U.S. patent application number 17/679439 was filed with the patent office on 2022-06-09 for tryptamine prodrugs.
The applicant listed for this patent is Field Trip Psychedelic Inc.. Invention is credited to Nathan Bryson.
Application Number | 20220177427 17/679439 |
Document ID | / |
Family ID | 1000006164753 |
Filed Date | 2022-06-09 |
United States Patent
Application |
20220177427 |
Kind Code |
A1 |
Bryson; Nathan |
June 9, 2022 |
Tryptamine Prodrugs
Abstract
The present invention provides a tryptamine prodrug compound. A
compound represented by the formula (I) ##STR00001## where each
symbol is as described in the specification, or a salt or
zwitterion thereof, is converted to an active which has 5HT2A
receptor agonist activity, and is useful as an agent for the
treatment of depression.
Inventors: |
Bryson; Nathan; (Toronto,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Field Trip Psychedelic Inc. |
Toronto |
|
CA |
|
|
Family ID: |
1000006164753 |
Appl. No.: |
17/679439 |
Filed: |
February 24, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17364047 |
Jun 30, 2021 |
11292765 |
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17679439 |
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63045901 |
Jun 30, 2020 |
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63109095 |
Nov 3, 2020 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 209/16 20130101;
A61K 9/20 20130101; A61K 9/0019 20130101; A61K 9/08 20130101; A61K
9/0053 20130101; C07D 209/08 20130101 |
International
Class: |
C07D 209/16 20060101
C07D209/16; A61K 9/00 20060101 A61K009/00; A61K 9/08 20060101
A61K009/08; C07D 209/08 20060101 C07D209/08 |
Claims
1. A compound of Formula (I) (II), (III) or (IV) or a
pharmaceutically acceptable salt or zwitterion thereof:
##STR00012## wherein: (1) R1, R2, and R6 are each independently
selected from hydrogen, linear or branched alkyl, or arylalkyl; (2)
R4 is a. --X--CO2H, where X is a linear, cyclic or branched,
saturated or unsaturated carbon chain, optionally substituted with
--OH or --CO2H; or an aromatic ring, optionally substituted with
alkyl or CO2H; or b. ##STR00013## wherein R9 is X--CO2H, where X is
as defined in (2)(a) above and R10 is hydrogen, linear or branched
alkyl or arylalkyl, optionally substituted by --OH or --CO2H; (3)
R5 is hydrogen, linear or branched alkyl, arylalkyl, or O--R5',
where R5' is hydrogen, linear or branched alkyl; and (4) R7 and R8:
a. are each independently selected from hydrogen, linear or
branched alkyl, or arylalkyl, or b. together form a non-aromatic
N-containing heterocycle, optionally substituted with alkyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 17/364,047, filed Jun. 30, 2021, and
entitled "Tryptamine Prodrugs," which claims priority to U.S.
Provisional Application Ser. No. 63/045,901 filed on Jun. 30, 2020,
entitled "Tryptamine Prodrugs", and to U.S. Provisional Application
Ser. No. 63/109,095 filed on Nov. 3, 2020, entitled "Tryptamine
Prodrugs". The entire contents of each of the foregoing
applications are hereby incorporated by reference in this
application.
FIELD OF THE INVENTION
[0002] The present invention relates to novel tryptamine compounds,
methods of making and using such compounds, compositions comprising
such compounds, and their uses.
BACKGROUND
[0003] Tryptamines are a class of 3-aminoethyl-indoles that bind
and activate the serotonin receptor, also called the 5HT receptor.
A psychedelic state may be achieved by activation of the 2A form of
the serotonin receptor by 5HT2A receptor agonist compounds. The
endogenous substance for this receptor is 5-hydroxy-tryptamine
(serotonin). The tryptamine 3-(2-aminoethyl)-indole is also an
endogenous neurotransmitter.
[0004] The serotonin receptor system is implicated in depression
and depressive states which are commonly treated with 5HT1A
antagonists (Affective Disorders: Depression in
Neuropsychopharmacology and Therapeutics, Chapter 6, First Edition.
Ivor S. Ebenezer, 2015). More recently, 5HT2A agonists have shown
potential as medicines for depression (Carhart-Harris 2018
Psychopharmacology).
[0005] Tryptamine molecules which produce a psychedelic state and
which have been used in traditional medicine, may have therapeutic
potential for the treatment of mood disorders, distress, depression
and others. For example, ayahuasca is a natural form of
dimethyltryptamine (DMT) which when combined with a monoamine
oxidase inhibitor can be ingested and produces a variable, but
prolonged psychedelic state that can last for 6 to 15 hours. DMT is
also naturally found to occur in small amounts in the brain and may
act as a neurotransmitter.
[0006] Lysergic acid diethylamide (LSD), is a diethylamide
derivative of a naturally occurring substance from fungus found in
rye grain, which also produces a prolonged psychedelic state up to
8 to 12 hours long.
[0007] Psilocybin is a naturally occurring plant-based tryptamine
found in Psilocybe mushrooms, and produces a prolonged psychedelic
state of about 6 to 8 hours. Psilocybin was first synthesized in
1958 and is currently being investigated as a treatment for
depression. Psilocybin is a prodrug, with psilocin being the active
species in vivo. Psilocybin contains a phosphate bound to the
4-hydroxy group of psilocin, which is cleaved in the gut when
Psilcybe mushrooms or the drug substance is taken orally:
##STR00002##
[0008] Simple mono-functional organic esters of psilocin have been
reported. Lower alkoxy radical modified psilocins have also been
described. Sulfate-bound psilocin has been produced and other mono-
and di-basic mineral acid modified psilocins have been described.
Psilocin acetate is known and has been used in underground
psychedelic subculture.
[0009] Psychedelic substances have been shown to be effective for
treating depression, and even more effective for treating
depression when associated with psychotherapy (Watts 2020 J
Contextual Behavioral Science).
[0010] A limited number of synthetic tryptamine substances have
been prepared since perhaps the earliest recorded work of Albert
Hoffman. Structure-activity relationships have been described for a
variety of tryptamine substances (Claire 1988).
[0011] Succinate and other diacid functions have been explored as
components of a prodrug delivery system toward water-soluble,
injectable forms of hydrophobic or poorly water soluble drug
substances, such as testosterone, haloperidol, chloramphenicol or
estradiol (Silverman and Holladay, Chapter 9.2: Prodrugs and Drug
Delivery Systems in The Organic Chemistry of Drug Design and Drug
Action (3.sup.rd Ed), 2014). Tetrahydrocannabinol ester of succinic
acid has been patented to treat glaucoma. However, ester cleavage
is not consistently rapid, is not predictable and can depend on the
structure of the moiety attached to the drug and therefore must be
investigated (Anderson 1984 JPharmaSci). Esterase enzymes are
responsible for active cleavage of the prodrug ester group in vivo
and species differences in esterase quantities and specificity in
various tissues complicate investigations and optimizations (Bahar
2012 JPharmSci).
[0012] This background information is believed to be relevant to a
basic understanding of the present invention. It is not an
admission that any of the foregoing is prior art against any aspect
of the claimed invention.
SUMMARY OF THE INVENTION
[0013] The present invention relates to novel tryptamine compounds,
which when administered, convert to an active form in vivo, and act
as a 5HT2A agonist. The compounds described herein may be useful to
treat mental disorders, such as a depressive condition, including
unipolar and bipolar depressive conditions, such as but not limited
to depression, depression from generalized anxiety, major
depression, treatment resistant depression and postpartum
depression.
[0014] In one aspect, the present invention relates to a tryptamine
or isotryptamine compound of Formula (I) (II), (III) or (IV) or a
pharmaceutically acceptable salt or zwitterion thereof:
##STR00003##
wherein: [0015] (1) R1, R2, and R6 are each independently selected
from hydrogen, linear or branched alkyl, preferably C.sub.1-5
alkyl, or arylalkyl; [0016] (2) R4 is [0017] a. --X--CO2H, where X
is a linear, cyclic or branched, saturated or unsaturated carbon
chain (preferably C.sub.1-5 alkyl), optionally substituted with
--OH or --CO2H, or an aromatic ring, optionally substituted with
alkyl or CO2H; or [0018] b. (R9)(R10)N--, wherein R9 is X--CO2H,
where X is defined as above, and R10 is hydrogen, linear or
branched alkyl (preferably C.sub.1-5 alkyl) or arylalkyl,
optionally substituted by --OH or --CO2H; [0019] (3) R5 is
hydrogen, linear or branched alkyl (preferably C.sub.1-5 alkyl),
arylalkyl, or O--R5', where R.sub.5' is hydrogen, linear or
branched alkyl (preferably C1-5 alkyl); and [0020] (4) R7 and R8:
[0021] a. are each independently selected from hydrogen, linear or
branched alkyl (preferably C.sub.1-5 alkyl), or arylalkyl, or
[0022] b. together form a non-aromatic N-containing heterocycle,
optionally substituted with alkyl, preferably where the entire
heterocyclic structure does not contain more than 12 atoms.
[0023] In another aspect, the invention comprises diacid esters of
a hydroxytryptamine, such as 4-hydroxy and 5-hydroxytryptamines and
6-hydroxy and 7-hydroxy isotryptamines, and other structural or
functional analogs of psychedelic tryptamines.
[0024] In some embodiments, R7 and R8 are the same or different,
and are linear or branched C.sub.1-4 alkyl; or are the same or
different, and are methyl or isopropyl; such as R7 and R8 are both
methyl, or R7 and R8 are both isopropyl, or where one of R7 and R8
is methyl and the other is isopropyl.
[0025] In some embodiments, X is a linear C1-C3 chain, optionally
substituted with OH or --CO2H, such as X is an unsubstituted linear
C3 chain.
[0026] In another aspect, the invention relates to a composition
comprising a compound described herein, and a pharmaceutically
acceptable excipient. In some embodiments, the composition
comprises an oral dosage formulation or an injectable
formulation.
[0027] In another aspect, the invention comprises a method of
treating a mental disorder, comprising the step of administering an
effective amount of a compound described herein. In some
embodiments, the mental disorder is a depressive condition,
including unipolar and bipolar depressive conditions, such as but
not limited to depression, depression from generalized anxiety,
major depression, treatment resistant depression and postpartum
depression.
[0028] In another aspect, the invention relates to the use of a
compound described herein to treat a mental disorder, or in the
manufacture of a medicament for treating a mental disorder, such as
depression.
[0029] In another aspect, the invention relates to a method of
making a compound described herein, comprising reacting a
tryptamine comprising a hydroxytryptamine or hydroxyisotryptamine
with a cyclic anhydride in a suitable anhydrous solvent. In some
embodiments, the solvent contains a base with pKa greater than 4
but less than 9, and the resulting compound is isolated as a
zwitterion. In some embodiments, the tryptamine comprises 4-hydroxy
or 5-hydroxy tryptamine or a 6-hydroxy or 7-hydroxy isotryptamine.
In some embodiments, the solvent is pyridine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1 is a graph showing plasma concentration of 4-HO-DiPT
(ng/ml) time after subcutaneous administration of N,N
diisopropyltryptamine-4-glutarate at a rate of 2 mg/kg.
[0031] FIG. 2 is a graph showing plasma concentration of 4-HO-DiPT
(ng/ml) after subcutaneous administration of N,N
diisopropyltryptamine-4-glutarate at a rate of 1.4 mg/kg
DETAILED DESCRIPTION
[0032] Embodiments of the present invention comprise novel
synthetic tryptamine prodrugs. The prodrugs may be useful for
treatment of mental disorders such as depression, including without
limitation, major depression, treatment resistant depression and
postpartum depression. As used herein, the term "mental disorder"
includes those disorders which may be diagnosed by a mental health
professional as a psychological or psychiatric disorder, including
those which may be diagnosed by reference to Diagnostic and
Statistical Manual of Mental Disorders (DSM-5).
[0033] The term "treating", "treat" or "treatment" as used herein
embraces both preventative, i.e., prophylactic, and palliative
treatment, i.e., relieve, alleviate, or slow the progression of the
patient's disease, disorder or condition.
[0034] As used herein, "psychedelic state" is an altered state of
consciousness experienced by a person, which may include
intensified sensory perception, perceptual distortion or
hallucinations, and/or feelings of euphoria or despair. Psychedelic
states have been described as resulting from psychedelic drugs such
as DMT (dimethyltryptamine), LSD, mescaline or psilocybin. Other
known psychedelic drugs include the 4-hydroxy analogs of
N-Methyl-N-isopropyltryptamine (MiPT) and N,N-diisopropyltryptamine
(DiPT).
[0035] The present invention comprises prodrugs of hydroxy-indole
5HT2A agonists which induce a psychedelic state or which still
provide a beneficial therapeutic effect without being associated
with a psychedelic state. The prodrugs may be used in combination
with other treatments known to be effective for treating mental
disorders, such as psychotherapy, electroconvulsive therapy and/or
other pharmaceutical compounds, for example, with concomitant use
of tricyclic antidepressants (TCAs), selective serotonin reuptake
inhibitors (SSRIs), selective norepinephrine reuptake inhibitors
(SNRIs), monoamine oxidase inhibitors (MOAIs) or other
anti-depressants. In preferred embodiments, the treatment may
produce lasting effects, for example longer than 1 month after a
single treatment, preferably longer than 3 months, and more
preferably longer than 6 months. In some embodiments, additional
therapy may not be required.
Compounds
[0036] "Compounds" when used herein includes any pharmaceutically
acceptable derivative or variation, including conformational
isomers (e.g., cis and trans isomers) and all optical isomers
(e.g., enantiomers and diastereomers), racemic, diastereomeric and
other mixtures of such isomers, as well as solvates, hydrates,
isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs.
The expression "prodrug" refers to compounds that are drug
precursors which following administration, release the drug (or
"active") in vivo via some chemical or physiological process (e.g.,
hydrolysis, enzymatic cleavage or hydrolysis, or metabolism is
converted to the desired drug form). The invention includes within
its scope the pharmaceutically acceptable salts of the compounds of
the invention. Accordingly, the phrase "or a pharmaceutically
acceptable salt thereof" is implicit in the description of all
compounds described herein unless explicitly indicated to the
contrary.
[0037] In some embodiments, the compounds of the present invention
comprise prodrug compounds that are readily purified, formulated
and stable, and preferably may be used to provide highly soluble
drug substances, with fast onset and elimination for convenient use
in a clinical setting. In some embodiments, the compounds may be
produced as a zwitterion, which may be converted to a
pharmaceutically acceptable salt.
[0038] In some embodiments, the compounds of the present invention
preferably allow for fast cleavage in vivo of the prodrug moiety to
give the active pharmacophore, for example, 90% conversion may
occur in under 4 hours, preferably in less than 2 hours, and more
preferably in less than 1 hour. Prodrugs may have lesser, little or
no pharmacological activity themselves, however when administered
to a patient, may be converted into an active compound, for
example, by hydrolytic cleavage.
[0039] Diacid hemiesters of tryptamines, such as psilocin or other
hydroxytryptamines or isotryptamines, have not previously been
described. A prodrug strategy implemented by combining a diacid and
a 4-hydroxy-tryptamine or 5-hydroxy-tryptamine has likely not been
proposed, as a prodrug strategy is typically not necessary when the
drug is already soluble. Therefore, aspects of this diacid
hemiester prodrug strategy, as described herein, are believed to be
novel and inventive.
[0040] In one aspect, the present invention comprises a tryptamine
or isotryptamine compound of Formula (I) (II), (III) or (IV), or a
pharmaceutically acceptable salt or zwitterion thereof:
##STR00004##
[0041] wherein: [0042] (1) R1, R2, and R6 are each independently
selected from hydrogen, linear or branched alkyl, preferably
C.sub.1-5 alkyl, or arylalkyl; [0043] (2) R4 is [0044] a.
--X--CO2H, where X is a linear, cyclic or branched, saturated or
unsaturated carbon chain (preferably C.sub.1-5 alkyl), optionally
substituted with --OH or --CO2H, or an aromatic ring, optionally
substituted with alkyl or CO2H; or [0045] b.
##STR00005##
[0045] wherein R9 is X--CO2H, where X is as defined (2)(a) above
and R10 is hydrogen, linear or branched alkyl (preferably C.sub.1-5
alkyl) or arylalkyl, optionally substituted by --OH or --CO2H;
[0046] (3) R5 is hydrogen, linear or branched alkyl (preferably
C.sub.1-5 alkyl), arylalkyl, or O--R5', where R5' is hydrogen,
linear or branched alkyl (preferably C.sub.1-5 alkyl); and [0047]
(4) R7 and R8: [0048] a. are each independently selected from
hydrogen, linear or branched alkyl (preferably C.sub.1-5 alkyl), or
arylalkyl, or [0049] b. together form a non-aromatic N-containing
heterocycle, optionally substituted with alkyl, preferably where
the entire heterocyclic structure does not contain more than 12
atoms, for example, pyrrolidine (NC4 ring) piperidine (NC5 ring),
or morpholine (NC4O ring).
[0050] "Alkyl," by itself or as part of another substituent, refers
to a saturated branched, straight-chain or cyclic monovalent
hydrocarbon radical derived by the removal of one hydrogen atom
from a single carbon atom of a parent alkane. The term "alkyl"
includes cycloalkyl. Typical alkyl groups include, but are not
limited to, methyl; ethyl; propyls such as propan-1-yl, propan-2-yl
(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,
butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),
2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the
like. In some embodiments, an alkyl group comprises from 1 to 20
carbon atoms (C.sub.1-C.sub.20 alkyl). In other embodiments, an
alkyl group comprises from 1 to 10 carbon atoms (C.sub.1-C.sub.10
alkyl). In still other embodiments, an alkyl group comprises from 1
to 6 carbon atoms (C.sub.1-C.sub.6 alkyl) or 1 to 4 carbon atoms
(C.sub.1-C.sub.4). C.sub.1-C.sub.6 alkyl is also known as "lower
alkyl".
[0051] The term "arylalkyl" is a term of the art and as used herein
refers to an alkyl group, for example a C.sub.1-6 alkyl group,
substituted with an aryl group, where the residue is linked to the
main molecule through the alkyl group. An example of arylalkyl is
the benzyl group, that is, the phenyl-methyl group.
[0052] "Substituted," when used to modify a specified group or
radical, means that one or more hydrogen atoms of the specified
group or radical are each, independently of one another, replaced
with the same or different substituent(s). The term "substituted"
specifically envisions and allows for one or more substitutions
that are common in the art. However, it is generally understood by
those skilled in the art that the substituents should be selected
so as to not adversely affect the useful characteristics of the
compound or adversely interfere with its function.
[0053] The term "optionally substituted" denotes the presence or
absence of the substituent group(s). That is, it means "substituted
or unsubstituted". For example, optionally substituted alkyl
includes both unsubstituted alkyl and substituted alkyl. The
substituents used to substitute a specified group can be further
substituted, typically with one or more of the same or different
groups selected from the various groups specified above.
[0054] These prodrug structures are converted to an active
hydroxy-indole 5HT2A agonist after hydrolysis or metabolization of
the ester function R4-CO--.
[0055] In some non-limiting examples, the compounds comprise diacid
esters of tryptamine structures such as
4-hydroxy-N,N-dimethyltryptamine (psilocin or 4-HO-DMT),
4-hydroxy-N,N-diethyltryptamine (4-HO-DET),
4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT),
4-hydroxy-N-methyl-N-isopropyltryptamine (4-OH-MIPT),
5-hydroxy-N,N-dimethyltryptamine,
4-methyl-5-hydroxy-N,N-dimethyl)tryptamine and
4-hydroxy-5-methyl-N,N-dialkyltryptamine. In some embodiments, the
compounds include the 4- and 5-substituted hemisuccinates,
hemiglutarates and citrates of 4-hydroxy derivatives of
N,N-dimethyltryptamine (psilocin), N,N-diisopropyltryptamine
(4-HO-DiPT), or N-methyl-N-isopropyl-tryptamine (4-HO-MiPT).
[0056] In some embodiments, the compound comprises a compound of
Formula I, II, III or IV, wherein R1, R2, R5, R6, are each
hydrogen; X is a linear C1-4 alkyl; and R7 and R8 are each methyl.
In a preferred embodiment, the compound is a compound of Formula I
or II and X is C2 alkyl, thus forming a 4- or 5-hemisuccinate of
psilocin.
[0057] In some embodiments, the compound comprises a compound of
Formula I, II, III or IV, wherein R1, R2, R5, R6, are each
hydrogen; X is a linear C1-C4 alkyl chain; and R7 and R8 are each
isopropyl. In some embodiments, the compound is a compound of
Formula I or II, X is C2 alkyl, thus forming a hemisuccinate of 4-
or 5-hydroxy-diisopropyltryptamine. In some embodiments, the
compound is a compound of Formula I or II, X is a C2 alkene, thus
forming a hemifumarate of 4- or 5-hydroxy-diisopropyltryptamine. In
some embodiments, the compound is a compound of Formula I or II and
X is a C3 alkyl chain, thus forming a hemiglutarate of 4- or
5-hydroxy-diisopropyltryptamine.
[0058] In some embodiments, R7 and R8 are each chosen on the basis
of retaining or enhancing the compound's ability to induce a
psychedelic state. It is known that psychedelic activity of a
tryptamine is reduced if R7 or R8 become larger than C.sub.4.
However, such compounds are still within the scope of the present
invention if they are still 5HT2A agonists which can produce
beneficial therapeutic effect without a psychedelic state.
[0059] In some embodiments, compounds of the present invention are
diacid zwitterions. Thus, where X is a linear saturated alkyl, the
diacid may comprise a common linear alkyl .alpha.,.omega.-diacid,
including without limitation oxalic, malonic, succinic, glutaric
(pentanedioic), adipic (hexanedioic), pimelic (heptanedioic) and
suberic acid (octanedioic). In some embodiments, where X is a
linear alkene, the diacid may comprise an acid such as maleic,
fumaric, or glutaconic acid. In other embodiments, the diacid may
comprise a branched acid such as citraconic, mesaconic,
2,2-dimethylsuccinic acid; a substituted acid such as tartronic,
2-(2-hydroxyethyl)-malonic acid, a-hydroxyglutaric; citric acid; or
an aryl dioic acid such as phthalic acid, isophthalic and
p-phthalic, optionally with organic substituents on the aromatic
ring.
[0060] In some embodiments, the compound may be one of the
following:
##STR00006## ##STR00007## ##STR00008##
[0061] In some embodiments, the diacid-modified tryptamines or
isotryptamines exhibit product stability (oxidation and hydrolysis)
and can be readily synthesized and purified. The diacid-modified
tryptamines or isotryptamines preferably exhibit solubility in
biological matrices in excess of the drug absent the diacid
modification, making them superior drug candidates. As well, the
diacid-modified tryptamines preferably exhibit relatively quick
rates of hydrolysis in vivo, so as to convert the prodrug rapidly
to the active form of the drug. This can result in improved and
desirable pharmacokinetic properties with the prodrug, including
more reproducible pharmacokinetic profiles. These properties can
depend on the nature of the indole, the various substituents
attached to the indole and the nature of the diacid ester.
Stability and hydrolysis rates can be determined
experimentally.
[0062] In some embodiments, the compound may comprise a carbamate
ester of tryptamine, where R4 is (R9)(R10)N-- where R9 and R10
define a carbamate residue and are defined as above. In some
embodiments, the carbamate function comprises a zwitterionic
amino-functional mono or dicarboxylic acid which is linked via the
carbamate, including without limitation, zwitterionic compounds
such as: [0063] natural and unnatural neutral or anionic amino
acids, such as glycine, alanine, leucine, isoleucine, serine,
theonine, glutamic acid, aspartic acid; [0064] linear alkyl
am-amino acids, such as 3-aminoproprionic acid, 4-amino-butyric
acid; [0065] other branched amino acids and aromatic amino acids,
such as 4-amino-benzoic acid.
[0066] In some embodiments, the invention may comprise zwitterionic
compounds where R4 comprises more than one non-ester carboxy
function, such as the citrate derivative of a 4-hydroxytryptamine
(V) or a glutamic acid carbamate of a 4-hydroxytryptamine (VI):
##STR00009##
[0067] In some embodiments, the zwitterionic compound is preferably
stable at neutral or slightly acidic pH. Acylation of the hydroxy
functions of an indole can prevent oxidative reactions typical of
substituted phenolic compounds and indoles specifically (Manevski
2010 Drug Metabolism and Disposition and Napolitano 1989
Tetrahedron), while also allowing for solubility. In some
embodiments, the zwitterion has sufficient solubility (>30
mg/ml) in the range of neutral and pharmaceutically-acceptable pH
values (3-8) to achieve the required potency/efficacy.
Conventionally, non-prodrug pharmacophore tryptamines must be
placed and held in acidic medium to achieve good solubility and
stability. Acidic medium can preclude use as an injectable
formulation and can cause irritation.
[0068] Embodiments of the zwitterion may also provide for
convenient purification and isolation by recrystallization from
common pharmaceutical solvents, such as water, methanol, ethanol,
propanol or isopropanol or acetone, or mixtures thereof.
[0069] The diacid moiety is cleaved metabolically in vivo providing
the active ingredient in doses and with kinetics sufficient to
achieve the psychedelic state believed to be necessary for use in
the treatment of depressive conditions, such as
psychedelic-assisted psychotherapy. This is particularly
advantageous in designing convenient medications that produce a
psychedelic experience with a duration of less than 8 hours,
preferably less than 6 hours, and more preferably less than 4
hours. In this sense, the requirement of hydrolysis is an
additional step and therefore can reduce the speed of onset of
psychoactive properties when compared to injection of the free drug
(with no acylation of the hydroxy function). A slightly slower
speed of onset may be preferred in some cases, so as to avoid a
sudden onset which can cause anxiety, particularly in the
psychedelic-naive patient. Thus, in preferred embodiments, the
speed of onset may be controlled by the rate of metabolism which
can be a function of the ester and the target enzyme required for
hydrolysis.
[0070] In some embodiments, certain prodrug diacid moieties, for
example a succinate, may reduce the potential for abuse by
inhalation or snorting. As a zwitterion, it is not likely to be
absorbed rapidly through tissue devoid of esterase activity.
Furthermore, the zwitterion is likely not absorbed directly by a
passive mechanism into the brain. The rate of cleavage in the gut
may be slower and absorption slower versus the non-acylated version
and thus delay peak rates and the "rush" feeling that may be sought
by persons with the intent to abuse.
Methods of Preparation
[0071] The compounds described herein can be synthesized using the
methods described below, or similar methods, together with
synthetic methods known in the art of synthetic organic chemistry,
or by variations thereon as appreciated by those skilled in the
art. Preferred methods may include, but are not limited to, those
described below. The reactions are performed in a solvent or
solvent mixture appropriate to the reagents and materials employed
and suitable for the transformations being affected. It will be
understood by those skilled in the art of organic synthesis that
the functionality present on the molecule should be consistent with
the transformations proposed. This will sometimes require a
judgment, well within the skill of a skilled artisan, to modify the
order of the synthetic steps or to select one particular process
scheme over another in order to obtain a desired compound of the
invention.
[0072] Protection and de-protection in the processes below may be
carried out by procedures generally known in the art (see, for
example, Greene, T. W. et al, Protecting Groups in Organic
Synthesis, 3rd Edition, Wiley (1999)). General methods of organic
synthesis and functional group transformations are found in: Trost,
B. M. et al, eds., Comprehensive Organic Synthesis: Selectivity,
Strategy & Efficiency in Modern Organic Chemistry, 1.sup.st
Edition, Pergamon Press, New York, N.Y. (1991); March, J., Advanced
Organic Chemistry.
[0073] 4- and 5-hydroxy-tryptamines can be made by adapting methods
described in the art by Baumann et al. (Beilstein 2011, 7, 442)
Shulgin (The Vaults of Erowid: TiHKAL: The Chemical Story, by
Alexander and Ann Shulgin) and Fricke (Eur Chem J 2019, 25, 897),
as well as in U.S. Pat. No. 3,075,992 and Chen (JOC 1994,
3738).
[0074] For example, succinate prodrug compounds described herein
may be prepared using the synthetic scheme as outlined in Scheme 1
starting from the corresponding hydroxy-indole and the diacid
anhydride. The reaction conditions such as temperature, time,
choice of solvent and workup procedures are selected which may be
suitable for experimental conditions recognized by one skilled in
the art. Restrictions to the substituents that are compatible with
the reaction conditions will be readily apparent to one skilled in
the art and alternate or analogous methods must then be used.
##STR00010##
[0075] Other diacid prodrugs may be prepared using other diacid
anhydrides, as may be readily visualized by those skilled in the
art.
[0076] A glutarate prodrug compound may be made using glutaric
anhydride, using Scheme 2 below:
##STR00011##
[0077] One skilled in the art may readily select suitable
conditions and solvents. The reaction with the diacid anhydride may
take place in dichloromethane and triethylamine, or pyridine. In
some embodiments, the solvent contains a base with pKa greater than
4 but less than 9. If pyridine is used, the product precipitates
directly from the reaction mixture in pure form as the
zwitterion.
[0078] The solid zwitterion may be converted to a suitable salt,
for example, a hydrochloride salt, by addition of anhydrous HCl
(gas) in a suitable solvent or by triturating in anhydrous ether
HCl or dioxane HCl.
[0079] Synthesis of the diacid hemiester prodrugs may also be
produced using a variety of other methods and techniques well known
to those skilled in the art (Rautio, Nature Rev in Drug Discovery
2018, 17, 559), for example, using anhydride or doubly-activated
forms of the diacids, such as dichloride, di-N-hydroxysuccinimide
(using dicyclohexylcarbodiimide (DCC) or
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC),
N-hydroxysuccinimide and DMAP), di-imizadolide (using
carbonyldimidizole), or other activated form of the diacid with the
hydroxy form of the active heterocyclic species. When using the
diactivated forms, it is preferable to use a 2-25-fold excess of
the doubly activated diacid to avoid covalently binding 2
tryptamines to the diacid.
[0080] Similarly, one skilled in the art can apply these methods to
6- or 7-hydroxy isotryptamines.
Formulations and Compositions
[0081] The invention also provides pharmaceutically acceptable
compositions which comprise a therapeutically effective amount of
one or more of the compounds described herein, formulated together
with one or more pharmaceutically acceptable carriers (additives)
and/or diluents, and optionally, one or more additional therapeutic
agents. While it is possible for a compound described herein to be
administered alone, it is preferable to administer the compound as
a pharmaceutical composition.
[0082] The term "pharmaceutical composition" means a composition
comprising a compound of the invention in combination with at least
one additional pharmaceutically acceptable carrier. A
"pharmaceutically acceptable carrier" refers to media generally
accepted in the art for the delivery of biologically active agents
to animals, in particular, mammals, including, i.e., adjuvant,
excipient or vehicle, such as diluents, osmotic complement,
preserving agents, fillers, flow regulating agents, disintegrating
agents, wetting agents, emulsifying agents, suspending agents,
sweetening agents, flavoring agents, perfuming agents,
antibacterial agents, antifungal agents, lubricating agents,
polymers, solubilizing agents, stabilizers, antioxidants and
dispensing agents, depending on the nature of the mode of
administration and dosage forms. Each carrier must be "acceptable"
in the sense of being compatible with the other ingredients of the
formulation and not injurious to the patient.
[0083] As used herein, "oral" administration includes swallowing
for ingestion in the stomach or gut, and further includes lingual,
sublingual, buccal and oropharyngeal administration. The compounds
of this invention can be administered for any of the uses or
methods described herein by any suitable means, for example,
orally, such as tablets, capsules (each of which may include
sustained release or timed release formulations), pills, powders,
granules, elixirs, suspensions (including nano suspensions, micro
suspensions, spray-dried dispersions), syrups, and emulsions;
sublingually (e.g. as thin films, effervescent tablets or tablets
that dissolve spontaneously under the tongue); parenterally, such
as by subcutaneous, intravenous, intramuscular injection, or
infusion techniques (e.g., as sterile injectable aqueous or
non-aqueous solutions or suspensions); nasally, including
administration to the nasal membranes, such as by inhalation spray;
or rectally such as in the form of suppositories.
[0084] The dosage regimen for the compounds described herein will,
of course, vary depending upon known factors, such as the
pharmacokinetic and pharmacodynamic characteristics of the
particular agent and its mode and route of administration; the
species, age, sex, health, medical condition, and weight of the
recipient; the nature and extent of the symptoms; the kind of
concurrent treatment; the frequency of treatment; the route of
administration, the renal and hepatic function of the patient; and,
the effect desired. The selected dosage level may also depend on
the additional factors including the activity of the particular
compounds and pharmaceutical compositions described herein, whether
an ester, salt or amide substituent is of the compound is used, the
time of administration, the rate of excretion or metabolism of the
particular compound being employed, the rate and extent of
absorption, the duration of the treatment, other drugs that may be
administered to the patient, compounds and/or materials used in
combination with the particular compound employed and like factors
well known in the medical arts.
[0085] Generally, the dosage of the prodrug for a therapy session,
when used for the indicated effects, will range between about 0.001
to about 500 mg per dose, preferably between about 0.01 to about
200 mg per dose, and most preferably between about 0.1 to about 50
mg per dose, such as 10, 20, 30, 40, 50, 100 or 200 mg.
Intravenously, the most preferred doses will range from about 0.01
to about 10 mg/kg/minute during a constant rate infusion.
[0086] Compounds of this invention may be administered in a single
daily dose, or the total daily dosage may be administered in
multiple divided doses, such as two, three, or four times daily.
Alternatively, the doses may be provided on a weekly, biweekly, or
monthly basis. In a preferred embodiment, only one or two doses are
required for an anti-depressant effect than may extend for 1, 2, 3
or 6 months, or more.
[0087] For tablet dosage forms, depending on dose, the drug may
make up from 1 wt % to 80 wt % of the dosage form, more typically
from 5 wt % to 60 wt % of the dosage form. In addition to the drug,
tablets generally contain a disintegrant. Examples of disintegrants
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.
Generally, the disintegrant will comprise from 1 wt % to 25 wt %,
preferably from 5 wt % to 20 wt % of the dosage form.
[0088] 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.
[0089] Tablets may also optionally include surface active agents,
such as sodium lauryl sulfate and polysorbate 80, and glidants such
as silicon dioxide and talc. When present, surface active agents
are typically in amounts of from 0.2 wt % to 5 wt % of the tablet,
and glidants typically from 0.2 wt % to 1 wt % of the tablet.
[0090] Tablets also generally contain lubricants such as magnesium
stearate, calcium stearate, zinc stearate, sodium stearyl fumarate,
and mixtures of magnesium stearate with sodium lauryl sulphate.
Lubricants generally are present in amounts from 0.25 wt % to 10 wt
%, preferably from 0.5 wt % to 3 wt % of the tablet.
[0091] Other conventional ingredients include anti-oxidants,
colorants, flavoring agents, preservatives and taste masking
agents.
[0092] Exemplary tablets contain up to about 80 wt % drug, from
about 10 wt % to about 90 wt % binder, from about 0 wt % to about
85 wt % diluent, from about 2 wt % to about 10 wt % disintegrant,
and from about 0.25 wt % to about 10 wt % lubricant.
[0093] Tablet blends may be compressed directly or by roller to
form tablets. Tablet blends or portions of blends may alternatively
be wet, dry, or melt granulated, melt congealed, or extruded before
tableting. The final formulation may include one or more layers and
may be coated or uncoated; or encapsulated.
[0094] The formulation of tablets is discussed in detail in
"Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and
L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0 8247 6918 X),
the disclosure of which is incorporated herein by reference in its
entirety.
[0095] A typical capsule for oral administration contains at least
one of the compounds of the present invention (e.g. 25 mg), lactose
(e.g. 75 mg), and magnesium stearate (e.g. 15 mg). The mixture is
passed through a 60 mesh sieve and packed into a No. 1 gelatin
capsule.
[0096] Liquid formulations include suspensions, solutions, syrups
and elixirs. Such formulations may be used as fillers in soft or
hard capsules and typically include 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.
[0097] The compounds of the invention may also be administered
directly into the blood stream, into muscle, or into an internal
organ. Suitable means for parenteral administration include
intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial,
intramuscular and subcutaneous. Suitable devices for parenteral
administration include needle (including micro needle) injectors,
needle free injectors and infusion techniques.
[0098] Parenteral formulations are typically aqueous solutions
which may contain excipients such as salts, carbohydrates and pH
adjusting or buffering agents (preferably to a pH of from 3.0 and
7.0, preferably 4.0 to 6.0, and more preferably 4.5 to 5.5), 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, pyrogen free
water or pre-fabricated, ready-to-mix aqueous buffer. Osmotic
agents may be included to control tonicity.
[0099] The preparation of parenteral kits for reconstitution at
point-of-care under sterile conditions, for example, by
lyophilization, may readily be accomplished using standard
pharmaceutical techniques well known to those skilled in the
art.
[0100] A typical injectable preparation is produced by aseptically
placing at least one of the compounds of the present invention
(e.g. 25 mg) into a vial as a sterile filtered solution,
aseptically freeze-drying and sealing. For use, the contents of the
vial are mixed with e.g. 2 mL of physiological saline for
injection, optionally with an appropriate amount of osmotic
complements and pH adjusters to achieve a slightly acidic to
neutral pH (e.g. pH 4-7), to produce an injectable preparation with
low irritation but retain solubility and/or stability of the
prodrug.
[0101] Compounds of the invention may be combined with soluble
macromolecular entities, such as cyclodextrin and suitable
derivatives thereof or polyethylene glycol containing polymers, in
order to improve their solubility, dissolution rate, taste masking,
bioavailability and/or stability for use in any of the
aforementioned modes of administration.
[0102] Drug cyclodextrin complexes, for example, are found to be
generally useful for most dosage forms and administration routes.
Both inclusion and non inclusion complexes may be used. As an
alternative to direct complexation with the drug, the cyclodextrin
may be used as an auxiliary additive, i.e. as a carrier, diluent,
or solubilizer. Most commonly used for these purposes are alpha,
beta and gamma cyclodextrins, examples of which may be found in PCT
Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the
disclosures of which are incorporated herein by reference in their
entireties.
[0103] Regardless of the route of administration selected, the
compounds of the present invention, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions of the
present invention, are formulated into pharmaceutically acceptable
dosage forms by conventional methods known to those of skill in the
art. Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration.
[0104] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0105] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
[0106] As used herein, a "therapeutically effective amount" refers
to that amount of a compound being administered which will relieve
to some extent one or more of the symptoms of the disorder being
treated. In reference to the treatment of depression, a
therapeutically effective amount refers to that amount which has
the effect of reducing the severity of depression. Depression
severity may be assessed using well-known structured assessment
tools such as Structured Clinical Interview for DSM-5 (SCID-5) and
the GRID-Hamilton Depression Rating Scale (GRID-HAMD). A
therapeutically effective amount may be less than that required for
a psychedelic state.
[0107] An effective dosage can be administered in one or more
administrations. For the purposes of this invention, an effective
dosage of drug, compound, or pharmaceutical composition is an
amount sufficient to accomplish prophylactic or therapeutic
treatment either directly or indirectly. As is understood in the
clinical context, an effective dosage of drug, compound or
pharmaceutical composition may or may not be achieved in
conjunction with another therapy, drug, compound or pharmaceutical
composition.
Therapeutic Methods and Uses
[0108] Treatment with the novel prodrugs of the present invention
may substantially alleviate clinical or subclinical depression and
may avoid relapse, particularly if used in combination with
psychotherapy for the treatment of depression. It is known that
administration of an effective dose of psilocybin produced rapid
and large reductions in depressive symptoms, and many subjects
achieve remission through a four-week follow up (Davis et. al.)
Without restriction to a theory, it is believed that the
psychedelic state is associated with the beneficial effects,
however, some compounds which are 5HT2A agonists may provide the
desired therapeutic effect without the psychedelic state. One
aspect of the invention comprises prodrugs of those 5HT2A agonists
which do provide a beneficial therapeutic state.
[0109] In general, the present invention includes the use of a
compound of the present invention herein, to treat any disease or
disorder which may be alleviated by a 5HT2A agonist, or the use of
a compound of the present invention herein to manufacture a
medicament to treat any disease or disorder which may be alleviated
by a 5HT2A agonist, or a method of treating any disease or disorder
which may be alleviated by a 5HT2A agonist.
[0110] In some embodiments, the invention may comprise the use of
the compounds of the present invention to treat mental disorders.
In some embodiments, the invention may comprise the use of the
compounds of the present invention to treat depression, and
particularly drug resistant depression. Other conditions that may
be treated include: anxiety disorders, including anxiety in
advanced stage illness e.g. cancer as well as generalized anxiety
disorder, depression including major depressive disorder,
postpartum depression, cluster headaches, obsessive compulsive
disorder, personality disorders including conduct disorder, drug
disorders including: alcohol dependence, nicotine dependence,
opioid dependence, cocaine dependence and other addictions
including gambling disorder, eating disorder and body dysmorphic
disorder, chronic pain, or chronic fatigue.
[0111] In some embodiments, the invention may comprise a method of
treating mental disorders comprising administering to a subject in
need thereof a therapeutically effective amount of a compound of
the present invention. In one embodiment, there is provided a
method of treating depression comprising administering to a subject
in need thereof therapeutically effective amount of a compound of
the present invention. The depression may be drug-resistant
depression or major depressive disorder.
[0112] For example, a patient diagnosed with depression may be
screened prior to treatment, and then prepared for a dosing session
by a trained psychotherapist. Within a dosing session, a compound
of the present invention may be administered by injection of a
sterile solution at a rate of 0.01-0.3 mg/kg to the patient. The
patient is preferably seated for the duration of the session while
being blindfolded. For safety, a trained health care professional
may monitor the patient throughout the dosing session, which may
last up to 12 hours. In some cases, music may be played for the
patient. When the health care professional can determine that the
drug substance has cleared, the psychotherapist may assist the
patient with any questions relating to the psychedelic experience,
and then the patient may be discharged.
[0113] To further alleviate any anxiety that may occur relative to
therapy, the physician may prefer to divide the therapeutic dose
and thereby reduce the initial onset of psychoactivity before
applying the full complement of the dosage to achieve the full
effect.
[0114] In some embodiments, treatment with a compound of the
present invention may be combined with concomitant treatment with
another anti-depressant drugs, either concurrently or
consecutively. In preferred embodiments, treatment with a compound
of the present invention is combined with psychotherapy, which may
be applied prior to or after treatment. If prior to, the session
may focus the patient on the intent of treatment. If after,
psychotherapy is preferably performed within 48 hours of the dosing
session to help the patient integrate any feelings, emotions,
visions or thoughts that may have occurred during the session, as
well as to allow the psychotherapist may offer advice on how best
to change thinking or behavior patterns so as to improve
anti-depression outcomes. Psychotherapy may continue as needed
after the dosing session, for example, up to an additional 3
months, to help the patient integrate any experiences or learnings
that occurred to the patient during the dosing session.
EXAMPLES
[0115] The present invention may be described with reference to the
following Examples. These Examples are provided for the purpose of
illustration only. All terms, names, abbreviations or acronyms are
those commonly understood by those skilled in the art. Compounds
shown in their zwitterionic form may readily be visualized in their
neutral form by one skilled in the art, and vice versa.
[0116] Where a compound is referred to as a glutaroyl or succinoyl,
or hemiglutarate or hemisuccinate, it is understood to be same as
the succinate or glutarate. For example, the 4-hemiglutarate of
psilocin is the same as psilocin-4-glutarate or N,N
dimethyltryptamine-4-glutarate. Similarly, the 4-hemiglutarate of
4-OH-DiPT is the same as N,N diisopropyltryptamine-4-glutarate.
Example 1. 4-Hemisuccinate of Psilocin
[0117] 4-Hydroxyindoles were prepared using methods or modestly
adapted from methods described in the literature, such as in Kargbo
2020 ACS Omega): Accordingly, 4-acetoxyindole was reacted with
oxalyl chloride in methyl-t-butyl ether (MTBE) and the resulting
intermediate was quenched with dimethylamine. The
indole-oxalyl-dimethylamide was reduced with Lithium Aluminum
Hydride (LAH) in tetrahydrofuran (THF) to give the
4-acetoxy-3-(N,N-dimethylaminoethyl)indole, which was deprotected
using aqueous base to give 4-hydroxy-dimethyltryptamine
(psilocin).
[0118] The 4-hydroxytryptamine was reacted with an excess of
succinic anhydride in dichloromethane (DCM) containing
triethylamine, and catalyzed by N,N-dimethylaminopyridine, to give
psilocin-4-succinate. A precipitate was formed which was recovered
after decantation and trituration with DCM. The solid was acidified
in aqueous HCl, purified by chromatography and recovered after
evaporation of solvents. The structure was confirmed by NMR. Purity
was determined by HPLC.
Example 2. 4-Hemisuccinate of 4-Hydroxy-Diisopropyltryptamine
(4-OH-DiPT)
[0119] 4-Acetoxyindole was reacted with oxalyl chloride in MTBE and
the resulting intermediate was quenched with diisopropylamine. The
resulting oxalyl-amide was reduced with Lithium Aluminum Hydride
(LAH) in THF to give the
4-acetoxy-3-(N,N-diisopropylaminoethyl)indole, which was in turn
deprotected with aqueous base to give
4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. In a 250 mL
round-bottom flask containing a stir bar was added 4-OH-DiPT (5.8
g, 22.3 mmol, 1 eq.), dissolved in dichloromethane (28 mL,
5.times.V) and stirred at room temperature. Then succinic anhydride
(1.3 eq.) was added slowly to the stirring solution, and the
resulting suspension was stirred overnight at room temperature. The
precipitate formed in the reaction was recovered by decantation and
trituration with DCM. The solid was acidified in aqueous HCl,
purified by chromatography and recovered after evaporation of
solvents. The structure was confirmed by NMR. Purity was determined
by HPLC.
Example 3. 4-Hemifumarate of 4-OH-DiPT
[0120] 4-Benzyloxyindole is reacted with oxalyl chloride in
diethylether in the presence of a Friedel-Kraft catalyst and the
resulting intermediate is quenched with di-isopropylamine. The
resulting oxalyl-amide is reduced with Lithium Aluminum Hydride
(LAH) in THF to give the
4-benzyloxy-3-(N,N-diisopropylaminoethyl)indole, which is in turn
deprotected using a H2 and Pd/C to give
4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. This substance is
reacted with an excess of a diactivated fumaric acid
(N-hydroxysuccinimide) in dichloromethane, followed by quenching
any unreacted N-hydroxysuccinimide ester with aqueous acid, leaving
4-fumaroyl-3-(N,N-diisopropylaminoethyl)indole.
Example 4. 5-Hemisuccinate of
5-Hydroxy-4-Methyl-Dimethyltryptamine
[0121] 4-methyl-5-hydroxyindole (1) is reacted with benzyl chloride
in the presence of K.sub.2CO.sub.3 in ACN to give
5-benzyloxy-4-methyl-indole, which is then reacted with oxalyl
chloride in diethylether in the presence of a Friedel-Kraft
catalyst and the resulting intermediate is quenched with
di-methylamine. The resulting oxalyl-amide is reduced with Lithium
Aluminum Hydride (LAH) in THF to give the
4-methyl-5-benzyloxy-3-(N,N-dimethylaminoethyl)indole, which is in
turn deprotected using a H2 and Pd/C to give
4-methyl-5-hydroxy-3-(N,N-dimethylaminoethyl)indole. This substance
is reacted with succinic anhydride in dichloromethane, catalyzed by
N,N-dimethylamino-pyridine to give
4-methyl-5-succinoyl-3-(N,N-dimethylaminoethyl)indole.
Example 5. N,N Dimethylisotryptamine-6-Succinate
[0122] Following methods outlined in Glennon (JMedChem 1984),
6-O-Benzyl-dimethylisotryptamine is prepared by N-alkylation of
5-BzO-indole using NaH. The benzyl group is removed by catalytic
hydrogenation using Pd/C/H2 to give the HO-- function which is
succinylated in a subsequent step using succinic anhydride,
resulting in the named species.
Example 6. N,N Diisopropyltryptamine-4-Glutarate
[0123] In an oven-dried 50 mL round bottom flask containing 1.2 mL
of anhydrous DCM was added glutaric anhydride (0.205 g, 1.8 mmol,
1.8 eq.) and the suspension was stirred under Ar. A solution of
4-OH-DiPT (0.26 g, 1 mmol, 1 eq.) in 1.5 mL anhydrous DCM was
added, followed by addition of 4-dimethylaminopyridine (DMAP) (37
mg, 0.3 mmol, 0.3 eq.) and trimethylamine (0.18 mL, 1.3 eq.) and
the resulting suspension was stirred overnight at r.t. under
Ar.
[0124] The mixture was decanted, and the solid was triturated with
anhydrous DCM (3 mL) with a few drops of anhydrous MeCN. The
suspension was acidified with 1M HCl (.about.1.1 eq.) and
concentrated to dryness. The crude product was purified by C18
reverse-phase column chromatography (40 g, A: 0.05% HCl in
H.sub.2O, B: 0.05% HCl in MeCN).
[0125] The structure was confirmed by NMR. Purity was determined by
HPLC (>97%). The solid was resuspended in 1M HCl-dioxane to form
the HCl salt which was filtered, washed with ether and dried. Yield
(>95%, purity >95%; DSC endotherm 174C). The solid could be
dissolved in water up to 50 mg/ml and lyophilized to form a white
"cake".
Example 7. Hemiester of 3,3-Dimethylglutaric Acid and
4-Hydroxydiisopropyltryptamine
[0126] 4-Hydroxy-3-(N,N-diisopropylaminoethyl)indole was reacted
with 3,3-dimethyl glutaric anhydride in pyridine to give
4-succinoyl-3-(N,N-diisopropylaminoethyl)indole with
stoichiometries and parameters mentioned in example 6. A
precipitate formed in the reaction was recovered by decantation and
trituration in THF. The solid was washed with DCM and dried. The
structure was confirmed by NMR.
Example 8. Psilocin-4-Glutarate
[0127] 4-Hydroxydimethyltryptamine (psilocin) was reacted with an
excess of glutaric anhydride in dichloromethane (DCM) containing
triethylamine to give psilocin-4-glutarate. In another example, the
reaction occurred in pyridine. In either case, a precipitate was
formed which was recovered after decantation and trituration with
THF. The solid was washed with DCM and then dried. The structure
was confirmed by NMR.
[0128] The reaction product was suspended in 1M HCl-ether to yield
the corresponding HCl salt form of the product which was recovered
by filtration in high yield and purity.
Example 9. HCl Salt of N,N Diisopropyltryptamine-4-Glutarate
[0129] In a 3-neck 1 L round bottom flask under argon was added
4-OH-DiPT (31.8 g, 0.122 mol, 1 eq.), dissolved in 160 mL of
anhydrous pyridine (160 mL). After stirring for 15 mins, glutaric
anhydride (18.1 g, 0.158 mol, 1.3 eq.) was added in portions. The
resulting suspension was stirred at r.t. overnight.
[0130] Anhydrous DCM (160 mL) was added to the suspension and it
was cooled to 0.degree. C. with for 2 h. The solid was filtered and
washed with 60 mL of cold anhydrous DCM and dried overnight.
[0131] The dried solid was triturated with 160 mL of anhydrous DCM,
followed by 160 mL of anhydrous THF, and then 160 mL of anhydrous
DCM at 0.degree. C. After drying, 33.0 g was obtained with 72%
yield and 98.1% purity by HPLC. The structure of the zwitterion was
confirmed by 1H-NMR (DMSO-d6) and MS [M+H]+=375.2.
[0132] In a 100 mL round bottom flask was charged 18 mL of
anhydrous diethyl ether HCl solution (4M in dioxane, 2.4 mL, 9.6
mmol, 1.2 eq.) was added slowly and stirred at r.t. for 10 mins.
The zwitterion from above (3.0 g, 8.0 mmol) was added in portions
and the resulting suspension was stirred for 2 h. The solid was
filtered off and washed with 6 mL of Et.sub.2O. The solid was dried
yielding 3.16 g of the corresponding hemiester tryptamine HCl salt
(96% yield, 99.0% purity by HPLC,[M+H].sup.+=375.1).
Example 10. Hemiglutarate of Psilocin
[0133] Psilocin is reacted with 1.2 equivalents glutaric anhydride
in warm THF to give psilocin-4-glutarate which precipitates from
the reaction mixture according to methods above. The precipitate is
recovered by filtration, is washed with cold 1:1 DCM/THF and
dried.
Example 11. 4-Hemimalonate of 4-OH-DiPT
[0134] 4-OH-DiPT was dissolved in pyridine and coupled with an
excess of malonic acid and 1.2 equivalents of DCC at room
temperature for 18 h. The reaction mixture was passed through a
flash column (5 parts diatomaceous earth), and the first fractions
containing the prodrug compound were isolated by precipitation and
washing. Yield approx. 50%. Purity >95% by HPLC.
Example 12. Comparative Rates of Prodrug Hydrolysis in Serum
[0135] Pooled mixed gender human plasma (2 ml), mouse plasma, rat
plasma and dog plasma were equilibrated at 37.degree. C. The
compound of example 9 was added so as to achieve a concentration of
1.0 ug/mL. Aliquots (50 uL) of the mixture were withdrawn at timed
intervals (0, 0.004, 0.5, 1, 2 and 4 hours) and quenched with 200
uL of methanol/acetonitrile (1:1). The samples were vortexed and
stored at -80.degree. C. until analysis. Assays were done in
triplicate. Control samples were done in phosphate buffered saline
(PBS, pH 7.4) and simulated gastric fluid (SGF, pH 2). Analysis of
samples as performed by HPLC-MS to determine the amounts of prodrug
and drug in each sample tested. Table 1 provides the mean
concentrations of prodrug remaining at different time points of the
experiment. The experiment demonstrates the rapid enzymatic
cleavage of the prodrug in plasma versus slow non-enzymatic
hydrolysis in relevant biological media.
TABLE-US-00001 TABLE 1 Percentage of remaining prodrug, N,N
diisopropyltryptamine-4-glutarate Time SGF PBS (h) Mouse Rat Dog
Human (pH 2) (pH 7) 0 100 100 100 100 100 100 0.004 0 0 100 100 100
-- 0.5 0 0 87 3.0 100 -- 1 0 0 79 0.23 100 -- 2 0 0 64 0 -- -- 4 0
0 39 0 101 93
Example 13. Pharmacokinetics in Rats
[0136] The compound from example 9 was administered to rats by
injection (intravenous and subcutaneous) with a sterile solution (2
mg/ml) at a rate of 1.4-2 mg/kg. Blood samples were taken at 15,
30, 45, 60, 120, 240 min and 360 min and analyzed by LCMS for drug
and prodrug. PK profile for the prodrug and active species were
obtained and relative bioavailability was determined for each of
the routes of administration.
[0137] PK-PD type curves were generated to demonstrate the activity
of the drug (FIGS. 1 and 2). In rodent, prodrug was not observed,
as it was rapidly converted to the active form. Relevant PK
parameters for i.v. and s.c administrations 4-HO-DiPT were
determined and are shown in Table 2:
TABLE-US-00002 TABLE 2 PK parameters (% coefficient of variation in
parentheses) for 4-HO-DiPT after subcutaneous administration of N,N
diisopropyltryptamine-4-glutarate (2 mg/kg). Route Cmax Tmax t1/2
AUC Bioavailability admin (ng/ml) (h) (h) h*ng/ml (%) i.v. 305
(9.8) n/a 0.601 (3.3) 146 (3.1) 97 (3.1)* s.c. 150 (30) 1.0 (0)
0.67 (0.1) 203 (21) n/a Based on PK parameters from the i.v.
administration of 4-HO-DIPT
[0138] In some cases, Head Twitch Response (HTR) or Wet Dog Shakes
(WDS) were recorded by visual observation and counting of the
relevant muscle twitches. In general, the intensity of the HTR was
proportional to the plasma concentration of 4-HO-DIPT with the
highest intensity of head twitch occurring at the Tmax of the PK
profile.
[0139] FIG. 1 show plasma concentration of 4-HO-DiPT (ng/ml) and
versus time after subcutaneous administration of N,N
diisopropyltryptamine-4-glutarate at a rate of 2 mg/kg.
[0140] Pharmacokinetics of 1.34 mg/ml 4-HO-DiPT HCl administered by
intravenous or subcutaneous injection were performed in parallel
under identical conditions as above. FIG. 2 shows show plasma
concentration of 4-HO-DiPT (ng/ml) versus time for the different
administrations. Immediately obvious is the increased variability
with the active species when administered s.c. and intravenous
administrations. PK parameters are shown in Table 3.
TABLE-US-00003 TABLE 3 PK parameters (% coefficient variation in
parentheses) for 4-HO-DiPT after subcutaneous administration of N,N
diisopropyltryptamine-4-glutarate (2 mg/kg). Route Cmax, Tmax,
t1/2, AUC, Bioavailability, admin ng/ml h h h*ng/ml % i.v. 458 (12)
n/a 0.74 (22) 152 (22) 100% s.c. 103 (21) 0.61 (77) 0.67 (15) 134
(48) 89%
Example 17. Pharmacokinetics in Human Volunteers
[0141] The compound from example 6 (N,N
diisopropyltryptamine-4-glutarate) is administered to human
volunteers by subcutaneous injection of a sterile solution (1
mg/ml) at a dosage of 0.1-0.6 mg/kg. Blood samples are taken at 5,
15, 30, 45, 60, 120, 240 and 480 min and 24 h. Samples are analyzed
by LCMS for drug and prodrug. Subjective effects are measured using
standardized questionnaires. The PK analysis shows a maximal plasma
concentration (CMax) at approx. 45 min after the injection.
Subjective effects show an intensity of psychoactivity that
correlates with blood levels.
[0142] The compound from example 2 (4-hemisuccinate of 4-OH-DiPT)
is administered to human volunteers by oral ingestion of a tablet
containing 50 mg of the prodrug. Blood samples are taken at 5, 15,
30, 45, 60, 120, 240 and 480 min and 24 h. Samples are analyzed by
LCMS for drug and prodrug. Subjective effects are measured using
standardized questionnaires. The PK analysis shows a CMax at
approx. 90 min for the injection. Subjective effects show an
intensity of psychoactivity that correlates with blood levels.
Example 18. Use in Treatment
[0143] The compound of example 6 (N,N
diisopropyltryptamine-4-glutarate) is administered by i.m. or s.c.
injection (ca. 25 mg; 0.4-0.5 mg/kg) to a human patient suffering
depression, or by oral administration (ca. 50-200 mg; 0.8-3.2
mg/kg) with tablets. In another example of use, the compound of
example 6 (4-hemiglutarate of 4-OH-DiPT) is similarly administered.
Prior to the dosing session, the patient is qualified for the
experience by measurement of depression scores, screened for
exclusions (e.g. history of psychoses, unfavorable heart condition,
pregnancy) and finally, the patient is encouraged to formulate an
intent for the dosing session. Dosing is performed in a quiet
clinic setting with the patient resting comfortably in an inclined,
but unrestrained, position to avoid falls. The patients' eyes are
covered, and music is applied. The drug is administered. After 4 h,
the patient reports no longer feeling the effects of the drug and
is asked to sit up while under supervision. Feeling normal, the
patient is allowed to stand (supervised) and feeling in control, is
allowed to move around. One hour later, the patient is discharged.
Later by 24 h, the patient returns to the clinic to meet with a
psychotherapist to recount the session. The patient records a
depression score via questionnaire and is again discharged. At
regular intervals the patient is consulted for recurrence of
depressive symptoms.
Example 19. Injectable Formulation Kit
[0144] A vial is prepared with 25 mg of compound in Example 6 as a
hydrochloride salt (sterilized powder or lyophilizate). In a
separate vial is placed 1 ml of a sterile filtered solution
containing 70 mM Na.sub.2HPO.sub.4. The final pH of the solution is
4.0-5.0. These 2 components constitute a kit for reconstitution of
a drug product for subcutaneous injection at point of care.
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Definitions and Interpretation
[0170] The description of the present invention has been presented
for purposes of illustration and description, but it is not
intended to be exhaustive or limited to the invention in the form
disclosed. Many modifications and variations will be apparent to
those of ordinary skill in the art without departing from the scope
and spirit of the invention. Embodiments were chosen and described
in order to best explain the principles of the invention and the
practical application, and to enable others of ordinary skill in
the art to understand the invention for various embodiments with
various modifications as are suited to the particular use
contemplated. To the extent that the following description is of a
specific embodiment or a particular use of the invention, it is
intended to be illustrative only, and not limiting of the claimed
invention.
[0171] The corresponding structures, materials, acts, and
equivalents of all means or steps plus function elements in the
claims appended to this specification are intended to include any
structure, material, or act for performing the function in
combination with other claimed elements as specifically
claimed.
[0172] References in the specification to "one embodiment", "an
embodiment", etc., indicate that the embodiment described may
include a particular aspect, feature, structure, or characteristic,
but not every embodiment necessarily includes that aspect, feature,
structure, or characteristic. Moreover, such phrases may, but do
not necessarily, refer to the same embodiment referred to in other
portions of the specification. Further, when a particular aspect,
feature, structure, or characteristic is described in connection
with an embodiment, it is within the knowledge of one skilled in
the art to combine, affect or connect such aspect, feature,
structure, or characteristic with other embodiments, whether or not
such connection or combination is explicitly described. In other
words, any element or feature may be combined with any other
element or feature in different embodiments, unless there is an
obvious or inherent incompatibility between the two, or it is
specifically excluded.
[0173] It is further noted that the claims may be drafted to
exclude any optional element. As such, this statement is intended
to serve as antecedent basis for the use of exclusive terminology,
such as "solely," "only," and the like, in connection with the
recitation of claim elements or use of a "negative" limitation. The
terms "preferably," "preferred," "prefer," "optionally," "may," and
similar terms are used to indicate that an element, item, condition
or step being referred to is an optional (not required) feature of
the invention.
[0174] The singular forms "a," "an," and "the" include the plural
reference unless the context clearly dictates otherwise. The term
"and/or" means any one of the items, any combination of the items,
or all of the items with which this term is associated.
[0175] As will be understood by one skilled in the art, for any and
all purposes, particularly in terms of providing a written
description, all ranges recited herein also encompass any and all
possible sub-ranges and combinations of sub-ranges thereof, as well
as the individual values making up the range, particularly integer
values. A recited range (e.g., weight percents or carbon groups)
includes each specific value, integer, decimal, or identity within
the range. Any listed range can be easily recognized as
sufficiently describing and enabling the same range being broken
down into at least equal halves, thirds, quarters, fifths, or
tenths. As a non-limiting example, each range discussed herein can
be readily broken down into a lower third, middle third and upper
third, etc.
[0176] As will also be understood by one skilled in the art, all
ranges described herein, and all language such as "between", "up
to", "at least", "greater than", "less than", "more than", "or
more", and the like, include the number(s) recited and such terms
refer to ranges that can be subsequently broken down into
sub-ranges as discussed above.
* * * * *
References