Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/005—Enzyme inhibitors
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/06—Fungi, e.g. yeasts
  • A61K36/07—Basidiomycota, e.g. Cryptococcus
  • A61K36/078—Psilocybe
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to a composition
• a composition comprising at least one psychedelic tryptamine and at least a MAOIs compound selected from [3- carboline inhibitors.
• the invention relates also to the pharmaceutical uses of the composition of the invention.
• Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a substituted indolealkylamine and belongs to the group of hallucinogenic tryptamines (tryptamine alkaloid). Psilocybin is isolated from various genera of fungi including the genus Psilocybe, which is known to have hallucinogenic, anxiolytic, and psychoactive activities.
• psilocybin is a prodrug: in fact, when it is orally administered, while passing through the liver it undergoes dephosphorylation to psilocin active drug, which can cross the blood-brain barrier and produce its psychoactive effects.
• Monoamine oxidases are metabolic enzymes attached to cytosolic side of the outer membrane of mitochondria of neuronal, glial and several cell types. Specifically, they catalyze the oxidative deamination of neuroactive and vasoactive biogenic compounds (including serotonin and tryptamines) and xenobiotic amines into the corresponding aldehyde and ammonia, both in the central nervous system and peripheral tissues.
• MAOIs monoamine oxidase inhibitors
• MAOIs monoamine oxidase inhibitors
• Monoamine oxidase A is predominantly responsible for the metabolism of psilocin (Reniers et al., “Synthesis and evaluation of [3-carboline derivatives as potential monoamine oxidase inhibitors”, Bioorg. Med. Chem. (2011 ) v. 19(1 ), p. 134-44).
• MAOIs monoamine oxidases inhibitors
• Psilocybe mushrooms and several plant species have been reported to contain monoamine oxidase inhibitors (MAOIs), in particular [3-carbolines, capable of increasing/enhancing the pharmacological effects of psilocybin (e.g., harmane, harmine, norharmane, perlolyrine, harmol, cordysinins, tetrahydroharmane) (Blei F. et al., “Simultaneous Production of Psilocybin and a Cocktail of [3-Carboline Monoamine Oxidase Inhibitors in "Magic” Mushrooms”, Chem. Eur. J. (2020). V. 26, p. 729-734).
• MAOIs monoamine oxidase inhibitors
• US20180021326A1 discloses compositions and methods for enhancing neuroregeneration and cognition by combining mushroom extracts containing active ingredients psilocin or psilocybin with erinacines or hericenones enhanced with niacin.
• W02022072808A1 describes psychedelic compositions comprising MAOIs, delivery systems and therapeutic uses thereof.
• psychedelic drugs or “psychedelic compounds” or “psychedelics” are synonymous, and they mean classes including tryptamines (“psychedelic tryptamines”), phenethylamines, and lysergamides.
• Some of the psychedelic drugs being researched for therapy include psilocybin, psilocin LSD (lysergic acid diethylamide), DMT (dimethyltryptamine), ibogaine, mescaline, and MDMA (3,4- methylenedioxymethamphetamine). Tryptamines are known to be a broad class of classical or serotonergic hallucinogens.
• the “psychedelic compounds”, in particular the psychedelic tryptamines used in the invention, are preferably derived from psychedelic psilocybin mushrooms, more preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
• the psychedelic psilocybin mushrooms include a polyphyletic, informal group of fungi that contain psilocybin, psilocin or both within their biomass, typically within their fruiting bodies, resulting in their activation of a psychedelic reaction in a subject
• Preferred psychedelic tryptamines used in the invention comprise psilocybin and/or psilocin and/or their derivatives, such as baeocystin, norpsilocin, norbaeocystin and/or aeruginascin, and combinations thereof. Also comprised in the definition of said psychoactive compounds are the extracts from psychedelic psilocybin mushrooms, preferably belonging to the Psilocybe genus.
• Psilocybe genus may refer to the following non-limiting examples of suitable mushrooms containing psilocybin-like psychedelic compounds: Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe wasaroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe y 11.
• pharmaceutically acceptable salts or derivatives refers to those salts or derivatives which possess the biological effectiveness and properties of the salified or derivatized compound and which and which do not produce adverse reactions when administered to a mammal, preferably a human.
• the pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include but are not limited to: carbonate, hydrochloride, hydrobromide, sulphate, hydrogen sulphate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulphonate, and para-toluenesulphonate. Further information on pharmaceutically acceptable salts can be found in Handbook of pharmaceutical salts, P. Stahl, C. Wermuth, WILEY-VCH, 127-133, (2008), herein incorporated by reference.
• the pharmaceutically acceptable derivatives include the esters, the ethers and the N-oxides.
• Psilocybin is the common name of 4-phosphoryloxy-N,N- dimethyltryptamine.
• Psilocin is the common name of 4-hydroxy-N,N-dimethyltryptamine.
• Boeocystin is the common name of 4-phosphoryloxy-N- methyltryptamine.
• Nepsilocin is the common name of 4-hydroxy-N-methyltryptamine.
• Nebaeocystin is the common name of 4-Hydroxytryptamine 4- phosphate.
• “Aeruginascin” is the common name of N,N,N-trimethyl-4- phosphoryloxytryptamine.
• MAOIs means monoamine oxidases inhibitors.
• the MAOIs used in the present invention belong to the p-carboline class of inhibitors and are selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl- tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4- tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p- carboline-3-carboxylate (PCCE), p-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X
• a further object of the invention relates to the composition comprising at least one psychedelic tryptamine, and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof and at least one MAOIs compound selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl- tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4- tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p- carboline-3-carboxylate (PCCE), p-carboline-3-carboxylate (PCCM), manzamine A, man
• the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
• the present invention relates to a composition
• a composition comprising at least one psychedelic tryptamine and at least one MAOI compound selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6- methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro-[3-carboline (THpC), methyl-tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p-carboline-3-carboxylate (PCCE), p- carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6- deoxymanzamine X, manzamine Y, 8-
• the at least one psychedelic tryptamine of the composition of the invention can be preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus and more preferably it can be baeocystin, norpsilocin, norbaeocystin, and/or aeruginascin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.
• the at least one psychedelic tryptamine of the composition of the invention is a combination of baeocystin and psilocybin and/or psilocin or it is a combination of baeocystin and norpsilocin and psilocybin and/or psilocin
• the psilocybin-containing mushrooms are of the genus Psilocybe.
• suitable psilocybin-containing mushrooms that are in the genus Psilocybe include Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe wasaroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe atlantis, Psiloc
• the at least one psychedelic tryptamine of the composition of the invention can be an extract of psychedelic psilocybin mushrooms, preferably an extract of psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
• the at least one MAOI compound of the composition of the invention belongs to the p-carboline class of inhibitors and it is selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6- methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl-tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p-carboline-3-carboxylate (PCCE), p- carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6- deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A,
• the at least one antioxidant is selected from ascorbic acid, tannic acid, carotenoids, melatonin, curcumin, retinol, silver derivatives, zinc derivatives and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.
• the preferred molar ratio between the at least one psychoactive tryptamine and the at least one MAOI compound used in the composition of the invention is comprised between about 10 : 1 to about 1 : 10.
• the composition disclosed herein comprise a molar ratio between about 100 : 1 to about 1 : 100 of the at least one psychoactive tryptamine and of the at least one MAOI compound used in the composition of invention.
• compositions disclosed herein comprise a molar ratio between about 1 ,000 : 1 to about 1 : 1 ,000 of the at least one psychoactive tryptamine and of the at least one MAOI compound used in the composition of invention.
• compositions disclosed herein comprise a molar ratio of about 10,000: 1 to about 1 : 10,000 of the at least one psychoactive tryptamine and of the at least one MAOI compound used in the composition of invention.
• a further object of the invention relates to the composition comprising at least one psychedelic tryptamine, and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof and at least one MAOIs compound selected from norharmane, perillartine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl- tetrahydro-[3-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4- tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl [3- carboline-3-carboxylate (PCCE), p-carboline-3-carboxylate (PCCM), manzamine A,
• the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.

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• 2023
  • 2023-10-11 WO PCT/IB2023/060210 patent/WO2024079647A1/en not_active Ceased
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