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WO2025166273A1 - Nouveaux analogues de la classe oxa-iboga d'agents thérapeutiques - Google Patents

Nouveaux analogues de la classe oxa-iboga d'agents thérapeutiques

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Publication number
WO2025166273A1
WO2025166273A1 PCT/US2025/014175 US2025014175W WO2025166273A1 WO 2025166273 A1 WO2025166273 A1 WO 2025166273A1 US 2025014175 W US2025014175 W US 2025014175W WO 2025166273 A1 WO2025166273 A1 WO 2025166273A1
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WIPO (PCT)
Prior art keywords
alkyl
alkenyl
aryl
heteroaryl
alkynyl
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English (en)
Inventor
Dalibor Sames
Vaclav Havel
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Columbia University in the City of New York
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Columbia University in the City of New York
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Publication of WO2025166273A1 publication Critical patent/WO2025166273A1/fr
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    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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

Definitions

  • Ibogaine is the major psychoactive alkaloid found in the root bark of Tabernanthe iboga, a plant native to West Central Africa (Alper, K.R. 2001). The root bark has been used as a religious and healing sacrament by the native people in Africa owing to its distinct psychedelic effects. The clinical claims of ibogaine’s anti-addictive properties, discovered in the U.S.
  • SUDs substance use disorders
  • ibogaine and its main metabolite, noribogaine show a plethora of effects relevant to different aspects of SUDs
  • SUDs are psychiatric disorders that affect nearly 20 million adults in the US. Unfortunately, limited treatment options are currently available to these patients. Considering the large unmet needs in SUDs and psychiatric disorders in general, there is a strong impetus to develop new analogs that increase ibogaine’s safety and therapeutic index for the treatment of such diseases.
  • the present invention represents novel ibogaine analogs of compounds previously disclosed (U.S. Patent No. 9,988,377; U.S. Application Serial No. 14/240,681, 15/528,339; PCT International Application No. PCT/US2012/052327, PCT/US2015/062726). These analogs represent a further elaboration and deconstruction of the iboga skeleton to yield simpler and distinct structural systems with distinct pharmacology as well as improved side effects.
  • the compounds described herein may be useful in 4924-6694-6837v.1 treating opioid use disorder (OUD) and other SUDs, mood disorders, depression, and anxiety disorders, migraine and cluster headaches.
  • OUD opioid use disorder
  • the present invention identified key structural features that enable the novel benzofurano-azepine analogs to exhibit potent kappa opioid activity with reduced side effect profile (reduced hERG inhibition and no proarrhythmic response). Moreover, the efficacy of the kappa activity can be readily modulated by choice of substitution.
  • These analogs may be useful in treating opioid use disorder (OUD) and other SUDs, mood disorders, depression, and anxiety disorders, migraine and cluster headaches.
  • the present invention provides a compound having the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR 5 , or CR 9 R 10 , and wherein one of D, E and F is NR 5 and the remaining two of D, E and F are CR 9 R 10 ; X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X 2 is NR 1 ; ⁇ is absent and ⁇ is present; R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -
  • Figure 1 A/ Kappa opioid receptor G-protein based assay for selected examples of novel compounds.
  • Figure 2. A/ Compounds 1 and 2 inhibit hERG ion channel to a lower extent than noribogaine.
  • B/ Primary adult human cardiomyocytes in the presence of compound 2 did not exhibit any pro-arrhythmic signs up to 10 ⁇ M.
  • the present invention provides a compound having the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR 5 , or CR 9 R 10 , and wherein one of D, E and F is NR 5 and the remaining two of D, E and F are CR 9 R 10 ; X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X 2 is NR 1 ; ⁇ is absent and ⁇ is present; R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl),
  • X1 when X1 is C, X2 is NR1, E is NR1 and D is CR9R10, then R1 and at least two of R2, R3, R4 and R8 are other than hydrogen.
  • X1 when X1 is C, X2 is NR1, E is NR1 and D is CR9R10, then one of R9 and R10 is other than H.
  • X1 when X1 is C, X2 is O, and D is NH, NCH3, NCH2CH3, or NCH(CH3)2, and one of R2, R3, R4 and R8 is -OCH3 or -SCH3, then at least two of R2, R3, R4 and R8 are other than H.
  • X1 when X1 is C, X2 is O, and D is NH, NCH3, NCH2CH3, or NCH(CH3)2, and one of R2, R3, R4 and R8 is -OCH3 or -SCH3, then one of R9 and R10 is other than H.
  • X1 is N
  • X2 is CR15
  • D is NR5
  • E is CR9R10
  • R5 is alkyl
  • R9 and R10 are H
  • R 15 is CH 3
  • at least one of R 2 , R 3 , R 4 and R 8 is other than H and CH 3
  • R 3 is other than a ketone and a carboxylic acid.
  • the present invention provides a compound having the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; ⁇ is absent and ⁇ is present; X2 is O, S, N, NR1 or CR15 and when X2 is NR1; ⁇ is absent and ⁇ is present; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, - (aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-()(al
  • D is NR5, and E and F are each independently CR9R10.
  • X1 is C.
  • X2 is O or NR1.
  • R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), - (alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH- (heteroaryl), -CO 2 (alkyl),
  • R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), - (alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, or -O(alkyl). 9 4924-6694-6837v.1 [0028] In some embodiments, R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -OH, or -O(alkyl).
  • R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), - (heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl-NH-(alkynyl), - NH-(aryl), -NH-(heteroaryl), -CO 2 (alkyl), -CONH 2 , -CN, -CF 3 , -CF 2 H, -OCF 3 or -NO 2 .
  • R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), - (heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl-NH-(alkynyl). [0031] In some embodiments, R5 is H, -(alkyl), or -O(alkyl). [0032] In some embodiments, R5 is H or -(alkyl).
  • R6 is -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl- alkynl), or -(alkyl-cycloalkyl).
  • R6 is -(C1-C6alkyl), -(C1-C6alkenyl), -(C1-C6alkynyl), -C1-C6cycloalkyl, - (C1-C6alkyl-alkenyl), -(C1-C6alkyl-alkynl), or -(C1-C6alkyl-cycloalkyl).
  • R6 is branched -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl- alkenyl), -(alkyl-alkynl), or -(alkyl-cycloalkyl).
  • R5 and R6 combine to form a 3-7 membered heterocycloalkyl, ring.
  • R5 and R6 combine to form a 5 membered heterocycloalkyl ring.
  • R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), - (alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); preferably; R7 is -H or -(alkyl).
  • R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl); preferably, R9 and R10 are each independently H or -(alkyl).
  • R15 is H, or -(alkyl).
  • the present invention provides a compound having the structure: wherein 10 4924-6694-6837v.1 ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR 5 , or CR 9 R 10 , and wherein one of D, E and F is NR 5 and the remaining two of D, E and F are CR 9 R 10 ; X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X 2 is NR 1 ; ⁇ is absent and ⁇ is present; R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl),
  • the present invention provides a compound having the structure: 11 4924-6694-6837v.1 wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NH, or CR 9 R 10 , and wherein one of D, E and F is NH and the remaining two of D, E and F are CR 9 R 10 ;
  • X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present;
  • X 2 is O, S, N, or CR 15 ;
  • R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkyny
  • the present invention provides a compound having the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NH, or CR 9 R 10 , and wherein one of D, E and F is NH and the remaining two of D, E and F are CR 9 R 10 ;
  • X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present;
  • X 2 is NR 1 and ⁇ is absent and ⁇ is present;
  • R 1, R2, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, - (aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O
  • R6 is -(C3-C12 alkyl) and R7 is -(alkenyl). [0045] In some embodiments, R6 is -(alkenyl) and R7 is -(C1-C3 alkyl).
  • the present invention provides a compound having the following structure: wherein X2 is NR1 or O; R1 is H or –(alkyl); R2, R3 and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O- (aryl), -O-(heteroaryl), -SH, -S(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl),
  • the present invention provides a compound having the following structure: wherein R1 is H or –(alkyl); R2, R3 and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O- (aryl), -O-(heteroaryl), -SH, -S(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH 2 , -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(aryl), -NH
  • the present invention provides a compound having the following structure: wherein R 2 , R 3 and R 4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O- (aryl), -O-(heteroaryl), -SH, -S(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH 2 , -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -NH 2 , -NH-
  • R2 is not H.
  • R1 is -H or -Me.
  • R2, R3, and R4 are each independently -H, -OH, -F, -Cl, -Br, -CN, or - C(O)NH2.
  • R5 is -H, methyl, or ethyl.
  • the present invention provides a compound having the following structure: , , [0056] [0057] The present invention provides a compound having the following structure: 17 4924-6694-6837v.1 O HO H 2 N HO , , or R 4 R R 4 3 R 3 . [0059] -Me. [0060] In some embodiments, R1, R2 and R3 are each independently H, -OMe, -OH, -F, -Cl, -Br, or -CN.
  • the present invention provides a compound having the following structure: 18 4924-6694-6837v.1 R R 3 4 N R5 , [0063] In some embodiments, R1, R2 and R3 are each independently H, -OMe, -OH, -F, -Cl, -Br, or -CN. [0064] The present invention provides a compound having the following structure: [0065] In some embodiments, the compounds in the present invention have monoamine transporter inhibition. [0066] In some embodiments, the compounds in the present invention have sufficient brain penetration. [0067] In some embodiments, the compounds in the present invention reduce hERG off-target activity.
  • the compounds in the present invention have no or limited proarrhythmic potential.
  • the present invention provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.
  • the present invention provides a method of activating 5HT2A, 5HT2C, or both 5HT2A and 5HT2C receptors comprising contacting the 5HT2A and 5HT2C receptors with a compound having the structure: 19 4924-6694-6837v.1 wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR 5 , or CR 9 R 10 , and wherein one of D, E and F is NR 5 and the remaining two of D, E and F are CR 9 R 10 ; X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X
  • the present invention provides a method of inhibiting SERT receptor comprising contacting the SERT receptor with a compound having the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; ⁇ is absent and ⁇ is present; X2 is O, S, N, NR1 or CR15 and when X2 is NR1; ⁇ is absent and ⁇ is present; 21 4924-6694-6837v.1 R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl),
  • the present invention provides a method of activating kappa-opioid receptor comprising contacting the kappa-opioid receptor with a compound having the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR 5 , or CR 9 R 10 , and wherein one of D, E and F is NR 5 and the remaining two of D, E and F are CR 9 R 10 ; X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X 2 is NR 1 ; ⁇ is absent and ⁇ is present; R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(
  • the present invention provides a method of inhibiting nicotinic acetylcholine receptor comprising contacting the nicotinic acetylcholine receptor with a compound having the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; 24 4924-6694-6837v.1 X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X 2 is NR 1 ; ⁇ is absent and ⁇ is present; R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -
  • the present invention provides a method of treating a subject afflicted with substance use disorder comprising administering to the subject a compound having the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR 5 , or CR 9 R 10 , and wherein one of D, E and F is NR 5 and the remaining two of D, E and F are CR 9 R 10 ; X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X 2 is NR 1 ; ⁇ is absent and ⁇ is present; R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH
  • the present invention provides a method of treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury comprising administering to the subject a compound having the structure: 27 4924-6694-6837v.1 wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR 5 , or CR 9 R 10 , and wherein one of D, E and F is NR 5 and the remaining two of D, E and F are CR 9 R 10 ; X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X 2 is NR 1 ; ⁇ is absent and ⁇ is present; R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -
  • X1 when X1 is C, X2 is NR1, E is NR1 and D is CR9R10, then R1 and at least two of R2, R3, R4 and R8 are other than hydrogen.
  • X1 when X1 is C, X2 is NR1, E is NR1 and D is CR9R10, then one of R9 and R10 is other than H.
  • X1 when X1 is C, X2 is O, and D is NH, NCH3, NCH2CH3, or NCH(CH3)2, and one of R2, R3, R4 and R8 is -OCH3 or -SCH3, then at least two of R2, R3, R4 and R8 are other than H.
  • X1 when X1 is C, X2 is O, and D is NH, NCH3, NCH2CH3, or NCH(CH3)2, and one of R2, R3, R4 and R8 is -OCH3 or -SCH3, then one of R9 and R10 is other than H.
  • X1 is N
  • X2 is CR15
  • D is NR5
  • E is CR9R10
  • R5 is alkyl
  • R9 and R10 are H
  • R 15 is CH 3
  • at least one of R 2 , R 3 , R 4 and R 8 is other than H and CH 3
  • R 3 is other than a ketone and a carboxylic acid.
  • the compound having the structure wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10;
  • X1 is C or N, and when X1 is N; ⁇ is absent and ⁇ is present;
  • X2 is O, S, N, NR1 or CR15 and when X2 is NR1; ⁇ is absent and ⁇ is present;
  • R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, - (aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-() (O
  • D is NR5, and E and F are each independently CR9R10.
  • X1 is C.
  • X2 is O or NR1.
  • R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), - (alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH 2 , -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH- (heteroaryl), -CO 2 (alkyl
  • R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), - (alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, or -O(alkyl).
  • R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -OH, or -O(alkyl).
  • R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), - (heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl-NH-(alkynyl), - NH-(aryl), -NH-(heteroaryl), -CO 2 (alkyl), -CONH 2 , -CN, -CF 3 , -CF 2 H, -OCF 3 or -NO 2 .
  • R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), - (heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl-NH-(alkynyl). [0093] In some embodiments, R5 is H, -(alkyl), or -O(alkyl). [0094] In some embodiments, R5 is H or -(alkyl).
  • R6 is -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl- alkynl), or -(alkyl-cycloalkyl).
  • R6 is branched -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl- alkenyl), -(alkyl-alkynl), or -(alkyl-cycloalkyl). [0098] In some embodiments, R5 and R6 combine to form a 3-7 membered heterocycloalkyl, ring. [0099] In some embodiments, R5 and R6 combine to form a 5 membered heterocycloalkyl ring.
  • R15 is H, or -(alkyl).
  • the compound has the structure: 32 4924-6694-6837v.1 wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR 5 , or CR 9 R 10 , and wherein one of D, E and F is NR 5 and the remaining two of D, E and F are CR 9 R 10 ; X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present; X 2 is O, S, N, NR 1 or CR 15 and when X 2 is NR 1 ; ⁇ is absent and ⁇ is present; R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl),
  • the compound has the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NH, or CR 9 R 10 , and wherein one of D, E and F is NH and the remaining two of D, E and F are CR 9 R 10 ;
  • X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present;
  • X 2 is O, S, N, or CR 15 ;
  • R 1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O- (
  • the compound has the structure: wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NH, or CR 9 R 10 , and wherein one of D, E and F is NH and the remaining two of D, E and F are CR 9 R 10 ;
  • X 1 is C or N, and when X 1 is N; ⁇ is absent and ⁇ is present;
  • X 2 is NR 1 and ⁇ is absent and ⁇ is present;
  • R 1, R2, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, - (aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(hex)
  • R6 is -(C3-C12 alkyl) and R7 is -(alkenyl). [0107] In some embodiments, R6 is -(alkenyl) and R7 is -(C1-C3 alkyl).
  • the compound has the following structure: wherein X2 is NR1 or O; R1 is H or –(alkyl); R2, R3 and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O- (aryl), -O-(heteroaryl), -SH, -S(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), 36 4924-6694-6837v.1 -NH 2 , -NH-(alkyl), -NH-(alkenyl), -NH-(
  • the compound has the following structure: wherein R 1 is H or –(alkyl); 37 4924-6694-6837v.1
  • R 2 , R 3 and R 4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O- (aryl), -O-(heteroaryl), -SH, -S(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH 2 , -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), - -(aryl),
  • the compound has the following structure: wherein R 2 , R 3 and R 4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O- (aryl), -O-(heteroaryl), -SH, -S(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), - CO2(alkyl),
  • R2 is not H.
  • R1 is -H or -Me.
  • R2, R3, and R4 are each independently -H, -OH, -F, -Cl, -Br, -CN, or - C(O)NH2.
  • R5 is -H, methyl, or ethyl.
  • the present invention provides a compound having the following structure: 39 4924-6694-6837v.1 , , [0118] [0119] The present invention provides a compound having the following structure: HO , , 40 4924-6694-6837v.1 or R 4 R R R 4 3 3 R5 R 5 . [0121] or -Me. [0122] In some embodiments, R1, R2 and R3 are each independently H, -OMe, -OH, -F, -Cl, -Br, or -CN.
  • the present invention provides a compound having the following structure: R R 4 R 4 R R 3 4 3 R 3 , - [0125]
  • R1, R2 and R3 are each independently H, -OMe, -OH, -F, -Cl, -Br, or -CN.
  • the compound has the following structure: 41 4924-6694-6837v.1 .
  • sporter inhibition In some embodiments, the compounds in the present invention have sufficient brain penetration.
  • the compounds in the present invention reduce hERG off-target activity.
  • the compounds in the present invention have no or limited proarrhythmic potential.
  • the present invention provides a compound having the following structure: . 4924-6694-6837v.1
  • the compounds disclosed in the present invention can be used in combination with other compounds disclosed in the U.S. Publication No. 2023/0382919 to treat opioid use disorder (OUD) and other SUDs, mood disorders, depression, and anxiety disorders, migraine and cluster headaches, the content of which is incorporated by reference.
  • the anxiety disorder includes, but is not limited to, anxiety, generalized anxiety disorder (GAD), panic disorder, social phobia, social anxiety disorder, acute stress disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD).
  • the depressive disorder includes, but is not limited to, depression, major depression, dysthymia, cyclothymia, postpartum depression, seasonal affective disorder, atypical depression, psychotic depression, bipolar disorder, premenstrual dysphoric disorder, situational depression or adjustment disorder with depressed mood. Depressive disorders can also include other mood disorders and is not limited to the above list.
  • the present invention provides compounds or composition for use in activating 5HT2A, 5HT2C, or both 5HT2A and 5HT2C receptors.
  • the present invention provides compounds or composition for use in inhibiting SERT receptor.
  • the present invention provides compounds or composition for use in activating kappa-opioid receptor.
  • the present invention provides compounds or composition for use in inhibiting nicotinic acetylcholine receptor. [0139] The present invention provides compounds or composition for use in treating a subject afflicted with substance use disorder. [0140] The present invention provides compounds or composition for use in treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury. [0141] The present invention provides use of compounds or composition to activate 5HT2A, 5HT2C, or both 5HT2A and 5HT2C receptors. [0142] The present invention provides use of compounds or composition to inhibit SERT receptor. [0143] The present invention provides use of compounds or composition to activate kappa-opioid receptor.
  • the present invention provides use of compounds or composition to inhibit nicotinic acetylcholine receptor. [0145] The present invention provides use of compounds or composition is to treat a subject afflicted with substance use disorder. [0146] The present invention provides use of compounds or composition to treat a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury.
  • the present invention provides a process of synthesizing a compound having the following structure: , wherein ⁇ and ⁇ represent a bond that is present or absent, and wherein either ⁇ or ⁇ is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; ⁇ is absent and ⁇ is present; X2 is O, S, N, NR1 or CR15 and when X2 is NR1; ⁇ is absent and ⁇ is present; R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(al
  • the compound of formula II has the following structure: (formula II). [0149] In some i s alkyl, alkyl-alkenyl, or alkyl-alkynyl, and R7 is H or CH3. [0150] In some embodiments, the process further comprises: (a) converting the compound of formula II to an oxime compound; 45 4924-6694-6837v.1 (b) converting the oxime compound to a lactam compound; and (c) performing reduction, protection and deprotection reactions to the lactam compound to produce a compound of formula III: .
  • the compound of formula III with followed by a deprotection reaction to produce a compound of formula IV , wherein X 2 is O.
  • the compound of formula IV has the following structure: (formula IV).
  • each H, and R5 is H or alkyl.
  • the compound of formula IV has the following structure: , 4924-6694-6837v.1 O HO HO H 2 N N Me , , or analgesic effect (Sharma, S.S. et al. 1998) or reverses analgesic tolerance to morphine (Bhargava, H.N. et al.1997).
  • the method wherein the subject is afflicted with pain.
  • Reports of stimulant effects of Tabernanthe iboga date back to late 1890’s and early 1900’s in the descriptions of ritual and medicinal use by the native inhabitants in Africa.
  • Ibogaine was recommended in France to treat “asthenia” (dose range of 10-30 mg per day).
  • ibogaine was commercially available in France as “Lambarène”, a “neuromuscular stimulant” (8 mg pills) recommended for fatigue, depression, and recovery from infectious diseases (Alper, K.R.2001).
  • VAS visual analog scale tests
  • ibogaine provides structural and functional restorative effects in subjects afflicted with Parkinson’s disease.
  • GDNF itself has been shown to exert desired effects in Parkinson’s rodent and monkey models (Gash, D.M. et al.1996).
  • the method wherein the subject is afflicted with Parkinson’s disease It has been shown in humans that ibogaine is useful in treating opioid and stimulant use disorders (Alper, K.R. et al. 1999; Mash, D.C. et al.
  • Opioid use disorder involves, but is not limited to, misuse of opioid medications or use of illicitly obtained opioids.
  • the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
  • opioid use disorder as a problematic pattern of opioid use leading to problems or distress, with at least two of the following occurring within a 12-month period: [0164] -Taking larger amounts or taking drugs over a longer period than intended. [0165] -Persistent desire or unsuccessful efforts to cut down or control opioid use. [0166] -Spending a great deal of time obtaining or using the opioid or recovering from its effects. [0167] -Craving, or a strong desire or urge to use opioids. 48 4924-6694-6837v.1 [0168] -Problems fulfilling obligations at work, school, or home.
  • Alcohol use disorder involves, but is not limited to, a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using.
  • the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition describes alcohol use disorder as a problematic pattern of alcohol use leading to problems or distress, with at least two of the following occurring within a 12-month period: [0176] -Being unable to limit the amount of alcohol you drink. [0177] -Wanting to cut down on how much you drink or making unsuccessful attempts to do so. [0178] -Spending a lot of time drinking, getting alcohol, or recovering from alcohol use. [0179] -Feeling a strong craving or urge to drink alcohol.
  • [0180] Failing to fulfill major obligations at work, school or home due to repeated alcohol use.
  • [0181] -Continuing to drink alcohol even though you know it is causing physical, social, or interpersonal problems.
  • [0182] -Giving up or reducing social and work activities and hobbies.
  • [0183] -Using alcohol in situations where it is not safe, such as when driving or swimming.
  • [0184] -Developing a tolerance to alcohol so you need more to feel its effect, or you have a reduced effect from the same amount.
  • 49 4924-6694-6837v.1 [0185] -Experiencing withdrawal symptoms — such as nausea, sweating and shaking — when you do not drink, or drinking to avoid these symptoms.
  • Stimulant use disorder involves, but is not limited to, a pattern of problematic use of amphetamine, methamphetamine, cocaine, or other stimulants except caffeine or nicotine, leading to at least two of the following problems within a 12-month period: [0187] -Taking more stimulants than intended. [0188] -Unsuccessful in trying to cut down or control use of stimulants, despite wanting to do so. [0189] -Spending excessive amounts of time to activities surrounding stimulant use. [0190] -Urges and cravings for stimulants. [0191] -Failing in the obligations of home, school, or work. [0192] -Carrying on taking stimulants, even though it has led to relationship or social problems.
  • MOR agonist is intended to mean any compound or substance that activates the mu- opioid receptor (MOR).
  • the agonist may be a partial, full, or super agonist.
  • the compounds of the present invention may be safer and have fewer adverse effects compared to existing treatments.
  • the compounds of the present invention may have better hERG profile/cardiac profile compared to ibogaine and noriboagine. 50 4924-6694-6837v.1
  • the compounds of the present invention may be useful as tool compounds for studying the mechanism of ibogaine.
  • a person skilled in the art may use the techniques disclosed herein to prepare deuterium analogs thereof.
  • a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, scalemic mixtures and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A.
  • isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • any notations of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as 12 C, 13 C, or 14 C. Furthermore, any compounds containing 13 C or 14 C may specifically have the structure of any of the compounds disclosed herein.
  • any notations of a hydrogen (H) in structures throughout this application, when used without further notation are intended to represent all isotopes of hydrogen, such as 1 H, 2 H (D), or 3 H (T) except where otherwise specified.
  • any compounds containing 2 H (D) or 3 H (T) may specifically have the structure of any of the compounds disclosed herein except where otherwise specified.
  • Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically labeled reagents in place of the non-labeled reagents employed. 51 4924-6694-6837v.1
  • Deuterium (2H or D) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen atom in a compound naturally occurs as a mixture of the isotopes 1 H (hydrogen or protium), D ( 2 H or deuterium), and T ( 3 H or tritium). The natural abundance of deuterium is 0.0156%.
  • a composition comprising molecules of a naturally occurring compound
  • the level of deuterium at a particular hydrogen atom site in that compound is expected to be 0.0156%.
  • a composition comprising a compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% is novel over its naturally occurring counterpart.
  • a hydrogen at a specific site in a compound is “deuterium-enriched” if the amount of deuterium at the specific site in the compound is more than the abundance of deuterium naturally occurring at that specific site in view of all of the molecules of the compound in a defined universe such as a composition or sample.
  • Naturally occurring as used above refers to the abundance of deuterium which would be present at a relevant site in a compound if the compound was prepared without any affirmative step to enrich the abundance of deuterium.
  • the substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, alkenyl, alkynyl, alkylaryl, cycloalkyl, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials.
  • C 1 -C n as in “C 1 –C n alkyl” is defined to include groups having 1, 2ising, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on.
  • An embodiment can be C 1 -C 12 alkyl, C 2 -C 12 alkyl, C 3 -C 12 alkyl, C 4 -C 12 alkyl and so on.
  • An embodiment can be C 1 -C 8 alkyl, C 2 -C 8 alkyl, C 3 -C 8 alkyl, C 4 -C 8 alkyl and so on.
  • Alkoxy represents an alkyl group as described above attached through an oxygen bridge.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon-to-carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present.
  • C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched, or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • An embodiment can be C2-C12 alkenyl or C2-C8 alkenyl.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon-to-carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present.
  • C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon- carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C2-Cn alkynyl. An embodiment can be C2-C12 alkynyl or C3-C8 alkynyl. [0218] The term “alkylaryl” refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above.
  • an “alkylaryl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group.
  • arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • cycloalkyl includes cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • alkylcycloalkyl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to a cycloalkyl group as described above.
  • alkylcycloalkyl is connected to a core molecule through a bond from the alkyl group and that the cycloalkyl group acts as a substituent on the alkyl group.
  • aryl is intended to mean any stable monocyclic, bicyclic, or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted.
  • aryl elements include but are not limited to: phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, phenanthryl, anthryl or acenaphthyl.
  • aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridazine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyr
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • heterocycle refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms.
  • Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation.
  • the heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed.
  • Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.
  • ester is intended to a mean an organic compound containing the R-O-CO-R’ group.
  • phenyl is intended to mean an aromatic six membered ring containing six carbons.
  • substitution refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such 55 4924-6694-6837v.1 as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; hal
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • the compounds used in the method of the present invention may be prepared by techniques well known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.
  • the compounds used in the method of the present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J.
  • Another aspect of the invention comprises a compound or composition of the present invention as a pharmaceutical composition.
  • the term “pharmaceutically active agent” means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject.
  • Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S. Department of Health and Human Services, 30 th edition, 2010), which are hereby incorporated by reference.
  • compositions which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect. 56 4924-6694-6837v.1 [0232]
  • the compounds used in the method of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols; alkali or organic salts of acidic residues such as carboxylic acids.
  • the salts can be made using an organic or inorganic acid.
  • Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the sodium, potassium, or lithium salts, and the like.
  • Carboxylate salts are the sodium, potassium, or lithium salts, and the like.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic, and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19).
  • treating means preventing, slowing, halting, or reversing the progression of a disease. Treating may also mean improving one or more symptoms of a disease.
  • the compounds used in the method of the present invention may be administered in various forms, including those detailed herein.
  • the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds.
  • This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • Liposomes are also a pharmaceutically acceptable carrier, as are capsules, coatings, and various syringes.
  • a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional agents.
  • the compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or onto a site of disease, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, rectal, topical, intravenous, or direct injection or parenteral administration.
  • the compounds can be administered alone or mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
  • the active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • suitable solid carriers include lactose, sucrose, gelatin, and agar.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavoring and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds may be administered as components of tissue- targeted emulsions.
  • the compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
  • Such polymers include polyvinylpyrrolidone, pyran 59 4924-6694-6837v.1 copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets.
  • Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours.
  • Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • liquid dosage forms examples include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 17th ed., 1989, a standard reference text in this field. 60 4924-6694-6837v.1
  • the compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); p (pentet); dd (doublet of doublets); td (triplet of doublets); dt (doublet of triplets); dq (doublet of quartets); ddd (doublet of doublet of doublets); ddt (doublet of doublet of triplets); m (multiplet); br (broad). All carbon peaks are rounded to one decimal place unless such rounding would cause two close peaks to become identical; in these cases, two decimal places are retained.
  • Compound 1 was prepared by a modification of a published procedure (Hu et al, 2020). To a solution of 4-bromophenol (69.2 g, 0.4 mol) in 2-propanol (60 mL), toluene (100 mL) and water (10 mL) was added KOH (22.44 g, 0.4 mol) and the mixture was stirred at 85 °C for 1.5h.
  • Impure ketone intermediate (17.20 g) was dissolved in MeOH (140 mL), H2O (35 mL), hydroxylamine hydrochloride (6.70 g, 96.4 mmol) and sodium acetate (7.91 g, 96.4 mmol) were added, and the reaction mixture was stirred at 80°C. After 2 h MeOH was evaporated under 62 4924-6694-6837v.1 reduced pressure, mixture was diluted with brine (50 mL) and extracted with CH 2 Cl 2 :iPrOH 9:1 (4 ⁇ 50 mL). Combined extracts were dried over Na 2 SO 4 , filtered and concentrated to a yellow oil that slowly crystallized.
  • reaction mixture was diluted with THF (28 mL), cooled in ice bath and slowly quenched by addition of H 2 O, 15% aq. NaOH and H 2 O, (1:1:3 mL per g of LiAlH 4 ), and stirred until all salts were off- white and loose. Solid was filtered off and rinsed with THF, until no further product elution was detected by TLC. Combined washings were acidified with aq. HCl (12.1M, 1.1 equiv.) and org. volatiles were evaporated under reduced pressure. To the residue was added 10% HCl (56 mL) and the mixture was further 64 4924-6694-6837v.1 stirred at room temperature for 3 days.
  • reaction mixture was diluted with THF (15 mL), cooled in ice bath and slowly quenched by addition of H2O, 15% aq. NaOH and H2O, (1:1:3 mL per g of LiAlH4), and stirred until all salts were off- white and loose. Solid was filtered off and rinsed with THF, until no further product elution was detected by TLC. Combined washings were acidified with aq. HCl (12.1M, 1.1 equiv.) and org. volatiles were evaporated under reduced pressure. To the residue was added 10% HCl (20 mL) and the mixture was further stirred at room temperature for 3 days.
  • Lactam intermediate (0.56 g) was dissolved in THF (9.8 mL, 0.25M), cooled in ice bath (0°C) and LiAlH 4 (0.28 g, 7.4 mmol) was carefully added in small portions at first, after exothermic reaction subsided, the entire remaining portion was added to the suspension (starting material precipitates from cold solution). Reaction mixture was allowed to warm to room temperature and further heated to reflux for 2.5 h.
  • Reaction mixture was further cooled in ice bath and quenched slowly by addition of H 2 O, 15% NaOH 68 4924-6694-6837v.1 and H 2 O (1:1:3 mL per g of LiAlH 4 ), thick suspension was diluted with AcOEt (10 mL) and stirred until all salts were off-white and loose. Solid was filtered off and rinsed with AcOEt, until no further product elution was detected by TLC. Combined washings were acidified with aq. HCl (12.1M) and org. volatiles were evaporated under reduced pressure. To the residue was added 10% HCl (25 mL) and the mixture was further stirred at room temperature for 2.5 days.
  • Crude material was purified by column chromatography using 5 to 10% AcOEt in hexanes. Compound 12 was further transformed according to general procedure B. Crude material was purified repeated column chromatography, 1 st column 95:5:0.5 (CH 2 Cl 2 :MeOH:NH 4 OH) and 2 nd column 0 to 5% MeOH in AcOEt + 0.5% NH 4 OH to. Slightly impure product was dissolved in 9:1 CH 2 Cl 2 /MeOH, treated with 2M HCl in diethyl ether, formed suspension was chilled in freezer, solid was collected by filtration and washed with cold 9:1 CH 2 Cl 2 /MeOH mixture.
  • Compound 15 was obtained as a beige foamy solid (81 mg, 26% yield based on O-(4-bromophenyl)hydroxylamine hydrochloride).
  • Analytical sample for characterization was obtained by transforming the product into hydrochloride in CH2Cl2/MeOH mixture and adding aq. HCl (12.1 M), until pH ⁇ 1 on pH paper. Solution was concentrated under reduced pressure and twice recrystallized from MeOH.
  • Crude material was purified column chromatography using 95:5:0.5 (CH 2 Cl 2 :MeOH:NH 4 OH) and used as is for next step. Intermediate 19 was further transformed according to general procedure B. Crude material was purified by column chromatography 95:5:0.5 (CH 2 Cl 2 :MeOH:NH 4 OH) and preparative TLC using 95:5:0.5 (CH 2 Cl 2 :MeOH:NH 4 OH), plate was developed twice. Solid material was dissolved in CH 2 Cl 2 /MeOH mixture and treated with aq. HCl (12.1 M), until pH ⁇ 1 on pH paper, resulting solution was concentrated and evaporated from MeOH. Solid residue was twice recrystallized from MeOH to obtain compound 20 as brown solid (30 mg, 23% yield).
  • Residue was further purified by a column chromatography using 5% MeOH in CH2Cl2. Intermediate was obtained as a brown foamy solid (164 mg, 0.45 mmol) that was further vigorously stirred in a mixture of 3:1 THF/H2O (1.8 mL) and LiOH ⁇ H2O (112 mg, 2.7 mmol). After 17.5 h reaction was diluted with brine (5 mL), extracted with CH2Cl2:iPrOH (3 x), combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Crude material was purified by preparative TLC using 95:5:0.5 (CH 2 Cl 2 :MeOH:NH 4 OH), plate was developed twice.
  • Reaction mixture was further cooled in ice bath, diluted with diethyl ether (20 mL) and quenched slowly by addition of H2O, 15% NaOH and H2O (1:1:3 mL per g of LiAlH4) and stirred until all salts were off-white and loose. Solid was filtered off and rinsed with diethyl ether, until no further product elution was detected by TLC. Combined washings were concentrated under reduced pressure. The crude intermediate (1.12 g) was immediately used for next step.
  • 1,4-dioxane (2 mL) followed by Co 2 (CO) 8 (103 mg, 0.3 mmol) and dipea (0.26 mL, 1.5 mmol) were added and vial was sealed using a Teflon-lined solid screw cap.
  • Reaction mixture was vigorously stirred at 80°C for 22 h. After cooling to room temperature reaction mixture was filtered through a plug of silica using 5% MeOH in CH 2 Cl 2 and concentrated. Residue was further purified by a column chromatography using 2.5% MeOH in CH 2 Cl 2 .
  • Alternans and Short-Term Variability are 93 4924-6694-6837v.1 visualized in Poincaré plots of Contraction Amplitude variability.
  • STV values were normalized to the vehicle control value of each cell.
  • AC, CF and Alternans were plotted and expressed as % of incidence of cells exhibiting each of the signals normalized by the total number of cardiomyocytes.
  • mice were administered subcutaneously (s.c.).10 mg/kg dose.
  • Compounds 13 and 22 were used as hydrochlorides and were solubilized using 0.85% saline (with addition of 1% tween80 for compound 22).
  • Formulations heated and sonicated until a clear solution was obtained (formulation strength 2 mg/mL).
  • the dosing volume for subcutaneous administration was 5 mL/kg.
  • Blood samples ⁇ 60 ⁇ L from mice) were collected under light isoflurane anesthesia (Surgivet®) from retro orbital plexus from a set of three animals at specified time points into labeled micro-tubes, containing K2EDTA solution (20% K2EDTA solution) as an anticoagulant.
  • Glipizide 500 ng/mL

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Abstract

La présente invention concerne un composé ayant la structure suivante :
PCT/US2025/014175 2024-02-02 2025-01-31 Nouveaux analogues de la classe oxa-iboga d'agents thérapeutiques Pending WO2025166273A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140163012A1 (en) * 2012-12-11 2014-06-12 Albany Molecular Research, Inc. Pyrido-/azepino-benzofuran and pyrido-/azepino-benzothiophene mch-1 antagonists, methods of making, and use thereof
WO2020176599A1 (fr) * 2019-02-27 2020-09-03 The Regents Of The University Of California Azépino-indoles et autres hétérocycles pour traiter des troubles du cerveau
WO2022170268A1 (fr) * 2021-02-08 2022-08-11 The Trustees Of Columbia University In The City Of New York Analogues inspirés d'oxa-ibogaïne pour le traitement de troubles neurologiques et psychiatriques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140163012A1 (en) * 2012-12-11 2014-06-12 Albany Molecular Research, Inc. Pyrido-/azepino-benzofuran and pyrido-/azepino-benzothiophene mch-1 antagonists, methods of making, and use thereof
WO2020176599A1 (fr) * 2019-02-27 2020-09-03 The Regents Of The University Of California Azépino-indoles et autres hétérocycles pour traiter des troubles du cerveau
WO2022170268A1 (fr) * 2021-02-08 2022-08-11 The Trustees Of Columbia University In The City Of New York Analogues inspirés d'oxa-ibogaïne pour le traitement de troubles neurologiques et psychiatriques
US20230382919A1 (en) * 2021-02-08 2023-11-30 The Trustees Of Columbia University In The City Of New York Oxa- ibogaine inspired analogues for treatment of neurological and psychiatric disorders

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