[go: up one dir, main page]

WO2024178504A1 - Dérivés de tryptamine à substitution tri-halo-alcoxy et procédés d'utilisation - Google Patents

Dérivés de tryptamine à substitution tri-halo-alcoxy et procédés d'utilisation Download PDF

Info

Publication number
WO2024178504A1
WO2024178504A1 PCT/CA2024/050242 CA2024050242W WO2024178504A1 WO 2024178504 A1 WO2024178504 A1 WO 2024178504A1 CA 2024050242 W CA2024050242 W CA 2024050242W WO 2024178504 A1 WO2024178504 A1 WO 2024178504A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
tri
halo
alkoxy
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2024/050242
Other languages
English (en)
Inventor
Jillian M. HAGEL
Xue CHEN
Peter J. Facchini
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Enveric Biosciences Canada Inc
Original Assignee
Enveric Biosciences Canada Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Enveric Biosciences Canada Inc filed Critical Enveric Biosciences Canada Inc
Publication of WO2024178504A1 publication Critical patent/WO2024178504A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom

Definitions

  • compositions and methods disclosed herein relate to a class of chemical compounds known as tryptamines. Furthermore, the compositions and methods disclosed herein relate to tri-halo-alkoxy-substituted tryptamine derivatives.
  • Tryptamines are a class of chemical compounds that share a common chemical structure (notably, a fused benzene and pyrrole ring, together known as an indole, and linked to the pyrrole ring, at the third carbon atom, a 2-aminoethyl group), and can be formulated as therapeutic drug compounds.
  • psilocybin has been evaluated as a drug for its clinical potential in the treatment of mental health conditions (Daniel, J. et al. Mental Health Clin., 2017;7(1): 24-28), including to treat anxiety in terminal cancer patients (Grob, C. et al. Arch. Gen.
  • Psychiatry 2011 , 68(1) 71-78
  • Other known drug compounds within the tryptamine class of compounds include, for example, melatonin, serotonin, bufotenin, dimethyltryptamine (DMT), and psilocin.
  • tryptamine-based drugs can produce their in vivo therapeutic effects by molecular interaction with macromolecules present in human cells, known as receptors.
  • receptors in broad terms, specific receptors can be thought of as being located in a relatively fixed anatomical space (e.g., a specific brain tissue).
  • the drug moves through the body to the receptor to interact therewith, and then back out of the body.
  • the drug is specifically active at the desired anatomical location within a patient’s body, such as, for example, in a specific brain tissue and/or at a specific receptor, a 5-hydroxytryptamine (5-HT) receptor, for example.
  • 5-HT 5-hydroxytryptamine
  • the administered drug additionally may interact with receptors other than the target receptor, and/or the specific molecular interaction between drug and target may not lead to the desired receptor modulation, and/or the concentration of the drug at the receptor may be suboptimal.
  • known tryptamine-based drugs can be said to frequently display suboptimal pharmacodynamic (PD) characteristics, /.e., suboptimal characteristics with respect to the pharmacological effect exerted by the drug on the body.
  • PD pharmacodynamic
  • the intensity of the drug’s effect, the concentration of the drug at the receptor, and the molecular interactions between the drug and receptor may not be as desired.
  • tryptamine compounds when administered can penetrate multiple tissues by diffusion, resulting in broad bodily distribution of the drug compound (Bodor, N. et al., 2001 , J. Pharmacy and Pharmacology, 53: 889 - 894).
  • a substantial proportion of the administered drug fails to reach the desired target receptor. This in turn may necessitate more frequent dosing of the drug.
  • Such frequent dosing is less convenient to a patient, and, moreover, may negatively affect patient compliance with the prescribed drug therapy.
  • known tryptamine containing drug formulations can be said to frequently display suboptimal pharmacokinetic (PK) characteristics, i.e., suboptimal characteristics with respect to movement of the drug through the body to and from the desired anatomical location, including, for example, suboptimal drug absorption, distribution, metabolism, and excretion.
  • PK pharmacokinetic
  • the present disclosure relates to tryptamines and derivative compounds thereof.
  • the present disclosure relates to tri-halo-alkoxy- substituted tryptamine derivative compounds.
  • the present disclosure provides, in at least one embodiment, in accordance with the teachings herein, a chemical compound, or a salt thereof, having chemical formula (I): wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group, or a hydrogen atom; wherein R3c1, R3c2, R3d1, and R3d2 are each independently or simultaneously selected from a optionally
  • the tri-halo-alkoxy group can be an -O-((C1-C9)-alkylene)-tri-halo-methyl group.
  • the tri-halo-alkoxy group can be a -O-((C1-C5)-alkylene)-tri-halo-methyl group.
  • the tri-halo-alkoxy group can be a -O-((C1-C3)-alkylene)-tri-halo-methyl group.
  • the tri-halo-alkoxy group can be a O-((C1-C3)-alkylene)-tri-halo-methyl group, wherein the O-((C1-C3)-alkylene)-tri- halo-methyl group is (-O-(C3H6)-C(X1X2X3) (tri-halo-butoxy); -O-(C2H4)-C(X1X2X3) (tri- halo-propoxy); or -O-(CH2)-C(X1X2X3) (tri-halo-ethoxy)), wherein X1, X2, and X3 are each an independently selected halogen atom.
  • the tri-halo-alkoxy group can be a tri-halo-methoxy group having the formula -O-C(X1X2X3), wherein X1, X2, and X3 are each an independently selected halogen atom.
  • the tri-halo-alkoxy group can be a tri-halo-methoxy group having the formula -O-C(X1X2X3), wherein X1, X2, and X3 are each an identical halogen atom.
  • the tri-halo-alkoxy group can be a tri-fluoro-methoxy group (-O-CF3) or a tri-fluoro-ethoxy group (-O-CH2-CF3).
  • the tri-halo-alkoxy group can be a tri-chloro-methoxy group (-O-CCl3) or a tri-chloro-ethoxy group (-O-CH2-CCl3).
  • the tri-halo-alkoxy group can be a tri-bromo-methoxy group (-O-CBr3) or a tri-bromo-ethoxy group (-O-CH2-CBr3).
  • the tri-halo-alkoxy group can be a tri-iodo-methoxy group (-O-CI3) or a tri-iodo-ethoxy group (-O-CH2-CI3).
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; R3c1, R3c2, R3d1, and R3d2; and R3a and R3b can each independently or simultaneously be an independently or simultaneously selected (C1-C10)-alkyl group, a (C1-C6)-alkyl group, or a (C1-C3)-alkyl group (propyl, ethyl, methyl).
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; R3c1, R3c2, R3d1, and R3d2; and R3a and R3b can each independently or simultaneously be an independently or simultaneously selected (C1-C10)-alkenyl group, a (C1-C6)-alkenyl group, or a (C1-C3)-alkenyl group.
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; R3c1, R3c2, R3d1, and R3d2; and R3a and R3b can each independently or simultaneously be an independently or simultaneously selected (C1-C10)-alkynyl group, a (C1-C6)-alkynyl group, or a (C1-C3)-alkynyl group.
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can each independently or simultaneously be an independently or simultaneously selected (C1- C10) heteroalkyl group, (C1-C6) heteroalkyl group, or a (C1-C3) heteroalkyl group, wherein the hetero atom is optionally at least one sulfur atom (S), oxygen atom (O), or nitrogen atom (N).
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can each independently or simultaneously be an independently or simultaneously selected (C1- C10) substituted alkyl group, (C1-C6) substituted alkyl group, (C1-C3) substituted alkyl group, wherein at least one of the non-distally positioned carbon atoms is substituted, and the substituent is optionally selected from a halogen atom (Cl, F, Br, I) to form a halo-alkyl group, or is optionally selected from a hydroxy group to form a hydroxy-alkyl group.
  • a halogen atom Cl, F, Br, I
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; R3c1, R3c2, R3d1, and R3d2; and R3a and R3b can independently or simultaneously be a methyl group (-CH3).
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can each independently or simultaneously be an independently or simultaneously selected O- (C1-C10)-alkyl group, an O-(C1-C6)-alkyl group, or an O-(C1-C3)-alkyl group (methoxy (-OCH3), ethoxy (-OC2H5), propoxy (-OC3H7)).
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can be an independently or simultaneously selected (C5-C12)-aryl group.
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can be a phenyl group.
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can be a (C1- C10)-alkaryl group, a (C1-C6)-alkaryl group, or a (C1-C3)-alkaryl group, wherein the aryl group is optionally an independently or simultaneously selected (C5-C12)-aryl group.
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can be independently or simultaneously selected to be an independently or simultaneously selected (C1-C10)-alkaryl group, a (C1-C6)-alkaryl group, or a (C1-C3)-alkaryl group, wherein the aryl group is optionally a phenyl group.
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can be -CH2- phenyl.
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can be an independently or simultaneously selected (C5-C12)-heteroaryl group.
  • the hetero atom can be selected from at least one of a nitrogen atom (N), a sulfur atom (S), and an oxygen atom (O).
  • N nitrogen atom
  • S sulfur atom
  • O oxygen atom
  • any or all of each non-tri-halo- alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can be independently or simultaneously selected to be an independently or simultaneously selected (C1-C10)-alkyl-heteroaryl group, a (C1-C6)-alkyl-heteroaryl group, or a (C1-C3)- alkyl-heteroaryl group, wherein the heteroaryl group is optionally a (C5-C12)-heteroaryl group.
  • At least one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom.
  • one of R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom.
  • At least one of R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy- substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom.
  • one of R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and wherein R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom.
  • At least one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom.
  • one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom.
  • At least one of R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and wherein R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and at least one R3a and R3b can be a hydrogen atom.
  • one of R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and wherein R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and both R3a and R3b can be a hydrogen atom.
  • At least one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and at least one R3a and R3b can be a hydrogen atom.
  • one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and both R3a and R3b can be a hydrogen atom.
  • At least one of R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and wherein R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and both R3a and R3b can be a (C1-C10)-alkyl group, a (C1-C6)-alkyl group, or (C1-C3)-alkyl group.
  • one of R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and wherein one of R3a and R3b can be a (C1-C10)-alkyl group, (C1- C6)-alkyl group, or (C1-C3)-alkyl group (methyl, ethyl, propyl), and one of R3a and R3b can be a hydrogen atom.
  • At least one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and both R3a and R3b can be a C1-C10 alkyl group, a C1-C6 alkyl group, or C1-C3 alkyl group.
  • one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and one of R3a and R3b can be a C1-C10 alkyl group, C1-C6 alkyl group, or C1-C3 alkyl group, and one of R3a and R3b can be a hydrogen atom.
  • At least one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and both R3a and R3b can be an aryl group or an alkaryl group, optionally (CH2)- phenyl.
  • one of R2, R4, R5, R6, or R7 can be a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and one of R3a and R3b can be an aryl group or an alkaryl group, optionally (CH2)-phenyl, and one of R3a and R3b can be a hydrogen atom.
  • the amino group (-NR3aR3b) can be protonated to form (-N + HR3aR3b), and the chemical formula (I) can further include a negatively charged anion balancing the nitrogen atom.
  • the compound in the compound having chemical formula (I), can be selected from the group consisting of A(I); A(II); A(III); A(IV); A(V); A(VI); A(VII); A(VIII); A(IX); A(X); A(XI); A(XIII); A(XIV); A(XV); A(XVI); A(XVII); A(XVIII); A(XIX); and A(XX): wherein in chemical compounds A(l) to A(V) and A(XI) to A(XV), X is Cl, F, Br, or I.
  • the present disclosure relates to pharmaceutical and recreational drug formulations comprising tri-halo-alkoxy-substituted tryptamine derivative compounds.
  • a pharmaceutical or recreational drug formulation comprising an effective amount of a chemical compound having a formula (I): wherein at least one of R2, R4, Rs, Re, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted substituted R2, R4, Rs, Re, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group
  • the present disclosure relates to methods of treatment of brain neurological disorders. Accordingly, the present disclosure further provides, in one embodiment, a method for treating a brain neurological disorder, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising a chemical compound having a formula (I): , wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group, or a hydrogen atom; where
  • the compound having formula (I) upon administration, can interact with a receptor in the subject to thereby modulate the receptor and exert a pharmacological effect.
  • the receptor can be a 5-HT1A receptor, a 5-HT2A receptor, a 5-HT1B receptor, or a 5-HT2B receptor.
  • the disorder can be a 5-HT1A receptor-mediated disorder, a 5-HT2A receptor-mediated disorder, a 5-HT1B receptor- mediated disorder, or a 5-HT2B receptor-mediated disorder.
  • a dose can be administered of about 0.001 mg to about 5,000 mg.
  • the present disclosure provides, in at least one embodiment, a method for modulating (i) a receptor selected from 5-HT1A receptor, a 5-HT2A receptor, a 5-HT1B receptor, or a 5-HT2B receptor, the method comprising contacting (i) the 5-HT1A receptor, the 5-HT2A receptor, the 5-HT1B receptor, or the 5- HT2B receptor, with a chemical compound having a formula (I): ), wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl
  • the reaction conditions can be in vitro reaction conditions.
  • the reaction conditions can be in vivo reaction conditions.
  • the present disclosure relates to methods of making tryptamine derivative compounds.
  • the N-methyl-transferase can comprise an enzyme encoded by a nucleic acid selected from: (a) SEQ.ID NO: 1 or SEQ.ID NO: 2; (b) a nucleic acid sequence that is substantially identical to any one of the nucleic acid sequences of (a);
  • nucleic acid sequence that hybridizes under stringent conditions to any one of the nucleic acid sequences set forth in (a), (b), (c), (d), (e) or (f).
  • the method can comprise contacting the compound having formula (III) with a host cell expressing the nucleic acid sequence; and growing the host cell to produce the chemical compound having formula (II).
  • the host cell can be a microbial cell.
  • the host cell can be a yeast cell or an E. coli cell.
  • the present disclosure relates to uses of tri-halo- alkoxy-substituted tryptamine derivative compounds. Accordingly, the present disclosure further provides, in at least one embodiment, a use of a chemical compound having a formula (I): wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group, or a hydrogen atom; wherein R3c1, R3c2, R3
  • the manufacture can comprise formulating the chemical compound with a pharmaceutically acceptable excipient, diluent, or carrier.
  • the present disclosure provides, in at least one embodiment, a use of a chemical compound having a formula (I): (I), wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group, or a hydrogen atom; wherein R3c
  • the pharmaceutical drug is a drug for the treatment of a brain neurological disorder.
  • FIG. 1 depicts the chemical structure of tryptamine.
  • FIG. 2 depicts a certain prototype structure of tryptamine and tryptamine derivative compounds, namely an indole.
  • Certain carbon and nitrogen atoms may be referred to herein by reference to their position within the indole structure, i.e., Ni , C2, C3 etc. The pertinent atom numbering is shown.
  • FIG. 3 depicts the chemical structure of a tri-halo-alkoxy group.
  • the oxygen atom, alkyl chain, and alkyl chain portions of the tri-halo-alkoxy group are denoted.
  • FIG. 4 depicts certain graphs (denoted “A” - “I”) obtained in the performance of certain experimental results, notably, graphs depicting binding affinity data for certain indolethylamine derivatives at a 5-HTi A receptor.
  • Indolethyl amine derivatives assayed are: tryptamine and dimethyl tryptamine (DMT) (results shown in graph A); 4-hydroxy-tryptamine and 4-hydroxy-DMT (results shown in graph B); serotonin and bufotenin (results shown in graph C); 5-methoxy-tryptamine, and 5- methoxy-DMT (results shown in graph D); 5-chloro-tryptamine, and 5-chloro-DMT (results shown in graph E); 5-fluoro-tryptamine, and 5-fluoro-DMT (results shown in graph F); 6-fluoro-tryptamine, and 6-fluoro-DMT (results shown in graph G); 6- trifluoromethoxy-tryptamine, and 6-trifluoromethoxy-DMT (results shown in graph H); and 2-methyl-tryptamine, and 2-methyl-DMT (re
  • Radioactive competitive displacement assays were carried out using the Scintillation Proximity Assay (SPA) and 8-hydroxy-DPAT [propyl-2,3-ring-1 ,2,3-3H] ligand as further described in Example 2.
  • SPA Scintillation Proximity Assay
  • 8-hydroxy-DPAT 2-propyl-2,3-ring-1 ,2,3-3H] ligand as further described in Example 2.
  • FIG. 5 depicts certain graphs (denoted “A” - “I”) obtained in the performance of certain experimental results, notably graphs depicting binding affinity data for certain indolethylamine derivatives at a 5-HT2A receptor.
  • Indolethyl amine derivatives assayed are: tryptamine and dimethyl tryptamine (DMT) (results shown in graph A); 4-hydroxy-tryptamine and psilocin (results shown in graph B); serotonin and bufotenin (results shown in graph C); 5-methoxy-tryptamine, and 5-methoxy-DMT (results shown in graph D); 5-chloro-tryptamine, and 5-chloro-DMT (results shown in graph E); 5-fluoro-tryptamine, and 5-fluoro-DMT (results shown in graph F); 6-fluoro- tryptamine, and 6-fluoro-DMT
  • FIG. 6 depicts certain graphs (denoted “A” - “I”) obtained in the performance of certain experimental results, notably, graphs representing Functional assay data for certain indolethylamine derivatives using 5-HTiA-expressing cell cultures.
  • Indolethyl amine derivatives assayed are: tryptamine and dimethyl tryptamine (DMT) (results shown in graph A); 4-hydroxy-tryptamine and psilocin (results shown in graph B); serotonin and bufotenin (results shown in graph C); 5- methoxy-tryptamine, and 5-methoxy-DMT (results shown in graph D); 5-chloro- tryptamine, and 5-chloro-DMT (results shown in graph E); 5-fluoro-tryptamine, and 5- fluoro-DMT (results shown in graph F); 6-fluoro-tryptamine, and 6-fluoro-DMT (results shown in graph G); 6-trifluoromethoxy-tryptamine, and 6-trifluoromethoxy-DMT (results shown in graph H); and 2-methyl-trytamine, and 2-methyl-DMT (re
  • FIG. 7 depicts certain graphs (denoted “A” - “I”) obtained in the performance of certain experimental results, notably, graphs representing Functional assay data for certain indolethylamine derivatives using 5-HT2A-expressing cell cultures.
  • Indolethyl amine derivatives assayed are: tryptamine and dimethyl tryptamine (DMT) (results shown in graph A); 4-hydroxy-tryptamine and psilocin (results shown in graph B); serotonin and bufotenin (results shown in graph C); 5- methoxy-tryptamine, and 5-methoxy-DMT (results shown in graph D); 5-chloro- tryptamine, and 5-chloro-DMT (results shown in graph E); 5-fluoro-tryptamine, and 5- fluoro-DMT (results shown in graph F); 6-fluoro-tryptamine, and 6-fluoro-DMT (results shown in graph G); 6-trifluoromethoxy-tryptamine, and 6-trifluoromethoxy-DMT (results shown in graph H); and 2-methyl-tryptamine, and 2-methyl-DMT (
  • FIG. 8 depicts certain graphs (denoted “A” - “I”) obtained in the performance of certain experimental results, notably, graphs depicting in vitro metabolic stability assay of certain primary indolethylamines (solid lines) and their N,N-dimethylated counterparts (dotted lines) during exposure to human liver microsome (HLM).
  • FIG. 9 depicts a graph obtained in the performance of certain experimental results, notably, a bar graph depicting quantification of head-twitch response (HTR) in mice as a measure of hallucination in mice following administration of certain indolethylamine drug compounds.
  • the administered drug is noted below each bar in the bar graph.
  • Mice were treated with vehicle or drug (3 mg/kg, i.p.) and HTR was counted during the subsequent 15-min interval. Quantifications show means ⁇ standard error.
  • compositions, systems or processes will be described below to provide an example of an embodiment of each claimed subject matter. No embodiment described below limits any claimed subject matter and any claimed subject matter may cover processes, compositions or systems that differ from those described below.
  • the claimed subject matter is not limited to compositions, processes or systems having all of the features of any one composition, system or process described below or to features common to multiple or all of the compositions, systems or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any claimed subject matter.
  • compositions, system or process described below may be the subject matter of another protective instrument, for example, a continuing patent application, and the applicant(s), inventor(s) or owner(s) do not intend to abandon, disclaim or dedicate to the public any such subject matter by its disclosure in this document.
  • compositions, systems or processes will be described below to provide an example of an embodiment of each claimed subject matter. No embodiment described below limits any claimed subject matter and any claimed subject matter may cover processes, compositions or systems that differ from those described below.
  • the claimed subject matter is not limited to compositions, processes or systems having all of the features of any one composition, system or process described below or to features common to multiple or all of the compositions, systems or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any claimed subject matter.
  • compositions, system or process described below may be the subject matter of another protective instrument, for example, a continuing patent application, and the applicant(s), inventor(s) or owner(s) do not intend to abandon, disclaim or dedicate to the public any such subject matter by its disclosure in this document.
  • any range of values described herein is intended to specifically include the limiting values of the range, and any intermediate value or sub-range within the given range, and all such intermediate values and sub-ranges are individually and specifically disclosed (e.g., a range of 1 to 5 includes 1 , 1.5, 2, 2.75, 3, 3.90, 4, and 5).
  • otherterms of degree such as “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of the modified term if this deviation would not negate the meaning of the term it modifies.
  • R4 and R6 reference chemical groups attached to the C4 and C6 atom, respectively.
  • R3a and R3b in this respect, reference chemical groups extending from the ethyl-amino group extending in turn from the C3 atom of the prototype indole structure.
  • tryptamine derivative refers to compounds that can be derivatized from tryptamine, wherein such compounds include an indole prototype structure and a C3 ethylamine or ethylamine derivative group having the formula (IV): (IV), Wherein at least one of R2, R3, R4, R5, R6, R7, R3a, R3b, R3c1, R3c2, R3d1, and R3d2 are a substituent (any atom or group other than hydrogen).
  • tryptamine derivatives include compounds having formula (IV), wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group (including a tri-halo-methoxy group), and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, R7, R3a, R3b, R3c1, R3c2, R3d1 and R3d2 are a substituent other than hydrogen.
  • Tryptamine derivatives further include compounds having formula (IV), wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group (including a tri-halo-methoxy group); wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from a first optionally substituted saturated or unsaturated alkyl group, a first heteroalkyl group, a first O-alkyl group, a first aryl group, a first alkaryl group, a first heteroaryl group, a first alkyl- heteroaryl group, a first hydroxy group, or a first hydrogen atom; wherein R3c1, R3c2, R3d1, and R3d2 are each independently or simultaneously selected from a second optionally substituted saturated or unsaturated alkyl group, a second heteroalkyl group, a second O-alkyl group, a second aryl group, a second
  • tryptamine derivatives containing a substituent atom or group at e.g., C2, C3, C4, C5, C6, or C7 may be referred to, respectively as C2, C3, C4, C5, C6, or C7-substituted tryptamine derivatives.
  • tri-halo-methoxy group refers to a molecule containing one atom of oxygen, bonded to one atom of carbon, the carbon being bonded to three halogen atoms, wherein the oxygen atom may be bonded to another atom or group.
  • a tri-halo-methoxy group can be depicted by the chemical formula (V) as follows: (V), wherein X1, X2, and X3 are each an independently selected halogen atom.
  • the term “tri-halo-alkoxy group”, as used herein, refers to a moiety containing one atom of oxygen, bonded to a straight or branched alkyl chain containing at least three halogen atoms.
  • Tri-halo-alkoxy groups include tri-halo-alkoxy groups wherein the most distally positioned carbon atom in the alkyl chain relative to the oxygen atom (i.e., the distal carbon atom of the alkoxy group) is bonded to three halogen atoms, wherein the oxygen atom may be bonded to another atom or group.
  • the tri-halo-alkoxy group is a tri-halo-methoxy group
  • halogen refers to the class of chemical elements consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Accordingly, halogenated compounds can refer to “fluorinated”, “chlorinated”, “brominated”, or “iodinated” compounds.
  • hydroxy group refers to a moiety containing one atom of oxygen bonded to one atom of hydrogen and having the formula -OH. A hydroxy group through its oxygen atom may be chemically bonded to another entity.
  • amino group refers to a moiety containing one atom of nitrogen bonded to hydrogen atoms and having the formula - NH2. An amino group also may be protonated and having the formula -NH3 + .
  • alkyl group refers to a straight and/or branched chain, saturated alkyl radical containing from one to “p” carbon atoms (“C1- Cp-alkyl”) and includes, depending on the identity of “p”, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl, and the like, where the variable p is an integer representing the largest number of carbon atoms in the alkyl radical.
  • Alkyl groups further include hydrocarbon groups arranged in a chain having the chemical formula - CnH2n+1, including, without limitation, methyl groups (-CH3), ethyl groups (-C2H5), propyl groups (-C3H7), and butyl groups (-C4H9).
  • hydrocarbon groups arranged in a chain having the chemical formula - CnH2n+1 including, without limitation, methyl groups (-CH3), ethyl groups (-C2H5), propyl groups (-C3H7), and butyl groups (-C4H9).
  • O-alkyl groups include, without limitation, O-methyl groups (-O- CH3) (i.e., methoxy), O-ethyl groups (-O-C2H5) (i.e., ethoxy), O-propyl groups (-O- C3H7) (i.e., propoxy) and O-butyl groups (-O-C4H9) (i.e., butoxy).
  • hetero as used herein (e.g., “hetero atom”, “heteroaryl”, “alkyl-heteroaryl”, “heteroalkyl”), means a hydrocarbon group, in which at least one carbon group is substituted with hetero atom selected from ⁇ , O, P, Si, or S, the remaining atoms in a ring, or straight or branched alkyl groups being C.
  • (C2-C20) straight or branched or straight alkyl groups comprising one or more hetero atoms or, for example, (C3-C20), (C3-C10), and (C3-C6) saturated, unsaturated, or aromatic cyclic groups, for example (C5-C12) aromatic groups, comprising one or more hetero atoms.
  • the saturated, unsaturated, or aromatic cyclic group can be optionally fused to an aryl or heteroaryl ring, or to a cyclo-alkyl ring.
  • hetero atoms may be placed at any interior position of a heteroalkyl group, or at the position at which the alkyl is attached to the remainder of a moiety.
  • Heteroalkyls are uncyclized.
  • up to 3 hetero atoms may be consecutive in a heteroalkyl, for example, -CH2- NH-OCH3.
  • alkylene refers to a divalent alkyl.
  • alkenyl group refers to a non-saturated alkene radical, i.e., a non-saturated hydrocarbon group which is formed when a hydrogen atom is removed from an alkene.
  • alkynyl group refers to a non-saturated alkyne radical, i.e., a non-saturated hydrocarbon group which is formed when a hydrogen atom is removed from an alkyne.
  • Alkynyl groups further include hydrocarbon groups arranged in a chain having the chemical formula -CnH((2n-1)-2). Examples include e ( [ 00113]
  • aryl group refers to a hydrocarbon group arranged in an aromatic ring and can, for example, be a C6-C14-aryl, a C6-C10-aryl.
  • Aryl groups can be a single ring or multiple rings fused together, wherein at least one ring is an aryl group.
  • Aryl groups further include phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, tolyl, xylyl, or indenyl groups, and the like.
  • heteroaryl refers to an aryl group, as defined herein, containing at least one hetero atom, including a nitrogen atom (N), an oxygen atom (O), or a sulfur atom (S).
  • alkaryl refers to an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • the alkylene and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • alcohol group or “hydroxyl-alkyl”, as used herein, refers to a hydrocarbon group arranged in a chain having the chemical formula CnHn+1OH.
  • receptor refers to a protein present on the surface of a cell, or in a cell not associated with a cellular surface (e.g., a soluble receptor) capable of mediating signaling to and/or from the cell, or within the cell and thereby affect cellular physiology.
  • Receptors may be classified in classes, such as the G-protein coupled receptors (“GPCRs”), families, such as 5-HT receptors, and sub- families such as 5-HTIA receptors, 5-HT2A receptors, and 5-HT2B receptors, and so on.
  • GPCRs G-protein coupled receptors
  • “signaling” refers to a response in the form of a series of chemical reactions which can occur when a molecule, including, for example, the fused heterocyclic mescaline derivatives disclosed herein, interacts with a receptor. Signaling generally proceeds across a cellular membrane and/or within a cell, to reach a target molecule or chemical reaction, and results in a modulation in cellular physiology.
  • signaling can be thought of as a transduction process by which a molecule interacting with a receptor can modulate cellular physiology, and, furthermore, signaling can be a process by which molecules inside a cell can be modulated by molecules outside a cell.
  • Signaling and interactions between molecules and receptors can be evaluated through a variety of assays, including, for example, assays known as receptor binding assays (for example, radioligand binding assays, such as e.g., [ 3 H]ketanserin assays may be used to evaluate receptor 5-HT2A receptor activity), competition assays, and saturation binding assays, and the like.
  • G-protein coupled receptor refers to a class of evolutionarily related transmembrane receptors capable of interacting with a class of proteins known as G-proteins (guanine nucleotide binding proteins). GPCRs can mediate cellular responses to external stimuli (Weis and Kobilka, 2018, Annual Review of Biochemistry 87: 897-919) and can be activated by interacting with a ligand, including neurotransmitters, such as serotonin or dopamine, for example, which, can then initiate an interaction of the receptor with a G-protein and can elicit dissociation of the G-protein into a and Py subunits.
  • G-protein coupled receptor or “GPCR”
  • GPCRs can also activate other signaling pathways, for example, through arrestin proteins and kinases. Certain ligands can preferentially activate a subset of all GPCR signaling pathways. Signaling pathways downstream of a GPCR can mediate therapeutic efficacy, or can cause drug adverse effects (Bock and Bermudez, 2021 , FEBS Journal 288: 2513-2528).
  • 5-HT receptor refers to a family of GPCRs receptors found in the central and peripheral nervous system and include sub-families, such as, 5-HTIA receptors, 5-HT2A receptors, and 5-HT2B receptors.
  • 5-HT receptors can mediate signaling through specific G-proteins, including notably Gai, Ga q /n, and Ga s and can be involved in the control of multiple physiological processes including cognition, mood, and modulation of sleep-wake cycles, for example (McCorvy and Roth, 2015, Pharmacology and Therapeutics 150: 129-142).
  • 5-HT receptors can further mediate signaling through arrestin as well as G-protein independent signaling pathways.
  • 5-HT-receptors are implicated in multiple brain neurological disorders including migraine headaches, and neuropsychiatric disorders, such as schizophrenia and depression, for example.
  • 5-HTIA receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HT IA receptors can mediate a plurality of central and peripheral physiologic functions of serotonin.
  • Ligand activity at 5-HTIA is generally not associated with hallucination, although many hallucinogenic compounds are known to modulate 5-HT IA receptors to impart physiological responses (Inserra et al., 2020, Pharmacol. Rev 73: 202).
  • 5-HTIA receptors are implicated in various brain neurological disorders, including depression and anxiety, schizophrenia, and Parkinson’s disease (Behav. Pharm. 2015, 26:45- 58).
  • 5-HTIB receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HTIB receptors can mediate a plurality of central and peripheral physiologic functions of serotonin.
  • Ligand activity at 5-HTI B is generally not associated with hallucination, although many hallucinogenic compounds are known to modulate 5-HT IA receptors to impart physiological responses (Inserra etal., 2020, Pharmacol. Rev. 73: 202).
  • 5-HTIB receptors are implicated in various brain neurological disorders, including depression (Curr. Pharm. Des. 2018, 24:2541-2548).
  • 5-HT2A receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HT2A receptors can mediate a plurality of central and peripheral physiologic functions of serotonin. Central nervous system effects can include mediation of hallucinogenic effects of hallucinogenic compounds.
  • 5-HT2A receptors are implicated in various brain neurological disorders (Nat. Rev. Drug Discov. 2022, 21 :463-473; Science 2022, 375:403-411).
  • the term “5-HT2B receptor”, as used herein, refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HT2B receptors can mediate a plurality of central and peripheral physiologic functions of serotonin. Central nervous system effects can include mediation of hallucinogenic effects of hallucinogenic compounds. 5-HT2B receptors are implicated in various brain neurological disorders, including schizophrenia (Pharmacol. Then 2018, 181 :143-155) and migraine (Cephalalgia 2017, 37:365-371 ).
  • modulating receptors refers to the ability of a compound disclosed herein to alter the function of receptors.
  • a receptor modulator may activate the activity of a receptor or inhibit the activity of a receptor depending on the concentration of the compound exposed to the receptor. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or maybe manifest only in particular cell types.
  • modulating receptors also refers to altering the function of a receptor by increasing or decreasing the probability that a complex forms between a receptor and a natural binding partner to form a multimer.
  • a receptor modulator may increase the probability that such a complex forms between the receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the receptor and the natural binding partner depending on the concentration of the compound exposed to the receptor, and or may decrease the probability that a complex forms between the receptor and the natural binding partner.
  • the C4-carboxylic acid-substituted tryptamine derivatives of the present disclosure may alter the function of a receptor by acting as an agonist or antagonist of the receptor, and that C4-carboxylic acid-substituted tryptamine derivatives according to the present disclosure may alter the function of a receptor by directly interacting therewith or binding thereto, or by indirectly interacting therewith through one or more other molecular entities.
  • the receptor may be any receptor, including any receptor set forth herein, such as any of a 5-HTIA, 5-HTI B, 5-HT2A, a 5-HT2B receptor, for example. Accordingly, it will be clear, that in order to refer modulating specific receptors, terms such as “modulating 5-HTIA receptors”, “modulating 5-HTIB receptors”, “modulating 5-HT2A receptors”, “modulating 5-HT2B receptors”, and so forth, may be used herein.
  • receptor-mediated disorder refers to a disorder that is characterized by abnormal receptor activity.
  • a receptor-mediated disorder may be completely or partially mediated by modulating a receptor.
  • a receptor-mediated disorder is one in which modulation of the receptor results in some effect on an underlying disorder e.g., administration of a receptor modulator results in some improvement in at least some of the subjects being treated.
  • the receptor may be any receptor, including any receptor set forth herein, such as any of a 5-HTIA, 5-HTI B, 5-HT2A, a 5-HT2B, receptor, for example.
  • NMT N-methyl transferase
  • any and all enzymes comprising a sequence of amino acid residues which is (i) substantially identical to the amino acid sequences constituting any NMT polypeptide set forth herein, including, for example, SEQ.ID NO: 2, or (ii) encoded by a nucleic acid sequence capable of hybridizing under at least moderately stringent conditions to any nucleic acid sequence encoding any NMT set forth herein, but for the use of synonymous codons.
  • nucleic acid sequence encoding NMT refers to any and all nucleic acid sequences encoding an NMT polypeptide, including, for example, SEQ.ID NO: 1 .
  • Nucleic acid sequences encoding a NMT polypeptide further include any and all nucleic acid sequences which (i) encode polypeptides that are substantially identical to the NMT polypeptide sequences set forth herein; or (ii) hybridize to any NMT nucleic acid sequences set forth herein under at least moderately stringent hybridization conditions or which would hybridize thereto under at least moderately stringent conditions but for the use of synonymous codons.
  • nucleic acid refers to a sequence of nucleoside or nucleotide monomers, consisting of naturally occurring bases, sugars and intersugar (backbone) linkages. The term also includes modified or substituted sequences comprising non-naturally occurring monomers or portions thereof.
  • the nucleic acids of the present disclosure may be deoxyribonucleic nucleic acids (DNA) or ribonucleic acids (RNA) and may include naturally occurring bases including adenine, guanine, cytosine, thymidine, and uracil. The nucleic acids may also contain modified bases.
  • modified bases include aza and deaza adenine, guanine, cytosine, thymidine and uracil, and xanthine and hypoxanthine.
  • a sequence of nucleotide or nucleoside monomers may be referred to as a polynucleotide sequence, nucleic acid sequence, a nucleotide sequence, or a nucleoside sequence.
  • polypeptide refers to any and all polypeptides comprising a sequence of amino acid residues which is (i) substantially identical to the amino acid sequence constituting the polypeptide having such reference SEQ.ID NO, or (ii) encoded by a nucleic acid sequence capable of hybridizing under at least moderately stringent conditions to any nucleic acid sequence encoding the polypeptide having such reference SEQ.ID NO, but for the use of synonymous codons.
  • a sequence of amino acid residues may be referred to as an amino acid sequence, or polypeptide sequence.
  • nucleic acid sequence encoding a polypeptide refers to any and all nucleic acid sequences encoding a polypeptide having such reference SEQ.ID NO.
  • Nucleic acid sequences encoding a polypeptide, in conjunction with a reference SEQ.ID NO further include any and all nucleic acid sequences which (i) encode polypeptides that are substantially identical to the polypeptide having such reference SEQ.ID NO; or (ii) hybridize to any nucleic acid sequences encoding polypeptides having such reference SEQ.ID NO under at least moderately stringent hybridization conditions or which would hybridize thereto under at least moderately stringent conditions but for the use of synonymous codons.
  • substantially identical it is meant that two amino acid sequences preferably are at least 70% identical, and more preferably are at least 85% identical and most preferably at least 95% identical, for example 96%, 97%, 98% or 99% identical.
  • amino acid sequences of such two sequences are aligned, using for example the alignment method of Needleman and Wunsch (J. Mol. Biol., 1970, 48: 443), as revised by Smith and Waterman (Adv. Appl. Math., 1981 , 2: 482) so that the highest order match is obtained between the two sequences and the number of identical amino acids is determined between the two sequences.
  • a particularly preferred method for determining the percentage identity between two polypeptides involves the Clustal W algorithm (Thompson, J D, Higgines, D G and Gibson T J, 1994, Nucleic Acid Res 22(22): 4673-4680 together with the BLOSUM 62 scoring matrix (Henikoff S & Henikoff, J G, 1992, Proc. Natl. Acad. Sci. USA 89: 10915-10919 using a gap opening penalty of 10 and a gap extension penalty of 0.1 , so that the highest order match obtained between two sequences wherein at least 50% of the total length of one of the two sequences is involved in the alignment.
  • the parameters in the wash conditions that determine hybrid stability are sodium ion concentration and temperature.
  • a 1 % mismatch may be assumed to result in about a 1 ° C. decrease in Tm, for example if nucleic acid molecules are sought that have a >95% identity, the final wash temperature will be reduced by about 5° C.
  • stringent hybridization conditions are selected.
  • Moderately stringent hybridization conditions include a washing step in 3xSSC at 42° C. It is understood however that equivalent stringencies may be achieved using alternative buffers, salts, and temperatures. Additional guidance regarding hybridization conditions may be found in: Current Protocols in Molecular Biology, John Wiley & Sons, N.Y., 1989, 6.3.1. -6.3.6 and in: Sambrook et al., Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratory Press, 1989, Vol. 3.
  • a functional variant refers to polynucleotides or polypeptides capable of performing the same function as a noted reference polynucleotide or polypeptide.
  • a functional variant of the polypeptide set forth in SEQ.ID NO: 2 refers to a polypeptide capable of performing the same function as the polypeptide set forth in SEQ.ID NO: 2.
  • Functional variants include modified a polypeptide wherein, relative to a noted reference polypeptide, the modification includes a substitution, deletion, or addition of one or more amino acids. In some embodiments, substitutions are those that result in a replacement of one amino acid with an amino acid having similar characteristics.
  • substitutions include, without limitation (i) glutamic acid and aspartic acid; (i) alanine, serine, and threonine; (iii) isoleucine, leucine, and valine, (iv) asparagine and glutamine, and (v) tryptophan, tyrosine, and phenylalanine.
  • Functional variants further include polypeptides having retained or exhibiting an enhanced N-methyl transferase biosynthetic bioactivity.
  • Chimeric nucleic acids refers to at least two linked nucleic acids which are not naturally linked.
  • Chimeric nucleic acids include linked nucleic acids of different natural origins.
  • a nucleic acid constituting a microbial promoter linked to a nucleic acid encoding a plant polypeptide is considered chimeric.
  • Chimeric nucleic acids also may comprise nucleic acids of the same natural origin, provided they are not naturally linked.
  • a nucleic acid constituting a promoter obtained from a particular cell-type may be linked to a nucleic acid encoding a polypeptide obtained from that same cell-type, but not normally linked to the nucleic acid constituting the promoter.
  • Chimeric nucleic acids also include nucleic acids comprising any naturally occurring nucleic acids linked to any non-naturally occurring nucleic acids.
  • pharmaceutical formulation refers to a preparation in a form which allows an active ingredient, including a psychoactive ingredient, contained therein to provide effective treatment, and which does not contain any other ingredients which cause excessive toxicity, an allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • the pharmaceutical formulation may contain other pharmaceutical ingredients such as excipients, carriers, diluents, or auxiliary agents.
  • the term “recreational drug formulation”, as used herein, refers to a preparation in a form which allows a psychoactive ingredient contained therein to be effective for administration as a recreational drug, and which does not contain any other ingredients which cause excessive toxicity, an allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • the recreational drug formulation may contain other ingredients such as excipients, carriers, diluents, or auxiliary agents.
  • the term “effective for administration as a recreational drug”, as used herein, refers to a preparation in a form which allows a subject to voluntarily induce a psychoactive effect for non-medical purposes upon administration, generally in the form of self-administration.
  • the effect may include an altered state of consciousness, satisfaction, pleasure, euphoria, perceptual distortion, or hallucination.
  • the term “effective amount”, as used herein, refers to an amount of an active agent, pharmaceutical formulation, or recreational drug formulation, sufficient to induce a desired biological or therapeutic effect, including a prophylactic effect, and further including a psychoactive effect. Such effect can include an effect with respect to the signs, symptoms or causes of a disorder, or disease or any other desired alteration of a biological system.
  • the effective amount can vary depending, for example, on the health condition, injury stage, disorder stage, or disease stage, weight, or sex of a subject being treated, timing of the administration, manner of the administration, age of the subject, and the like, all of which can be determined by those of skill in the art.
  • treating and “treatment”, and the like, as used herein, are intended to mean obtaining a desirable physiological, pharmacological, or biological effect, and includes prophylactic and therapeutic treatment.
  • the effect may result in the inhibition, attenuation, amelioration, or reversal of a sign, symptom or cause of a disorder, or disease, attributable to the disorder, or disease, which includes mental and psychiatric diseases and disorders.
  • Clinical evidence of the prevention or treatment may vary with the disorder, or disease, the subject, and the selected treatment.
  • pharmaceutically acceptable refers to materials, including excipients, carriers, diluents, or auxiliary agents, that are compatible with other materials in a pharmaceutical or recreational drug formulation and within the scope of reasonable medical judgement suitable for use in contact with a subject without excessive toxicity, allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • substantially pure and “isolated”, as may be used interchangeably herein describe a compound, e.g., a C4-carboxylic acid-substituted tryptamine derivative, which has been separated from components that naturally or synthetically accompany it.
  • a compound is substantially pure when at least 60%, more preferably at least 75%, more preferably at least 90%, 95%, 96%, 97%, or 98%, and most preferably at least 99% of the total material (by volume, by wet or dry weight, or by mole percent or mole fraction) in a sample is the compound of interest. Purity can be measured by any appropriate method, e.g., by chromatography, gel electrophoresis or HPLC analysis.
  • the present disclosure relates to tryptamine derivatives.
  • the present disclosure provides novel tri-halo-alkoxy- substituted tryptamine derivatives.
  • the herein provided compositions exhibit functional properties which deviate from the functional properties of tryptamine.
  • the tri-halo-alkoxy-substituted tryptamine derivatives can exhibit pharmacological properties which deviate from tryptamine.
  • the tri-halo- alkoxy-substituted tryptamine derivatives may exhibit physico-chemical properties which differ from tryptamine.
  • the tri-halo-alkoxy-substituted tryptamine derivatives may exhibit superior solubility in a solvent, for example, an aqueous solvent.
  • the tri-halo-alkoxy-substituted tryptamine derivatives may exhibit pharmacokinetics or pharmacodynamics which are different from a non- substituted compound.
  • the tri-halo-alkoxy-substituted tryptamine derivatives in this respect are useful in the formulation of pharmaceutical or recreational drug formulations.
  • the present disclosure provides derivatives of a compound known as tryptamine of which the chemical structure is shown in FIG. 1.
  • the derivatives herein provided are, in particular, the tri-halo-alkoxy-substituted tryptamine derivatives , i.e., derivatives, wherein a C2, C4, C5, C6, or C7 atom is bonded to a substituent group, notably a tri-halo-alkoxy substituent group.
  • the present disclosure provides, in accordance with the teachings herein, in at least one embodiment, a compound having chemical formula (I): ), wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group, or a hydrogen atom; wherein R3c1, R3c2, R3d1, and R3d2 are each independently or simultaneously selected from a optionally substituted alkyl, al
  • the tri-halo-alkoxy group can be selected to be an -O-(C1-C9)-alkylene-tri-halo-methyl group, for example, an -O-(C9)-alkylene tri- halo-methyl group, -O-(C8)-alkylene tri-halo-methyl group, -O-(C7)-alkylene tri-halo- methyl group, -O-(C6)-alkylene tri-halo-methyl group, -O-(C5)-alkylene tri-halo-methyl group, -O-(C4)-alkylene tri-halo-methyl group, -O-(C3)-alkylene tri-halo-methyl group ((tri-halo-butoxy), -O-(C2)-alkyl
  • the tri-halo-alkoxy group can be selected to be a tri-halo-methoxy group.
  • the tri-halo-alkoxy group can be selected to be a -O-(C0-C2)-alkylene-tri-halo-methyl group ((-O-(C3H6)-C(X1X2X3); -O-(C2H4)- C(X1X2X3); or -O-(CH2)-C(X1X2X3)), wherein X1, X2, and X3 are each an independently selected halogen atom (F, Cl, Br, I).
  • the tri-halo-alkoxy group can be selected to be a tri-halo-methoxy group (-O-C(X1X2X3)), wherein X1, X2, and X3 are each an independently selected halogen atom (F, Cl, Br, I).
  • the tri-halo-alkoxy group can be selected to be a tri-halo-methoxy group having the formula -O-C(X1X2X3), wherein X1, X2, and X3 are each an independently selected halogen atom, wherein, in some embodiments, two or all three of X1, X2, and X3 are selected to be identical halogen atoms, and wherein, in some embodiments, all of X1, X2, and X3 are selected to be non-identical halogen atoms.
  • the tri-halo-alkoxy group can be selected to be a tri-fluoro-methoxy group (-O-CF3) or a tri-fluoro-ethoxy group (-O-CH2-CF3).
  • the tri-halo-alkoxy group can be selected to be a tri-chloro-methoxy group (-O-CCl3) or a tri-chloro-ethoxy group (-O-CH2-CCl3).
  • the tri-halo-alkoxy group can be selected to be a tri-bromo-methoxy group (-O-CBr3) or a tri-bromo-ethoxy group (-O-CH2-CBr3).
  • the tri-halo-alkoxy group can be selected to be a tri-iodo-methoxy group (-O-CI3) or a tri-iodo-ethoxy group (-O-CH2-CI3).
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; R3c1, R3c2, R3d1, and R3d2; and R3a and R3b can each independently or simultaneously be an independently or simultaneously selected (C1-C10)-alkyl group, a (C1-C6)-alkyl group, or a (C1-C3)-alkyl group (propyl, ethyl, methyl).
  • the first, second, or third alkyl group can independently or simultaneously be a methyl group (- CH3).
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; R3c1, R3c2, R3d1, and R3d2; can independently or simultaneously be an independently or simultaneously selected (C1-C10)-alkynyl group, a (C1-C6)-alkynyl group, or a (C1- C3)-alkynyl g hynyl ( ), propynyl, ( ), and 1-butynyl, ( ).
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can each independently or simultaneously be an independently or simultaneously selected (C1-C10) heteroalkyl group, (C1-C6) heteroalkyl group, or a (C1-C3) heteroalkyl group, wherein the hetero atom is selected to be at least one sulfur atom (S), oxygen atom (O), or nitrogen atom (N).
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can each independently or simultaneously be an independently or simultaneously selected (C1-C10) substituted alkyl group, (C1-C6) substituted alkyl group, (C1-C3) substituted alkyl group, wherein at least one of the carbon atoms is substituted.
  • the substituent can be selected from a halogen atom (Cl, F, Br, I) to form a halo-alkyl group.
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can each independently or simultaneously be an independently or simultaneously selected from an O-(C1-C10)-alkyl group, an O-(C1- C6)-alkyl group, or an O-(C1-C3)-alkyl group (methoxy (-OCH3), ethoxy (-OC2H5), propoxy (-OC3H7)).
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can be an independently or simultaneously selected (C5- C12) aryl group, including, for example a phenyl group.
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can independently or simultaneously be an independently or simultaneously selected (C1-C10)-alkaryl group, a (C1-C6)-alkaryl group, or a (C1-C3)-alkaryl group, wherein the aryl group is optionally an independently selected (C5-C12) aryl group, for example, a phenyl group.
  • the first or second alkaryl group can be -CH2-phenyl or -C2H4-phenyl.
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 can independently or simultaneously be an independently or simultaneously selected (C5-C12) heteroaryl group.
  • the hetero atom can be at least one of a nitrogen atom (N), a sulfur atom (S), and an oxygen atom (O).
  • any or all of each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7; and R3c1, R3c2, R3d1, and R3d2 alkyl-heteroaryl group can independently or simultaneously be an independently or simultaneously selected (C1-C10)-alkyl heteroaryl group, a (C1-C6)-alkyl-heteroaryl group, or a (C1-C3)-alkyl heteroaryl group, wherein the heteroaryl group is optionally a (C5-C12) heteroaryl group.
  • the hetero atom can be selected from at least one of a nitrogen atom (N), a sulfur atom (S), and an oxygen atom (O).
  • N nitrogen atom
  • S sulfur atom
  • O oxygen atom
  • at least one of, or one of, R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, including a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom.
  • At least one, or one of, R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, including a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom.
  • At least one, or one of, R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, including a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and at least one or both of R3a and R3b can be a hydrogen atom, or a (C1-C10)-alkyl group, or a (C1-C6)-alkyl group, or (C1-C3)-alkyl group.
  • At least one, or one of, R2, R4, R5, R6, or R7 can be a tri-halo-alkoxy group, wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, including a tri-halo-methoxy group, and each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 can be a hydrogen atom, and R3c1, R3c2, R3d1, and R3d2 can each be a hydrogen atom, and at least one or both of R3a and R3b can be a hydrogen atom, an aryl group or an alkaryl group, optionally (CH2)-phenyl.
  • the amino group (-NR3aR3b) can be protonated to form (-N + HR3aR3b), and the chemical formula (I) can further include a negatively charged anion balancing the nitrogen atom, including, for example, inorganic anions, such as a chloride (Cl-), fluoride (F-), or sulfate (SO4 2- ), or organic anions, such as acetate (CH3COO-).
  • inorganic anions such as a chloride (Cl-), fluoride (F-), or sulfate (SO4 2- )
  • organic anions such as acetate (CH3COO-).
  • the present disclosure provides, in one embodiment, a compound having the formula A(I): , wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(II:): A(II), wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(III): (lll), wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(IV): wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(V): wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(VI):
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(VII): [00177] Continuing to refer to the compound having formula (I), in an aspect, the present disclosure provides, in one embodiment, a compound having the chemical formula A(VIII):
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(IX):
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(X):
  • the present disclosure provides, in one embodiment, a compound having the formula A(XI): wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(XII :): wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(XIII): wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(XIV): wherein X is Cl, F, Br, or I.
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(XV):
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(XVII):
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(XVIII):
  • the present disclosure provides, in one embodiment, a compound having the chemical formula A(XIX): [00189] Continuing to refer to the compound having formula (I), in an aspect, the present disclosure provides, in one embodiment, a compound having the chemical formula A(XX): [00190] Thus, to briefly recap, the present disclosure provides tri-halo-alkoxy- substituted tryptamine derivatives.
  • the disclosure provides, in particular, a chemical compound having a formula (I): , wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from a first optionally substituted saturated or unsaturated alkyl group, a first heteroalkyl group, a first O-alkyl group, a first aryl group, a first alkaryl group, a first heteroaryl group, a first alkyl- heteroaryl group, a first hydroxy group, or a first hydrogen atom; wherein R3c1, R3c2, R3d1, and R3d2 are each independently or simultaneously selected from a second optionally substituted saturated or unsaturated alkyl group, a second heteroalkyl group, a
  • Example compounds in accordance with example embodiments, in his respect, include each of compounds A(I), A(II), A(III), A(IV), A(V), A(VI), A(VII), A(VIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XIV), A(XV), A(XVI), A(XVII), A(XVIII), A(XIX), and A(XX) set forth herein.
  • the tri-halo-alkoxy-substituted tryptamine derivatives of the present disclosure may be used to prepare a pharmaceutical or recreational drug formulation.
  • the present disclosure further provides in another aspect, pharmaceutical and recreational drug formulations comprising tri-halo-alkoxy- substituted tryptamine derivatives.
  • a pharmaceutical or recreational drug formulation comprising a chemical compound having a formula (I): ), wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group, or a hydrogen atom;
  • the pharmaceutical or recreational drug formulations may be prepared as liquids, tablets, capsules, microcapsules, nanocapsules, trans-dermal patches, gels, foams, oils, aerosols, nanoparticulates, powders, creams, emulsions, micellar systems, films, sprays, ovules, infusions, teas, decoctions, suppositories, etc. and include a pharmaceutically acceptable salt or solvate of the tri-halo-alkoxy-substituted tryptamine derivative compound together with an excipient.
  • excipient as used herein means any ingredient other than the chemical compound of the disclosure.
  • the tri-halo-alkoxy- -substituted tryptamine derivative compounds are generally initially prepared and obtained in a substantially pure form, most preferably, at least in a 98%, 99% or 99.9% pure form, and thereafter formulated with a pharmaceutically acceptable excipient.
  • excipient may depend on factors such as the particular mode of administration, the effect of the excipient on solubility of the chemical compounds of the present disclosure and methods for their preparation will be readily apparent to those skilled in the art.
  • Such compositions and methods for their preparation may be found, for example, in “Remington’s Pharmaceutical Sciences”, 22 nd Edition (Pharmaceutical Press and Philadelphia College of Pharmacy at the University of the Sciences, 2012).
  • the dose when using the compounds of the present disclosure can vary within wide limits, and as is customary and is known to those of skill in the art, the dose can be tailored to the individual conditions in each individual case.
  • the dose depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated, or prophylaxis is conducted, on the mode of delivery of the compound, or on whether further active compounds are administered in addition to the compounds of the present disclosure.
  • Representative doses of the present invention include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to about 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg.
  • Representative doses of the present disclosure include, but are not limited to, about 0.0001 to about 1 ,000 mg, about 10 to about 160 mg, about 10 mg, about 20 mg, about 40 mg, about 80 mg or about 160 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4, doses. Depending on the subject and as deemed appropriate from the patient’s physician or care giver it may be necessary to deviate upward or downward from the doses described herein.
  • the pharmaceutical and drug formulations comprising the tri-halo- alkoxy-substituted tryptamine derivative compounds of the present disclosure may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include both solid and liquid formulations.
  • Solid formulations include tablets, capsules (containing particulates, liquids, microcapsules, or powders), lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solutions, liposomal preparations, microencapsulated preparations, creams, films, ovules, suppositories, and sprays.
  • Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agents and/or suspending agents may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.
  • diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80.
  • surface active agents may comprise from 0.2% (w/w) to 5% (w/w) of the tablet.
  • Tablets may further contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25% (w/w) to 10% (w/w), from 0.5% (w/w) to 3% (w/w) of the tablet.
  • tablets may contain a disintegrant.
  • disintegrants examples include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from 1 % (w/w) to 25% (w/w) or from 5% (w/w) to 20% (w/w) of the dosage form.
  • auxiliary ingredients include anti-oxidants, colourants, flavouring agents, preservatives, and taste-masking agents.
  • the chemical compound of the present disclosure may make up from 1% (w/w) to 80 % (w/w) of the dosage form, more typically from 5% (w/w) to 60% (w/w) of the dosage form.
  • Example tablets contain up to about 80% (w/w) of the chemical compound, from about 10% (w/w) to about 90% (w/w) binder, from about 0% (w/w) to about 85% (w/w) diluent, from about 2% (w/w) to about 10% (w/w) disintegrant, and from about 0.25% (w/w) to about 10% (w/w) lubricant.
  • the pharmaceutical and recreational drug formulations comprising the tri-halo-alkoxy-substituted tryptamine derivative compound of the present disclosure may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • the pharmaceutical and recreational drug formulations can be administered parenterally (for example, by subcutaneous, intravenous, intraarterial, intrathecal, intraventricular, intracranial, intramuscular, or intraperitoneal injection).
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffering agents (in one embodiment, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile water.
  • excipients such as salts, carbohydrates, and buffering agents (in one embodiment, to a pH of from 3 to 9)
  • a suitable vehicle such as sterile water.
  • Formulations comprising the tri-halo-alkoxy-substituted tryptamine derivative compound of the present disclosure for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the chemical compounds of the disclosure may be formulated as a solid, semi- solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
  • the pharmaceutical or recreational drug formulations of the present disclosure also may be administered topically to the skin or mucosa, i.e., dermally, or transdermally.
  • Example pharmaceutical and recreational drug formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, cosmetics, oils, eye drops, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Example carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporate (see: for example, Finnin, B. and Morgan, T.M., 1999 J. Pharm. Sci, 88 (10), 955-958).
  • Topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g., PowderjectTM, BiojectTM, etc.) injection.
  • Pharmaceutical and recreational drug formulations for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid pharmaceutical compositions can contain suitable pharmaceutically acceptable excipients.
  • the pharmaceutical compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Pharmaceutical compositions in pharmaceutically acceptable solvents can be nebulized by use of inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder pharmaceutical compositions can be administered, e.g., orally, or nasally, from devices that deliver the formulation in an appropriate manner.
  • the chemical compounds in the pharmaceutical formulation may act as pro-drugs.
  • Pro-drugs represent a modality to control drug bioavailability, control timing of drug release, and/or reduce negative side- effects.
  • formulation and delivery considerations can achieve these outcomes.
  • adjustment and optimization of all three variables together can be an effective strategy in drug development. Examples of ‘targeting systems’ designed to specifically reach cells within the brain, obtained by simultaneously leveraging pro-drug, nanoparticle. And nasal administration strategies are described, for example by Botti et al., 2021 Pharmaceutics 13:1114).
  • the tri-halo-alkoxy-substituted tryptamine derivative compounds of present disclosure are used as a recreational drug
  • the compounds may be included in compositions such as a food or food product, a beverage, a food seasoning, a personal care product, such as a cosmetic, perfume or bath oil, or oils (both for topical administration as massage oil, or to be burned or aerosolized).
  • a personal care product such as a cosmetic, perfume or bath oil, or oils (both for topical administration as massage oil, or to be burned or aerosolized).
  • the chemical compounds of the present disclosure may also be included in a “vape” product, which may also include other drugs, such as nicotine, and flavorings.
  • the tri-halo-alkoxy-substituted tryptamine derivative compounds may be used as a pharmaceutical or recreational drug.
  • the present disclosure provides, in at least one embodiment, a use of a chemical compound having a formula (I): (I), wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group, or a hydrogen atom; wherein R3c1, R3c2, R3d1, and R3d2 are each independently or simultaneously selected from a optionally substituted alkyl, alkenyl, or alky
  • the pharmaceutical formulations comprising the chemical compounds of the present disclosure may be used to treat a subject, and to treat a brain neurological disorder in a subject.
  • the present disclosure includes in a further embodiment, a method for treating a brain neurological disorder, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising a chemical compound having a formula (I): (I), wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-hetero
  • Brain neurological disorders include psychiatric disorders that may be treated include, for example, neurodevelopmental disorders such as intellectual disability, global development delay, communication disorders, autism spectrum disorder, and attention-deficit hyperactivity disorder (ADHD); bipolar and related disorders, such as mania, and depressive episodes; anxiety disorder, such as generalized anxiety disorder (GAD), agoraphobia, social anxiety disorder, specific phobias (natural events, medical, animal, situational, for example), panic disorder, and separation anxiety disorder; stress disorders, such as acute stress disorder, adjustment disorders, post-traumatic stress disorder (PTSD), and reactive attachment disorder; dissociative disorders, such as dissociative amnesia, dissociative identity disorder, and depersonalization/derealization disorder; somatoform disorders, such as somatic symptom disorders, illness anxiety disorder, conversion disorder, and factitious disorder; eating disorders, such as anorexia nervosa, bulimia nervosa, rumination disorder, pica, and binge-eating disorder; sleep disorders, such as narcol
  • Brain neurological disorders further include headache disorders, including migraines, including, for example, aural migraine
  • the compounds of the present disclosure may be used to be contacted with a receptor to thereby modulate the receptor.
  • Such contacting includes bringing a compound of the present disclosure and receptor together under in vitro conditions, for example, by introducing the compounds in a sample containing a receptor, for example, a sample containing purified receptors, ora sample containing cells comprising receptors.
  • In vitro conditions further include the conditions described in Example 2 hereof.
  • Contacting further includes bringing a compound of the present disclosure and receptor together under in vivo conditions.
  • Such in vivo conditions include the administration to an animal or human subject, for example, of a pharmaceutically effective amount of the compound of the present disclosure, when the compound is formulated together with a pharmaceutically active carrier, diluent, or excipient, as hereinbefore described, to thereby treat the subject.
  • the compound may activate the receptor or inhibit the receptor.
  • receptors with which the compounds of the present disclosure may be contacted include, for example, G-protein coupled receptor (GPCR).
  • receptors with which the compounds of the present disclosure may be contacted include, for example, 5-HT receptors.
  • receptors with which the compounds of the present disclosure may be contacted include, for example, the 5-HTIA receptor, the 5-HT2A receptor, the 5-HTIB receptor, or the 5-HT2B receptor.
  • condition that may be treated in accordance herewith can be any receptor mediated disorder including, for example, a G-protein coupled receptor (GPCR)-mediated disorder.
  • GPCR G-protein coupled receptor
  • condition that may be treated may be a 5-HT receptor-mediated disorder.
  • the condition that may be treated for example, a 5- HTIA receptor-mediated disorder, a 5-HT2A receptor-mediated disorder, a 5-HTIB receptor-mediated disorder, or a 5-HT2B receptor-mediated disorder.
  • a 5- HTIA receptor-mediated disorder for example, a 5-HT2A receptor-mediated disorder, a 5-HTIB receptor-mediated disorder, or a 5-HT2B receptor-mediated disorder.
  • disorders include, but are not limited to schizophrenia, psychotic disorder, attention deficit hyperactivity disorder, autism, and bipolar disorder.
  • the compound upon having contacted a receptor and a receptor, may modulate the receptor. However, at the same time, other receptors may not be modulated.
  • a compound may activate or inhibit a first receptor, e.g., a 5-HTIA receptor, however the compound may at the same time not modulate a second receptor, e.g., a 5-HT2A receptor, or upon having contacted a first 5-HT2A receptor and a second 5-HTIA receptor, the compound may modulate the first 5-HT2A receptor, e.g., activate or inhibit the 5-HT2A receptor, however the compound may at the same time not modulate the second 5-HTIA receptor.
  • the compounds of the present disclosure can interact with an enzyme or transmembrane transport protein in the subject to thereby modulate the enzyme or transmembrane transport protein and exert a pharmacological effect.
  • Such contacting includes bringing a compound of the present disclosure and enzyme or transmembrane transport protein together under in vitro conditions, for example, by introducing the compounds in a sample containing an enzyme or transmembrane transport protein, for example, a sample containing a purified enzyme or transmembrane transport protein, or a sample containing cells comprising an enzyme or transmembrane transport protein.
  • Contacting further includes bringing a compound of the present disclosure and an enzyme or transmembrane transport protein together under in vivo conditions.
  • Such in vivo conditions include the administration to an animal or human subject, for example, of a pharmaceutically effective amount of the compound of the present disclosure, when the compound is formulated together with a pharmaceutically active carrier, diluent, or excipient, as hereinbefore described, to thereby treat the subject.
  • a pharmaceutically active carrier diluent, or excipient, as hereinbefore described, to thereby treat the subject.
  • reaction conditions which permit the reactants to chemically react with each other and form a product, i.e., the tri-halo-alkoxy-substituted tryptamine derivative compounds of the present disclosure.
  • reaction conditions may be selected, adjusted, and optimized as known by those of skill in the art.
  • the reactions may be conducted in any suitable reaction vessel (e.g., a tube, bottle).
  • suitable solvents that may be used are polar solvents such as, for example, dichloromethane, dichloroethane, toluene, and so- called participating solvents such as acetonitrile and diethyl ether.
  • Suitable temperatures may range from, for example, e.g., from about -78 °C to about 60 °C.
  • catalysts also known as promoters, may be included in the reaction such as iodonium dicollidine perchlorate (IDCP), any silver or mercury salts, trimethylsilyl trifluoromethanesulfonate (TMS-triflate, TMSOTf), or trifluoronmethanesulfonic acid (triflic acid, TfOH), N-iodosuccinimide, methyl triflate.
  • IDCP iodonium dicollidine perchlorate
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • TfOH trifluoronmethanesulfonic acid
  • reaction times may be varied.
  • the reaction conditions may be optimized, for example, by preparing several reactant preparations and reacting these in separate reaction vessels under different reaction conditions, for example, different temperatures, using different solvents etc., evaluating the obtained tri-halo-alkoxy-substituted tryptamine derivative compounds product, adjusting reaction conditions, and selecting a desired reaction condition.
  • the chemical compounds may be isolate in pure or substantially pure form.
  • the compounds may be, for example, at least 90%, 95%, 96%, 97%, or 98%, or at least 99% pure.
  • the tri-halo-alkoxy tryptamine derivatives may be formed biosynthetically.
  • a chemical compound having chemical formula (II): wherein at least one of R2, R4, R5, R6, or R7, is a tri-halo-alkoxy group wherein the tri-halo group is positioned at the distal carbon atom of the alkoxy group, and wherein each non-tri-halo-alkoxy-substituted R2, R4, R5, R6, or R7 is independently or simultaneously selected from an optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group, a O-alkyl group, an aryl group, an alkaryl group, a heteroaryl group, an alkyl-heteroaryl group, a hydroxy group, or a hydrogen atom; wherein R3c1, R3c2, R3d1, and R3d2 are each independently or simultaneously selected from a optionally substituted alkyl, alkenyl, or alkynyl group, a heteroalkyl group
  • the N-methyl transferase enzyme can be an enzyme
  • the N-methyl-transferase can comprise an enzyme encoded by a nucleic acid selected from: (a) SEQ.ID NO: 1 or SEQ.ID NO: 2; (b) a nucleic acid sequence that is substantially identical to any one of the nucleic acid sequences of (a); (c) a nucleic acid sequence that is substantially identical to any one of the nucleic acid sequences of (a) but for the degeneration of the genetic code; (d) a nucleic acid sequence that is complementary to any one of the nucleic acid sequences of (a);
  • nucleic acid sequence that hybridizes under stringent conditions to any one of the nucleic acid sequences set forth in (a), (b), (c), (d), (e) or (f).
  • any compounds of the formula (III) may be used including any and all compounds wherein, in particular, one or two of Rsa and Rsb are a hydrogen atom.
  • host cells that can be used in accordance with the present disclosure, it is initially noted that a variety of host cells may be selected in accordance with the present disclosure, including microorganism host cells, plant host cells, and animal host cells.
  • the host cell includes an N-methyl transferase.
  • Such cells can be obtained in at least two ways. First, in some embodiments, host cells may be selected in which an N-methyl transferase is naturally present. Second, in some embodiments, a host cell that not naturally produces a suitable N-methyl transferase may modulated to produce an N-methyl transferase. Thus, for example, a nucleic acid sequence encoding an N-methyl transferase may be introduced into a host cell, and upon cell growth the host cells can make the N-methyl transferase.
  • a host cell which upon cultivation expresses the chimeric nucleic acid can be selected and used in accordance with the present disclosure.
  • Suitable host cells in this respect include, for example, microbial cells, such as bacterial cells, yeast cells, for example, and algal cells or plant cells.
  • microbial cells such as bacterial cells, yeast cells, for example, and algal cells or plant cells.
  • algal cells or plant cells A variety of techniques and methodologies to manipulate host cells to introduce nucleic acid sequences in cells and attain expression exists and are well known to the skilled artisan. These methods include, for example, cation-based methods, for example, lithium ion or calcium ion- based methods, electroporation, biolistics, and glass beads-based methods.
  • the methodology to introduce nucleic acid material in the host cell may vary, and, furthermore, methodologies may be optimized for uptake of nucleic acid material by the host cell, for example, by comparing uptake of nucleic acid material using different conditions. Detailed guidance can be found, for example, in Sambrook eta/., Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratory Press, 2012, Fourth Ed. It is noted that the chimeric nucleic acid is a non-naturally occurring chimeric nucleic acid sequence and can be said to be heterologous to the host cell.
  • the N-methyl transferase can be selected a nucleic acid sequence selected from the nucleic acid sequences consisting of:
  • nucleic acid sequence that encodes a functional variant of the amino acid sequence set forth in SEQ.ID NO: 3; and (g) a nucleic acid sequence that hybridizes under stringent conditions to any one of the nucleic acid sequences set forth in (a), (b), (c), (d), (e) or (f).
  • any of the nucleic acid sequences set forth in (a), (b), (c), (d), (e), (f) or (g) may be selected and introduced into a host cell.
  • E. coli Escherichia coli.
  • the preparation of the E. coli vectors may be accomplished using commonly known techniques such as restriction digestion, ligation, gel electrophoresis, DNA sequencing, the polymerase chain reaction (PCR) and other methodologies.
  • PCR polymerase chain reaction
  • a wide variety of cloning vectors is available to perform the necessary steps required to prepare a recombinant expression vector.
  • vectors with a replication system functional in E. coli are vectors such as pBR322, the pUC series of vectors, the M13 mp series of vectors, pBluescript etc. Suitable promoter sequences for use in E.
  • coli include, for example, the T7 promoter, the T5 promoter, tryptophan (trp) promoter, lactose (lac) promoter, tryptophan/lactose (tac) promoter, lipoprotein (Ipp) promoter, and A phage PL promoter.
  • cloning vectors contain a marker, for example, an antibiotic resistance marker, such as ampicillin or kanamycin resistance marker, allowing selection of transformed cells.
  • Nucleic acid sequences may be introduced in these vectors, and the vectors may be introduced in E. coli by preparing competent cells, electroporation or using other well-known methodologies to a person of skill in the art.
  • E. coli may be grown in an appropriate medium, such as Luria-Broth medium and harvested. Recombinant expression vectors may readily be recovered from cells upon harvesting and lysing of the cells.
  • yeast cell Another example host cell that may be conveniently used is a yeast cell.
  • Example yeast host cells that can be used are yeast cells belonging to the genus Candida, Kluyveromyces, Saccharomyces, Schizosaccharomyces, Pichia, Hansenula, and Yarrowia.
  • the yeast cell can be a Saccharomyces cerevisiae cell, a Yarrowia lipolytica cell, or Pichia pastoris cell.
  • yeast host cells include, for example, Yip type vectors, YEp type vectors, YRp type vectors, YCp type vectors, pGPD-2, pAO815, pGAPZ, pGAPZa, pHIL-D2, pHIL-S1 , pPIC3.5K, pPIC9K, pPICZ, pPICZa, pPIC3K, pHWO10, pPUZZLE and 2 pm plasmids.
  • Such vectors are known to the art and are, for example, described in Cregg etal., Mol.
  • Suitable promoter sequences for use in yeast host cells are also known and described, for example, in Mattanovich et al., Methods Mol. Biol., 2012, 824:329-58, and in Romanos et al., 1992, Yeast 8: 423-488.
  • suitable promoters for use in yeast host cells include promoters of glycolytic enzymes, like triosephosphate isomerase (TPI), phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH or GAP) and variants thereof, lactase (LAC) and galactosidase (GAL), P. pastoris glucose-6-phosphate isomerase promoter (PPGI), the 3-phosphoglycerate kinase promoter (PPGK), the glycerol aldehyde phosphate dehydrogenase promoter (PGAP), translation elongation factor promoter (PTEF), S.
  • TPI triosephosphate isomerase
  • PGK phosphoglycerate kinase
  • GPDH or GAP glyceraldehyde-3-phosphate dehydrogenase
  • LAC lactase
  • GAL galactosidase
  • ENO-1 S. cerevisiae enolase
  • GAL1 S. cerevisiae galactokinase
  • ADH1 S. cerevisiae alcohol dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase
  • TPI S. cerevisiae triose phosphate isomerase
  • CUP1 S. cerevisiae metallothionein
  • PGK S. cerevisiae 3-phosphoglycerate kinase
  • MAL maltase gene promoter
  • Marker genes suitable for use in yeast host cells are also known to the art.
  • antibiotic resistance markers such as ampicillin resistance markers
  • yeast can be used in yeast, as well as marker genes providing genetic functions for essential nutrients, for example, leucine (LEU2), tryptophan (TRP1 and TRP2), uracil (URA3, URA5, URA6), histidine (HIS3), and the like.
  • LEU2 leucine
  • TRP1 and TRP2 tryptophan
  • URA5 uracil
  • HIS3 histidine
  • Methods for introducing vectors into yeast host cells can, for example, be found in S. Kawai et al., 2010, Bioeng. Bugs 1 (6): 395-403.
  • a host cell comprising a chimeric nucleic acid comprising (i) a nucleic acid sequence controlling expression in a host cell and (ii) a nucleic acid sequence encoding an N-methyl transferase, can be prepared in accordance with the present disclosure.
  • host cells are grown to multiply and to express a chimeric nucleic acid. Expression of the chimeric nucleic acid results in the biosynthetic production in the host cell of an N-methyl transferase.
  • Growth media and growth conditions can vary depending on the host cell that is selected, as will be readily appreciated to those of ordinary skill in the art.
  • Growth media typically contain a carbon source, one or several nitrogen sources, essential salts including salts of potassium, sodium, magnesium, phosphate and sulphate, trace metals, water soluble vitamins, and process aids including but not limited to antifoam agents, protease inhibitors, stabilizers, ligands and inducers.
  • Example carbon sources are e.g., mono- or disaccharides.
  • Example nitrogen sources are, e.g., ammonia, urea, amino acids, yeast extract, corn steep liquor and fully or partially hydrolyzed proteins.
  • Example trace metals are e.g., Fe, Zn, Mn, Cu, Mo and H3BO3.
  • Example water soluble vitamins are e.g., biotin, pantothenate, niacin, thiamine, p- aminobenzoic acid, choline, pyridoxine, folic acid, riboflavin, and ascorbic acid.
  • specific example media include liquid culture media for the growth of yeast cells and bacterial cells including, Luria-Bertani (LB) broth for bacterial cell cultivation, and yeast extract peptone dextrose (YEPD or YPD), for yeast cell cultivation.
  • LB Luria-Bertani
  • YEPD yeast extract peptone dextrose
  • the cells are provided with a tri-halo-alkoxy tryptamine derivative having chemical formula (III).
  • host cells may be contacted with a tri-halo-alkoxy tryptamine derivative having chemical formula (III).
  • the tri-halo-alkoxy tryptamine derivative having chemical formula (III) can be exogenously supplied, for example, by including a tri-halo-alkoxy tryptamine derivative having chemical formula (III) in the growth medium of the host cells and growing the host cells in a medium including the tri-halo-alkoxy tryptamine derivative having chemical formula (III).
  • the tri-halo-alkoxy tryptamine derivative having chemical formula (II) may be extracted from the host cell suspension and separated from other constituents within the host cell suspension, such as media constituents and cellular debris. Separation techniques will be known to those of skill in the art and include, for example, solvent extraction (e.g., butane, chloroform, ethanol), column chromatography-based techniques, high-performance liquid chromatography (HPLC), for example, and/or countercurrent separation (CCS) based systems.
  • solvent extraction e.g., butane, chloroform, ethanol
  • HPLC high-performance liquid chromatography
  • CCS countercurrent separation
  • the recovered tri-halo-alkoxy tryptamine derivative having chemical formula (II) may be obtained in a more or less pure form, for example, a preparation of tri-halo-alkoxy tryptamine compounds of at least about 60% (w/v), about 70% (w/v), about 80% (w/v), about 90% (w/v), about 95% (w/v) or about 99% (w/v) purity may be obtained.
  • tri-halo-alkoxy tryptamine derivative having chemical formula (II) in more or less pure form may be prepared.
  • tri-halo-alkoxy- - substituted tryptamine derivatives are disclosed herein.
  • the tri-halo-alkoxy-substituted tryptamine derivatives may be formulated for use as a pharmaceutical drug or recreational drug.
  • Example embodiments and implementations of the present disclosure are further illustrated by certain examples below.
  • SEQ.ID NO: 1 sets forth a Rhinella murina nucleic acid sequence encoding an N-methyl-transferase polypeptide.
  • SEQ.ID NO: 2 sets forth a Rhinella murina nucleic acid sequence, codon-optimized for expression in Saccharomyces cerevisieae, encoding an N- methyl-transferase polypeptide.
  • SEQ.ID NO: 3 sets forth a Rhinella murina deduced amino acid sequence of an N-methyl-transferase polypeptide, including an N-terminally positioned Histidine-tag.
  • SEQ.ID NO: 4 sets forth a nucleic acid sequence of a cloning vector, notably cloning vector pET28(+).
  • Yeast codon-optimization was performed (i) to facilitate alternative potential expression in Saccharomyces cerevisiae, and (ii) to avoid overabundant protein accumulation and inclusion body formation in Escherichia coli.
  • the E. coli strain ArcticExpress (DE3) (Agilent T echnologies) was used as the host for large-scale preparative biosynthesis of N,N-di methylated indolethylamine derivative.
  • pET28a(+) encoding tagged RmNMT was transformed into competent E. coli ArcticExpress (DE3) cells. Fresh colonies were inoculated into 60 mL of TB medium supplemented with 50 pg/ml kanamycin for overnight culturing at 30°C with shaking at 250 rpm. The seed culture (60 ml) was inoculated into 660 mL of TB medium supplemented with 50 ug/mL kanamycin and 80 mg/L 6- trifluoromethoxytryptamine. 6-Trifluoromethoxytryptamine substrate was purchased from AstaTech (astatechinc.com). All other reagents were from Sigma-Aldrich and BioShop Canada (bioshopcanada.com).
  • the volume was separated into two one-litre baffled flasks each containing 330 ml of culture medium to maintain sufficient aeration. Cultures were grown at 37°C for ⁇ 5 h to an Aeoo of 2.5, cooled to 30°C, and supplemented with IPTG (0.2 mM). After 24 h incubation at 30°C and 250 rpm, the culture was harvested and subjected to centrifugation at 7000 g for 10 min. The supernatant was stored at 4°C until further processing.
  • 6-trifluoromethoxy-DMT 6-trifluoromethoxy- /V,/V-dimethyltryptamine
  • the culture medium was thawed, and 10 M sodium hydroxide was added to pH ⁇ 12.
  • the culture was extracted with ethyl acetate (3x300 ml).
  • the organic layer was combined and dried over sodium hydroxide, followed by concentration under reduced pressure.
  • the residue was purified by flash chromatography on silica gel [1 ⁇ 3 % (v/v) methanol in dichloromethane with 1.5% (w/v) sodium hydroxide].
  • a compound with formula A(XIX) was assessed using the following experiments, alongside a variety of tryptamine-type control and calibrator compounds with similar but structurally distinct characters.
  • psychedelic tryptamines are emerging as potential psychiatric medicines. DMT and 5-methoxy-DMT are under investigation in US-based clinical trials (clinicaltrials.gov) for the treatment of major depressive disorder (MDD), and psilocybin is being evaluated for as a treatment for conditions including substance abuse disorder, post-traumatic stress disorder (PTSD) and anxiety.
  • MDD major depressive disorder
  • psilocybin is being evaluated for as a treatment for conditions including substance abuse disorder, post-traumatic stress disorder (PTSD) and anxiety.
  • tryptamine derivatives bear structural similarity to the neurotransmitter serotonin and thereby interact to varying degrees with serotonin receptors.
  • Agonism at the 5-HT2A receptor is suggested as key to a hallucinogenic response, although it is currently unknown which of target receptors mediate the therapeutic actions of psychedelics (Kwan et al., 2022, Nature Neuroscience 25:1407- 1419)). It is established that substitutions on the core tryptamine structure elicit differential in vitro and in vivo effects.
  • the 5-HTIA receptor has long been associated with psychiatric disorders (Haleem, 2019, Current Neuropharmacology 17:1098-1108; Staroh et al., 2018, Expert Opinion on Therapeutic Patents 28:679-689; Kaufman et al., 2016, European Neuropsychopharmacology 26:397-410) and the 5-HT2A receptor, while generally associated with hallucinations imparted by psychedelic drugs, has recently emerged as a target for the treatment of a wide range of mental health illnesses (McClure- Begley and Roth, 2022, Nature Reviews Drug Discovery 21 :463-473).
  • HTR head-twitch response
  • 5-HTIA receptor 5-HTIA receptor.
  • Competition assays were performed as follows: SPA beads (RPNQ0011 ), radiolabeled 8-hydroxy-DPAT [propyl-2,3-ring-1 ,2,3- 3 H] (labelled 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1 -ol; NET929250UC), membranes containing 5HTIA (6110501400UA), and isoplate-96 microplate (6005040) were from Perkin Elmer (perkinelmer.com). Radioactive binding assays were carried out using a scintillation proximity assay (SPA; Maguire et al., 2012, Methods in Molecular Biology 897:31-77).
  • SPA scintillation proximity assay
  • binding buffer [50 mM Tris-HCI pH 7.4, 10 mM magnesium sulfate, 0.5 mM EDTA, 3.7% (v/v) glycerol, 1 mM ascorbic acid, 10 pM pargyline HCI].
  • the beads and membrane were aliquoted in an isoplate-96 microplate with increasing amounts of 8-hydroxy-DPAT [propyl-2,3-ring-1 ,2,3- 3 H] (0.1525 nM to 5 nM) and incubated for two hours at room temperature in the dark with shaking. After incubation, the samples were read on a MicroBeta 2 Microplate Counter (perkinelmer.com). Non-specific binding was carried out in the presence of 100 pM of metergoline (M3668-500MG, Sigma-Aldrich). Equilibrium binding constant for 8- hydroxy-DPAT (KD) was determined from a saturation binding curve using one-site saturation binding analysis from GraphPad PRISM software (Version 9.2.0).
  • Test compound was dissolved to 100 mM in dimethylsulfoxide (DMSO), and dilutions were carried out in assay buffer. Competition binding assays were performed using 0.5 nM hot 8-hydroxy-DPAT and different concentrations of DMSO (up to 1 %), or with unlabelled test compound (3 nM to 1 mM), similar to the saturation binding assay. Ki values were calculated from the competition displacement data using the competitive binding analysis from GraphPad PRISM software. Table 1 summarizes resulting Ki values for all compounds, and FIG. 4 illustrates supporting data used in K calculations for all compounds. Compound with formula A(XIX) displays a K value of 2.119 ⁇ 0.106 pM, reflecting binding ability at 5-HTIA receptor.
  • DMSO dimethylsulfoxide
  • 5-HT2A receptor [00260] 5-HT2A receptor. Competition assays were performed as for 5-HTIA assays with the following differences. SPA beads (RPNQ0010), [ 3 H]ketanserin (NET1233025UC), and membranes containing 5-HT2A (ES-313-M400UA) were from PerkinElmer. After pre-coupling, the beads and membrane were aliquoted in an isoplate-96 microplate with increasing amounts of [ 3 H]ketanserin (0.1525 nM to 5 nM). Determination of non-specific binding was carried out in the presence of 20 mM of spiperone (S7395-250MG, Sigma-Aldrich).
  • stimulation of 5-HT1A activates the G ⁇ i/o protein leading to inhibition of adenylyl cyclase (AC) type I (Rojas and Felder, 2016, , Frontiers in Cellular Neuroscience 10:272; Polter and Li, 2010, Cell Signalling 22:1406-1412).
  • AC adenylyl cyclase
  • tissue culture- treated, white-walled, clear-bottom 96-well plates (Corning, corning.com) at a density of 30,000 cells/well in 100 mL complete growth media. Cells were cultured for 24 h in a humidified incubator at 37°C and 5% CO2.
  • test compounds were then stimulated for 20 min with test compounds, prepared in titration beginning at 1 mM and dissolved in an induction medium (serum-free culture medium containing 4 ⁇ M forskolin (Sigma-Aldrich), 500 ⁇ M isobutyl-1-methylxanthine (IBMX, Sigma-Aldrich) and 100 ⁇ M RO 20-1724 (Sigma-Aldrich).
  • induction medium serum-free culture medium containing 4 ⁇ M forskolin (Sigma-Aldrich), 500 ⁇ M isobutyl-1-methylxanthine (IBMX, Sigma-Aldrich) and 100 ⁇ M RO 20-1724 (Sigma-Aldrich).
  • Changes in intracellular cAMP levels were measured using the commercially available cAMP-Glo Assay Kit (Promega, promega.ca) following the manufacturers protocol. The level of luminescence derived from cells stimulated with induction medium alone was used to establish the max level of intracellular cAMP
  • Table 2 summarizes resulting EC50 values for all compounds
  • FIG.6 illustrates supporting data used in EC50 calculations for all compounds. Treating the target cell line with compound A(XIX) not reveal sufficient stimulation to reliably calculate an EC50, reflecting inability of the compound to engage 5-HT1A receptor under the specified experimental conditions.
  • Table 2 Functional cell-based assay summary
  • 5-HT 2A receptor The Chinese hamster ovary (CHO)-derived cell line, CHO-K1/5-HT2A (GenScript, genscript.com) stably transformed to express 5-HT2A serotonin receptor, was used to evaluate specific agonist-mediated stimulation of 5- HT2A signal transduction.
  • HLM Human liver microsomes
  • FIG. 8 illustrates results for in vitro metabolic stability assays, with graph H summarizing results for Compound A(XIX) (open circles) and the comparable primary amine compound, 6- trifluoromethoxytryptamine (closed back circles). Head-twitch response assays.
  • mice were obtained from Charles River (8 weeks old). Until the first experiment, mice were group-housed, then single-housed on a 12:12 h light/dark schedule (lights on at 07:00 hours) with ad libitum access to food and water. Before any behavioral screening, mice were handled and exposed to the testing chamber for at least 5 minutes each day for three successive days and habituated to the experimental room 1 hour before testing. The testing chamber was cleaned with a 70% (v/v) ethanol solution between experiments to eliminate odor from other mice.
  • HTR Head twitch response
  • mice Prior to intraperitoneal (i.p.) drug administration, mice were video monitored for 30 minutes in plexiglass testing chamber (25.5 x 12.5 x 12.5 cm [length x width x height]) to allow for acclimation to testing environment and to examine pre-drug spontaneous HTR and behavior. Following drug administration, mice were video monitored for 60 min and returned to their home cage. Behavioral analysis was conducted by an individual blinded to subject treatment group using Behavioral Observation Research Interactive Software (BORIS, version 7, DOI: 10.1111/2041 -21 OX.12584). Post-drug behavior was analyzed during the 0-to-15-min window following drug administration.
  • FIG. 9 illustrates overall results for HTR assay, with statistical comparison to vehicle treatment.
  • Compound A(XIX) caused significant HTR compared to vehicle (*p ⁇ 0.05).
  • FIG. 10 illustrates HTR assay results wherein dimethylated compounds (tertiary amines) are compared to their primary amine equivalents. Quantifications show means ⁇ standard error with Unpaired, two-tailed t-test: *p ⁇ 0.05, **p ⁇ 0.01 , ***p ⁇ 0.001.
  • Compound A(XIX) graph H caused significant HTR compared to the primary amine, 6-trifluoromethoxytryptamine (**p ⁇ 0.01).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Wood Science & Technology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés dérivés de tryptamine à substitution tri-halo-alcoxy et des formulations de médicament pharmaceutiques et récréatives les contenant. Les formulations pharmaceutiques peuvent être utilisées pour traiter des troubles neurologiques cérébraux.
PCT/CA2024/050242 2023-02-27 2024-02-27 Dérivés de tryptamine à substitution tri-halo-alcoxy et procédés d'utilisation Ceased WO2024178504A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363448483P 2023-02-27 2023-02-27
US63/448,483 2023-02-27

Publications (1)

Publication Number Publication Date
WO2024178504A1 true WO2024178504A1 (fr) 2024-09-06

Family

ID=92589052

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2024/050242 Ceased WO2024178504A1 (fr) 2023-02-27 2024-02-27 Dérivés de tryptamine à substitution tri-halo-alcoxy et procédés d'utilisation

Country Status (1)

Country Link
WO (1) WO2024178504A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024613A1 (fr) * 2007-08-22 2009-02-26 4Sc Ag Indolopyridines tétracycliques en tant qu'inhibiteurs de eg5
WO2017046258A1 (fr) * 2015-09-16 2017-03-23 Janssen Pharmaceuticals, Inc. Dérivés d'indole monosubstitués ou disubstitués utilisés en tant qu'inhibiteurs de la réplication du virus de la dengue
WO2017167950A1 (fr) * 2016-03-31 2017-10-05 Janssen Pharmaceuticals, Inc. Dérivés d'indole substitués utilisés en tant qu'inhibiteurs de la réplication du virus de la dengue
WO2019183245A1 (fr) * 2018-03-20 2019-09-26 Icahn School Of Medicine At Mount Sinai Composés inhibiteurs de kinase, compositions et procédés d'utilisation
WO2022047579A1 (fr) * 2020-09-01 2022-03-10 Magicmed Industries Inc. Dérivés de psilocybine halogénés et leurs procédés d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024613A1 (fr) * 2007-08-22 2009-02-26 4Sc Ag Indolopyridines tétracycliques en tant qu'inhibiteurs de eg5
WO2017046258A1 (fr) * 2015-09-16 2017-03-23 Janssen Pharmaceuticals, Inc. Dérivés d'indole monosubstitués ou disubstitués utilisés en tant qu'inhibiteurs de la réplication du virus de la dengue
WO2017167950A1 (fr) * 2016-03-31 2017-10-05 Janssen Pharmaceuticals, Inc. Dérivés d'indole substitués utilisés en tant qu'inhibiteurs de la réplication du virus de la dengue
WO2019183245A1 (fr) * 2018-03-20 2019-09-26 Icahn School Of Medicine At Mount Sinai Composés inhibiteurs de kinase, compositions et procédés d'utilisation
WO2022047579A1 (fr) * 2020-09-01 2022-03-10 Magicmed Industries Inc. Dérivés de psilocybine halogénés et leurs procédés d'utilisation

Similar Documents

Publication Publication Date Title
US12138276B2 (en) Halogenated psilocybin derivatives and methods of using
US11891360B2 (en) Glycosylated psilocybin derivatives and methods of using
US20230040398A1 (en) Nitrated psilocybin derivatives and methods of using
US11931338B2 (en) Nitrilated psilocybin derivatives and methods of using
US12187679B2 (en) Hydroxylated psilocybin derivatives and methods of using
AU2022218921A9 (en) Multi-substituent psilocybin derivatives and methods of using
WO2022155751A1 (fr) Dérivés de psilocybine prénylés et leurs procédés d'utilisation
US12378195B2 (en) Aminated psilocybin derivatives and methods of using
WO2024178504A1 (fr) Dérivés de tryptamine à substitution tri-halo-alcoxy et procédés d'utilisation
US12428408B2 (en) Fused heterocyclic mescaline derivatives
US12195439B1 (en) C1-substituted isopropylamine fused heterocyclic mescaline derivatives
US12358885B2 (en) Substituted n-propylamine fused heterocyclic mescaline derivatives
US12338231B1 (en) N-heterocycle substituted tryptamine derivatives and methods of using
US20240246924A1 (en) Substituted ethylamine fused heterocyclic mescaline derivatives
WO2023102659A1 (fr) Dérivés de mescaline d'isopropylamine glycosylés et leurs méthodes d'utilisation
CN120424058A (zh) 一种新型二氧并环类aak1抑制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24762847

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE