Note: Descriptions are shown in the official language in which they were submitted.
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N-SUBSTITUTED NOM BOGAINE PRODRUGS
Field of the Invention
[0001] This invention relates generally to prodrugs of noribogaine or
noribogaine
derivatives. This invention also relates to pharmaceutical compositions
comprising the
prodrugs of noribogaine or noribogaine derivatives as well as methods of
treating pain,
addiction and/or stress using such compounds and/or pharmaceutical
compositions.
State of the Art
[0002] Noribogaine is a metabolite of ibogaine and is sometimes referred to as
12-
hydroxyibogamine. US Patent No. 2,813,873 claims noribogaine albeit as "12-0-
demethylibogaine" while providing an incorrect structural formula for
ibogaine. The
structure of noribogaine has now been thoroughly evaluated and is found to
combine the
features of tryptamine, tetrahydrohavaine and indolazepines. Noribogaine can
be depicted by
the following formula:
HO r.
[0003] Noribogaine and its pharmaceutically acceptable salts have recently
received
significant attention as a non-addictive alkaloid useful in treating drug
dependency (U.S.
Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737).
100041 Certain noribogaine derivatives and their uses are described in, for
example, U.S.
Patent No. 8,362,007 which is incorporated herein by reference in its
entirety.
[0005] Noribogaine is typically administered orally or intravenously and
becomes
systemically available to the treated patient. While noribogaine
allosterically binds tightly to
the u and K receptors, the systemic circulation of noribogaine increases the
likelihood of
undesirable side effects while the availability of noribogaine is limited by
the efficiency of its
passage across the blood brain barrier.
[0006] Accordingly, there is a need to reduce the systemic circulation of
noribogaine while
maintaining or increasing its concentration in the brain particularly at the g
and x receptors.
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Summary of the Invention
(00071 This invention relates, in part, to a class of noribogaine prodrugs
which, after
administration, release noribogaine in vivo. The prodrug moiety is selected to
be readily
cleavable either by a cleavable linking arm or by cleavage of the prodrug
entity that binds to
noribogaine such that noribogaine is generated in vivo. In one preferred
embodiment, the
prodrug moiety is selected to facilitate binding to the and/or ic receptors in
the brain either
by facilitating passage across the blood brain barrier or by targeting brain
receptors other than
the fa and/or K receptors. This invention also relates, in part, to a class of
prodrugs of
noribogaine derivatives.
[00081 Accordingly, in one embodiment, this invention is directed to compounds
which are
represented by Formula I or II below:
Rio Rii
110 N\
Li
R1
N
L.
Ri
wherein L is selected from the group consisting of a covalent bond and a
cleavable
linker group;
R is selected from the group consisting of hydrogen, a hydrolysable group
selected
from the group consisting of-C(0)R2, -C(0)NR3R4 and -C(0)0R5, where R2 is
selected from
the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl,
alkynyl and substituted alkynyl,
R3 and R4 are independently selected from the group consisting of hydrogen,
alkyl,
substituted alkyl, alkenyl. substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic,
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
heteroaryl, substituted
heteroaryl, heterocyclic and substituted heterocyclic provided that R is not a
saccharide or an
oligosaccharide;
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RI is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl.
cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic
provided that RI is not a saccharide or an oligosacchatide;
RI is hydrogen or ¨OR;
RI I is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkoxy,
substituted alkoxy, (CH2)m0C(0)alkyl, (CH2)m0H, (CH2)mOalkyl, C112-X-CH3 or
(CH2).0(CH2)p0(C1-12),10(CH2),CII3, where each of m, p and q is I, 2 or 3; and
r is 0. 1 or 2,
X is 0 or NH;
or a pharmaceutically acceptable salt and/or solvate thereof,
provided that when L is a covalent bond and RI is hydrogen, then either R is
selected
from the group consisting of -C(0)NR3R4 and -C(0)0R5 or R'1 is not alkyl; and
further provided that when R is hydrogen or -C(0)R2 and L is a covalent bond,
then
RI is not hydrogen.
100091 In one embodiment, R11 is selected from the group consisting of
hydrogen, C1-C3
alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy and substituted C1-C3 alkoxy.
100101 In one embodiment, R11 is H. In one embodiment, R" is C1-C3 alkyl, such
as ethyl.
In one embodiment, is CH2CH2OH. In one embodiment, R" is CH2CH2OCH3. In one
embodiment, R" is CH2CH2OCH2Ph. Ph represents a phenyl group. In one
embodiment,
R'1 is CH2CH20C(0)alkyl, such as CH2CH20C(0)(CH2)10CH3. In one embodiment, R"
is
CH2C1-120(CH2)p0(CH2)0(CH2),CH3.
100111 In one embodiment, R11 is C1-C3 alkyl optionally substituted with YII,
YRI2,
YC(0)R.12, C(0)YR12, C(0)NH2, C(0)NHR12, C(0)NR12R13, NH2, NHR12, NR12R13,
NHC(0)R12, or NR12C(0)R13, where Y is 0 or S, R12 and R13 are independently C1-
C3 alkyl.
100121 In one embodiment, R11 is C1-C3 alkoxy optionally substituted with YfI,
YRI2,
YC(0)R12, C(0)YR12, C(0)NH2, C(0)NHR12, C(0)NR12R13, NH2, NHRI2, NR12R13,
NFIC(0)R12, or NRI2C(0)R13, where Y is 0 or S, R12 and R13 are independently
C1-C3 alkyl.
100131 In one embodiment, R is hydrogen and L is a cleavable group.
100141 In one embodiment, R is hydrogen, L is a -C(0)-, -C(0)0-, or -C(0)NH-,
and RI is
substituted alkyl. Preferably RI is alkyl substituted with -NR6R7 where R6 and
R7 are
independently selected from the group consisting of hydrogen, alkyl, alkenyl,
substituted
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alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic.
[00151 In one embodiment, R is selected from the group consisting of -
C(0)NR3R4 and
-C(0)01t5 and RI is hydrogen.
[00161 In one embodiment, provided is a compound of Formula H which is
selected from
those as set forth in Table 1 below or a pharmaceutically acceptable salt
and/or solvate
thereof:
Table I
, _____________________________________________________________________
Compound It L RI 1
No. :
_______________________________________________ ¨ .................
1 -q0)CH2CH2N(CH3)2 -C(0) -CH2CH2N(CII3)2 -I I
2 H -C(0) -CH2CFI2N(CH3)2 I
3 j..... -C(0 )CH2CH2N(C, F13)2 bond H
4 i= 4:::-(b)CH2CH2N(CH3)2 _____________ bond -C1-12N(C1-13k
H bond -C11.2N CI13)2
6 -C(0)NHCH2CH2N(CH3)2 -C(0) II
7 -C(0)NHCH2CH2N(CH3)2 -C(0)NH 1 ___________ -
CII2CH2N(C1113)2
,---- 8 H -C(0)NH I -CH2CH2N(CH3)2
9 -COINHCH2CH2N(CH3)2 -C(0)NH H
-C(0)NHCII2CH2N(CH3)2 I -C(0) -CH3
,
11
\....0 -C(0) -CH2CH2N(CH3)2
______________________________________________________________________ :
12 -C(0)NIICH2CH2N(C113)2 -C(0) -CH2CH2N(CH3)2
13 -C(0)NHCH2CH2N(CH3)2 -C(0)0 -CI-13
14 -C(0)NHCH2CH2N(CH3)2 -C(0)0 -CH2CH2N(C143)2
H -C(0)0 -CH2CH2N(CH3)2
16 ----e-(-656-13 -C(0)NH -CH2CH2N(CF13)2
17 -C(2)CH3 -C(0)NH H
18 -C(0)C113 -C(0)NH -CH3
19 -C(0)00-13 -C(0)NH -CH2C112N(CH3)2
_
-C(0)0(21:13 -C(0)NH H ________ 1
I
21 -C(0)NHCH2CH2N(CH3)2 -C(0)NH '
i---1---\\O
22 H i -C(0)NH
.7---N\ 7
23 -C(0)NHCH2CH2N(CH02 -C(0)NH MOM
24 -C(0)NHCH2CH2N(CH3)2 -C(0) /-----\
7--N\ /0
-... ___________________________________________________
H -C(0) j ¨\\
I . , 7¨CH3
7----
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, __________________________
Compound R L R.1
No.
26 -C(0)NFICH2C112N(CH3)2 -C(0) /--\
¨N 1N-CH3
\.....
27 -C(0)NUICH2CH2N(CH3)2 -C(0)0 ¨7\
______________________________________________________________ .,_./
, 28 -C(0)NHCH3 -C(.0)
i ¨N N-C1-13
29 H -C(0)
[. ..... --,-- _____________________________________ ¨N N-CH3
30 0 r--\ -C(0)NUI -CH2CH2N(CF13)2
µ¨N N-CH3
/ \____/
31 -C(0)CH3, -C(0)0 , -CH3
32 0 7---\ -C(0)0 -CH2CH3
)\¨N N-CH3
33 -C(0)CH3 , -P(0)(011)-0- H --,
34 -C(0)CH3 I -P(0)(OCH3)-0- -CH2CH2N(CH3)2
35 H ...... ..1 -P(9)(OH)-0- H
36 H i -P(0)(OCH3)-0- -CH3
+-
37 -C(0)NHCH2CH2N(C1-13)2 1 -P(0)(OCH3)-
0- -CII3
I 38 H __________________ -C(0)NH -CH3
1 ___ 39 H -C(0)0 -C112C1-13
1"---\
I 40 H -C(0) -N N-CH3
I 0
41 /---,,
\\
)¨N N-CH -P(0)(00-13)-0- -CH3
, \....../ !
...................................................................... a
[00171 In one embodiment, the compound of Formula I is a compound wherein R1
is H. L
and R1 are as defined in Table I above, and R11 is C1-C3 alkyl optionally
substituted with YH,
YR12, YC(0)R.12, C(0)YR12, C(0)N112, C(0)NHR12, C(0)NRI2R13, NH2, NHR12,
NRI2R135
NTIC(0)R12, or NR12C(0)R13, where Y is 0 or S. R12 and It" are independently
CI-C3 alkyl,
or a pharmaceutically acceptable salt and/or solvate thereof
100181 In one embodiment, the compound of Formula I is a compound wherein R1t)
is -OR,
R, L and R1 are as defined in Table I above, and R11 is CI-C3 alkyl optionally
substituted with
YH, 'YR12, YC(0)R12, C(0)YR12, C(0)NH2, C(0)NHR12, C(0)NR121e3, NH2, NHR12,
NR12R13, NHC(0)R12, or NR12C(0)R13, where Y is 0 or S. R12 and Ri3 are
independently C --
C3 alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
[0019] In one of its composition aspects, this invention is directed to a
pharmaceutical
composition comprising a pharmaceutically acceptable excipient and a
therapeutically
effective amount of a compound of Formula I or II or Table I above.
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f00201 In one of its method aspects, this invention is directed to a method
for treating
addiction in a patient which method comprises administering to the patient a
pharmaceutical
composition comprising a pharmaceutically acceptable excipient and a
therapeutically
effective amount of a compound of Formula I or II or Table I above.
[0021] In another of its method aspects, this invention is directed to a
method for treating
pain, addition and/or stress in a patient which method comprises administering
to the patient
a pharmaceutical composition comprising a pharmaceutically acceptable
excipient and a
therapeutically effective amount of a compound of Formula I or II or Table I
above.
Detailed Description
100221 This invention is directed to noribogaine prodrugs, pharmaceutical
compositions of
such prodrugs and methods for their use. However, prior to describing this
invention in
greater detail, the following terms will first be defined.
100231 It is to be understood that this invention is not limited to particular
embodiments
described, as such may, of course, vary. It is also to be understood that the
terminology used
herein is for the purpose of describing particular embodiments only, and is
not intended to be
limiting, since the scope of the present invention will be limited only by the
appended claims.
[0024] It must be noted that as used herein and in the appended claims, the
singular forms
"a", "an", and "the" include plural referents unless the context clearly
dictates otherwise.
Thus, for example, reference to "a pharmaceutically acceptable excipient"
includes a plurality
of such excipients.
1. Definitions
100251 Unless defined otherwise, all technical and scientific terms used
herein have the
same meaning as commonly understood by one of ordinary skill in the art to
which this
invention belongs. As used herein the following terms have the following
meanings.
100261 As used herein, the term "comprising" or "comprises" is intended to
mean that the
compositions and methods include the recited elements, but not excluding
others.
"Consisting essentially of' when used to define compositions and methods,
shall mean
excluding other elements of any essential significance to the combination for
the stated
purpose. Thus, a composition consisting essentially of the elements as defmed
herein would
not exclude other materials or steps that do not materially affect the basic
and novel
characteristic(s) of the claimed invention. "Consisting or shall mean
excluding more than
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trace elements of other ingredients and substantial method steps. Embodiments
defined by
each of these transition terms are within the scope of this invention.
100271 The term "about" when used before a numerical designation, e.g.,
temperature, time,
amount, and concentration, including range, indicates approximations which may
vary by (
)or(-) 10 %, 5 %or %.
[0028] In some embodiments, the invention is directed to compositions
comprising the
procirtms described herein and an excipient to facilitate transport across the
blood brain
barrier.
[0029] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups
having from 1
to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by
way of
example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl
(CH3CH2-),
n-propyl (CI-I3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2C1-12-),
isobutyl
KII3)20-1C12-), sec-butyl OCH3)(CH3CH2)CH-), ((CH3)3C-), n-pentyl
(CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
100301 "Alkenyl" refers to straight or branched hydrocarbyl groups having from
2 to 6
carbon atoms and preferably 2 to 4 carbon atoms and having at least I and
preferably from l
to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for
example, by
vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and
trans isomers or
mixtures of these isomers.
[00311 "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups
having
from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at
least 1 and
preferably from 1 to 2 sites of acetylenic (-CC-) unsaturation. Examples of
such alkynyl
groups include acetylenyl (-CHECK and propargyl (-CH2CEECH).
100321 "Substituted alkyl" refers to an alkyl group having from 1 to 5,
preferably 1 to 3, or
more preferably 1 to 2 substituents selected from the group consisting of
alkoxy, substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
antinothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,
carboxyl ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,
cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
cycloalkenylthio,
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substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,
heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy,
heteroarylthio, substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,
substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H,
substituted
sulfonyl, sultbnyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,
wherein said
substituents are defined herein.
[00331 "Substituted alkenyl" refers to alkenyl groups having from 1 to 3
substituents, and
preferably 1 to 2 substituents, selected from the group consisting of alkoxy,
substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
arninocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfbnylamino, amidino, aryl,
substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,
carboxyl ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,
cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
cycloalkenylthio,
substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,
heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy,
heteroarylthio, substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,
substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H,
substituted
sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,
wherein said
substituents are defined herein and with the proviso that any hydroxy or thiol
substitution is
not attached to a vinyl (unsaturated) carbon atom.
[00341 "Substituted alkynyl" refers to alkynyl groups having from 1 to 3
substituents, and
preferably 1 to 2 substituents, selected from the group consisting of alkoxy,
substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
aminothiocarbonyl, aminocarbonylarnino, aminothiocarbonylamino,
aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,
carboxyl ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,
cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
cycloalkenylthio,
substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,
heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy.
heteroarylthio, substituted
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heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,
substituted
heterocyclyloxy, heterocyclylthio, substituted hewmcyclylthio, nitro, SO3H,
substituted
sulfonyl, sulfonyloxy, tbioacyl, thiol, alkylthio, and substituted alkylthio,
wherein said
substituents are defined herein and with the proviso that any hydroxy or thiol
substitution is
not attached to an acetylenic carbon atom.
[00351 "Alkoxy" refers to the group -0-alkyl wherein alkyl is defined herein.
Alkoxy
includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
1-butoxy,
sec-butoxy, and n-pentoxy.
100361 "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein
substituted
alkyl is defined herein.
[00371 "Acyl" refers to the groups H-C(0)-, alkyl-C(0)-, substituted alkyl-
C(0)-,
alkenyl-C(0)-, substituted alkenyl-C(0)., alkynyl-C(0)-, substituted alkynyl-
C(0)-,
cycloalkyl-C(0)-, substituted cycloalkyl-C(0)-, cycloalkenyl-C(0)-,
substituted
cycloalkenyl-C(0)-, aryl-C(0)-, substituted aryl-C(0)-, heteroaryl-C(0)-,
substituted
heteroaryl-C(0)-, heterocyclic-C(0)-, and substituted heterocyclic-C(0)-,
wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
herein. Acyl includes the "acetyl" group CH3C(0)-.
[0038) "Acylamino" refers to the groups -NR' 7C(0)alkyl, -NR' 7C(0)substituted
alkyl,
-NR
'7C(0)cycloalkyl, -NR' 7C(0)substituted cycloalkyl, -NR17C(0)cycloalkenyl,
-NR' 'C(0)substituted cycloalkenyl, -NR17C(0)alkenyl, -NR' 7C(0)substituted
alkenyl,
-NR 17C(0)alkynyl, -NR 7C(0)substituted alkynyl, -NR' 7C(0)aryl, -NR'
7C(0)substituted
aryl, -NR17C(0)heteroaryl, -NR' 7C(0)substituted heteroaryl, -
NR17C(0)heterocyclic, and
-NR' 7C(0)substituted heterocyclic wherein R17 is hydrogen or alkyl and
wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
herein.
[0039) "Acyloxy" refers to the groups alkyl-C(0)O-, substituted alkyl-C(0)O-,
alkenyl-C(0)O-, substituted alkenyl-C(0)O-, alkynyl-C(0)O-, substituted
alkynyl-C(0)O-,
aryl-C(0)O-, substituted aryl-C(0)O-, cycloalkyl-C(0)0-, substituted
cycloalkyl-C(0)0-,
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cycloalkenyl-C(0)O-, substituted cycloalkenyl-C(0)O-, heteroaryl-C(0)O-,
substituted
heteroaryl-C(0)O-, heterocyclic-C(0)O-, and substituted heterocyclic-C(0)0-
wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
herein.
[00401 "Amino" refers to the group -141-12.
[00411 "Substituted amino" refers to the group -NR18R19 where R18 and R19 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic, -S02-alkyl, -S02-
substituted
-S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted
cylcoalkyl,
-S02-cycloalkenyl, -S02-substituted cylcoalkeny1,-S02-aryl, -S02-substituted
aryl,
-S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, and -S02-
substituted
heterocyclic and wherein R18 and R19 are optionally joined, together with the
nitrogen bound
thereto to form a heterocyclic or substituted heterocyclic group, provided
that R18 and R19 are
both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl.
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein. When R18 is hydrogen and R19 is alkyl, the
substituted
amino group is sometimes referred to herein as allcylamino. When R18 and R19
are alkyl, the
substituted amino group is sometimes referred to herein as dialkylamino. When
referring to a
monosubstituted amino, it is meant that either R18 or R19 is hydrogen but not
both. When
referring to a disubstituted amino, it is meant that neither R18 nor R19 are
hydrogen.
[00421 "Aminocarbonyl" refers to the group -C(0)NR20R2i where R2 and R21 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R2 and R21
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
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aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein.
[00431 "Arninothiocarbonyl" refers to the group -C(S)NR20R21 where R2 and R21
are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R2 and R21
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein.
[0044] "Aminocarbonylamino" refers to the group -NR17C(0)NR20R21 where R17 is
hydrogen or alkyl and R2 and R2I are independently selected from the group
consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted
cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic and
where R2 and R21 are optionally joined together with the nitrogen bound
thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[00451 "Aminothiocarbonylamino" refers to the group -NRI7C(S)
NR2o¨ 21
K where R17 is
hydrogen or alkyl and R2 and R21 are independently selected from the group
consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted
cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic and
where R2 and R2I are optionally joined together with the nitrogen bound
thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
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100461 "Aminocarbonyloxy" refers to the group -O-C(0)NR20R21 where R2 and R21
are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R2 and R21
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein.
[00471 "Aminosulfonyl" refers to the group -S02NR20R21 where RN) and R21 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R2 and R21
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein.
[00481 "Aminosulfonyloxy" refers to the group -0-S02NR20'-'21
where R2 and R2I are
independently selected from the group consisting of hydrogen. alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R2 and R21
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein.
[00491 "Aminosulfonylamino" refers to the group -NR'7-SO2NR2 R21 where R17 is
hydrogen or alkyl and R2 and R21 are independently selected from the group
consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyh
substituted alkynyl,
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aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted
cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic and
where R2 and R2I are optionally joined together with the nitrogen bound
thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted
alkyl, alkeny1,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[00501 "Arnidino" refers to the group -C(=NR22)NR20R2I where R20, R2I, and R22
are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R2 and R2I
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein.
[00511 "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of
from 6 to 14
carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings
(e.g., naphthyl or
anthryl) which condensed rings may or may not be aromatic (e.g., 2-
benzoxazolinone,
2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of
attachment is at
an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
100521 "Substituted aryl" refers to aryl groups which are substituted with I
to 5, preferably
1 to 3, or more preferably 1 to 2 substituents selected from the group
consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino,
aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,
carboxyl ester, (carboxyl
ester)atnino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,
cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
cycloalkenylthio,
substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,
heteroaryl,
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substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy,
heteroarylthio, substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,
substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H,
substituted
sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,
wherein said
substituents are defined herein.
100531 "Aryloxy" refers to the group -0-aryl, where aryl is as defined herein,
that includes,
by way of example, phenoxy and naphthoxy.
100541 "Substituted aryloxy" refers to the group -0-(substituted aryl) where
substituted
aryl is as defined herein.
100551 "Arylthio" refers to the group -S-aryl, where aryl is as defined
herein.
[00561 "Substituted arylthio" refers to the group -S-(substituted aryl), where
substituted
aryl is as defined herein.
[00571 "Carbonyl" refers to the divalent group -C(0)- which is equivalent to -
C(=0)-.
100581 "Carboxy" or "carboxyl" refers to -COOH or salts thereof.
100591 "Carboxyl ester" or "carboxy ester" refers to the groups -C(0)0-alkyl,
-C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-
alkynyl,
-C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-
cycloalkyl,
-C(0)0-substituted cycloalkyl, -C(0)0-cycloalkenyl, -C(0)0-substituted
cycloalkenyl.
-C(0)0-heteroaryl, -C(0)0-substituted heteroaryl, -C(0)0-heterocyclic, and
-C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
100601 "(Carboxyl ester)amino" refers to the group -NR17-C(0)0-alkyl, -NR17-
C(0)0-
substituted alkyl, -1.4R17-C(0)0-alkenyl, -NR'7-C(0)0-substituted alkenyl,
-NR'7-C(0)0-allcynyl, -NR'7-C(0)0-substituted alkynyl, -NR'7-C(0)0-aryl,
-NR 17-C(0)0-substituted aryl, -NR'7-C(0)0-cycloalkyl, -NR'7-C(0)0-substituted
cycloalkyl, -NR'7-C(0)0-cycloalkenyl, -NR17-C(0)0-substituted cycloalkenyl,
-NR'7-C(0)0-heteroaryl, -NR17-C(0)0-substituted heteroaryl, -NR17-C(0)0-
heterocyclic,
and -NR'7-C(0)0-substituted heterocyclic wherein R17 is alkyl or hydrogen, and
wherein
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, cycloalkyl,
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substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
herein.
100611 "(Carboxyl ester)oxy" refers to the group -0-C(0)0-alkyl, substituted
-0-C(0)0-alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-
alkynyl,
-0-C(0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl,
-0-C(0)0-cycloalkyl, -0-C(0)0-substituted cycloalkyl, -0-C(0)0-cycloalkenyl,
-0-C(0)0-substituted cycloalkenyl, -0-C(0)0-heteroaryl, -0-C(0)0-substituted
heteroaryl,
-0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic wherein alkyl,
substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl,
substituted heteroaryl, heterocyclic, and substituted heterocyclic are as
defined herein.
100621 "Cyano" refers to the group -CN.
100631 "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms
having
single or multiple cyclic rings including fused, bridged, and Spiro ring
systems. One or more
of the rings can be aryl, heteroaryl, or heterocyclic provided that the point
of attachment is
through the non-aromatic, non-heterocyclic ring carbocyclic ring. Examples of
suitable
cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl,
cyclopentyl, and
cyclooctyl. Other examples of cycloalkyl groups include bicycle[2,2,2Joetanyl,
norbomyl,
and spirobicyclo groups such as spiro[4.5]dec-8-yl:
100641 "Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to
10 carbon
atoms having single or multiple cyclic rings and having at least one >0=C<
ring unsaturation
and preferably from I to 2 sites of >C=C ring unsaturation.
{00651 "Substituted cycloalkyl" and "substituted cycloalkenyl" refers to a
cycloalkyl or
cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents
selected from the
group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl,
substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy,
amino, substituted
amino, aminocarbonyl, aminothiocarbonyl, atninocarbonylarnino,
aminothiocarbonylamino,
aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylarnino,
antidino, aryl,
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substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted
arylthio, carboxyl,
carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl,
substituted
cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio,
substituted
cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,
substituted
cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino,
substituted
guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy,
substituted
heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,
substituted
heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,
substituted
heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl,
thiol, alkylthio, and
substituted alkylthio, wherein said substituents are defmed herein.
100661 "Cycloalkyloxy" refers to -0-cycloalkyl.
100671 'Substituted cycloalkyloxy" refers to -0-(substituted cycloalkyl).
100681 "Cycloalkylthio" refers to -S-cycloalkyl.
100691 "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).
[00701 "Cycloalkenyloxy" refers to -0-cycloalkenyl.
100711 "Substituted cycloalkenyloxy" refers to -0-(substituted cycloalkenyl).
100721 "Cycloalkenylthio" refers to -S-cycloalkenyl.
100731 "Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl).
[00741 "Guanidino" refers to the group -NHC(=NH)NH2.
[00751 "Substituted guanidino" refers to -NR23C(=NR23)N(R23)2 where each R23
is
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl,
substituted aryl. heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic
and two R23 groups attached to a common guanidino nitrogen atom are optionally
joined
together with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic
group, provided that at least one R23 is not hydrogen, and wherein said
substituents are as
defined herein.
(0076) "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and
preferably is
fluor or chloro.
100771 "Haloalkyl" refers to alkyl groups substituted with 1 to 5, 1 to 3, or
1 to 2 halo
groups, wherein alkyl and halo are as defined herein.
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[00781 "Haloalkoxy" refers to alkoxy groups substituted with 1 to 5, 1 to 3,
or 1 to 2 halo
groups, wherein alkoxy and halo are as defmed herein.
[00791 "Haloalkylthio" refers to alkylthio groups substituted with 1 to 5, 1
to 3, or 1 to 2
halo groups, wherein alkylthio and halo are as defined herein.
[00801 "Hydroxy" or "hydroxyl" refers to the group -OH.
[00811 "Heteroaryl" refers to an aromatic group of from I to 10 carbon atoms
and I to 4
heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur
within the
ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl)
or multiple
condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed
rings may or may
not be aromatic and/or contain a heteroatom provided that the point of
attachment is through
an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen
and/or the sulfur
ring atom(s) of the heteroaryl group are optionally oxidized to provide for
the N-oxide
(N--40), sulfinyl, and/or sulfonyl moieties. Preferred heteroaryls include
pyridinyl, pyrrolyl,
indolyl, thiophenyl, and furanyl.
100821 "Substituted heteroaryl" refers to heteroaryl groups that are
substituted with from I
to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from
the group
consisting of the same group of substituents defined for substituted aryl.
[00831 "Heteroaryloxy" refers to -0-heteroaryl.
100841 "Substituted heteroaryloxy" refers to the group -0-(substituted
heteroaryl).
100851 "Heteroarylthio" refers to the group -S-heteroaryl.
[00861 "Substituted heteroarylthio" refers to the group -S-(substituted
heteroaryl ).
100871 "Heterocycle' or "heterocyclic" or "heterocycloalkyl" or "heterocycly1"
refers to a
saturated or partially saturated, but not aromatic, group having from 1 to 10
ring carbon
atoms and from 1 to 4 ring heteroatoins selected from the group consisting of
nitrogen, sulfur,
or oxygen. Heterocycle encompasses single ring or multiple condensed rings,
including
fused bridged and spiro ring systems. In fused ring systems, one or more the
rings can be
cycloalkyl, aryl, or heteroaryl provided that the point of attachment is
through the
non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur
atom(s) of the
heterocyclic group are optionally oxidized to provide for the N-oxide,
sulfinyl, and/or
sulfonyl moieties.
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100881 "Substituted heterocyclic" or "substituted heterocycloalkyl" or
"substituted
heterocycly1" refers to heterocyclyl groups that are substituted with from 1
to 5 or preferably
1 to 3 of the same substituents as defined for substituted cycloalkyl.
100891 "Heterocyclyloxy" refers to the group -0-heterocycyl.
100901 "Substituted heterocyclyloxy" refers to the group -0-(substituted
heterocycyl).
100911 "Heterocyclylthie refers to the group -S-heterocycyl.
100921 "Substituted heterocyclylthie refers to the group -S-(substituted
heterocycyl).
100931 Examples of heterocycle and heteroaryls include, but are not limited
to, azetidine,
pyrrole, imidazole, pyrazole, pyridine, pymzine, pyrimidine, pyridazine,
indolizine, isoindole,
indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine,
naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole,
carboline,
phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole,
phenoxazine,
phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline,
phthalimide,
1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole,
thiazolidine,
thiophene, benzo[b]thiophene, morpholinyl, thiommpholinyl (also referred to as
thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and
tetrahydrofuranyl.
100941 "Nitro" refers to the group -NO2. =
100951 "Oxo" refers to the atom (=0) or (-0).
100961 "Spiro ring systems" refers to bicyclic ring systems that have a single
ring carbon
atom common to both rings.
[00971 "Sulfon.y1" refers to the divalent group -S(0)2-.
100981 "Substituted sulfonyl" refers to the group -S02-alkyl, -S02-substituted
alkyl,
-S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted
cylcoalkyl,
-S02-cycloalkenyl, -S02-substituted cylcoalkenyl, -S02-aryl, -S02-substituted
aryl,
-S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-
substituted
heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl,
substituted alleynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein. Substituted sulfonyl includes groups such
as methyl-S02-.
phenyl-S02-, and 4-methylphenyl-S02-. The term "alkylsulfonyl" refers to -S02-
alkyl. The
term lialoalkylsulfonyl" refers to -S02-haloalkyl where haloalkyl is defined
herein. The
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term "(substituted sulfonyl)amino" refers to -NH(substituted sulfonyl), and
the term
"(substituted sulfonyl)aminocarbonyl" refers to -C(0)NH(substituted sulfonyl),
wherein
substituted sulfonyl is as defined herein.
[00991 "Sulfonyloxy" refers to the group -0S02-alkyl, -0S02-substituted alkyl,
-0S02-alkenyl, -0S02-substituted alkenyl, -0S02-cycloalkyl, -0S02-substituted
cylcoalkyl,
-0S02-cycloalkenyl, -0S02-substituted cylcoalkeny1,-0S02-aryl, -0S02-
substituted aryl,
-0S02-heteroaryl, -0S02-substituted heteroaryl, -0S02-heterocyclic, -0S02-
substituted
heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic are as defined herein.
10100) "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-
C(S)-,
alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-
C(S)-,
cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-,
substituted
cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-,
substituted
heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-,
wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
herein.
[01011 "Thiol" refers to the group -SH.
[01021 "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent
to -C(=S)-.
101031 "Thione" refers to the atom (=S).
[01041 "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined
herein.
101051 "Substituted alkylthio" refers to the group -S-(substituted alkyl)
wherein substituted
alkyl is as defined herein.
[01061 "Compound" or "compounds" as used herein is meant to include the
stereoiosmers
and tautomers of the indicated formulas.
[01071 "Stereoisomer" or "stereoisomers" refer to compounds that differ in the
chirality of
one or more stereocenters. Stereoisomers include enantiomers and
diastereomers.
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101081 "Tautomer" refer to alternate forms of a compound that differ in the
position of a
proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms
of heteroaryl
groups containing a ring atom attached to both a ring -NH- moiety and a ring
=N- moiety
such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0109i As used herein, the term "noribogaine" refers to the compound:
HO
N
as well as its pharmaceutically acceptable salts and/or solvates thereof.
Conventionally,
noribogaine is prepared by demethylation of naturally occurring ibogaine:
0
N
which is isolated from Tabernanth iboga, a shrub of West Africa. Demethylation
may be
accomplished by conventional techniques such as by reaction with boron
tribromide/methylene chloride at room temperature followed by conventional
purification.
Methods for the synthesis and purification of noribogaine are disclosed in US
Patent
Application No. 61/333,476, entitled Methods and Compositions for Preparing
and Purifying
Noribogaine, filed on May 11, 2010, which is hereby incorporated by reference
in its entirety.
This invention is not limited to any particular chemical form of noribogaine
and the drug may
be given to patients either as a free base or as a pharmaceutically acceptable
addition salt or a
pharmaceutically acceptable solvate of noribogaine or the salt.
[01101 As used herein, the term "pharmaceutically acceptable salt" refers to
salts derived
from organic or inorganic acids. Examples of such acids include, without
limitation,
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfitric acid, methane
sulfbnic acid,
phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid,
lactic acid, succinic
acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid,
thalic acid, embonic
acid, enanthic acid, and the like.
101111 As used herein, the term solvate refers to a solid form of a compound
that
crystallizes with solvent molecules trapped inside and includes, but is not
limited to,
complexes of a compound of the invention with less than one, one or more
solvent molecules,
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or from about 0.1 to about 100, or about 1 to about 10, or about 0.5, 1, 2, 3
or 4 solvent
molecules. A "pharmaceutically acceptable solvate" of a compound of the
invention refers to
a solvate complex that is pharmaceutically acceptable and that possesses the
desired
pharmacological activity of the parent compound. A few examples of solvents
that can be
used to create solvates, such as pharmaceutically acceptable solvates,
include, but are
certainly not limited to, water, methanol, ethanol, isopropanol, butanol, Cl -
C6 alcohols in
general (and optionally substituted), tetrahydrofuran, acetone, ethylene
glycol, propylene
glycol, acetic acid, formic acid, water, and solvent mixtures thereof. Other
biocompatible
solvents which may aid in making a pharmaceutically acceptable solvate are
well known in
the art and applicable to the present invention. Additionally, various organic
and inorganic
acids and bases can be added or used alone as the solvent to create a desired
solvate. Such
acids and bases are known in the art. When the solvent is water, the solvate
is referred to as
hydrate, such as hemihydrate (two compound molecules are complexed with one
water
molecule), monohydrate (one compound molecule is complexed with one water
molecule) or
dehydrate (one compound molecule is complexed with two water molecules).
101121 As used herein, the term "therapeutically effective amount" refers to
the amount of a
composition of this invention that is sufficient to effect treatment, as
defined herein, when
administered to a subject in need of such treatment. The therapeutically
effective amount
will vary depending upon the subject and condition being treated, the weight
and age of the
subject, the severity of the condition, the particular composition or
excipient chosen, the
dosing regimen to be followed, timing of administration, the manner of
administration and
the like, all of which can be determined readily by one of ordinary skill in
the art.
[01131 As used herein, the term "treatment" or "treating" means any treatment
of a disease
or condition in a patient, including:
= preventing or protecting against the disease or condition, that is,
causing the clinical
symptoms not to develop, for example, in a subject at risk of suffering from
such a
disease or condition, thereby substantially averting onset of the disease or
condition;
= inhibiting the disease or condition, that is, arresting or suppressing
the development of
clinical symptoms; and/or
= relieving the disease or condition that is, causing the regression of
clinical symptoms.
101141 As used herein, the term "pain" refers to all types of pain, including
neuropathic and
nociceptive pain. It is also contemplated that the compositions disclosed
herein can be used
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to treat other types of pain such as phantom pain which is the sensation of
pain from a limb or
organ that has been lost or from which a person no longer receives physical
signals, and is an
experience almost universally reported by amputees and quadriplegics.
[0115] As used herein, the term "addiction" refers to a persistent behavioral
pattern marked
by physical and/or psychological dependency to a substance, particularly drugs
such as
narcotics, stimulants, and sedatives, including but not limited to heroin,
cocaine, alcohol,
nicotine, caffeine, amphetamine, desoxyephedrine, methadone and combinations
thereof. As
used herein, the "treatment of addiction in a patient" refers to reducing the
withdrawal
symptoms associated with drug dependency as well as alleviating drug cravings
in addicts.
Such symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle
pain, chills and
headache.
101161 As used herein, the terms "blood-brain barrier" or "BBB" refer to the
barrier
between the peripheral circulation and the brain and spinal cord which is
formed by tight
junctions within the brain capillary endothelial plasma membranes, creating an
extremely
tight barrier that restricts the transport of molecules into the brain. The
blood-brain barrier
within the brain, the blood-spinal cord barrier within the spinal cord, and
the blood-retinal
barrier within the retina, are contiguous capillary barriers within the
central nervous system
(CNS), and are collectively referred to herein as the blood-brain barrier or
BBB.
[0117] As used herein, the term "cleavable linking group" refers to a linking
group that can
be attached to noribogaine or a derivative at any possible position.
Preferably, the linker is
biocompatible (i.e. does not produce undesired side effects or have an
intolerable toxicity), is
readily cleaved in the body (preferably in the brain), and does not inhibit or
alter the desired
physiological effect of noribogaine or derivative. Specifically, the linking
group is preferably
sufficiently stable in the circulatory system (serum or blood), but is cleaved
to release the
noribogaine or derivative upon entry into the brain. Suitable biocompatible,
cleavable linking
groups comprise from 1 to 20 atoms selected from carbon, nitrogen, oxygen,
sulfur, and
phosphorus, and are, in general, susceptible to cleavage conditions or agents
in the brain (i.e.
pH, redox potential or the presence of degradative molecules such as enzymes).
The
biocompatible, cleavable linking group can be an ester-based cleavable linking
group (-
C(0)0- or -0C(0)-), an amide-based cleavable linking group (-C(0)NR9- or -
NR9C(0)-), or
a phosphate-based cleavable linking group (-P(0)(0R9)-0-, -0-P(S)(0R9)-0-, -0-
P(S)(SR)-
0-, -S-P(0)(0R9)-0-, -0-P(0)(0R9)-S-, -S-P(0)(0R9)-S-, -0-P(SX0R9)-S-, -S-
P(S)(0R9)-
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0-, -0-P(0)(R9)-0-, -0-P(S)(R9)-0-, -S-P(0)(R9)-0-, -S-P(S)(R9)-0-, -S-
P(0)(R9)-S-, or -0-
P(S)(R9)-S-) where R9 can be hydrogen or alkyl.
[0 I 181 As used herein, the term "saccharide" or "monosaccharide" refers to a
saccharide or
derivative thereof, having at least 6 carbon atoms (which may be linear,
branched or cyclic)
with an oxygen, nitrogen or sulfur atom bonded to each carbon atom. The term
"oligosa.ccharides" includes oligosaccharides containing from about 2-9
monosaccharide
units. Specific monosaccharides include C5 and above (preferably Cs-Cs)
saccharides such as
ethritol, zylitol, galactose, lactose, xylose, dulcitol, myo-insoitol,
fructose, mannitol, sorbitol,
glucose, arabinose, arabinose, celloboise, maltose, raffinose, rhamnose,
melibiose, ribose,
adonitol, arabitol, arabitol, fitcose, lyxose, lyxose, lyxose, glucosamine,
mannosamine, and
galactosamine; di- and trisaccharides include saccharides having two or three
monosaccharide units.
101191 As used herein, the term "patient" refers to mammals and includes
humans and
non-human mammals.
2. Compounds
[01.201 Accordingly, in one embodiment, this invention is directed to
compounds which are
represented by Formula I below:
R10 R11
-N
L,W
wherein L is selected from the group consisting of a covalent bond and a
cleavable
linker group;
RI is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic
provided that RI is not a saccharide or an oligosaccharide;
RI is hydrogen or --OR;
RI I is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkoxy,
substituted alkoxy, (CH2).0C(0)alkyl, (CH2).0H, (CH2),õ0alkyl, CH2-X-alkyl or
(CH2),n0(CH2)p0(CH2)0(CH2),CH3, where each of m, p and q is I, 2 or 3: and r
is 0, 1 or 2,
X is 0 or NH;
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R is selected from the group consisting of hydrogen, a hydrolysable group
selected
from the group consisting of -C(0)R2, -C(0)NR3R4 and -C(0)0R5, where R2 is
selected from
the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl,
alkynyl and substituted alkynyl,
R3 and R4 are independently selected from the group consisting of hydrogen,
alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic, and
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
heteroaryl, substituted
heteroaryl, heterocyclic and substituted heterocyclic provided that R is not a
saccharide or an
oligosaccharide;
or a pharmaceutically acceptable salt and/or solvate thereof,
provided that when L is a covalent bond and R1 is hydrogen, then R is selected
from
the group consisting of -C(0)NR3R4 and -C(0)0R5; and
further provided that when R is hydrogen or -COW and L is a covalent bond,
then
R1 is not hydrogen.
[01211 In one embodiment, R" is selected from the group consisting of
hydrogen, C1-C3
alkyl, substituted C1-C3 alkyl, CI-C3 alkoxy and substituted CI-C3 alkoxy.
[01221 In one embodiment, R11 is H. In one embodiment, R" is C1-C3 alkyl, such
as ethyl.
In one embodiment, R" is CH2CH2011. In one embodiment, R11 is CH2CH2OCH3. In
one
embodiment, R11 is CH2CH2OCH2Ph. In one embodiment, R11 is CH2CH20C(0)alkyl,
such
as CH2CH20C(0)(C112)30CH3. In one embodiment, R" is CH2-X-CH3. In one
embodiment,
R11 is CH2CH20(CH2)p0(CH2),10(CH2),CH3.
101231 In one embodiment, R11 is C1-C3 alkyl optionally substituted with YH,
YR12,
YC(0)R12, C(0)Y11.12, C(0)NH2, C(0)NHR12, C(0)NRI2R", NH2, NHR12, NR12R13.
NHC(0)R12, or NR12C(0)R13, where Y is 0 or S, R12 and R13 are independently C1-
C3 alkyl.
[01241 In one embodiment, R11 is C1-C3 alkoxy optionally substituted with YH,
YR12,
YgO)R12, C(0)YR12, C(0)NH2, C(0)NHR12, C(0)NR12R13, NH2, NHRI2, NR12R13,
NHC(0)R12, or NR12C(0)R13, where Y is 0 or S, R12 and R13 are independently C1-
C3 alkyl.
101251 In one embodiment, L is a suitable biocompatible, cleavable linking
group described
herein.
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101261 In one embodiment, L is -C(0)-. In another embodiment, L is -C(0)0-. In
still
another embodiment, L is -C(0)NR-, where R is hydrogen or alkyl.
101271 In one embodiment, L is selected from the group consisting of -
P(0)(0R9)-0-, -0-
P(S)(0R9)-0-, -0-P(S)(SR9)-0-, -S-P(0)(0R9)-0-, -0-P(0)(0R9)-S-, -S-P(OX0R9)-S-
,
-0-P(S)(0R9)-S-, -S-P(S)(0R9)-0-, -0-P(0)(R9)-0-, -0-P(S)(R9)-0-, -S-P(0)(R9)-
0-,
-S-P(S)(R9)-0-, -S-P(0)(R9)-S-, and -0-P(S)(R9)-S-, where R9 is hydrogen or
alkyl.
101281 In one embodiment, R is hydrogen, L is a covalent bond or -C(0)-, and
RI is
substituted alkyl. In one embodiment, RI is alkyl substituted with -NR6R7
where R6 and R7
are independently selected from the group consisting of hydrogen, alkyl,
alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic.
[0129] In one embodiment, R is selected from the group consisting of -
C(0)NR3R4 and
-C(0)0R5 and RI is hydrogen.
101301 In one embodiment, the compound of Formula! is a compound wherein RI
is H, L
and RI are as defined in Table II below, and R11 is C1-C3 alkyl optionally
substituted with
YH, YR12, YC(0)R12, C(0)YR12, C(0)NH2, C(0)NHR12, C(0)NRI2R13, NH2, NHR 12,
NR12-- 13,
K NHC(0)R12, or NRI2C(0)R13, where Y is 0 or S, R12 and R13 are
independently C1-
C3 alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
101311 In one embodiment, the compound of Formula I is a compound wherein RI
is H, L
and RI are as defined in Table II below, and R11 is selected from H, CH2C1-
1201-1,
CH2CH2OCH3, CH2CH2OCH2Ph, CH2CH20C(0)alkyl, and
CH2CH20(CH2)p0(CH2),P(CH2),CH3, or a pharmaceutically acceptable salt and/or
solvate
thereof.
101321 In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R, L and RI are as defined in Table II below, and R11 is C1-C3 alkyl
optionally substituted
with YH, YR12, YC(0)R12, C(0)YR12, C(0)NH2, C(0)NHR12, C(0)NR12R13, NH2,
NHR12,
NR12R13, NHC(0)R12, or NR12C(0)R13, where Y is 0 or S, R12 and R13 are
independently C1-
C3 alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
[0133] In one embodiment, the compound of Formula I is a compound wherein RI
is -0R,
R, L and R1 are as defined in Table ll below, and R" is selected from H,
CH2CH2OH,
CH2CH2OCH3, CH2CH2OCH2Pli, CH2CH20C(0)alkyl, and
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CH2CH20(0-12)p0(CH2)0(CH2)rCH3, or a pharmaceutically acceptable salt and/or
solvate
thereof.
[0134] In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R, L and RI are as defined in Table II below, and RI' is selected from H,
CH2CH2OH,
CH2CH2OCH3, CH2CH2OCH2Ph, CH2CH20C(0)alkyl, and
CH2CH20(CH2)p0(CH2)(10(CH2)rCH3, or a pharmaceutically acceptable salt and/or
solvate
thereof.
[01351 In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R, L and RI are as defined in Table II below, and R" is H, or a
pharmaceutically acceptable
salt and/or solvate thereof.
101361 In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R. L and RI are as defined in Table II below, and R" is CH2CH2OH, or a
pharmaceutically
acceptable salt and/or solvate thereof.
101371 In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R, L and RI are as defined in Table II below, and R" is CH2CH2OCH3, or a
pharmaceutically
acceptable salt and/or solvate thereof.
[01381 In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R, L and RI are as defined in Table II below, and RI I is CH2OCH3, or a
pharmaceutically
acceptable salt and/or solvate thereof.
[0139) In one embodiment, the compound of Formula I is a compound wherein R is
-OR,
R, L and R1 are as defined in Table II below, and R" is CH2CH2OCH2Ph, or a
pharmaceutically acceptable salt and/or solvate thereof.
101401 In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R, L and RI are as defined in Table II below, and R" is CH2CH20C(0)alkyl, such
as C12
alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
[0141) In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R. L and RI are as defined in Table II below, and R" is
CH2CH20(CH2)p0(CH2)Q0(CH2)rCH3, or a pharmaceutically acceptable salt and/or
solvate
thereof.
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[01421 In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R. Land RI are as defined in Table H below, and RH is methyl, or a
pharmaceutically
acceptable salt and/or solvate thereof
101431 In one embodiment, the compound of Formula I is a compound wherein RI
is -OR,
R, L and RI are as defined in Table II below, and RH is C3 alkyl, or a
pharmaceutically
acceptable salt and/or solvate thereof.
Table H
1 _______________________________________________________________
R T R1
............1
-c(o)cH2cH2N(cH3)2 -cm -a-2cH2N(cH02 ,
.....
H -C(0) -CH2CH2N(CH3
-C(0)CH2CH2N(CH3)2 bond H
-C(0)CI-I2CH2N(CH3)2 bond -CH2N(C'õ1-
13)2__ ,
H bond
1-CH2N(CH3)2
-C(0)NHCH2CH2N(CH3)2 -C(0) l H
...._..............___.
-C(0)NHCH2CH2N(CH3)2 -C(0)NH -CH2CH2N(CH3)2 .
H -C(0)NH -CH2C1:12K(d43)2
1 -C(0)NHCH2CH2N(CH3)2 -C(0)NH H ......... __
-C(0)NHCH2CH2N(CH3)2 -C(0) , -CH3 .....
\ 0 -C(0) -CH2CH2N(CH3)2
-C(0)NHCH2CH2N(CH3)2 -C(0) -CH2CH2N(C'.H3)2
-C(0)NHCH2CH2N(CH3)2 -C(0)0 -CH3 .._
I -C(0)NHCH2CH2N(CH3)2 1 -C(0)0 -CH2CH2N(CH3)2 ¨1
: H ' -C(0)0 -CH2CH2N(CH3)2
-C(0)CH3, -C(0)NH -CH2CH2N(CI-13)2
-C(0)CH3, -C(0)NH H
-C(0)CH3, -C(0)NH -CH3
-C(0)0CH3, -C(0)NH . -CH2CH2k-c-113)2
..........
-C(0)0CH3, -C(0)NH I H ________
-C(0)NHCH2CH2N(CH3)2 -C(0)NH r"."\
/--N 0
/ \ /
H -C(0)NH 7------" \ \
/--N \ /0
-C(0)NFICH2CH2N(C143)2 -C(0)NH
--0
-C(0)NHCH2CH2N(CH3)2 -C(0) i \c.)
H -C(0) ir---\
/----tqv ii¨cH3
-C(0)NHCH2CH2N(C1-13)2 -C(0) i"-=c
¨N N-C H3
\---i ________________________________________________________
-C(0)N11C1-12C1-12N(C 1-13 )2 -C(0)0
---D--- I
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R L R' ...
-C(0)NHCH3 -C(0)
¨N N- CH3
H -C(0) /¨\
¨N N-CH3
\_.1
q 1--N -C(0)NH -CH2CH2N(CH3)2
)1-N\ N-CH3
-C(0)CH3, -C(0)0 1 -CH3
0 õ,-----\ -C(0)0 -CH2CH3
"--N N-CH3
-C(0)CH3, -P(0)(OH)-0- H
-C(0)CH3, -P(0)(OCH3)-0- -CH2CII2N(CH3)2
H -P(0)(OH)-0- H .
H -P(0)(OCH3)-0- ....... -CH3 I
i
-C(0)NHCII2C112N(CH3)2 -P(OXOCH3)-0- -CH3
--I
H -C(0)NH -CH3
H ................................... -C(0)0 -CH2CH3
/---1
H -C(0) ¨N N¨CH3
0
)\--N N--CH3 -P(0)(H
OC3)-0- -CH3
,
101441 hi one embodiment, provided are compounds represented by Formula II
below:
I \ .
L,R1
II
wherein
R is selected from the group consisting of hydrogen, a hydrolysable group
selected
from the group consisting of -C(0)R2, -C(0)NR3R4 and -C(0)0R5, where R2 is
selected from
the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl,
alkynyl and substituted alkynyl, R3 and R4 are independently selected from the
group
consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic and
substituted heterocyclic, R5 is selected from the group consisting of alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, heteroaryl,
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substituted heteroaryl, heterocyclic and substituted heterocyclic, provided
that R is not a
saccharide or an oligosaccharide;
L is selected from the group consisting of a covalent bond and a cleavable
linker
group;
RI is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic,
provided that RI is not a saccharide or an oligosaccharide;
or pharmaceutically acceptable salts thereof,
provided that when L is a covalent bond and RI is hydrogen, then R is selected
from
the group consisting of -C(0)NR3R4 and -C(0)0R5; and
further provided that when R is hydrogen or -C(0)R2 and L is a covalent bond,
then
RI is not hydrogen.
101451 In one embodiment, R is hydrogen and L is a cleavable group.
101.461 In one embodiment, L is a suitable biocompatible, cleavable linking
group. Suitable
biocompatible, cleavable linking groups comprise a covalent bond and a linking
group having
from I to 20 atoms selected from carbon, nitrogen, oxygen, sulfur, and
phosphorus, and are,
in general, susceptible to cleavage conditions or agents in the brain (i.e.
pH, redox potential
or the presence of degradative molecules such as enzymes, e.g., proteases,
lipases, etc.).
Generally, the cleavage conditions or agents should be more prevalent or found
at higher
levels or activities in the brain than in serum or blood. Examples of
degradative agents
include: redox agents which are selected for particular substrates or which
have no substrate
specificity, including, e.g., oxidative or reductive enzymes or reductive
agents such as
esterases; enzymes that can hydrolyze or degrade an acid cleavable linking
group by acting as
a general acid, peptidases (which can be substrate specific), and
phosphatases.
[01471 In general, the suitability of a candidate cleavable linking group can
be evaluated by
testing the ability of a cleaving agent (or condition) to cleave the linking
group. It will also
be desirable to also test the linking group for the ability to resist cleavage
in the serum, blood
or when in contact with other non-target tissue. Thus one can determine the
relative
susceptibility to cleavage between a first and a second condition, where the
first is indicative
of cleavage in the brain and the second is indicative of cleavage in serum,
blood or other non-
target tissue. Such evaluations can be carried out in cell-free systems, in
cells, in cell culture,
in organ or tissue culture, or in whole animals. In preferred embodiments, the
cleavable
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linking group is cleaved at least 2, 4, 10 or 100 times faster in the brain as
compared to
serum, blood or other non-target tissue.
[01481 In one embodiment, the linking group is an ester-based linking group.
In another
embodiment, the linking group is an amide-based linking group. In yet another
embodiment,
the linking group is a phosphate-based linking group. In another embodiment of
the
compounds of this invention, L is a covalent bond.
101491 In one embodiment, L is -C(0)-. In another embodiment, L is -C(0)0-. In
still
another embodiment, L is -C(0)NR-, where R is hydrogen or alkyl.
101501 In one embodiment, L is selected from the group consisting of -
P(0)(0R9)-0-, -0-
P(S)(0R9)-0-, -0-P(S)(SR9)-0-, -S-P(0)(0R9)-0-, -0-P(0)(0R9)-S-, -S-P(0)(0R9)-
S-,
-0-P(S)(0R9)-S-, -S-P(S)(0R9)-0-, -0-P(0)(R9)-0-, -0-P(S)(R9)-0-, -S-P(0)(R9)-
0-,
-S-P(S)(R9)-0-, -S-P(0)(R9)-S-, and -0-P(S)(R9)-S-, where R9 is hydrogen or
alkyl.
101511 In one embodiment, R is hydrogen, L is a covalent bond or -C(0)-, and
RI is
substituted alkyl. Preferably RI is alkyl substituted with -NR6R7 where R6 and
R7 are
independently selected from the group consisting of hydrogen, alkyl, alkenyl,
substituted
alkenyl, alkynyl, substituted allcynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic.
101521 In one embodiment, R is selected from the group consisting of -
C(0)NR3R4 and
-C(0)0R5 and RI is hydrogen.
[01531 In one embodiment, the compound of Formula 11 is a compound as set
forth in Table
I below or a pharmaceutically acceptable salt and/or solvate thereof:
Table I
Compound
RI
No. i
-C(0)CH2CH2N(CH3)2 -C(0) -CH2CH2N(CIT;)2
-C(0) -CH2CH2N(CI-13)2
I 3 -C(0)CH2CH2N(CH3)2 bond
4 -C(0)CH2CH2N(CH3)2I bond -CH2N(C113)2
bond -CH2N(CH3)2
6 -C(0)NHCH2CH2N(CH3)2 -C(0)
7 -C(0)NHCH2CH2N(CH3)2 -C(0)N1-1 -CH2CH2N(CH3)2
8 H _____________ -C(0)NH -CH2CH2N(CH3)2
.........
9 -C(0)NHCH2CH2N(CH3)2 -C(0)NH H
i------- -
E10 -cojmicH20-12N(cH3)2 .... -C(0) I -CI-13
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Compound ' R L ¨R1
No.
11 \--0 -C(0) -CH2C H2N(C H3)2
12 . -C(0)NHCH2CH2N(CH3)2 -C(0) -CH2CH2N(CH3)2
13 -C(0)NHCH2CH2N(CH3)2 -C(0)0 -CH3
14 -C(0)NHCH2CH2N(CH3)2 -C(0)0 F -CH2CH2N(CH3)-2
15 Fi -C(0)0 -CH2CH2N(CH3)2
i 16 -C(0)CH3, -C(0)NH -
CH2CH2N(CH3)2 ,
1 17 -C(0)CH3, -C(0)NH H
r 18 -C(0)CH3, -C(0)NH -CH3 i
19 -C(0)0CH3, -C(0)NH -CH2CH2N(CH3)2
20 -C(0)0CH3, -C(0)NH ' H
21 -C(0)NHCH2CH2N(CH3)2 -C(0)NH F
1
/ /---- /
N 0
\ ,
22 H -C(0)NH / \
/ \\____/ i
i
23 -C(0)NHCH2CH2N(CH3)2 -C(0)NH I
0 1
1 24 -C(0)NHC H2CH2N (CH3)2 -C(0) /------ \
I I ,¨N ,f)
/ \./
1 25 H 1 -C(0) /--- \
r-
N
____/ `N--cH,
..
26 -C(0)NHCH2CH2N(CH3)2 -C(0)
--N N ¨ CH3 i
_ _____________________________________________________________________
27 -C(0)NHCH2CH2N(CH3)2 -C(0)0 /-----\
¨ ii¨ ¨ -C(0)NHCH3 -C(0) ,----;
--N/ isi-CH3
\_../
_ _______
29 H -C(0) /¨\
-- N ft¨CH.1
_______________________________ ¨ r---
) ' 30 0 /--- \ ¨C(0)NH -CH2CH2N(CH3)2
\--N N¨CH3
\--/
31 -C(0)0.13, -C(0)0 -C113 ¨I
32 0ra-N -C(0)0 -CH2CH3
"---NN¨cH3
\,......J
33 -C(0)CH3, -P(0)(OH)-0- H
34 -C(0)CH3, -12.(0)(C)CH3)-0- -
CH2CH2N(CH3)2
35 H "P(.9).(914.1 - .. ... H
36 H -P(0)(0CF13)-0- -CH3 1
---I
37 -C(0)/NIFICH2CH2N(CH3)2 -P(0)ç0CFla):0- I -CH3
38 H -C(0)NH -CH3 1
39 H -c(p)s) -cti2oi3 ,
/-----\
40 H ¨C(0) --N N¨CH3 i
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Compound 1-
No.
0 7"--\
41 )\--N N¨CH3 -P(0)(OCH3)-0- -CH3
3. Methods of Use
101541 Compounds of this invention are contemplated to be useful in treating
pain and/or
addiction as an active ingredient or a prodrug. In some embodiments, the
compounds of this
invention are prodrugs whose R and/or -L-R' groups are cleaved in vivo to
produce
noribogaine or a noribogaine derivative. In a preferred embodiment, the
compound is at least
2, 5 or 10 times more stable in serum plasma than in the central nervous
system, such as the
brain. In a more preferred embodiment, the prodrugs have improved BBB
penetration
property as compared with noribogaine or the noribogaine derivative, for
example, the
compounds of this invention have at least 20 %, 50 % or 100 % more BBB
penetration ability
than noribogaine or the noribogaine derivative.
Treatment of Pain
[01551 In one of its method aspects, the present invention is directed to a
method for
treating a pain in a patient which method comprises administering to said
patient a compound
of this invention or a pharmaceutically acceptable salt and/or solvate thereof
or a
pharmaceutical composition comprising a compound of this invention and a
pharmaceutically
acceptable excipient. The pain can be any type of pain including, but not
limited to
neuropathic or nociceptive pain, and various types thereof including somatic,
visceral and
phantom pain. The use of noribogaine for treatment of pain is described, for
example, in U.S.
Provisional Patent Application Serial No. 61/952,738, filed on March 13, 2014
and titled
"USE OF NORIBOGAINE FOR THE TREATMENT OF PAIN", which is incorporated
herein by reference in its entirety.
[0156] In another of its method aspects, the present invention is directed to
a method for
reducing tolerance to opioid analgesics in a patient undergoing treatment for
pain. The use of
noribogaine for reducing tolerance to opioid analgesics is described, for
example, in U.S.
Provisional Patent Application Serial No. 61/952,741, filed on March 13, 2014
and titled
"METHODS AND COMPOSITIONS FOR REDUCING TOLERANCE TO OPIO1D
ANALGESICS", which is incorporated herein by reference in its entirety.
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Treament of Addiction
[0157] In another of its method aspects, the present invention is directed to
a method for
treating addiction in a patient which method comprises administering to said
patient a
compound of this invention or a pharmaceutically acceptable salt and/or
solvate thereof or a
composition comprising a compound of this invention and a pharmaceutically
acceptable
excipient.
[0158] In certain embodiments, the treatment of addiction in a patient
comprises alleviating
the symptoms associated with withdrawal from drug dependency. Such symptoms
include
nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
In addition,
it is contemplated that treatment with a compound of this invention decreases
the drug
cravings normally experienced by addicts after cessation of the self-
administration of the
abused substance. It is contemplated that the compositions disclosed herein
are especially
useful in the treatment of addiction to opioids such as heroin and methadone.
However, it is
also useful in treating patients addicted to other substances, including
cocaine, alcohol,
amphetamines, tobacco, caffeine, opioid-like drugs, cannabinoids,
benzodiazepines, and any
other illicit, prescription, or generally available addictive substance, as
well as combinations
of these drugs.
[01591 The invention is also directed to a method for treating drug addiction
(involving
drug dependency or drug abuse) during withdrawal therapy by administering a
compound of
this invention to a patient at a dosage sufficient to reduce or eliminate one
or more symptoms
associated with withdrawal. Symptoms of acute withdrawal include nausea,
vomiting,
anxiety, abdominal cramps, muscle pain, chills and headache. In addition,
treatment with a
compound of this invention is contemplated to decrease the drug cravings
normally
experienced by addicts after cessation of the self-administration of the
abused substance, for
example, opioids such as heroin and methadone. However, compounds of this
invention are
contemplated to be also useful in treating patients addicted to other
substances, cocaine,
alcohol, amphetamines, tobacco, caffeine, opioid-like drugs, cannabinoids,
benzodiazepines,
and any other illicit, prescription, or generally available addictive
substance, as well as
combinations of these drugs. Compounds of this invention may be administered
to patients
suffering from drug dependence or abuse in conjunction with an opioid
antagonist such as
naloxone, naltrexone or nalorphine, for example, at a concentration of between
0.15 mg and
0.5 mg for each mg of the compound of this invention administered.
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101601 The invention is also directed to a method for preventing relapse to
drug use after
drug use has been stopped (e.g., after treatment to ameliorate drug abuse), by
administering a
compound of this invention to a patient at a dosage sufficient to reduce or
eliminate one or
more symptoms associated with post-acute withdrawal, including cravings. The
compound
may be administered at a lower (e.g., "maintenance") dose compared to that
used for
treatment of addiction and acute withdrawal symptoms.
101611 The use of noribogaine for acute and long-term treatment of drug abuse
and
withdrawal symptoms is described, for example, in U.S. Patent Application
Serial
Nos.14/214,157, 14/346,655, 14/195,822; and U.S. Provisional Patent
Application Serial
Nos. 61/941,390, filed February 18, 2014 and titled "LOW DOSE NORIBOGA1NE FOR
TREATING NICOTINE ADDICTION AND PREVENTING RELAPSE OF NICOTINE
USE"; 61/952,731, filed March 13, 2014 and titled "METHODS FOR ACUTE AND LONG-
TERM TREATMENT OF ALCOHOL DEPENDENCE"; and 61/952,727, filed March 13,
2014 and titled "METHODS FOR ACUTE AND LONG-TERM TREATMENT OF
SUBSTANCE ABUSE"; each of which is incorporated herein by reference in its
entirety.
Treatment of Depression
[01621 in another of its method aspects, the present invention is directed to
a method for
treating depressive disorders in a patient in need of the treatment, which
method comprises
administering to said patient a compound of this invention or a
pharmaceutically acceptable
salt and/or solvate thereof or a composition comprising a compound of this
invention and a
pharmaceutically acceptable excipient. Depressive disorders include major
depressive
disorder and dysthymic disorder (American Psychiatric Association, 1994a;
American
Psychiatric Association, 1994b). Major depressive disorder is characterized by
the occurrence
of one or more major depressive episodes without manic or hypomanic episodes.
A major
depressive episode is defined as a prominent and relatively persistent
depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at
least 2 weeks); it
can include at least 4 of the following 8 symptoms: change in appetite, change
in sleep,
psychomotor agitation or retardation, loss of interest in usual activities or
decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking
or impaired
concentration, and a suicide attempt or suicidal ideation. Dysthymic disorder
involves a type
of depression that is not severe enough to be called a major depressive
episode, but that lasts
much longer than major depressive disorder, without high phases. The use of
noribogaine for
treatment of depression is described, for example, in U.S. Provisional Patent
Application
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Serial No. 61/952,733. tiled on March 13, 2014 and titled "METHODS AND
COMPOSITIONS FOR TREATING DEPRESSION", which is incorporated herein by
reference in its entirety.
Treatment of Stress and'Or Anxiety
[0163] In another of its method aspects, the present invention is directed to
a method for
treating stress, such as post-traumatic stress disorder, in a patient in need
of the treatment,
which method comprises administering to said patient a compound of this
invention or a
pharmaceutically acceptable salt and/or solvate thereof or a composition
comprising a
compound of this invention and a pharmaceutically acceptable excipient.
101641 Stress or anxiety refers to the consequence when a patient fails to
respond
appropriately to emotional or physical threats, which may be actual or
imagined. Stress
symptoms or conditions may be cognitive, emotional, physical or behavioral,
including, but
not limited to a state of alarm and adrenaline production, short-term
resistance as a coping
mechanism, exhaustion, irritability, muscular tension, inability to
concentrate, poor judgment,
a general negative outlook, excessive worrying, moodiness, irritability,
agitation, inability to
relax, feeling lonely, isolated or depressed, aches and pains, diarrhea or
constipation, nausea,
dizziness, chest pain, headache, rapid heartbeat, eating too much or not
enough, sleeping too
much or not enough, social withdrawal, procrastination or neglect of
responsibilities,
increased alcohol, nicotine or drug consumption, and nervous habits such as
pacing about or
nail-biting. Stress can develop into a disabling disorder of excessive and
irrational fears, such
as obsessive-compulsive disorder, panic disorder, acute stress disorder and
post traumatic
stress disorder (PTSD).
[0165] PTSD is a severe stress disorder that can develop after exposure to an
event which
results in psychological trauma. Such events usually involve death of someone
else, threat of
death to oneself or to someone else, or trauma to the physical, sexual, or
psychological
integrity of one's own or someone else. PTSD may be an acute stress response
or a long term
stress response to such an event when it overwhelms one's ability to cope.
10166] Symptoms of PTSD include some or all of the following: recurrent re-
experiencing
of the trauma, for example, intrusive, upsetting memories of the event,
flashbacks of the
traumatic events (acting or feeling like the event is happening again),
recurring nightmares
(either of the event or of other frightening things); feelings of intense
distress and/or intense
physical reactions when reminded of the trauma; avoidance to the point of
having a phobia of
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places, people, and experiences that remind the sufferer of the trauma and a
general numbing
of emotional responsiveness; inability to remember important aspects of the
trauma; and
physical signs of hyperarousal, including sleep problems, trouble
concentrating, irritability,
anger, poor concentration, blackouts or difficulty remembering things,
increased tendency
and reaction to being startled, and hypervigilance to threat. Other symptoms
include
anhedonia, lack of interest in activities that used to be enjoyed, emotional
deadness,
distancing oneself from people, and/or a sense of a limited future (for
example, not being able
to think about the future or make future plans, not believing one will live
much longer), guilt,
shame, self-blame, depression and hopelessness, suicidal thoughts and
feelings, feeling
alienated and alone, headaches, stomach problems, chest pain and substance
abuse.
101671 The use of noribagaine for treatment of PTSD is described, for example,
in U.S.
Provisional Patent Application Serial No. 61/952,733, filed on March 13, 2014
and titled
"METHODS AND COMPOSITIONS FOR TREATING DEPRESSION", which is
incorporated herein by reference in its entirety. Combination therapy
[0168] Compounds of this invention maybe used alone or in combination with
other
compounds to treat the diseases or disorders described above. When
administered with
another agent, the co-administration can be in any manner in which the
pharmacological
effects of both are manifest in the patient at the same time. Thus, co-
administration does not
require that a single pharmaceutical composition, the same dosage form, or
even the same
route of administration be used for administration of both the compound of
this invention and
the other agent or that the two agents be administered at precisely the same
time. However,
co-administration will be accomplished most conveniently by the same dosage
form and the
same route of administration, at substantially the same time. Obviously, such
administration
most advantageously proceeds by delivering both active ingredients
simultaneously in a
novel pharmaceutical composition in accordance with the present invention.
[01691 In some embodiments, a compound of this invention can be used as an
adjunct to
conventional drug withdrawal therapy, specifically providing for the
administration of a
compound of this invention with one or more opioid antagonists.
4. Compositions
[01701 In another aspect, this invention is also directed to pharmaceutical
compositions
comprising a pharmaceutically acceptable excipient and a compound of this
invention or
mixtures of one or more of such compounds.
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101711 Although compositions suitable for oral, intravenous or intraarterial
delivery will
probably be used most frequently, other routes that may be used include
peroral, pulmonary,
rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal,
intracutaneous and subcutaneous
routes. In addition, it is contemplated that the composition can be
administered transdermally
in which drug is applied as part of a cream, gel, or patch (for examples of
transdermal
formulations, see U.S. Pat. Nos. 4,806,341; 5,149,538; and 4,626,539). Other
dosage forms
include tablets, capsules, pills, powders, aerosols, suppositories,
parenterals, and oral liquids,
including suspensions, solutions and emulsions. Sustained release dosage forms
may also be
used, for example, in a transdermal patch form. All dosage forms may be
prepared using
methods that are standard in the art (see e.g., Remington's Pharmaceutical
Sciences, 16th ed.,
A. Oslo editor, Easton Pa. 1980). Intranasal administration is an effective
method for
delivering a therapeutic agent directly to the respiratory tract, where the
therapeutic agent
may be quickly absorbed.
101721 The compositions are comprised of in general, a compound of this
invention or a
mixture thereof in combination with at least one pharmaceutically acceptable
excipient.
Acceptable excipients are non-toxic, aid administration, and do not adversely
affect the
therapeutic benefit of the compound of this invention. Such excipients may be
any solid,
liquid, semi-solid or, in the case of an aerosol composition, gaseous
excipient that is
generally available to one of skill in the art. Pharmaceutical compositions in
accordance with
the invention are prepared by conventional means using methods known in the
art.
101731 Solid pharmaceutical excipients include starch, cellulose, talc,
glucose, lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate,
sodium stearate,
glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid
and semisolid
excipients may be selected from glycerol, propylene glycol, water, ethanol and
various oils,
including those of petroleum, animal, vegetable or synthetic origin, e.g.,
peanut oil, soybean
oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for
injectable solutions,
include water, saline, aqueous dextrose, and glycols.
[0174] Compressed gases may be used to disperse a compound of this invention
in aerosol
form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable
pharmaceutical excipients and their formulations are described in Remington's
Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th
ed.,
1990).
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[01751 The compositions disclosed herein may be used in conjunction with any
of the
vehicles and excipients commonly employed in pharmaceutical preparations,
e.g., talc, gum
arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-
aqueous solvents,
oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may
also be added to
preparations, particularly to those for oral administration. Solutions can be
prepared using
water or physiologically compatible organic solvents such as ethanol, 1,2-
propylene glycol,
polyglycols, dirnethylsulfoxide, fatty alcohols, triglycerides, partial esters
of glycerine and
the like. Parenteral compositions containing the compounds described herein
may be
prepared using conventional techniques that may include sterile isotonic
saline, water, 1,3-
butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water,
Ringer's solution,
etc.
[01761 The amount of the compound in a formulation can vary within the full
range
employed by those skilled in the art. Typically, the formulation will contain,
on a weight
percent (wt %) basis, from about 0.01 to 99.99 wt % of a compound of this
invention based
on the total formulation, with the balance being one or more suitable
pharmaceutical
excipients. Preferably, the compound is present at a level of about I to 80 wt
%. In a liquid
composition, a compound of this invention should generally be present in such
compositions
at a concentration of between about 0.1 and 20 mg/ml. When either naloxone or
naltrexone is
combined with a compound of this invention, they should be present at 0.05 to
0.5 mg for
each mg of the compound of this invention.
[0177i The choice of formulation depends on various factors such as the mode
of drug
administration and bioavailability of the drug substance. For delivery via
inhalation the
compound can be formulated as liquid solution, suspensions, aerosol
propellants or dry
powder and loaded into a suitable dispenser for administration. There are
several types of
pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers
(NMI) and dry
powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air
that causes
the therapeutic agents (which are formulated in a liquid form) to spray as a
mist that is carried
into the patient's respiratory tract. MDI's typically are formulation packaged
with a
compressed gas. Upon actuation, the device discharges a measured amount of
therapeutic
agent by compressed gas, thus affording a reliable method of administering a
set amount of
agent. DPI dispenses therapeutic agents in the form of a free flowing powder
that can be
dispersed in the patient's inspiratory air-stream during breathing by the
device. In order to
achieve a free flowing powder, the therapeutic agent is formulated with an
excipient such as
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lactose. A measured amount of the therapeutic agent is stored in a capsule
form and is
dispensed with each actuation.
101781 Recently, pharmaceutical formulations have been developed especially
for drugs
that show poor bioavailability based upon the principle that bioavailability
can be increased
by increasing the surface area i.e., decreasing particle size. For example,
U.S. Patent No.
4,107,288 describes a pharmaceutical formulation having particles in the size
range from 10
to 1,000 nm in which the active material is supported on a crosslinked matrix
of
macromolecules. U.S. Patent No. 5,145,684 describes the production of a
pharmaceutical
formulation in which the drug substance is pulverized to nanoparticles
(average particle size
of 400 mn) in the presence of a surface modifier and then dispersed in a
liquid medium to
give a pharmaceutical formulation that exhibits remarkably high
bioavailability.
[0179] In a preferred embodiment, a narrow therapeutic dose of a compound of
the
invention is administered to a patient such that the patient's QT interval is
not prolonged to
unacceptable levels. In some embodiments, patients are administered
therapeutic doses of the
compound in a clinical setting with cardiac monitoring. In some embodiments,
the patient
will be pre-screened to evaluate tolerance for prolongation of QT interval,
e.g., to determine
whether the patient has any pre-existing cardiac conditions which would
disqualify them
from treatment with the compound. In some embodiments, the patient's QT
interval is not
prolonged by more than about 50 ms, preferably, not more than about 30 ms, and
more
preferably, not more than about 20 ms. In some embodiments, the patient's QT
interval does
not exceed about 500 ms, preferably, does not exceed about 450 ms, and more
preferably
does not exceed about 420 ms.
[0180] In some embodiments, the dosage of a compound of this invention that is
administered to the patient is sufficient to provide an average serum
concentration of about
50 ng/ml, to about 850 ng/mL (area under the curve/24 hours, AUC/24 h), or any
subrange or
subvalue there between. In a preferred embodiment, the dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof
administered to the
patient provides an average serum concentration of about 50 ng/mL to about 400
nWmL
(AUC/24 h).
101811 Generally, the compound of this invention is administered in an
effective amount. It
is contemplated that the dosage required for treating pain or addiction, or a
combination
thereof may differ according to the condition(s) being treated, however, the
dosing regimen
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can be readily determined by the attending clinician based on the desired
treatment. It is
contemplated that generally, the aggregate dosage of a compound of this
invention
administered to a patient may be from about I to about 8 mg per kg of body
weight per day
(mg/kg/day), or from about 1 to about 4 mg/kg/day, preferably, from about 1 to
about 3
mg/kg/day. For example, for administration to a 70 kg person, the dosage range
would
preferably be about 70 to 210 mg per day. In some embodiments, a lower dosage
of a
compound of this invention is administered, for example from about 50 ng to
less than 10 pg
per kg of body weight per day. In other embodiments, a maintenance dosage of a
compound
of this invention is administered, for example approximately 80% or less of
the
therapeutically effective dose may be effective for prevention of relapse of
drug use in an
addicted patient treated to ameliorate their substance abuse.
101821 In some embodiments, a patient is pre-screened with a compound of the
invention to
determine whether the patient is a candidate for treatment with the compound,
for example
whether the patient's QT interval will be prolonged to an unacceptable level
by treatment
with the compound. In a preferred embodiment, the patient is treated with a
sub-therapeutic
dosage of the compound, for example about 50% to about 90% of the
therapeutically
effective dosage of compound, and the patient's response to the compound is
monitored. In
an especially preferred embodiment, the patient's QT interval is monitored
before and during
treatment with the compound. Methods for pre-screening a patient before
treatment can be
found, for example, in U.S. Provisional Patent Application Serial No.
61/952,744, filed
March 13,2014 and titled "METHODS AND COMPOSITIONS FOR PRE-SCREENING
PATIENTS FOR TREATMENT WITH NORIBOGAINE," which is incorporated herein by
reference in its entirety.
(0183) In addition to the methods discussed above, the present invention is
directed to a
pharmaceutical composition, preferably in unit dose form, comprising a
compound of this
invention. When administered to a patient, one or more unit doses provide an
amount of a
compound of this invention effective to treat a disease or condition as
described above,
including pain, depression, stress, and/or addiction.
[0184] The amount of the composition administered will depend on a number of
factors,
including but not limited to the desired final concentration of the compound,
the
pharmacokinetic and pharmacodynamic properties of the compound, the size, age,
and
physiological profile of the patient, and the like. The active compound is
effective over a
wide dosage range and is generally administered in a pharmaceutically
effective amount. It
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will be understood, however, that the amount of the compound actually
administered will be
determined by a physician, in the light of the relevant circumstances,
including the condition
to be treated, the chosen route of administration, the actual compound
administered, the age,
weight, and response of the individual patient, the severity of the patient's
symptoms, and the
like.
[0185] Determination of dosages is well within the empiric knowledge of
persons skilled in
the art; nonetheless, it can be appreciated that estimates of final dosages
can be made by
approximating the concentration of compound necessary to achieve a desired
therapeutic
activity, such as treatment of pain and/or addiction. Extrapolation to a
specified mammalian
dosage range, or more particularly a human dosage range is well within the
skill of the
practitioner.
101861 In some embodiments, compositions are administered in one dosing of a
single
formulation and in other embodiments, compositions are administered in
multiple dosing of a
single formulation within a specified time period. In some embodiments, the
time period is
between about 3 hours to about 6 hours. In other embodiments, the time period
is between
about 6 hours and 12 hours. In additional embodiments, the time period is
between about 12
hours and 24 hours. In yet further embodiments, the time period is between
about 24 hours
and 48 hours. The administration of separate formulations can be simultaneous
or staged
throughout a specified time period, such that all ingredients are administered
within the
specified time period.
S. Synthetic Methods
101871 The compounds of this invention can be prepared from readily available
starting
materials using the following general methods and procedures. It will be
appreciated that
where typical or preferred process conditions (i.e., reaction temperatures,
times, mole ratios
of reactants, solvents, pressures, etc.) are given, other process conditions
can also be used
unless otherwise stated. Optimum reaction conditions may vary with the
particular reactants
or solvent used, but such conditions can be determined by one skilled in the
art by routine
optimization procedures.
[01881 Additionally, as will be apparent to those skilled in the art,
conventional protecting
groups may be necessary to prevent certain functional groups from undergoing
undesired
reactions. Suitable protecting groups for various functional groups as well as
suitable
conditions for protecting and deprotecting particular functional groups are
well known in the
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art. For example, numerous protecting groups are described in T. W. Greene and
G. M.
Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York,
1999, and
references cited therein.
101891 Furthermore, the compounds of this invention will typically contain one
or more
chiral centers. Accordingly, if desired, such compounds can be prepared or
isolated as pure
stereoisomers, i.e., as individual enantiomers or diastereoiners, or as
stereoisomer-enriched
mixtures. All such stereoisomers (and enriched mixtures) are included within
the scope of
this invention, unless otherwise indicated. Pure stereoisomers (or enriched
mixtures) may be
prepared using, for example, optically active starting materials or
stereoselective reagents
well-known in the art. Alternatively, racemic mixtures of such compounds can
be separated
using, for example, chiral column chromatography, chiral resolving agents and
the like.
101901 Still further, some of the compounds defined herein include vinyl
groups which can
exist in cis, trans or a mixture of cis and trans forms. All combinations of
these forms are
within the scope of this invention.
101911 The starting materials for the following reactions are generally known
compounds
or can be prepared by known procedures or obvious modifications thereof For
example,
many of the starting materials are available from commercial suppliers such as
Aldrich
Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-
Chemce or
Sigma (St. Louis, Mo., USA). Others may be prepared by procedures, or obvious
modifications thereof, described in standard reference texts such as Fieser
and Fieser's
Reagents for Organic Synthesis, Volumes 115 (John Wiley and Sons, 1991),
Rodd's
Chemistry of Carbon Compounds, Volumes 1 5 and Supplementals (Elsevier Science
Publishers, 1989), Organic Reactions, Volumes 1 40 (John Wiley and Sons,
1991), March's
Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and
Larock's
Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
[0192] Compounds of Formula II can be readily prepared from noribogaine by
methods
described herein and those known to one of skill in the art. A skilled artisan
would appreciate
that the reactivity of the hydroxy group and the indole nitrogen is different
so that selectivity
can be achieved by selecting suitable reagents and suitable reaction
conditions for one of
them to react but leaving the other intact to form the desired product. For
example, the
hydroxy group is expected to selectively react with an acid R2C(0)0H in the
presence of
triphenylphosphine (Ph313) and diethyl azodicarboxylate (DEAD) to give
compound 1-1 and
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1-3. Thus, as shown in Scheme I, noribogaine can react with LG-R where LG is a
leaving
group such as hydroxy, alkoxy, halo, etc., to give compound 1-1, which may
further react
with LG-L-R' to form compound 1-2. In other embodiments (i.e. when R is H),
the phenol is
protected by reaction with a suitable protecting group, PG-LG, where LG is a
leaving group
such as defined above, such that the indole nitrogen is derivatized with L-R'.
Suitable
protecting groups are well known in the art (see T. W. Greene, P. G. M. Wuts,
Protective
Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006).
In another
alternative embodiment (i.e. when L is a bond and RI is H), the indole
nitrogen is protected
with a suitable protecting group, PG (see Greene et al., supra), such phenol
that is derivatized
with R.
Scheme 1
HO C2116
I \ 2. LG-R
1. 1.43-1,12'
1-1 1-2
HO, ,C2H6
HO, C2115 protecdon %.,2116 \> 1. LG-L-R
2. denrolecdon ....N
L-R
14 1-4
HOrc2HeHO.., Ho,. C21-is 1.
2. deprotection
1
PG
14
14
101931 Alternatively, as shown in Scheme 2, compounds of this invention
wherein L-R' is
not hydrogen may be prepared by reacting ibogaine with LG-L-R to give compound
2-1.
Compound 2-1 can be demethylated by methods known in the art, such as reaction
with
boron tribromide/methylene chloride at room temperature to give compound 1-4,
which may
further react with LG-R to give compound 1-2.
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Scheme 2
H3C0
-14 ../C2H5 - , -
/C2H5 1 cle-methylation= C2145
i L-111
2-1 1.4
R-0 4.<2H5
2 1G-R
L-81
1-2
[0194J Compounds described herein can also be prepared as shown in any of
Schemes 3-5,
wherein R, RI, L, RI and RI are as defined herein, L0 is a leaving group such
as hydroxy,
alkoxy, halo, etc., and X is iodo (I) or bromo (Br) . Compounds 3-1 and 4-1
can be prepared
according to procedures described in, for example, U.S. Patent 6,211,360 or
U.S. Patent
Publication No. 2013/0165647.
101951 In Scheme 3, Compound 3-1 reacts with LG-L-RI to give compound 3-2.
Compound 3-2 can be de-carboxylated by methods described herein or known in
the art,
such as using refluxing hydrazine, or hydrolyzing the ¨COOCH3 group to an
acid, and
reacting the corresponding sodium or lithium salt with aqueous mineral acid to
give
compound 3-3. An exemplifying decarboxylation procedure for preparing an
intermediate 7-
3 is illustrated in Scheme 7 below, which includes a procedure for preparing
an
enantiomerically pure intermediate 7-3 when the starting material 7-1 is a
racemic mixture or
when racemization occurs during redcution. Intermediate 7-3 can react with LG-
L-RI to
give compounds of this invention.
[0196i In Scheme 4, Compound 4-1 is halogenated to compound 4-2. When X is
iodo, the
iodo group can be conveniently incorporated into the indole ring by reacting
compound 4-1,
e.g. and without limitation, with N-iodosuccinimide (NIS). The iodo group can
be also
incorporated using a phenyl iodonium intermediate by reaction with PhI(OH)OTs,
followed
by removal of the phenyl group through reaction with Off. When X is iodo or
bromo, the
iodo or the bromo group can be incorporated by nitration to form a nitro
intermediate,
followed by reducing the nitro group to an amino group, diazotizing the amino
group to form
a diazoniurn group, and reacting the diazonium compound with CuI or CuBr.
Exemplifying
halogenation procedures are illustrated in Scheme 6 below. Compound 4-2 is
then converted
to compound 4-3 by reacting with ROB or RO-, e.g., in presence of a copper
catalyst, such as
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Cut and a ligand, such as tetramethyl phenanthroline (see, for example, "An
Improved Cu-
Based Catalyst System for the Reactions of Alcohols with Aryl Halides", Altman
et al., J.
Org. Chem., 2008, 73, 284-286, incorporated herein by reference), or CuBr
(U.S. Patent No.
4,422,955, incorporated herein by reference) useful for incorporating an -OR
group, such as,
benzyloxy or substituted benzyloxy group. Compound 4-3 reacts with 1,G-1,-W to
give
compound 4-4, which is de-carboxylated by methods described herein or known in
the art to
provide compound 4-5.
[01971 In Scheme 5, compound 4-1 is de-carboxylated by methods described
herein or
known in the art to provide compound 5-1. Compound 5-1 is halogenated to
compound 5-2,
which reacts with ROH to provide compound 5-3, followed by reaction with I.,G-
L-R1 to give
compound 4-5 using methods described herein.
Scheme 3
N =-= oil r-N.
R" R1, ,
2. de-carboxylate
................................................. . ) \
1:. RI
CO2CH3
H CO2CH3 1:-R'
34 3-2 34
Scheme 4
-1!Ix sc...t. 1.-----.....
il ROH; .0
12-- \.õ.....cr-------N
i \ ii
) R11 1 \ Li R
catayst ,,,, , /\__ õ..,--
,.....
NEI,Z..õ..-1,3.
H3C0 H3C0 µ H3C0 µ,
b
o o
4-1 4-2 44
R-0r------N R- µ
,r------.N
) R11
LG-L-R1 1 \
. ) 11 decarboxylation
..N /
. _......-.
R c_11
---..
111
õ.L. o= L-R,
R1 tocH3
4-4 4-5
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Scheme 5
=
N
R11 r------N
x
____... NH halogenation
'NH , NH 1
---e\
H3C0 v
0
5-1 5-2
4-1
ROH;
--- R"
Copper catayst 1 \ ) R" L.G-L-R1
\ 1---(/'
'NH 1.õ....--....õ:, 1..-R1
5-3 4-5
Scheme 6
MO' I
Ph--1 (+)
R11 O
.--
,...\.2 / \ : R11
,
H- \.,
NH õ.......-L...A NH
H3C0 H3C0 µ.
0 0
6-2 6-3
Phi(OH)07s
I
rt.-- N, R" 02N -----N H2N
) R11
\ / \ - nitration
-=,.i., õ D R1 I NO2 =cti % / \
ITh/ 2 re u on .õ.. .
__________________________ 17,1\ NH ,11.-(..4
H300 H3C0-.. H3C0 \
0
0 0
. 6-1 6-4 6-5
+N2, ..f.,12) . X r----N
.....-
N.,--)_.
\ '
diazotization I \ R1
CuX
......õ .."NH /1õ......1Z/
H3C0--", H3C0-0
0
6-8 6-7
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Scheme 7
R1 Reduction RioR1
).\ R11 LiAIH4 or 1
1.
NaBH4 c \ ,-.{R Retro aldoi =
,) R11
= \
== NH NH
tõ,...AF13.,A
r.,-v-^(kk
HO
0
7-1 7-2 7-3
Esterification with
chiral caroxylic acid I Retro aldol
R*COOH, wherein R
is chiral group
Rio R1
R _______________________________________________
NH Diastereomer
" NH
9 separation HO
Crystallization.
column
0 7-2A
chromatography,
7.4 etc.
Examples
10198) The present invention is further defined by reference to the following
examples. It
will be apparent to those skilled in the art that many modifications, both to
materials and
methods, may be practiced without departing from the scope of the current
invention.
Table HI. List of abbreviations and acronyms.
Abbreviation Meaning
C Degree Celcius
Ac Acetyl
bs Broad singlet
ca. Approximately
CDI N,N7-Carbonyl diimidazole
Doublet
dd Doublet of doublets
DEAD Diethyl azodicarboxylate
DIPEA N,N-Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DMF Dimethylformamide
Et Ethyl
Gram
Hour
HPLC High-performance liquid chromatography
Hz Hertz
Intravenous
Kg Kilogram
Molar
in Multiplet
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Abbreviation Meaning
M+1 Mass peak
Me Methyl
mg Milligram
MHz Megahertz
min Minute
mL Milliliter
mmol Millimole
MS Mass spectrometry
Normal
NaHDMS Sodium hexamethyldisilazane
NMR Nuclear magnetic resonance
Ph Phenyl
Quartet
q.s. Sufficient amount
r.t./rt Room temperature
Singlet
Triplet
TBAF Tetra-n-butylammonium fluoride
TBS tert-Butyldimethylsily1
TBSCI tert-Butyldimethylsilyl chloride
td Triplet of doublets
THF Tetrahydrofuran
TLC Thin layer chromatography
v/v Volume/volume
wt% Weight percent
8 Chemical shift
AL Microliter
[0199] Compounds of the invention can be prepared from readily available
starting
materials using, for example, the following general methods and procedures. It
will be
appreciated that where typical or preferred process conditions (i.e., reaction
temperatures,
times, mole ratios of reactants, solvents, pressures, etc.) are given, other
process conditions
can also be used unless otherwise stated. Optimum reaction conditions may vary
with the
particular reactants or solvent used, but such conditions can be determined by
one skilled in
the art by routine optimization procedures.
[0200] Additionally, as will be apparent to those skilled in the art,
conventional protecting
groups may be necessary to prevent certain functional groups from undergoing
undesired
reactions. Suitable protecting groups for various functional groups as well as
suitable
conditions for protecting and deprotecting particular functional groups are
well known in the
art. For example, numerous protecting groups are described in T. W. Greene, P.
G. M. Wuts,
Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New
York, 2006,
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and references cited therein. The starting materials for the following
reactions are generally
known compounds or can be prepared by known procedures or obvious
modifications
thereof. For example, many of the starting materials are available from
commercial suppliers
such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance,
California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may
be
prepared by procedures, or obvious modifications thereof; described in
standard reference
texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15
(John Wiley,
and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and
Supplementals
(Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John
Wiley, and
Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th
Edition,
2001), and Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989).
Example 1. Preparation of Compound 1
9H3 'N= c2H5
H3C-N."--Thro-
6 \
CH3
102011 Compound 1 may be prepared by reacting noribogaine with at least two
equivalents
of (C1-13)2NCH2CH2C(0)C1 in the presence of a base in a suitable solvent. In
one
embodiment, the reaction is conducted in a polar solvent. Upon reaction
completion,
compound 1 can be recovered by conventional techniques such as neutralization,
extraction,
precipitation, chromatography, filtration and the like; or, alternatively,
used without
purification and/or isolation.
Example 2. Preparation of Compound 2
HO
\
C2Hs
eH3
102021 Compound 2 may prepared by reacting noribogaine with at least one
equivalent of
(CH3)2NCH2CH2C(0)CI in the presence of a base in a suitable solvent to give an
intermediate
product. In one embodiment, the reaction is conducted in a polar solvent. The
intermediate
product can be demethylated by reaction with boron tribromide/methylene
chloride at room
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temperature to give compound 2, Upon reaction completion, compound 2 can be
recovered
by conventional techniques such as neutralization, extraction, precipitation,
chromatography,
filtration and the like; or, alternatively, used without purification and/or
isolation.
Example 3. Preparation of Compound 3
CH3 N--
H3c-L---r _,,C2115
I
(02031 Compound 3 may prepared by reacting noribogaine with one equivalent of
(CI-13)2NCH2CII2C(0)C1 in the presence of a base, such as pyridine, in a
suitable solvent, or
with one equivalent oKI-I3)2NCH2C}12C(0)011 in the presence of
triphenylphosphine (P11313)
and diethyl azodicarboxylate (DEAD). In one embodiment, the reaction is
conducted in a
polar solvent. Upon reaction rational completion, compound 3 can be recovered
by
conventional techniques such as neutralization, extraction, precipitation,
chromatography,
filtration and the like; or, alternatively, used without purification and/or
isolation.
Example 4. Preparation of Compound 8
a
y
TBSO 0 TBSO,
02N
\ \
NaHMDS, THF, -78 C to r.t. N
0 NH
8-A
8-B
HO,
TBAF, THF N
__________ =
- 78 C
0 NH
8
a) Preparation of TBS-Noribogaine 8-A
102041 A suspension of noribogaine hydrochloride (852 mg, 2.56 mmol), TBS-CI
(444 mg.
2.94 mmol) and imidazole (227 mg. 3.33 mmol) in DMF (6 mI,) was stirred at
room
temperature for 20 h. The resulting clear solution was diluted with 10% 2-
propanol/dichloromethane and washed with water and brine. The aqueous phase
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extracted with Et0Ac. The combined organic layers were concentrated and
purified by
column chromatography (Et0Ac/Hexanes, v/v, 2/1) to give compound 8-A (911 mg,
87%) as
a white solid.
[0205] MS calculated for (C251-1381\120S1): 410; MS found, (M.1): 411.
b) Preparation of Compound 8-B
[0206] NaHMDS (0.75 mL, 1.0 M solution in THF) was added into a solution of
TBS-
noribogaine 8-A (205 mg, 0.5 mmol) in THF (10 mL) at -78 C. The resulting
solution was
stirred for 10 min at -78 C then a solution of 4-nitrophenyl chloroformate
(182 mg, 0.9
mmol) in THF (8 mL, pre-cooled to -78 C) was added quickly. The reaction
mixture was
allow to warm to room temperature and stir for 1 hour, followed by the
addition of N,N-
dimethylethylenediarnine (0.22 mL, 2.0 mmol). After stirring at room
temperature for an
additional hour, the reaction mixture was diluted with 10% 2-
propanol/dichloromethanc and
washed with water and brine. The aqueous phase was extracted with Et0Ac. The
combined
organic layers were concentrated and purified by column chromatography
(Et0Ac/Hexanes.
v/v, 2/1 to 99:1 Et0Ac:triethylamine). The desired product compound 8-B (138
mg, 53%)
was obtained as white solid.
102071 MS calculated for (C301148N402SO: 524; MS found, (M+1): 525.
c) Preparation of C'ompound 8
[02081 TBAF (0.68 mL, 1.0 M solution in THF, 0.68 inmol) was added to a
solution of
compound 8-B (178 mg, 0.34 mmol) in THF (12 mL) at -78 C. The resulting
solution was
stirred for 40 min at -78 C before it was quenched by addition of IN aqueous
HC1 (2 mL).
The reaction mixture was allowed to warm to room temperature and was
concentrated. The
residue was purified by Preparative-HPLC to give compound 8 as the
hydrochloride salt (110
mg, HC1 salt, 72%) as a white solid.
[02091 MS calculated for (C24H34/4402): 410; MS found, (M+1): 411. ill NMR
(300
MHz, CD30D) 8 8.20 (bs, IF!), 7.49 (d, 1H), 6.87 (s, 1H), 6.80 (d, 1H), 3.50 -
3.92 (m, 6H),
3.36- 3.58 (m, 4H), 3.00 - 3.36 (m, 2H) , 2.80 - 3.00 (m, 6H), 2.50 (td, 1H),
1.85 - 2.20 (m,
3H), 1.48 - 1.82 (m, 3H), 1.22- 1.46 (m, 1H), 1.04 (t, 3H).
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Example 5. Preparation of Compound 15
HCI
DMAP
HO,
acetic anhydride
141, N 40 C, overnight
15-A
1 NaHMDS NN
4-nitrophenyi chioroforrnate HO 46
THF, -78 C to rt
N
=
2
Na0 N \ N--
4
Na/THF
HON
-
a) Preparation of Noribogaine acetate 15-A
102101 A mixture of noribogaine (300 mg, 0.9 mmol) and DMAP (10 mg, 0.09 mmol)
in
acetic anhydride (6 mL) was heated at 40 C for 16 h. The acetic anhydride was
co-
evaporated with toluene at 40 C under reduced pressure. The residue was
dissolved in ethyl
acetate (100 mL), and the resulting solution was stirred with saturated NaHCO3
solution (50
mL) at rt for 2 h. The organic phase was separated and concentrated under
reduced pressure.
The crude product was purified by chromatography on silica gel (ethyl
acetate/hexane : ¨1/2)
to give compound 15-A (280 mg, 90%) as white solid.
102111 MS calculated for (C211126N202)+: 338; MS found, (M+1): 339. 1H NMR
(300
MHz, CD30D) 8 7.18 (d, J=8.4 Hz. 1H), 7.06 (d, J=2.4 Hz, 1H), 6.7 (dd, J=8.4
Hz, J=2.4 Liz,
1H), 3.38 (m, 1H), 3.1 (m, 4H), 2.95 (m, 2H), 2.65 (m, 1H), 2.27 (s, 3H), 2.14
(in, IH), 1.88
(m, 2H), 1.64-1.45 (m, 4H), 1.23 (m, 1H), 0.94 (t, .1=7.5 Hz, 3H).
b) Preparation of Compound 15
[02121 To a solution of N,N-dimethylethanolamine (0.6 mL, 6 mmol) in THF (1.4
mL) was
added sodium (46 mg, 2 mmol) at rt. The reaction mixture was stirred at rt
until the sodium
disappeared. The resulting solution of sodium N,N-dimethylethanolamine was
used for the
reaction below.
[02131 To a solution of compound 15-A (200 mg, 0.59 mmol) in THF (2 mL) was
added
dropwise NaHMDS (0.59 mL, 0.59 mmol) at -78 'C. The reaction mixture was
stirred at -78
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c'e for 10 min, and then the resulting reaction mixture was transferred via a
cannula to a
solution of 4-nitrophenyl chlorofonnate (143 mg, 0.71 mmol) in THE (1 mL) at -
78 "C. The
reaction mixture was allowed to warmed to it and stirred for 30 min. The
reaction mixture
was then cooled to -78 "C, and sodium N,N-dimethylethanolamine solution (1.4
mL, 1.4
mmol, 1 M in THE) was added. The reaction mixture was allowed to warm to rt
and stirred
for 30 min. Water (5 mL) was added, and the reaction mixture was extracted
with ethyl
acetate (2 x 20 mL). The combined organic layers were concentrated under
reduced pressure,
and the crude product was purified by Flash Chromatography (ethyl
acetate/methanol/triethylamine : =100/5/1). The resulting yellow oil was
further purified by
prep-HPLC to give compound 15 (66 mg, 30%) as a white solid.
102141 MS calculated for (C24H33N303)+: 411; MS found, (M-1-1); 412. ill NMR
(300
MHz, CD30D) 8 7.79 (d, J=8.7 Hz, 1H), 6.7 (d, 3=2.4 Hz, 1H), 6.66 (dd, J=2.4
and 8.7 Fiz,
1H), 4.4 (m, 3H), 3.75 (m, 1H), 3.0 (m, 3H), 2.87 (m, 2H), 2.8 (m, 2H), 2.7
(m, 3H), 2.5 (m,
3H), 2.29 (s, 6H), 2.14 (m, 1H), 1.85 (m, 2F1), 1.61-1.23 (m, 5H), 1.1 (m,
1H), 0.94 (t, J=7.2
Hz, 3H).
Example 6. Preparation of Compound 16
1 NaHMDS
4-nitrophenyl ehloroformate /r)72.
THF, -78 C to rt
II
-.1(0
0 N
2.N,N-dimethyl ethylene-
diernine, -78 cC
15-A 16
[0215I To a solution of compound 15-A (310 mg, 0.92 mmol) in THF (3 mL) was
added
dropwise NaHMDS (0.87 mL, 0.87 mmol) at -78 'C. The reaction mixture was
stirred at -78
"C for 10 min, and then the resulting reaction mixture was transferred via a
cannula to a
solution of 4-nitrophenyl chloroformate (185 mg, 0.92 mmol) in THF (1 mL) at -
78 "C. The
reaction mixture was allowed to warm to rt and stirred for 30 mm. The reaction
mixture was
recooled to -78 C, and NõN-dimethyl ethylenediamine (79 mg, 0.9 mmol) was
added. The
reaction mixture was warmed to rt and stirred for 30 min. Water (5 mL) was
added, and the
reaction mixture was extracted with ethyl acetate (2 x 20 mL). The combined
organic layers
were concentrated under reduced pressure, and the crude product was purified
by Flash
Chromatogaphy (ethyl acetate/methanol/triethylamine : =100/5/1). The resulting
yellow oil
was further purified by prep-HPLC to give compound 16(50 mg, 14%) as a white
solid.
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[02161 MS calculated for (C26H36N403)i.: 452; MS found, (M4-1): 453. 1H NMR
(300
MHz, CD30D) 8 7.5 (d, 3=8.7 Hz, 1H), 7.12 (d, .1=2.4 Hz, 1H), 6.8 (dd, 3=2.4
and 8.7 Hz,
1H), 3.5 (m, 3H), 3.4 (m, 1H), 3.2 (m, 2H), 3.0 (m, 3H), 2.8 (m, 1H), 2.6 (m,
3H), 2.3 (s, 6H),
2.27 (s, 3H), 2.14 (m, 1H), 1.85 (m, 2H). 1.61-1.23 (m, 5H), 1.1 (m, 1H), 0.94
(t, 3=6.9 Hz,
3H).
Example 7. Preparation of Compound 38
NaHMDS
N r¨ 4-mtrophenyl chloroformate N r---
THF, -78 C to rt
6
..-0
15-A c?
38-A
NO2
methylamine
or- N
CH2C12
0NH
/ \
38
a) Preparation of Compound 38-A
[02171 To a solution of compound 15-A (42 mg, 012 mmol) in THF (1 mL) was
added
dropwise NaHMDS (0.14 mL, 0.14 mmol) at -78 C. The reaction mixture was
stirred at -78
C for 10 min and then 4-nitrophenyl chloroforrnate (27 mg, 0.14 mmol) was
added at -78 'C.
The reaction mixture was allowed to warm to rt and stirred for 1 h. Saturated
NaHCO3
solution (5 mL) was added, and the reaction mixture was extracted with ethyl
acetate (2 x 10
mL). The combined organic layers were concentrated under reduced pressure. The
crude
product was purified by chromatography on silica gel (ethyl
acetate/hexane=1/1) to give
compound 38-A (20 mg) as a yellow oil in 33% yield.
[02181 MS calculated for (C28H29N306)+: 503; MS found, (M4.1): 504.
b) Preparation of Compound 38
[02191 A reaction mixture of compound 2 (150 mg, 0.3 mmol) and methylamine (1
mL, 33
wt% in ethanol) in CH2C12 (5 mL) was stirred at rt for 1 h. The reaction
mixture was washed
with saturated NaliCO3 solution, and the aqueous layer was extracted with
ethyl acetate (2 x
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20 mL). The combined organic extracts were concentrated under reduced
pressure. The crude
product was purified by chromatography on silica gel (ethyl
acetate/methanol/triethylamine
100/2/1) to give compound 3 (80 mg) as a yellow oil in 80% yield.
[0220] MS calculated for (C21H27N302)+: 353; MS found, (M+1): 354.
Example 8. Preparation of Compound 18
HO e-Co
"'=-=
DMAP
_____________________________________________ oil 1
NN
acetic anhydride
0 ti NH
\
38 18
10221) A reaction mixture of compound 38 (80 mg, 0.22 mmol) and DMAP (10 mg,
0.09
mmol) in acetic anhydride (3 mL) was heated at 40 C for 16 h. The acetic
anhydride was co-
evaporated with toluene at 40 C under reduced pressure. The residue was
dissolved in ethyl
acetate (50 mL), and the resulting solution was stirred with saturated NaHCO3
solution (50
mL) at rt for 30 min. The organic phase was separated and concentrated under
reduced
pressure. The crude product was purified by chromatography on silica gel
(ethyl
acetate/methanol/triethylamine : =100/2/1) to afford a crude residue, which
was further
purified by preparative HPLC give compound 18 (50 mg, 60%) as a yellow solid.
[02221 MS calculated for (C231429N303)s: 395; MS found, (M+1): 396. ill NMR
(300
MHz, CD30D) 8 7.44 (d, 3=8.7 Hz, 1H), 7.13 (d, 3=2.4 Hz, 1H), 6.7 (dd, J=2.4
and 8.7 Hz,
1H), 3.2 (m, 1H), 3.05 (n, 4H), 2.98 (s, 3H), 2.95 (in, 2H), 2.83 (m, 1H), 2.6
(m, 1H), 2.27
(s, 3H), 2.14 (m, 1H), 1.88 (m, 2H), 1.64-1.45 (m, 4H), 1.23 (n, 1H), 0.92 (t,
J=7.2 Hz, 3H).
Example 9. Preparation of Compound 31
NaHMDS
N -- methyl ohloroformate
0 THF, -78 C to rt
__________________________________________ - ")r
,
15-A 31 v
[02231 To a solution of compound 15-A (200 mg, 0.59 mmol) in THF (2 mL) was
added
dropwise NaHlviDS (0.68 mL, 0.68 mmol) at -78 C. The reaction mixture was
stirred at -78
C for 10 min, and then methyl choroformate (78.6 uL, 0.68 mmol) was added at -
78 C. The
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reaction mixture was allowed to warm to rt and stirred for 1 h. Saturated
NaHCO3 solution (5
mL) was added, and the reaction mixture was extracted with ethyl acetate (2 x
20 mL). The
combined organic extracts were concentrated under reduced pressure to afford a
crude
product which was purified by preparative-HPLC to give compound 31 (116 mg,
55%) as a
white solid.
[02241 MS calculated for (C23H28N204)+: 396; MS found, (M+1): 397. NMR (400
MHz, CD30D) 8 7.95 (d,1=9.2 Hz, 1H), 7.06 (d, .1=1.2Hz, 1H), 6.7 (dd,1=9.2 Hz,
J=1.2 Hz,
111), 4.84 (s, 3H), 3.8 (m, 11-1), 3.1 (m, 3H), 2.99 (m, 2H), 2.8 (m, 1H),
2.68 (m, 111), 2.15 (s,
3H), 2.14 (m, 11.1), 1.85 (m, 2H), 1.61 (m, 2H), 1.58 (m, 1H), 1.46 (m, 111),
1.23 (in, 111),
0.94 (t, .1=7.2 Hz, 3H).
Example 10. Preparation of Compound 39
HO. TBSO\ TBSO
N TBSCI. azol!
DMF, r.t. = NaHMDS, THF
HCI
8-A
9-A
HO
TBAF, THF
\)- ,<X" - =
- 78 C to r.t. 1,J=
39
a) Preparation of TBS-Noribogaine 8-A
[02251 A suspension of noribogaine hydrochloride (852 mg, 2.56 mmol), TBS-Cl
(444 mg,
2.94 mmol) and imida7ole (227 mg, 3.33 mmol) in DMF (6 mL) was stirred at room
temperature for 20 h. The resulting clear solution was diluted with 10% 2-
propanol/dichloromethane and washed with water and brine. The aqueous phase
was
extracted with Et0Ac. The combined organic extracts were concentrated and
purified by
column chromatography (Et0Ac/Hexanes, v/v, 2/1) to give compound 8-A (911 mg,
87%) as
a white solid.
[02261 MS calculated for (C25H38N20Si): 410; MS found, (M+1): 411.
h) Preparation of compound 9-A
[02271 NaHMDS (0.9 mL, 1.0 M solution in THF, 0.9 mmol) was added into the
solution
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of compound 8-A (246 rug, 0.6 mmol) in THF (6 mL) at -78 C. The resulting
solution was
stirred for 15 min at -78 C before ethyl chloroformate (0.12 mL, 1.2 mmol)
was added. The
reaction mixture was warmed up to room temperature and stirred for 1 hour,
then it was
partitioned between Et0Ac and water. The organic layer was washed with brine
and dried
over Na2SO4. The crude product was obtained as a pale yellow oil after
concentration, which
was used in the next step without further purification.
102281 MS calculated for (C281-142N203Si): 482; MS found, (M+1): 483.
e,) Preparation of compound 39
102291 Tf3AF (1.5 mL, 1.0 M solution in TI-IF) was added into a solution of
compound 9-A
(crude, ca. 0.6 mmol) in THF (12 mL) at -78 C. The resulting solution was
stirred for 20 min
at -78 C before it was allowed to warm to room temperature. After one hour,
the reaction
mixture was diluted with 10% 2-propanolidichloromethane and washed with water
and brine.
The aqueous phase was extracted with Et0Ac. The combined organic layers were
concentrated and purified by column chromatography (dichloromethane/Me0H, viv,
10/1) to
give compound 39 (187 mg, 85% over two steps) as a white solid.
102301 MS calculated for (C22H28N203): 368; MS found, (M+ I): 369. IHNMR. (300
MHz, CD30D) 5 7.83 (d, 1H), 6.82 (s, 1H), 6.78 (d, 1H), 4.49 (q, 2H), 4.08
(dd, I H), 3.65 -
3,92 (m, 2H), 3.40- 3.62 (m, 2H), 3.15 -3.20 (m, 1H) , 2.95 -3.07 (m, 21-1),
2.42 - 2.62 (m,
1H), 2.20 (bs, 1H), 1.80 - 2.10 (m, 21-1), 1.40- 1.80 (m, 4H), 1.48 (t, 3H),
1.05 U. 311).
Example ii. Preparation of Compound 32
N
/
HO
,
CD, THF / N
-N NH
0 0
39
32
[02311 A solution of compound 39 (137 mg, 0.37 mmol) and CDI (181 mg, 1.12
mol) in
THF (10 mL) was stirred at 50 C for two hours. The mixture was then cooled to
room
temperature, and N-methylpiperizine (0.27 mL, 0.24 mmol) was added. After one
hour, the
reaction mixture diluted with 10% 2-propanolidichloromethane and washed with
water and
brine. The aqueous phase was extracted with Et0Ac. The combined organic
extracts were
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concentrated and purified by preparative-IIPLC to give compound 32 as the
hydrochloride
salt (159 mg, HC1 salt, 81%) as a white solid.
(0232] MS calculated for (C281-138N404): 494; MS found, (M+1): 495. IFINMR
(400
MHz, CD30D) 8 8.07 (d, 1H), 7.35 (s, 1H), 7.09 (d, 1H), 4.57 (q, 2H), 4.40
4.60 (m, 1H),
4.25 - 4.40 (m, 1H), 4.12 (dd, 1H), 3.80- 3.92 (m, 1H), 3.84 (s, 1H), 3.42 --
3.62 (m, 5H).
3.16 -3.42 (m, 5H), 2.98 (s, 3H), 2.57(td, 1H), 2.24 (bs, 1H), 1.98 - 2.11
(in, 21-1), 1.50 -
1.82 (m, 3H), 1.42- 1.50 (m, 2H), 1.51 (t, 3H), 1.05 (t, 3H).
Example 12. Preparation of Compound 40
rs ,1 NaHMDS k r
aish
/
methyl chloroformate
6 --N
-rHF -78 C to rt
0 N -
os-Csr
15-A 40
(0233) To a solution of compound 15-A (200 mg, 0.59 mmol) in THF (2 mL) was
added
dropwise NaHMDS (0.68 mL, 0.68 mmol) at -78 'C. The reaction mixture was
stirred at -78
C for 10 mm, and then methyl chorofomiate (78.61AL, 0.68 mmol) was added at -
78 'C. The
reaction mixture was allowed to warm to rt and stirred for 1 h. Saturated
NaHCO3 solution (5
mL) was added, and the reaction mixture was extracted with ethyl acetate (2 x
20 mL). The
combined organic extracts were concentrated under reduced pressure to afford a
crude
product which was purified by preparative-HPLC to give compound 40(116 1112,
55%) as a
white solid.
102341 MS calculated for (C23H28N204)+: 396; MS found, (M+1): 397. IHNMR (400
MHz, CD30D) 8 7.95 (d, J=9.2 Hz, 111), 7.06 (d, J=1.211z, 1H), 6.7 (dd, J=9.2
Hz, J=1.2 Hz,
1H), 4.84 (s, 311), 3.8 (m, 11-1), 3.1 (m, 311), 2.99 (m, 2H), 2.8 (m, 111),
2.68 (in, 11), 2.15 (s,
3H), 2.14 (m, 111), 1.85 (m, 211), 1.61 (m, 211), 1.58 (m, 111), 1.46 (m,
111), 1.23 (m, 11-1),
0.94 (t, J=7.2 Hz, 3H).
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Example 13. Preparation of Compound 36
TBSO TBSO
\ P¨NN TBAF,
THF
*
NaHMDS, THF, -78 QC to r.t.
0
ikOMe N - 78 3C
I 0
8-A CI Otvle o
36-A
HO,
0- 0
36
a) Preparation of Compound 36-A
102351 NaHMDS (1.05 la, 1.0 M solution in 'rim was added into a solution of
TBS-
noribogaine 8-A (288 mg, 0.7 rnrnol) in 8 mL of THF at -78 C. The resulting
solution was
stirred for 10 min at -78 C before a solution of chlorodimethyl phosphate
(0.15 mL, 1.4
mmol) in 2 m1, of THF was added dropwise. The reaction mixture was allowed to
warm to
room temperature and stirred for 1 hour, before it was diluted with 5% 2-
propanolidichloromethane and washed with water and brine. The aqueous phase
was
extracted with Et0Ac. The combined organic extracts were concentrated and
purified by
column chromatography (Et0Ac/Hexanes, v/v, 2/1 to pure Et0Ac). The desired
product
compound 36-A (305 mg, 84%) was obtained as a white solid.
102361 MS calculated for (C271-143N204PS1): 518; MS found, (M+1): 519.
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b) Preparation of Compound 36
[02371 TBAF (1.1 mL, 1.0 M solution in THF) was added into a solution of
compound 36-
A (305 mg, 0.59 mmol) in 8 mL of THF at -78 C. The resulting solution was
stirred for 40
min at -78 C.: before it was quenched by addition of 2 mL of IN aqueous HC1.
The reaction
mixture was diluted with 5% 2-propanol/dichloromethane and washed with water
and brine,
The aqueous phase was extracted with Et0Ac. The combined organic layers were
concentrated and purified by column chromatography (dichloromethane/2-
propanol, v/v, 15/1
. to 10/1) and then preparative-HPLC to give pure compound 36 as the
hydrochloride salt (220 .
mg, HC1 salt, 85%) as a white solid.
102381 MS calculated for (C211129N204P): 404; MS found, (M+1): 405. Ill NMR
(300
MHz, CDC13) 8 10.38 (bs, 1H), 7.45 (d, 1H), 6.97 (s, 1H), 6.91 (d, 1H), 3.98 -
4.15 (m, 1H),
3.40 - 3.85 (m, 10H), 2.70 - 3.20 (m, 3H) , 2.40- 2.60 (m, 1H), 2.18 (bs, 1H),
1.72 -2.05
(in, 4H), 1.38 - 1.50 (m, 1H), 0.95 (t, 3H).
Example 14. Preparation of Compound 41
HO
nsCD!, DEPEA, THF 0
I'll 0
-N NH 1-0
0" 0 Cf;PµstD
36
41
102391 A solution of compound 36 (44 mg, 0.11 mmol), CD1 (54 mg, 0.33 mol) and
one
drop of DIPEA in 2 mL of THY was stirred at 50 C for two hours, before it was
cooled down
to room temperature. N-methylpiperizine (3 drops) was added. After one hour,
the reaction
mixture was concentrated and purified by preparative TLC (dichloromethane/
MeOFI/triethylamine, viv, 200/20/1). Pure compound 41 (28 mg, 48%) was
obtained as a
white solid.
[0240] MS calculated for (C271139N405P): 530; MS found, (M+1): 531. Ili NMR
(300
MHz, CDC13) 67.95 (d, 1H), 7.13 (s, 1H), 6.95 (d, 1H), 3.65 - 3.82 (m, 8H),
3.55 -3.65 (m.
31I), 3.47 (s, 1H), 3.40 - 3.45 (m, 1H) , 2.96 - 3.40 (m, 5H), 2.72 - 2.95 (m,
1H), 2.40 -2.70
(m, 41-1), 2.35 (s, 3H), 2.08 2.25 (m, 1H), 1.78 - 1.95 (m, 2H), 1.38 - 1.70
(m, 211), 1.15 -
1.20 (m, 2H), 0.89 (t, 3H).
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Example 15
[0241] The following example illustrates how to treat an opioid addicted
patient having an
immediate craving for the opioid. In particular, a 65 kg cocaine addicted male
patient
presenting with an immediate craving for a cocaine "fix" is administered a
bolus comprising
0.1% weight/volume of a compound of this invention in sterile buffered saline.
The aqueous
composition is administered in an i.v. format and the serum concentrations of
the compound
of Formula II and noribogaine which is produced by in vivo cleavage of the
compound of this
invention are monitored. A sufficient amount of the compound is administered
until a
therapeutic serum concentration of the compound and or noribogaine is
achieved. The
patient is then monitored until the craving is diminished or relieved.
Example 16
[0242] The following example illustrates how to treat severe pain in a
patient. In particular,
a 80 kg male patient presenting severe trauma due to several gunshots to the
chest and legs is
administered a bolus comprising l gm of a compound of Formula ll in 10 ml, of
sterile
buffered saline. The aqueous composition is injected into the patient to
provide immediate
analgesia for the pain. A transdermal patch is then placed on the patient's
back. The patch
contains a sufficient amount of the compound in a sustained release form
wherein the amount
of noribogaine released is sufficient to maintain serum concentration of the
compound or
noribogaine which is produced by in vivo cleavage of the compound of this
invention in the
patient for a period of 48 hours.
Example 17: Tablet formulation
[0243] The following ingredients are mixed intimately and pressed into single
scored
tablets.
Ingredient Quantity per tablet, mg
Compound of Formula 1 40
Cornstarch 50
Croscarmellose sodium /5
I Lactose 120 ..
1 Mmuesium stearate 1 5
Example 18: Capsule formulation
[0244] The following ingredients are mixed intimately and loaded into a hard-
shell gelatin
capsule.
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Ingredient Quantity per capsule, mg
Compound of Formula I 20
Lactose, spray-dried 148
Magnesium stearate 2
Example 19: Suspension formulation
102451 The following ingredients are mixed to form a suspension for oral
administration
(q.s. sufficient amount).
Ingredient Amount
Compound of Formula I 1.0 g
Fumaric acid 0.5 g
Sodium chloride 2.0 g
Methyl paraben 0.15g
?rup_yl_paraben 0.05 g
Granulated sugar 25.01 ...........
Sorbitol (70% solution) 13.0
Veegum K (Vanderbilt Co) LO &_
flavoring ______________________________ ._2!!L _____________
colorings 0.5 mg
distilled water q.s. to 100 mL
Example 20: Injectable formulation
102461 The following ingredients are mixed to form an injectable formulation.
1 Ingredient Quantity per 20 mL
I Compound of Formula I 0.2 mg-20 mg
sodium acetate buffer solution, 0.4 M 2.0 mL
HCI (IN) or NaOH (1N) q.s. to suitable pH
water (distilled, sterile) q.s. to 20 mL
Example 21: Suppository formulation
[02471 A suppository of total weight 2.5 e is prepared by mixing the compound
of the
invention with WitepsolOD H-15 (triglycerides of saturated vegetable fatty
acid;
Riches-Nelson, Inc., New York), and has the following composition:
Ingredient 1 Quantity
Comp_ound of Formula I 500 n
Witepsol 11-15 .......................... balance
62
