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US-12616706-B2 - Compositions and methods of use comprising substances with neural plasticity actions administered at non-psychedelic/psychotomimetic dosages and formulations

US12616706B2US 12616706 B2US12616706 B2US 12616706B2US-12616706-B2

Abstract

Compositions and methods of use comprising serotonin (5-HT) receptor agonists and NMDAR modulating substances, including especially certain substances classified as 5-HT2A agonists presently disclosed to exert NMDAR modulating effects, administered as modulators of neural plasticity, at non-psychedelic/psychotomimetic dosages, posology and formulations, for treatment of diseases and conditions and for improving functions (neuroplastogens).

Inventors

  • Paolo L. Manfredi
  • Franco Folli
  • Andrea ALIMONTI
  • JACOPO SGRIGNANI
  • Andrea Cavalli
  • Charles E. Inturrisi
  • Sara De Martin
  • ANDREA MATTAREI
  • Maurizio Rolando
  • Giovanni Giordano
  • Claudia Lodovichi
  • Paola Brun
  • Marco Pappagallo

Assignees

  • Arbormentis LLC

Dates

Publication Date
20260505
Application Date
20200306

Claims (20)

  1. 1 . A method for treating diseases and conditions or improving functions in patients or subjects, the method comprising: administering a compound to a subject; wherein the compound is chosen from a structural analogue of psilocin, a structural analogue of norpsilocin, a structural analogue of psilocybin, a structural analogue of baeocystin, a structural analogue of norbaeocystin, and a structural analogue of N,N-dimethyltryptamine; wherein the compound is of formula I: wherein R 1 and R 2 are, independently, hydrogen, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl (independently or ring close with the nitrogen), C 3 -C 8 cycloalkenyl (independently or ring close with the nitrogen), aryl or heterocyclyl, optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R 3 is hydrogen, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl or heterocyclyl, optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or R 3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, and nitrate; R 4 is hydrogen, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or R 4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, and alkylamino; R 5 represents 1-3 substituents selected from the group consisting of hydrogen, deuterium, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl or heterocyclyl, optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R 6 is hydrogen, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl or heterocyclyl any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or R 6 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, —OP(O)(OH) 2 , —OC(O)R 7 , —OSO 2 OH, —OC(O)NHR 7 , —OC(O)NR 7 R 8 and —SONH; and n is 1 to 5; and wherein the compound is administered at doses, dosages, posology, or formulations devoid of clinically meaningful psychedelic or psychotomimetic actions or effects.
  2. 2 . The method of claim 1 , wherein said clinical effects are of those exerted by human plasma psilocin Cmax of 2 ng/ml or less or 5-HT2A human CNS receptor occupancy of 40% or less.
  3. 3 . The method of claim 1 , wherein said clinical effects are of those exerted by human plasma psilocin Cmax of 1 ng/ml or less or 5-HT2A human CNS receptor occupancy of 30% or less.
  4. 4 . The method of claim 1 , wherein said PD effects are of those exerted by human plasma psilocin Tmax in excess of 120 minutes.
  5. 5 . The method of claim 1 , wherein said PD effects are of those exerted by human plasma psilocin Tmax in excess of 180 minutes.
  6. 6 . The method of claim 1 , wherein the administering of the compound occurs under conditions that may modulate NMDARs and their subunits in addition to modulate 5-HT2A receptors.
  7. 7 . The method of claim 1 , wherein the administering of the compound may provide excitotoxicity protection.
  8. 8 . The method of claim 1 , wherein the administering of the compound may modulate neurogenesis.
  9. 9 . The method of claim 1 , wherein the administering of the compound occurs under conditions effective for the substance to exert neuroplastogen effects, including modulation of neural plasticity.
  10. 10 . The method of claim 1 , wherein the administration of the compound is repeated over days or months or is chronic.
  11. 11 . The method of claim 1 , wherein the administration of the compound is intermittent and occurs every second day, every third day or every other week or every 2 weeks or every other month.
  12. 12 . A method for treating diseases and conditions or improving functions in patients or subjects, the method comprising: administering a 5-HT2A agonist substance to a subject; wherein the 5-HT2A agonist substance is chosen from a structural analogue of psilocin, a structural analogue of norpsilocin, a structural analogue of psilocybin, a structural analogue of baeocystin, a structural analogue of norbaeocystin, and a structural analogue of N, N-dimethyltryptamine; wherein the compound is of formula I: wherein R 1 and R 2 are, independently, hydrogen, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl (independently or ring close with the nitrogen), C 3 -C 8 cycloalkenyl (independently or ring close with the nitrogen), aryl or heterocyclyl, optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R 3 is hydrogen, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl or heterocyclyl, optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or R 3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, and nitrate; R 4 is hydrogen, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or R 4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, and alkylamino; R 5 represents 1-3 substituents selected from the group consisting of hydrogen, deuterium, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl or heterocyclyl, optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R 6 is hydrogen, deuterium, C 1 -C 8 alkyl, C 2 -C 5 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl or heterocyclyl any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or R 6 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, —OP(O)(OH) 2 , —OC(O)R 7 , —OSO 2 OH, —OC(O)NHR 7 , —OC(O)NR 7 R 8 and —SONH; and n is 1 to 5; and wherein the compound is administered at doses, dosages, posology, or formulations devoid of clinically meaningful psychedelic or psychotomimetic actions or effects.
  13. 13 . The method of claim 12 , wherein said clinical effects are of those exerted by human plasma psilocin Cmax of 2 ng/ml or less or 5-HT2A human CNS receptor occupancy of 40% or less.
  14. 14 . The method of claim 12 , wherein said clinical effects are of those exerted by human plasma psilocin Cmax of 1 ng/ml or less or 5-HT2A human CNS receptor occupancy of 30% or less.
  15. 15 . The method of claim 12 , wherein said PD effects are of those exerted by human plasma psilocin Tmax in excess of 120 minutes.
  16. 16 . The method of claim 12 , wherein said PD effects are of those exerted by human plasma psilocin Tmax in excess of 180 minutes.
  17. 17 . The method of claim 12 , wherein the administering of the 5-HT2A agonist substance occurs under conditions that may modulate NMDARs and their subunits in addition to modulate 5-HT2A receptors.
  18. 18 . The method of claim 12 , wherein the administering of the 5-HT2A agonist substance may provide excitotoxicity protection.
  19. 19 . The method of claim 12 , wherein the administering of the 5-HT2A agonist substance may modulate neurogenesis.
  20. 20 . The method of claim 12 , wherein the administering of the 5-HT2A agonist substance occurs under conditions effective for the substance to exert neuroplastogen effects, including modulation of neural plasticity.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of the filing date of U.S. Patent Application No. 62/814,929, filed on Mar. 7, 2019, and U.S. Patent Application No. 62/844,151, filed on May 7, 2019, the disclosures of which are incorporated by reference herein in their entireties. FIELD OF THE INVENTION Various aspects of the present invention relate to compositions and methods including substances providing neural plasticity, and the administration of those substances at non-psychedelic and/or psychotomimetic dosages. BACKGROUND OF THE INVENTION The sections below are intended to introduce the reader to various aspects of art that may be related to various aspects of the present invention, which are described and/or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of various aspects of the present invention. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art. Both the medical establishment and conventional wisdom define psychedelic substances, (including those in in the triptan family, and including substances classified as 5-HT2A agonists), by their ability to determine certain alterations in consciousness, emotion, and cognition, including positive and negative psychotomimetic symptoms (e.g., psychedelic effects, psychedelic experience, psychotomimetic effects). These psychedelic/psychotomimetic effects are known to laymen and doctors for their potential recreational misuse and to researchers in the psychiatric field for their potential therapeutic uses in psychiatry and research applications for the study of brain function. In the case of substances in the triptan family, these psychedelic/psychotomimetic effects are thought to be primarily induced by agonist actions at the 5-HT 2A receptor in the 5-HT receptor family. Psychedelic substances are presently under investigation for the treatment of several psychiatric diseases and symptoms, including depression, PTSD, OCD, addiction, end-stage-cancer-associated anxiety. From the available scientific literature and other disclosures (including patents and patent applications), and from clinical studies currently underway, the psychedelic experience, which includes positive and negative psychotomimetic effects induced by a serotonin agonist substance, is an integral part of the intended treatment, the research applicability, and even the recreational misuses of these substances. In particular for therapeutic purposes, serotonin agonist psychedelic drugs are administered in a particular “setting” and preceded and followed by counseling and or psychotherapy and the whole session is supervised and closely monitored (Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008 August; 22(6):603-20). According to researchers and therapists, to achieve therapeutic efficacy for certain psychiatric disorders, the administration of the serotonin agonist at a dose that produces psychedelic and or psychotomimetic symptoms should be paired with ancillary therapies, which include a particular physical setting, in addition to pre, during and post drug administration counseling and/or psychotherapy (talk therapy). The psychedelic experience (which includes alterations in consciousness, emotion, and cognition, and positive and negative psychotomimetic symptoms) is thus viewed by researchers and scientists, to this day, as integral part of the potential therapeutic efficacy of psychedelic drugs. The psychedelic drug is generally administered once in a single session (single dose of a psychedelic substance) with acute psychedelic/psychotomimetic effects lasting approximately four to six hours. In addition to the acute effects, psychological beneficial effects lasting months after a single session have been described and contribute to the current understanding of the potential beneficial effects of treatment with 5-HT agonist drugs [Griffiths R R, Richards W A, Johnson M W, McCann U D, Jesse R. Mystical-type Experiences Occasioned by Psilocybin Mediate the Attribution of Personal Meaning and Spiritual Significance 14 Months Later. J Psychopharmacol. 2008 August; 22(6):621-32); Carhart-Harris R L, Roseman L, Bolstridge M, Demetriou L, Nienke J Pannekoek, Wall M B, Tanner M, Kaelen M, McGonigle J, Murphy K, Leech R, Curran H V, Nutt D J. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms Scientific Reports volume 7, Article number: 13187 (2017)]. The mechanisms underlying the potential effectiveness of 5-HT2A agonists administered in large “psychedelic/psychotomimetic” dosages (single sessions) for depression has been recently linked to BDNF and mToR pathways and has been potentially related to neural plasticity (Ly C, Greb A C, Cameron L P, et al. Psychedelics Promote Structural and Function