composition disclosed herein.

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  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
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  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dans certains aspects, la divulgation concerne des composés pharmaceutiques qui peuvent être utiles pour traiter l'anxiété et/ou d'autres troubles. Selon un autre aspect, une composition pharmaceutique comprend une quantité thérapeutiquement efficace du composé et un véhicule pharmaceutiquement acceptable associé. Dans un autre aspect encore, une méthode de traitement de l'anxiété, de la dépression, d'un trouble obsessionnel compulsif, de la dépendance au tabac, de la dépendance à l'alcool, de la dépendance à la cocaïne, de la céphalée, ou de la détresse psychologique liée au cancer ou à la fin de vie ou autre consiste à administrer la composition pharmaceutique à un individu en ayant besoin.
PCT/US2023/061381 2022-01-28 2023-01-26 Composés anxiolytiques, compositions pharmaceutiques et méthodes de traitement de l'anxiété et d'autres troubles WO2023147423A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130230577A1 (en) * 2010-10-22 2013-09-05 Duke University Slow-release formulations of 5-hydroxytryptophan as an adjunct to pro-serotonergic therapies
US20210395201A1 (en) * 2019-11-07 2021-12-23 Small Pharma Ltd Synthesis of n,n-dimethyltryptamine-type compounds, methods, and uses
US20210403425A1 (en) * 2020-06-30 2021-12-30 Field Trip Psychedelics Inc. Tryptamine prodrugs
US20220081396A1 (en) * 2021-03-22 2022-03-17 Small Pharma Ltd. Deuterated compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130230577A1 (en) * 2010-10-22 2013-09-05 Duke University Slow-release formulations of 5-hydroxytryptophan as an adjunct to pro-serotonergic therapies
US20210395201A1 (en) * 2019-11-07 2021-12-23 Small Pharma Ltd Synthesis of n,n-dimethyltryptamine-type compounds, methods, and uses
US20210403425A1 (en) * 2020-06-30 2021-12-30 Field Trip Psychedelics Inc. Tryptamine prodrugs
US20220081396A1 (en) * 2021-03-22 2022-03-17 Small Pharma Ltd. Deuterated compounds

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