Note: Descriptions are shown in the official language in which they were submitted.
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NON-BASIC MELANIN CONCENTRATING HORMONE
RECEPTOR-1 ANTAGONISTS AND METHODS
FIELD OF THE INVENTION
[0001] The present invention relates to non-basic melanin concentrating
hormone
receptor-1 (MCHR1) antagonists, pharmaceutical compositions containing MCHR1
antagonists and methods of treating diabetes, obesity and related diseases
employing
such MCHRl antagonists.
BACKGROUND OF THE INVENTION
[0002] Several lines of pharmacological and genetic evidence support the role
of
Melanin Concentrating Hormone Receptor-1 (hereafter "MCHRl") as a modulator of
food intake and body weight. Central administration of melanin concentrating
hormone (MCH) increases food intake and body weight both in rats and in mice.
Chronic ICV infusion of MCH causes increased food intake and ultimately
obesity in
mice, while infusion of an MCH peptide antagonist blocks MCH-induced food
intake
and results in weight loss and decreased feeding in diet-induced obese mice.
[0003] The expression of both the MCH peptide and receptor are modulated by
nutritional status. MCH mRNA is upregulated both in hyperphagic obese mice
(ob/ob), and fasted animals. Targeted disruption of the gene for MCH peptide
results
in hypophagia and leanness. Disruption of the MCHRl gene causes leanness,
altered
metabolism, and hyperlocomotion accompanied by mild hyperphagia. Conversely,
over-expression of MCH peptide results in hyperphagia, obesity and diabetes.
Small
molecule MCHRl antagonists have been shown to cause weight loss in rodent
weight
and feeding models after both oral and intraperitoneal administration; Eur. J.
Pharmacol., 438:129-135 (2002), Nat. Med., 8:825-830 (2002), Eur. J.
Pharmacol.,
497:41-47 (2004).
[0004] Numerous non-peptide MCHRl antagonists have been disclosed. The
scope of the genus for each reflects a common perception regarding the
criteria
required for ligand recognition as MCHRl agonists. A recent review of MCHRl
patent disclosures emphasized the commonality of these structures by the
following
description; "Ubiquitous throughout the MCH patent literature are molecules
-1-
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consisting of a central scaffold to which linkers to an aryl or heteroaryl
group and a
basic amino functionality are attached." (Kowalski, T.J. et al., Expert Opin.
Investig.
Drugs, 13:1113-1122 (2004)). Pharmacophore models of these geni consistently
envision a presumed prerequisite electrostatic interaction between a basic
amine
center of the antagonist ligand and aspartic acid 123 of the receptor which
presumably is envisaged to emulate the mandatory interaction between arginine
14 of
MCH peptide agonists with aspartic acid 123 of the MCHR1 receptor. (Ulven, T.,
J.
Med. Chem., 48:5684-5697 (2005)) However, incorporation of this basic amine in
a
MCHR1 antagonist increases substantially the probability of binding to off-
target ion-
channels and biogenic amine receptors.
[0005] In accordance with the present invention, there is provided a series of
novel high affinity selective MCHR1 antagonists for which binding affinity is
not
dependent upon inclusion of a basic amine functionality that is common to most
of
the disclosed MCHR antagonists. As a consequence, the absence of the basic
center
greatly reduces the probability of off-target interactions such as binding to
other
biogenic amine receptors as well as binding to ion channels such as the HERG
receptor in the heart. The reduction/abolition of affinity for the HERG
receptor is
especially important since ligand occupancy is associated with initiation of
fatal
arrhythmias.
SUMMARY OF THE INVENTION
[0006] In one embodiment of the present invention, a compound of the Formula I
or a pharmaceutically acceptable salt thereof is provided
R8
RZ
O
R~
N A R3
NI /J R9
wherein
A
is a phenylene ring or a heteroaryl ring which is a monocyclic ring or a
bicyclic ring which contains one or two nitrogen atoms or one oxygen atom;
-2-
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Ri is Z-Y-X-, wherein
0
o 11 õ -s=o
XisO,S, -s- ,or I ;
Y is a bond, a 3- to 6-membered cycloalkyl, or an alkyl chain; and
Z is aryl such as phenyl and naphthyl, or heteroaryl such as pyridinyl,
pyridimidinyl, pyrazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or
other "heteroaryl";
R2 is -E-G-(J),,,, with m being an integer from 1 to 3;
E is 0, S, or a bond;
G is lower alkyl, phenylalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl,
cycloalkoxy, alkylcycloalkoxy, or cycloalkoxyalkyl;
each J is independently hydrogen, hydroxyl, CN, -S02R7, -SR', -SOR7, lower
alkyl, lower alkoxy, CF3, CF3O-, -COOR 5 (wherein R5 is H, Ci_3 alkyl, or
cycloalkyl),
or -CO-NR5aR6 wherein Rsa and R6 are each independently selected from H, Ci_3
alkyl, or cycloalkyl, or Rsa and R6 taken together can be propanediyl,
butanediyl or
pentanediyl to form with the N atom to which they are attached a 4-, 5- or 6-
membered cyclic amine, such as azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl, or
piperazinyl, optionally substituted with substituents as set out for
"heterocyclo";
R7 is lower alkyl;
R3 is Ci_6 alkyl, cycloalkyl,Ci_6 alkoxy, halogen, hydrogen, -S-Ci_6 alkyl,
CN,
CF3O, or CF3;
and wherein R2 and R3 can be taken together to form a 5- to 7-membered ring
which is saturated, unsaturated, or partially unsaturated and may include an E
heteroatom, which is 0, or 0, 1 or 2 N atoms, which ring is substituted with
one or
two of -O-G-(J),,, groups, wherein at least one J is OH, and optionally other
substituents as set out for "alkyl", "aryl", or "heteroaryl", such as alkyl
and/or OH;
with the proviso that where (~) is a phenylene ring, E-G and R3 are not
identical unsubstituted lower alkoxy groups, and when G is lower alkyl and J
is H, R3
is not hydrogen; and
R8 and R9 are each independently hydrogen, halogen, or lower alkyl;
-3-
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including esters thereof, prodrugs thereof, solvates thereof, and all
stereoisomers thereof.
[0007] Any of the foregoing Z moieties may either be unsubstituted or
substituted
with 1, 2 or 3 of amino, halo, Ci_6 alkyl, Ci_3 alkylamino, di-Ci_3
alkylamino, Ci_3
alkoxy, Ci_3 thioalkyl, Ci_3 trifluoroalkoxy, trifluoromethyl, cycloalkyl,
cycloalkoxy,
or heteroaryl such as pyridyl or substituted with any of the substituents as
set out for
"aryl", "heteroaryl", or "alkyl".
[0008] Examples of substituents for the J group in the form of a cyclic amine
include but are not limited to lower alkyl, lower alkoxy, OH, CF3, or CF3O, or
other
substituents as set out for "alkyl" and "heteroaryl".
[0009] In a further aspect of the invention, there is provided a
pharmaceutical
composition which contains a therapeutically effective amount of the compound
of
the invention Formula I as defined above, in association with a
pharmaceutically
acceptable carrier or diluent.
[0010] There is also provided a method for the treatment of diabetes, obesity
and
other related conditions involving the MCHR1 in a mammal (such as a human, dog
or
cat) in need thereof, which includes the steps of administering to the mammal
a
therapeutically effective amount of the compound of Formula I of the invention
as
defined above.
[0011] The invention also sets forth one or more methods for making the
compound of Formula I of the invention. In one embodiment, there is provided a
process for the preparation of the compound of Formula I of the invention,
wherein
the compound a
R8
RZ
O
II A
CI N ~ R3
IYNI J R9
a
is reacted with the alkali metal salt of Z-Y-XiH (b) (Xi = 0 or S), preferably
Z-
(CHz)ri XiH (n = 0, 1, 2 or 3).
-4-
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[0012] In another embodiment of the invention, there is provided a process for
the
preparation of the compound of Formula I of the invention, wherein the
compound c
R8
RZ
O
A
O
N R3
~N J R9
C
is reacted with Z-Y-XiH (b), preferably Z-(CHz)ri XiH (n = 0, 1, 2 or 3), and
preferably in the presence of an activating agent.
[0013] The present invention is directed to these, as well as other important
ends,
hereinafter described.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present application provides compounds, including all
stereoisomers,
solvates, prodrugs and pharmaceutically acceptable forms thereof according to
Formula I. Additionally, the present application provides pharmaceutical
compositions containing at least one compound according to Formula I of the
invention alone and optionally at least one additional therapeutic agent.
Finally, the
present application provides methods for treating a patient suffering from an
MCHR-
1 modulated disease or disorder such as, for example, obesity, diabetes,
depression or
anxiety by administration of a therapeutically effective dose of a compound
according
to Formula I of the invention as defined above.
DEFINITIONS
[0015] Unless otherwise indicated, the term "lower alkyl" as may be employed
herein alone or as part of another group includes both straight and branched
chain
hydrocarbons containing 1 to 8 carbons, and the terms "alkyl", "alk", "alkyl
chain",
"alkylene", or "alkylene chain" as may be employed herein alone or as part of
another
group includes both straight and branched chain hydrocarbons containing 1 to
20
carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the
normal
chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,
pentyl, hexyl,
isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl,
decyl,
-5-
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undecyl, dodecyl, the various branched chain isomers thereof, and the like as
well as
such groups including 2 free bonds and thus are linking groups, namely
"alkylene", as
well as such groups including 1 to 4 substituents such as halo, for example F,
Br, Cl
or I or CF3, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,
arylalkyloxy,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
cycloalkylalkyloxy,
hydroxy, hydroxyalkyl, acyl, alkanoyl, heteroaryl, heteroaryloxy,
cycloheteroalkyl,
arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy,
aryloxyalkyl,
aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano,
thiol,
haloalkyl, trihaloalkyl and/or alkylthio.
[0016] Unless otherwise indicated, the term "cycloalkyl" or "lower cycloalkyl"
as
may be employed herein alone or as part of another group includes saturated or
partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon
groups
containing 1 to 3 rings, any one of which may optionally be a spiro
substituted
cycloalkyl, including monocycloalkyl, bicycloalkyl and tricycloalkyl,
containing a
total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons,
forming the ring
and which may be fused to 1 or 2 aromatic rings as described for aryl, which
include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclodecyl
and cyclododecyl, cyclohexenyl,
, , M, ,
9-~ , \ Q
as well as such groups including 2 free bonds and thus are linking groups, any
of
which groups may be optionally substituted with 1 to 4 substituents such as
halogen,
alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido,
alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and/or
alkylthio
and/or any of the substituents set for "alkyl".
[0017] Unless otherwise indicated, the term "cycloalkoxy" or "lower
cycloalkoxy" as employed herein alone or as part of another group, represents
a 4-, 5-
0
or 6-membered saturated ring containing an oxygen in the ring and includes
0
~ and as well as such groups including 2 free bonds and thus are
-6-
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linking groups, and which may be optionally substituted with 1 or two of any
of the
substituents as set out for cycloalkyl.
[0018] The term "heterocyclo", "heterocycle", "heterocyclyl", "heterocyclic"
or
"cycloheteroalkyl" ring, as may be used herein, represents an unsubstituted or
substituted stable 4- to 7-membered monocyclic ring system which may be
saturated
or unsaturated, preferably saturated or partially unsaturated, and which
consists of
carbon atoms, with one to four heteroatoms selected from nitrogen, oxygen or
sulfur,
and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized,
and the
nitrogen heteroatom may optionally be quaternized, and including any bicyclic
group
in which the heterocyclic ring is fused to a benzene ring. The heterocyclic
ring may
be attached at any heteroatom or carbon atom which results in the creation of
a stable
structure. Examples of such heterocyclic groups include, but is not limited
to,
piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl,
oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl,
pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl,
morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl,
tetrahydropyranyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,
oxadiazolyl,
0
OO S__/
O N
Ca No > O~ 0 l
C~ O
> > > > > >
S O~ i0 O 0
S
O N N
C~
N , ,~/ , N~ , and other heterocycles
described in Katritzky, A.R. et al., eds., Comprehensive Heterocyclic
Chemistry: The
Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds, Pergamon
Press, New York, NY, publ. (1984); and Katritzky, A.R. et al., eds.,
Comprehensive
Heterocyclic Chemistry II: A Review of the Literature 1982-1995, Elsevier
Science,
Inc., Tarrytown, NY, publ. (1996); and references therein, as well as such
groups
including 2 free bonds and thus are linking groups, as well as such groups
optionally
substituted with 1 to 3 of F, Br, Cl or I or CF3, alkyl, alkoxy, aryl,
aryloxy, aryl(aryl)
or diaryl, arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl,
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cycloalkylalkyl, cycloalkylalkyloxy, hydroxy, hydroxyalkyl, acyl, alkanoyl,
heteroaryl, heteroaryloxy, cycloheteroalkyl, arylheteroaryl,
arylalkoxycarbonyl,
heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido,
alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl,
trihaloalkyl, and/or
alkylthio.
[0019] The term "alkanoyl" as may be used herein alone or as part of another
group refers to alkyl linked to a carbonyl group.
[0020] The term "halogen" or "halo" as may be used herein alone or as part of
another group refers to chlorine, bromine, fluorine, and iodine, with chlorine
or
fluorine being preferred.
[0021] The term "metal ion" refers to alkali metal ions such as sodium,
potassium
or lithium and alkaline earth metal ions such as magnesium and calcium, as
well as
zinc and aluminum.
[0022] Unless otherwise indicated, the term "aryl" or "Aryl" as may be
employed
herein alone or as part of another group refers to monocyclic and bicyclic
aromatic
groups containing 6 to 10 carbons in the ring portion (such as phenyl or
naphthyl
including 1-naphthyl and 2-naphthyl) and may optionally include one to three
additional rings fused to a carbocyclic ring or a heterocyclic ring (such as
aryl,
cycloalkyl, heteroaryl or cycloheteroalkyl rings), for example
> > > > > >
5 ~ O O
~ I I \N I / ~~N I / \N I /
~ ~ O O O
> > > > >
N \ N \ N \ \ \ / / i
N~ S~ ~ N and O 0
> > > > >
and as well as such groups including 2 free bonds and thus are linking groups,
and
may be optionally substituted through available carbon atoms with 1, 2, or 3
groups
selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy,
alkenyl,
trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl,
cycloheteroalkyl,
cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl,
arylalkoxy,
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alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio,
arylsulfinyl,
arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl,
heteroaryloxy,
hydroxy, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio,
arylthioalkyl,
alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,
arylaminocarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,
arylsulfonylamino and arylsulfonaminocarbonyl and/or any of the substituents
for
"alkyl" set out herein.
[0023] Unless otherwise indicated, the term "heteroaryl" as may be used herein
alone or as part of another group refers to a 5- or 6-membered aromatic ring
which
includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur. Such
rings may
be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl and include
possible N-
oxides as described in Katritzky, A.R. et al., eds., Comprehensive
Heterocyclic
Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic
Compounds,
Pergamon Press, New York, NY, publ. (1984); and Katritzky, A.R. et al., eds.,
Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995,
Elsevier Science, Inc., Tarrytown, NY, publ. (1996); and references therein as
well as
such groups including 2 free bonds and thus are linking groups. Further,
"heteroaryl", as defined herein, may optionally be substituted with one or
more
substituents such as the substituents included above for "alkyl" and/or
"aryl".
Examples of heteroaryl groups include the following:
N $ O \ NNN N
CO- N \` ~
. , ' ~-- I , NN ' N-N
N
N~/O N`~/S ~ ,_ IIII N, ~N1 N
V V
N S N" O
= N-'
N, O, \ S\ NN~
U-N\
\ -9-
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ON, ~ 0 = \/ N~ :~-X,
N
S ,
N-N N-N N~ N=N
N V ~o ,and N
and the like.
[0024] Unless otherwise indicated, the term "lower alkoxy", "alkoxy",
"aryloxy"
or "aralkoxy" as may be employed herein alone or as part of another group
includes
any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
[0025] Unless otherwise indicated, the term "lower alkylthio", alkylthio",
"arylthio" or "aralkylthio" as may be employed herein alone or as part of
another
group includes any of the above alkyl, aralkyl or aryl groups linked to a
sulfur atom.
[0026] The term "polyhaloalkyl" as may be used herein refers to an "alkyl"
group
as defined above which includes from 2 to 9, preferably from 2 to 5, halo
substituents,
such as F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2.
[0027] The term "polyhaloalkyloxy" as may be used herein refers to an "alkoxy"
or "alkyloxy" group as defined above which includes from 2 to 9, preferably
from 2
to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2O, CF3O
or
CF3CFzCHzO.
[0028] Unless otherwise indicated, the term "alkenyl" as used herein alone or
as
part of another group refers to straight or branched chain radicals of 2 to 20
carbons,
preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal
chain,
which include one to six double bonds in the normal chain, such as vinyl, 2-
propenyl,
3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-
heptenyl, 3-
heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-
dodecenyl,
4,8,12-tetradecatrienyl, and the like. Optionally, said alkenyl group may be
substituted with one or substituents, such as those substituents disclosed for
alkyl.
[0029] Unless otherwise indicated, the term "alkynyl" as used herein alone or
as
part of another group refers to straight or branched chain radicals of 2 to 20
carbons,
preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal
chain,
which include one triple bond in the normal chain, such as 2-propynyl, 3-
butynyl, 2-
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butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl,
4-
heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the
like.
Optionally, said alkynyl group may be substituted with one or substituents,
such as
those substituents disclosed for alkyl.
[0030] The term "cycloalkenyl" as employed herein alone or as part of another
group refers to partially unsaturated cyclic hydrocarbons containing 3 to 12
carbons,
preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplary cycloalkenyl
groups
include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,
cyclooctenyl,
cyclohexadienyl, and cycloheptadienyl. Optionally, said cycloalkenyl group may
be
substituted with one or substituents, such as those substituents disclosed for
alkyl.
[0031] The term "bicycloalkyl" as employed herein alone or as part of another
group includes saturated bicyclic ring groups such as, without limitation,
[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
[2.2.2]bicyclooctane, and so forth.
[0032] The term "polycycloalkyl" as employed herein alone or as part of
another
group includes two or more cycloalkyl ring systems, as defined herein, wherein
at
least one carbon atom is a part of at least two separately identifiable ring
systems. The
polycycloalkyl group may contain bridging between two carbon atoms, for
example,
bicyclo[ 1. 1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl,
tricycl[2.2.1.01
]heptyl, norbornyl and pinanyl. The polycycloalkyl group may contain one or
more
fused ring systems, for example, decalinyl (radical from decalin) and
perhydroanthracenyl. The polycycloalkyl group may contain a spiro union, in
which a
single atom is the only common member of two rings, for example,
spiro[3.4]octyl,
spiro[3.3]heptyl and spiro[4.5]decyl.
[0033] The term "acyl" as employed herein by itself or part of another group,
as
~o~
defined herein, refers to an organic radical linked to a carbonyl c group;
examples of acyl groups include a substituent group attached to a carbonyl,
such as
alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaryl, cycloalkanoyl,
cycloheteroalkanoyl
and the like.
[0034] "Optional" or "optionally" means that the subsequently described event
or
circumstance may or may not occur, and that the description includes, without
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limitation, instances where said event or circumstance occurs and instances in
which
it does not. For example, optionally substituted alkyl means that alkyl may or
may not
be substituted by those groups enumerated in the definition of substituted
alkyl.
[0035] "Substituted," as used herein, whether express or implied and whether
preceded by "optionally" or not, means that any one or more hydrogen on the
designated atom (C, N, etc.) is replaced with a selection from the indicated
group,
provided that the designated atom's normal valency is not exceeded, and that
the
substitution results in a stable compound. For instance, when a CH2 is
substituted by a
keto substituent (=0), then 2 hydrogens on the atom are replaced. Combinations
of
substituents and/or variables are permissible only if such combinations result
in stable
compounds. Further, when more than one position in a given structure may be
substituted with a substituent selected from a specified group, the
substituents may be
either the same or different at every position.
[0036] The designation "nr " or attached to a ring or other group refers
to a free bond or linking group.
SPECIFIC EMBODIMENTS
[0037] The (~) group may be phenylene or a heteroaryl which is monocyclic or
bicyclic and includes rings such as
R$ R2 RZ
I
RZ N RZ ~ N N O
N / R3 /
R3 N R3
R9 R$ R$
(pyridinyl) (quinolinyl) (benzimidazolyl) (quinolin-2(1H)-one)
I~ O RZ O RZ
/ R3 R3
R9 R$ R9 R$
(chromanyl) or (chromenyl) , with phenylene and pyridinyl being
preferred.
[0038] The Formula I compound of the invention may have the structure
-12-
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R8
RZ
O /
1 ll
\\ R3
RY\N
INI~ R9
IA , or
R8
RZ
O /
R' N
N J R9
IB , or
\ N\ Rz
O
R' ~ N R3
I I
N J R8
lc , or
R2
O \ N\ O
Ri \ ~ N / / Rs
~N"I R8
ID , or
R2
N
R O / >- R3
1 J~
N N
NI
1 E , or
O RZ
O \
R1 I N / R3
N J R9 R8
IF , or
13-
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RZ
R'` ~O j:)ZR3
N NIG
[0039] In the compound of Formula I of the invention, it is desired that
A
is phenylene or pyridinyl;
X is O or S; and/or
Y is a bond or an alkylene chain of 1, 2 or 3 atoms; and/or
Z is phenyl; or
Z is a heteroaryl such as pyridinyl or benzothiazole; and/or
R2 is E-G-J; and/or
E is O or S; and/or
G is a lower alkyl or alkylcycloalkyl; and/or
J is H, OH, S02R7, lower alkyl, lower alkoxy, or CF3, more preferably OH;
and/or
R3 is Ci_6 alkyl, Ci_6 alkoxy, H, or halo; and/or
R8 and R9 are independently H or CH3; and/or
wherein R2 and R3 can be taken together to form a 5- to 7-membered ring
which is saturated, unsaturated, or partially unsaturated and may include an E
heteroatom, which is 0, or 0, 1 or 2 N atoms, which ring is substituted with
one or
two of -O-G-(J),,, groups, wherein at least one J is OH and optionally other
substituents as set out for "alkyl", "aryl", or "heteroaryl", such as alkyl
and/or OH.
[0040] The above groups may be substituted as indicated herein.
[0041] Examples of the various groups of the compounds of Formula I of the
invention are set out below:
A
is phenylene or pyridinyl;
Z is
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(1) aryl, such as phenyl or naphthyl, each of which is optionally
substituted with:
a) halogen such as Cl, Br or F,
b) alkyl such as CH3, C2H5 or i-C3H7,
c) alkoxy such as CH3O,
d) polyhaloalkyl such as CF3,
e) polyhaloalkoxy such as CF3O,
CH3`
N-
f) amino, alkylamino or dialkylamino such as ~Hs
g) alkylthio such as CH3S,
h) OH,
i) esters such as -COOCH3, or
j) aryl such as phenyl,
(2) monocyclic heteroaryl such as
a) pyridinyl,
b) pyrazinyl, or
c) pyrimidinyl,
each of a), b) or c) being optionally substituted with alkyl such as
methyl, polyhaloalkyl such as trifluoromethyl, halogen such as Cl or F,
or alkoxy such as CH3O;
(3) benzothiazole optionally substituted with halo such as F, Cl,
alkoxy such as CH3O,
(4) benzoxazole optionally substituted with halo such as Cl,
(5) benzimidazole,
(6) thiazole optionally substituted with aryl such as phenyl, and
alkyl such as t-C4H9,
(7) indanyl,
(8) quinolinyl optionally substituted with CF3, or
(9) imidazolidinyl; and/or
Y is a bond or alkylene such as methylene, or ethylene or propylene; and/or
X is S, 0, SO, or SOz; and/or
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J is
(1) H,
(2) -CO-NR 5'R6 where Rsa and R6 together with the N to which
they are attached form a pyrrolidinyl ring,
(3) OH,
(4) COOH,
(5) COOalkyl such as COOCH3,
(6) S02R7 such as SOzCzHs, or
1~1~NHZ
(7) prodrug esters such as glycine o , phosphate
HO OH
P04 (-o -P o and the corresponding Na salt thereof), and valine
0
-O NHZ
; and/or
m is 1 or 2; and/or
-CH2-CH- CH3 CH3
G is CH2, (CH2)2, (CH2)3, cH3 , -cHz-C-
~
.nr
-cH2-cH-cH2OCH3 ~ cycloalkyl such as cycloalkoxy such as
~ L,
t~
0 cHz-cH-cF3 , or alkylcycloalkyl such as CH2
s s,
F F
~
~' SS
~CHZ
CH2 .S's and ; and/or
E is 0; and/or
R3 is H, alkoxy such as CH3O, hydroxyalkyl such as HOCH2CH2-, alkyl such
as CH3 or CzHs, halo such as F or Cl, CN, or hydroxyalkoxy such as HOCHzCHzO-;
and/or
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R2 and R3 can be optionally taken together to form a 5- or 6-membered
unsaturated or aromatic ring containing one or two N atoms, which ring is
optionally
CH3 CH3
substituted with hydroxyalkyl such as c OH , for example
OH OH
OH
N\ N N O
N~ an \ I /
d
or where R2 and R3 can be optionally taken together to form a 6-membered
saturated, unsaturated or partially unsaturated 0-containing ring, which ring
is
CH3 CH3
optionally substituted with hydroxyalkyl such as c OH , alkyl such as CH3 and
OH, for example
OH \ O O
O
I\ I/ OH I/ I
OH
OH O OH
Sj -k O \ ~)X I / OH
, OH , and ; and/or
R8 is H, halo such as F and Cl, or alkyl such as methyl; and/or
R9 is H.
[0042] In a further embodiment of the compound of Formula I of the invention,
X
= 0 and 0 is phenylene or pyridinyl. In another embodiment, X = S and 0 is
phenylene.
[0043] In a further embodiment in Formula I of the invention, Y is a bond.
Also
in a further embodiment, Y is methylene, ethylene or propylene. In addition,
the
alkyl chain or alkyl moiety in Y may be attached to the ortho-position of Z to
generate a bicyclic moiety. In this embodiment, the bicyclic moiety is
preferably 1-
indanyl or 2-indanyl when Z is phenyl.
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[0044] In a further embodiment, Z is selected from phenyl, naphthyl,
pyridinyl,
pyrazinyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl, preferably phenyl
and
pyridinyl.
[0045] Furthermore, in the embodiment wherein R5 and R6 taken together form a
4-, 5- or 6-membered cyclic amine, it is preferred that this component be
selected
from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl, and
piperazinyl.
[0046] Also preferred is the embodiment wherein R3 is Ci-C6 alkoxy. Especially
preferred is the embodiment wherein R3 is Ci-C3 alkoxy or Ci-C3 alkyl. Even
more
preferably, R3 is methoxy or methyl.
[0047] In one embodiment of the invention, Ri may be selected from the group
consisting of:
\ s o \ O
cl \ I s
cl cl
O I/ \ S S
cl S I N N
> > > >
S
s \ s \ s
cl / cl cF3o / and
[0048] It is also desirable that in Formula I, R2 is -0-2-hydroxy-propane, R3
is
methoxy, and Ri is selected from the group consisting of:
\ O \ s / \ s
cl cl
0 0 o
11 11 11
s s=o s
N S cl cl
O
I I g
S= \
I \ / and cl
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[0049] In another embodiment of the invention, it is desirable that
is phenylene;
OH
H3C, CH3 O\
X z
R2 is CHz OH or ; or
R2 and R3 can be optionally taken together to form a 5- or 6-membered
unsaturated or aromatic ring containing one or two N atoms, which ring is
optionally
CH3 CH3
substituted with hydroxyalkyl such as c OH , for example
OH OH
OH
N\ N N O
N~ and I / = and
, d , R3 is methoxy or methyl, and Ri is selected from the group consisting
of:
F
~~\ S I\ S S \ S
~N NI /
> > > >
N S
I I/ S a S F s \ I / I S
F3C CI CI CI
S / S
S S
CP- F \ I \ I
FsC
N\ S / S / S S
Po S
\ I FsC. \ I CF3
CF3OS O > >
S S a S Oc S S
C
> > > > >
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/ I s / I s / I s / I s / I s
> > > > >
CI
S
/ I 0 CI 0 b
\ N F3C CI CI S \ S N S O
\ I CI
> > F S
\ Or F /
> > > >
N S
~
N~/S N~/S ~ ~ S N:/S
O S (5SI CI ~ ~ O'
/ - - CI -
S
s S N--<
N-\ J N-< s
F S S N ~r S
liI\ I/ ~
/ , F , F , and -~ NH
[0050] Also desired is the prodrug embodiment, hereinafter described, wherein
in
Formula I,
O
R2 is E-G-hydroxyl-Pro-Drig or more preferably -'o"-XO)t'-' NHz
0
O OH
NHZ
-O-P=O
, and OH R3 is methoxy; and
s s s
F3C,
O~ \/ \ I \ I
R1 is selected from and
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[0051] Also desired are compounds of Formula I wherein
A
is phenylene;
Ri is Z-Y-X- wherein
X is S,
Y is an alkyl chain of 1 to 3 carbons or a bond,
Z is heteroaryl or phenyl,
each of which Z is optionally substituted with CF3, CF3O, or halo;
R2 is -E-G-J wherein
E is O,
CH3 CH3
X/ G is lower alkyl such as ~-cHz-c-~ or alkylcycloalkyl such as
,nr
CHZ-CH
x,and
J is OH;
R3 is H, alkoxy such as CH3O, or alkyl such as CH3;
R8 and R9 are independently H or CH3; and
R2 and R3 can be optionally taken together to form a 5- or 6-membered
unsaturated or aromatic ring containing one or two N atoms, which ring is
optionally
CH3 CH3
substituted with hydroxyalkyl such as c OH , for example
OH OH
OH
N N O
N and ,
[0052] In still more preferred compounds of Formula I,
A
is phenylene;
X is S;
Y is a bond or (CH2)2;
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N ~
/ I \ I \ I \
Z is 0 F3C CF3O F3C
> > > >
N
or F ,
OH
-O-CHZ-CH
E-G-J is ~O~oH or
R3 is CH3O or CH3;
R8 and R9 are each H; and
R2 and R3 can be optionally taken together to form a 5- or 6-membered
unsaturated or aromatic ring containing one or two N atoms, which ring is
optionally
CH3 CH3
substituted with hydroxyalkyl such as c OH , for example
OH OH
OH
N~ N N O
N~ and ,
[0053] Some preferred compounds of the invention include the following:
O O v OH
s`
N O
INI
CF3
O O v OH
s` ~
I ~ ~; -N O
CF3` INI
O
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O \ O v OH
S
I \ " N
iN NJ
CF3
O \ O v OH
s I /
" N
N
O O OH
S I /
I N
F / N
O O v _OH
S
\ N
iN NJ
or
O \ O v OH
S` ~ N O/
N INIJ
[0054] Also desired are compounds of Formula I wherein
R2
A Ri is Z-Y-X- wherein
X is S,
Y is an alkyl chain of 1 to 3 carbons such as (CH2)2 or a bond,
Z is heteroaryl such as 2-pyridyl or phenyl,
each of which Z is optionally substituted with CF3, CF3O, or halo such
as F,
so that Ri can be selected from:
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S
I\ S I\ S \ I / I S
CF
s F ~ F
S S / S / S
I / \ I \ I \ I
~ CF O CF CF O
F 3 3 3 , or
S
\ N .
R2 is -E-G-J wherein
E is O,
G is lower alkyl or alkylcycloalkyl, and
J is OH,
OH
I
-O-CHZ-CH
for example, R2 is 1-110"'X0H or Z&
R3 is alkoxy such as CH3O, alkyl such as CH3, or halo such as Cl; and
R8 and R9 are independently H or CH3.
[0055] In still more desired compounds of Formula I,
RZ
/ I
N
is
X 1s S;
Y is a bond or (CH2)2;
\ I \ I
Zis or
E-G-J is 10"~OH ; and
R3 is CH3, H or Cl.
METHODS OF PREPARATION
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[0056] The compounds of Formula I according to the various embodiments herein
described can be prepared as shown in the following non-limiting reaction
schemes
and description thereof, as well as relevant published literature procedures
that may
be used by one skilled in the art.
[0057] Scheme 1 below portrays a generalized reaction sequence for the
synthesis
of compounds of Formula I.
[0058] Compounds of Formula I, for which Ri is Z-Y-O or Z-Y-S and R2 does
not contain a tertiary alcohol, can be prepared by condensation of compounds
of
Formula II in a solvent such as THF with alkali metal salts such as Na+ or K+
of
compounds of Formula III. The alkali salts of compounds of Formula III had
been
previously prepared by addition of compounds of Formula III to a stirred
dispersion
of NaH or KH in a solvent such as THF under an inert atmosphere of N2 or Ar.
Compounds of Formula II can be prepared by treatment of compounds of Formula
IV
with thionyl chloride in a solvent such as DMF. Compounds of Formula III are
commercially available or may be readily prepared by one skilled in the arts.
[0059] Alternatively, a general synthesis of compounds of Formula I, for which
Ri is Z-Y-O, Z-Y-S or Z-Y-NR4H, entails condensation of compounds of Formula
IV
with compounds of Formula III by stirring these components in a solvent such
as
DMF containing benzotriazo-l-yl-oxy-trispyrrolidinophosphonium
hexafluoroborate
(PyBOP) as an activating agent, DMAP and a hindered amine such as Et(iPr)2N.
Other activating agents may be utilized by the skilled artisan.
[0060] Compounds of Formula IV can be prepared by heating compounds of
Formula V to 120-150 C in microwave in a 1:1.1 mixture of HOAc/TFA.
Compounds of Formula V can be prepared by stirring compounds of Formula VI
with
2,2-dimethoxyethylamine in a solvent such as EtOAc. Compounds of Formula VI
can be prepared by treatment of compounds of Formula VII with ethyl oxalyl
chloride
in a mixture of EtOAC and water containing a weak base such as potassium
carbonate. Compounds of Formula VII are either commercially available or can
be
prepared as described in USSN 11/586,255.
[0061] Compounds of Formula I for which Ri is Z-Y-SO or Z-Y-SOz can be
prepared by treatment of compounds of Formula I where Ri is Z-Y-S with one or
two
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equivalents of an oxidant such as m-chloroperbenzoic acid in a solvent such as
CHzC1z.
Scheme 1
0
R3 R8 OEt R3 R8 H 0 H2N OMe R3 R8 H
NHZ CI /N ~--( N
Z A O
0 ~OEt OMe
A ~N~OMe
R i RZ A O Ryi 0 H
R9 Ry Ry Me0
VII VI V
R9 R8 R9 R8
O A Z-Y-X'H (III) O A
TFA O 1
~RZ tIN
~ RZ
N PyBop, Et(iPr)ZN, DMAP, DMF R HOAc HN J R3 Xl = O or S R3
IV I
SOCIZ
R9 R8 /X1H
RZ
A
CI O
T1 Ra
NJ
II
[0062] Alternatively compounds of formula I can be prepared as outlined in
Scheme 2. by Cu catalyzed arylation of compounds of formula X by heating X
with
aryl halides or iodides of formula XI in a solvent such as dioxane containing
a
cuprous salt such as cuprous iodide along with potassium tribasic phosphate
and a
chelating agent such as N-methyl, N'-methyl ethylene diamine. Compounds of
formula X can be prepared by heating compounds of formula IX in TFA. Compounds
of formula IX can be prepared by condensation of compound of Formula VIII with
compounds of Formula III by stirring these components in a solvent such as DMF
containing benzotriazo-l-yl-oxy-trispyrrolidinophosphonium hexafluoroborate
(PyBOP) as an activating agent, DMAP and a hindered amine such as Et(iPr)2N.
Compound of formula VIII is readily obtained from p-methoxybenzyl amine
utilizing
the chemistry described in Scheme 1. Aryl halides of formula XI are readily
prepared
by one skilled in the arts by alkylation of the corresponding commercially
available
halogenated phenol.
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Scheme 2
0
NHz OEt HZN OMe
CI
O Me0 / H O OMe Me0 / H O
N` ~ \ N\ ~
ff\OEt Jr N OMe
OMe 0 0 H
MeO
O O
O
TFA N Z-Y-X'H (III) R1 N TFA
HOAc HN J OMe PyBop, Et(iPr)zN, DMAP, DMF NIJ OMe
Xl =OorS
VIII D(
R8
R9
R2 R9` /Ra
O A O Rz
~ Xz Xz = Br R
R '` }II~ A
NH XI R3 orl 'N
NI J Cul, K3P04, dioxane NI R3
X -N/--\ I
H HN-
Ra Ra
R9
Xz (J)m G -Leaving R9 z
OH Group R
A
Xz
R3 R3
XII XI
Xz=Brorl X2 =Bror1
[0063] Other methods of preparing the compounds of Formula I are within the
scope of the invention as well.
PRODRUGS, SALTS, ESTERS AND STEREOISOMERS
[0064] The compounds of the invention also include "prodrugs". The term
"prodrug" as used herein encompasses both the term "prodrug esters" and the
term
"prodrug ethers". The term "prodrug esters" as employed herein includes esters
and
carbonates formed by reacting one or more hydroxyls of compounds of Formula I
with either alkyl, alkoxy, or aryl substituted acylating agents or
phosphorylating agent
employing procedures known to those skilled in the art to generate acetates,
pivalates,
methylcarbonates, benzoates, amino acid esters, phosphates, half acid esters
such as
malonates, succinates or glutarates, and the like. In certain embodiments,
amino acid
esters may be especially preferred.
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[0065] Examples of such prodrug esters include
O
o O 0 Si R O
o ~
NH2 (R = H or
0
:~Ci
isopropyl or other alkyl group) (for example, H2NoS' and H2N c-O~ )
o ~
Ii"O Z_~OS'
OR; P" OR, (where Ri is H or an alkali metal such as Na), that is HOzc
[0066] The term "prodrug ethers" include both phosphate acetals and 0-
glucosides. Representative examples of such prodrug ethers include
OH
O O
R O
O~
II'O HO OH
O1 P" 0 ~ OH
[0067] The compounds of Formula I can also be present as salts, which are
further within the scope of this invention. Pharmaceutically acceptable (i.e.,
non-
toxic, physiologically acceptable) salts are preferred. If the compounds of
Formula I
have, for example, at least one basic center, they can form acid addition
salts. These
are formed, for example, with strong inorganic acids, such as mineral acids,
for
example sulfuric acid, phosphoric acid (phosphate ester) or a hydrohalic acid,
with
organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon
atoms, for
example acetic acid, which are unsubstituted or substituted, for example, by
halogen
as chloroacetic acid, such as saturated or unsaturated dicarboxylic acids, for
example
oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid,
such as
hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic,
tartaric or
citric acid, such as amino acids, (for example aspartic acid, glutamic acid,
glycine,
valine, lysine, or arginine), or benzoic acid, or with organic sulfonic acids,
such as
(Ci-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted,
for example
by halogen, for example methyl- or p-toluene- sulfonic acid. Corresponding
acid
addition salts can also be formed having, if desired, an additionally present
basic
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center. The compounds of Formula I having at least one acid group (for example
COOH) can also form salts with bases. Suitable salts with bases are, for
example,
metal salts, such as alkali metal or alkaline earth metal salts, for example
sodium,
potassium or magnesium salts, or salts with ammonia or an organic amine, such
as
morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower
alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl,
tributyl or
dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for
example
mono, di or triethanolamine. Corresponding internal salts may furthermore be
formed.
Salts which are unsuitable for pharmaceutical uses but which can be employed,
for
example, for the isolation or purification of free compounds of Formula I or
their
pharmaceutically acceptable salts, are also included.
[0068] Preferred salts of the compounds of Formula I which contain a basic
group
include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate,
nitrate or
acetate.
[0069] Preferred salts of the compounds of Formula I which contain an acid
group include sodium, potassium and magnesium salts and pharmaceutically
acceptable organic amines.
[0070] All stereoisomers of the compounds of the invention are contemplated,
either in admixture or in pure or substantially pure form. The compounds of
the
present application can have asymmetric centers at any of the carbon atoms
including
any one of the R substituents. Consequently, compounds of Formula I can exist
in
enantiomeric or diastereomeric forms or in mixtures thereof The processes for
preparation can utilize racemates, enantiomers or diastereomers as starting
materials.
When diastereomeric or enantiomeric products are prepared, they can be
separated by
conventional methods for example, chromatographic or fractional
crystallization.
UTILITY
[0071] The compounds of the present application can be administered to
mammals, preferably humans, for the treatment of a variety of conditions and
disorders, including, but not limited to metabolic and eating disorders as
well as
conditions associated with metabolic disorders (e.g., obesity, diabetes,
arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular
disease,
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osteoarthritis, dermatological disorders, impaired glucose hemostasis, insulin
resistance, hypercholesterolemia, hypertriglyceridemia, choletithiasis,
dislipidemic
conditions, bulimia nervosa and compulsive eating disorders); sleep disorders;
and
psychiatric disorders, such as depression, anxiety, schizophrenia, substance
abuse,
cognition-enhancement and Parkinson's disease.
[0072] The compounds described in the present application could be used to
enhance the effects of cognition-enhancing agents, such as
acetylcholinesterase
inhibitors (e.g., tacrine), muscarinic receptor-I agonists (e.g., milameline),
nicotinic
agonists, glutamic acid receptor (AMPA and NMDA) modulators, and nootropic
agents (e.g., piracetam, levetiracetam). Examples of suitable therapies for
treatment of
Alzheimer's disease and cognitive disorders for use in combination with the
compounds of the present application include donepezil, tacrine,
revastigraine, 5HT6,
gamma secretase inhibitors, beta secretase inhibitors, SK channel blockers,
Maxi-K
blockers, and KCNQs blockers.
[0073] The compounds described in the present application could be used to
enhance the effects of agents used in the treatment of Parkinson's Disease.
Examples
of agents used to treat Parkinson's Disease include: levadopa with or without
a
COMT inhibitor, antiglutamatergic drugs (amantadine, riluzole), alpha-2
adrenergic
antagonists such as idazoxan, opiate antagonists, such as naltrexone, other
dopamine
agonists or transporter modulators, such as ropinirole, or pramipexole or
neurotrophic
factors such as glial derived neurotrophic factor (GDNF).
PHARMACEUTICAL COMBINATIONS
[0074] The present application includes within its scope pharmaceutical
compositions comprising, as an active ingredient, a therapeutically effective
amount
of at least one of the compounds of Formula I, alone or in combination with a
pharmaceutical carrier or diluent. Optionally, compounds of the present
application
can be used alone, in combination with other suitable therapeutic agents
useful in the
treatment of the aforementioned disorders including: anti-obesity agents; anti-
diabetic
agents, appetite suppressants; cholesterol/lipid-lowering agents, HDL-raising
agents,
cognition enhancing agents, agents used to treat neurodegeneration, agents
used to
treat respiratory conditions, agents used to treat bowel disorders, anti-
inflammatory
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agents; anti-anxiety agents; anti-depressants; anti-hypertensive agents;
cardiac
glycosides; and anti-tumor agents.
[0075] Such other therapeutic agent(s) may be administered prior to,
simultaneously with, or following the administration of the melanin-
concentrating
hormone receptor (MCHR) antagonists in accordance with the application.
[0076] Examples of suitable anti-obesity agents for use in combination with
the
compounds of the present application include melanocortin receptor (MC4R)
agonists, cannabinoid receptor modulators, growth hormone secretagogue
receptor
(GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK
agonists,
GLP-1 agonists, and other Pre-proglucagon-derived peptides; NPY1 or NPY5
antagonist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists,
histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators,
PPAR delta modulators, acetyl-CoA carboxylase (ACC) inhibitors, 11-(3-HSD-1
inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, such
as
AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other
known beta 3 agonists as disclosed in U.S. Patent Nos. 5,541,204, 5,770,615,
5,491,134, 5,776,983 and 5,488,064, a thyroid receptor beta modulator, such as
a
thyroid receptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO 99/00353
(KaroBio) and WO 00/039077 (KaroBio), a lipase inhibitor, such as orlistat or
ATL-
962 (Alizyme), serotonin receptor agonists, (e.g., BVT-933 (Biovitrum)),
monoamine
reuptake inhibitors or releasing agents, such as fenfluramine,
dexfenfluramine,
fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex,
clortermine, picilorex, sibutramine, dexamphetamine, phentermine,
phenylpropanolamine or mazindol, anorectic agents such as topiramate (Johnson
&
Johnson), CNTF (ciliary neurotrophic factor) /Axokine (Regeneron), BDNF
(brain-
derived neurotrophic factor), leptin and leptin receptor modulators, or
cannabinoid-1
receptor antagonists, such as SR-141716 (Sanofi) or SLV-319 (Solvay).
[0077] Examples of suitable anti-diabetic agents for use in combination with
the
compounds of the present application include: insulin secretagogues or insulin
sensitizers, which may include biguanides, sulfonyl ureas, glucosidase
inhibitors,
aldose reductase inhibitors, PPAR y agonists such as thiazolidinediones, PPAR
a
agonists (such as fibric acid derivatives), PPAR b antagonists or agonists,
PPAR a/y
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dual agonists, 11-(3-HSD-1 inhibitors, dipeptidyl peptidase IV (DP4)
inhibitors
including saxagliptin, SGLT2 inhibitors including dapagliflozin and
serglifozin,
glycogen phosphorylase inhibitors, and/or meglitinides, as well as insulin,
and/or
glucagon-like peptide-1 (GLP-1), GLP-1 agonist, incretin modulators, AMP
kinase
activators, glucocortical antagonists, fructose bis 1,6-phosphatase
inhibitors,
glucokinase inhibitors and/or a PTP-1B inhibitor (protein tyrosine phosphatase-
1B
inhibitor).
[0078] The antidiabetic agent may be an oral antihyperglycemic agent
preferably
a biguanide such as metformin or phenformin or salts thereof, preferably
metformin
HC1. Where the antidiabetic agent is a biguanide, the compounds of the present
application will be employed in a weight ratio to biguanide within the range
from
about 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.
[0079] The antidiabetic agent may also preferably be a sulfonyl urea such as
glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Patent
No.
4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas
or
other antihyperglycemic agents which act on the ATP-dependent channel of the
beta-
cells, with glyburide and glipizide being preferred, which may be administered
in the
same or in separate oral dosage forms. The oral antidiabetic agent may also be
a
glucosidase inhibitor such as acarbose (disclosed in U.S. Patent No.
4,904,769) or
miglitol (disclosed in U.S. Patent No. 4,639,436), which may be administered
in the
same or in a separate oral dosage forms.
[0080] The compounds of the present application may be employed in
combination with a PPAR y agonist such as a thiazolidinedione oral anti-
diabetic
agent or other insulin sensitizers (which has an insulin sensitivity effect in
NIDDM
patients) such as rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-
555
(disclosed in U.S. Patent No. 5,594,016), Glaxo-Wellcome's GL-262570,
englitazone
(CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J),
JTT-
501 (JPNT/P&U), L-895645 (Merck), R-1 19702 (Sankyo/WL), NN-2344 (Dr.
Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.
[0081] The compounds of the present application may also be employed with a
PPARa/y dual agonist such as MK-767/KRP-297 (Merck/Kyorin; as described in
Yajima, K. et al., Am. J. Physiol. Endocrinol. Metab., 284:E966-E971 (2003)),
AZ-
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242 (tesaglitazar; Astra-Zeneca; as described in Ljung, B. et al., J. Lipid
Res.,
43:1855-1863 (2002)); muraglitazar; or the compounds described in U.S. Patent
No.
6,414,002.
[0082] The compounds of the present invention may be employed in combination
with anti-hyperlipidemia agents, or agents used to treat arteriosclerosis. An
example
of an hypolipidemic agent would be an HMG CoA reductase inhibitor which
includes, but is not limited to, mevastatin and related compounds as disclosed
in U.S.
Patent No. 3,983,140, lovastatin (mevinolin) and related compounds as
disclosed in
U.S. Patent No. 4,231,938, pravastatin and related compounds such as disclosed
in
U.S. Patent No. 4,346,227, simvastatin and related compounds as disclosed in
U.S.
Patent Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which
may be employed herein include, but are not limited to, fluvastatin, disclosed
in U.S.
Patent No. 5,354,772, cerivastatin disclosed in U.S. Patent Nos. 5,006,530 and
5,177,080, atorvastatin disclosed in U.S. Patent Nos. 4,681,893, 5,273,995,
5,385,929
and 5,686,104, pitavastatin (Nissan/Sankyo's nisvastatin (NK-104) or
itavastatin),
disclosed in U.S. Patent No. 5,011,930, Shionogi-Astra/Zeneca rosuvastatin
(visastatin (ZD-4522)) disclosed in U.S. Patent No. 5,260,440, and related
statin
compounds disclosed in U.S. Patent No. 5,753,675, pyrazole analogs of
mevalonolactone derivatives as disclosed in U.S. Patent No. 4,613,610, indene
analogs of mevalonolactone derivatives as disclosed in PCT application WO
86/03488, 6-[2-(substituted-pyrrol-l-yl)-alkyl)pyran-2-ones and derivatives
thereof as
disclosed in U.S. Patent No. 4,647,576, Searle's SC-45355 (a 3-substituted
pentanedioic acid derivative) dichloroacetate, imidazole analogs of
mevalonolactone
as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-
phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-
disubstituted pyrrole, furan and thiophene derivatives as disclosed in
European Patent
Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in
U.S.
Patent No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Patent
No.
4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in European
Patent
Application No.0142146 A2, and quinoline and pyridine derivatives disclosed in
U.S.
Patent Nos. 5,506,219 and 5,691,322. In addition, phosphinic acid compounds
useful
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in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB
2205 83 7.
[0083] The squalene synthetase inhibitors suitable for use herein include, but
are
not limited to, a-phosphono-sulfonates disclosed in U.S. Patent No. 5,712,396,
those
disclosed by Biller, et al., J. Med. Chem., 31:1869-1871 (1998) including
isoprenoid
(phosphinyl-methyl)phosphonates as well as other known squalene synthetase
inhibitors, for example, as disclosed in U.S. Patent Nos. 4,871,721 and
4,924,024 and
in Biller, S.A. et al., Current Pharmaceutical Design, 2:1-40 (1996).
[0084] In addition, other squalene synthetase inhibitors suitable for use
herein
include the terpenoid pyrophosphates disclosed by Ortiz de Montellano, P. et
al., J.
Med. Chem., 20:243-249 (1977), the farnesyl diphosphate analog A and
presqualene
pyrophosphate (PSQ-PP) analogs as disclosed by Corey et al., J. Am. Chem.
Soc.,
98:1291-1293 (1976), phosphinylphosphonates reported by McClard, R.W. et al.,
J.
Am. Chem. Soc., 109:5544 (1987) and cyclopropanes reported by Capson, T.L.,
Ph.D., dissertation, June, 1987, Dept. Med. Chem., U. of Utah, Abstract, Table
of
Contents, pp. 16, 17, 40-43, 48-5 1, Summary.
[0085] Other hypolipidemic agents suitable for use herein include, but are not
limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,
clofibrate,
bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related
compounds
as disclosed in U.S. Patent No. 3,674,836, probucol and gemfibrozil being
preferred,
bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex
(SECHOLEX, POLICEXIDE) and cholestagel (Sankyo/Geltex), as well as lipostabil
(Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative),
imanixil
(HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC,
Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene
derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-
277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid
(niacin),
acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,
poly(diallylmethylamine)
derivatives such as disclosed in U.S. Patent No. 4,759,923, quaternary amine
poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S.
Patent No. 4,027,009, and other known serum cholesterol lowering agents.
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[0086] The other hypolipidemic agent may be an ACAT inhibitor (which also has
anti-atherosclerosis activity) such as disclosed in, Drugs of the Future, 24:9-
15
(1999), (Avasimibe); Nicolosi et al., "The ACAT inhibitor, Cl-1011 is
effective in the
prevention and regression of aortic fatty streak area in hamsters",
Atherosclerosis
(Shannon, Irel.), 137(1):77-85 (1998); Ghiselli, G., "The pharmacological
profile of
FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated
by
selective suppression of the hepatic secretion of ApoB100-containing
lipoprotein",
Cardiovasc. Drug Rev., 16(1):16-30 (1998); Smith, C. et al., "RP 73163: a
bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Bioorg. Med.
Chem.
Lett., 6(1):47-50 (1996); Krause, B.R. et al., Chapter 6: "ACAT Inhibitors:
Physiologic Mechanisms for Hypolipidemic and Anti-Atherosclerotic Activities
in
Experimental Animals", Inflammation: Mediators and Pathways, CRC Press, Inc.,
publ., Ruffolo, Jr., R.R. et al., eds., pp. 173-198 (1995); Sliskovic et al.,
"ACAT
inhibitors: potential anti-atherosclerotic agents", Curr. Med. Chem., 1(3):204-
225
(1994); Stout et al., "Inhibitors of acyl-CoA:cholesterol 0-acyl transferase
(ACAT) as
hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with
lipid-
regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase
(ACAT). 7.
Development of a series of substituted N-phenyl-N'-[(1-phenylcyclopentyl)-
methyl]ureas with enhanced hypocholesterolemic activity", Chemtracts: Org.
Chem.,
8(6):359-362 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd), as well as F-
1394,
CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.
[0087] The hypolipidemic agent may be an upregulator of LDL receptor activity
such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly). The
hypolipidemic agent may be a cholesterol absorption inhibitor preferably
Schering-
Plough's SCH48461 (ezetimibe) as well as those disclosed in Atherosclerosis,
115:45-63 (1995) and J. Med. Chem., 41:973 (1998).
[0088] The other lipid agent or lipid-modulating agent may be a cholesteryl
transfer protein inhibitor (CETP) such as Pfizer's CP-529,414 as well as those
disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496, and
Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.
[0089] The hypolipidemic agent may be an ileal Na+/bile acid co-transporter
inhibitor such as disclosed in Drugs of the Future, 24:425-430 (1999). The ATP
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citrate lyase inhibitor which may be employed in the combination of the
application
may include, for example, those disclosed in U.S. Patent No. 5,447,954.
[0090] The other lipid agent also includes a phytoestrogen compound such as
disclosed in WO 00/30665 including isolated soy bean protein, soy protein
concentrate or soy flour as well as an isoflavone such as genistein, daidzein,
glycitein
or equol, or phytosterols, phytostanol or tocotrienol as disclosed in WO
2000/015201;
a beta-lactam cholesterol absorption inhibitor such as disclosed in EP 675714;
an
HDL upregulator such as an LXR agonist, a PPAR a-agonist and/or an FXR
agonist;
an LDL catabolism promoter such as disclosed in EP 1022272; a sodium-proton
exchange inhibitor such as disclosed in DE 19622222; an LDL-receptor inducer
or a
steroidal glycoside such as disclosed in U.S. Patent No. 5,698,527 and GB
2304106;
an anti-oxidant such as beta-carotene, ascorbic acid, a-tocopherol or retinol
as
disclosed in WO 94/15592 as well as Vitamin C and an antihomocysteine agent
such
as folic acid, a folate, Vitamin B6, Vitamin B 12 and Vitamin E; isoniazid as
disclosed
in WO 97/35576; a cholesterol absorption inhibitor, an HMG-CoA synthase
inhibitor,
or a lanosterol demethylase inhibitor as disclosed in WO 97/48701; a PPAR b
agonist
for treating dyslipidemia; or a sterol regulating element binding protein-I
(SREBP-1)
as disclosed in WO 2000/050574, for example, a sphingolipid, such as ceramide,
or
neutral sphingomyelenase (N-SMase) or fragment thereof. Preferred
hypolipidemic
agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin,
pitavastatin
and rosuvastatin, as well as niacin and/or cholestagel.
[0091] The compounds of the present invention may also be employed in
combination with anti-hypertensive agents. Examples of suitable anti-
hypertensive
agents for use in combination with the compounds of the present application
include
beta adrenergic blockers, calcium channel blockers (L-type and/or T-type;
e.g.,
diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,
chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide,
benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide,
musolimine,
bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE
inhibitors
(e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril,
delapril,
pentopril, quinapril, ramipril, lisinopril), AT-I receptor antagonists (e.g.,
losartan,
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irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan
and
compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265), Dual ET/AII
antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase
(NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g.,
omapatrilat and gemopatrilat), and nitrates.
[0092] MCHR1 antagonists could also be useful in treating other diseases
associated with obesity, including sleep disorders. Therefore, the compounds
described in the present application could be used in combination with
therapeutics
for treating sleep disorders. Examples of suitable therapies for treatment of
sleeping
disorders for use in combination with the compounds of the present application
include melatonin analogs, melatonin receptor antagonists, ML 1 B agonists,
GABA
receptor modulators; NMDA receptor modulators, histamine-3 (H3) receptor
modulators, dopamine agonists and orexin receptor modulators.
[0093] MCHR1 antagonists may reduce or ameliorate substance abuse or
addictive disorders. Therefore, combination of cannabinoid receptor modulators
with
agents used to treat addictive disorders may reduce the dose requirement or
improve
the efficacy of current addictive disorder therapeutics. Examples of agents
used to
treat substance abuse or addictive disorders are: selective serotonin reuptake
inhibitors (SSRI), methadone, buprenorphine, nicotine and bupropion.
[0094] MCHR1 antagonists may reduce anxiety or depression; therefore, the
compounds described in this application may be used in combination with anti-
anxiety agents or antidepressants. Examples of suitable anti-anxiety agents
for use in
combination with the compounds of the present application include
benzodiazepines
(e.g., diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide,
clonazepam,
chlorazepate, halazepam and prazepam), 5HT1A receptor agonists (e.g.,
buspirone,
flesinoxan, gepirone and ipsapirone), and corticotropin releasing factor (CRF)
antagonists.
[0095] Examples of suitable classes of anti-depressants for use in combination
with the compounds of the present application include norepinephrine reuptake
inhibitors (tertiary and secondary amine tricyclics), selective serotonin
reuptake
inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine and sertraline),
monoamine
oxidase inhibitors (MAOIs) (isocarboxazid, phenelzine, tranylcypromine,
selegiline),
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reversible inhibitors of monoamine oxidase (RIMAs) (moclobemide), serotonin
and
norepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropin
releasing
factor (CRF) receptor antagonists, alpha-adrenoreceptor antagonists, and
atypical
antidepressants (bupropion, lithium, nefazodone, trazodone and viloxazine).
[0096] The combination of a conventional antipsychotic drug with a MCHR1
antagonist could also enhance symptom reduction in the treatment of psychosis
or
mania. Further, such a combination could enable rapid symptom reduction,
reducing
the need for chronic treatment with antipsychotic agents. Such a combination
could
also reduce the effective antipsychotic dose requirement, resulting in reduced
probability of developing the motor dysfunction typical of chronic
antipsychotic
treatment.
[0097] Examples of suitable antipsychotic agents for use in combination with
the
compounds of the present application include the phenothiazine
(chlorpromazine,
mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and
trifluoperazine), thioxanthine (chlorprothixene, thiothixene), heterocyclic
dibenzazepine (clozapine, olanzepine and aripiprazole), butyrophenone
(haloperidol),
diphenylbutylpiperidine (pimozide) and indolone (molindolone) classes of
antipsychotic agents. Other antipsychotic agents with potential therapeutic
value in
combination with the compounds in the present application include loxapine,
sulpiride and risperidone.
[0098] Combination of the compounds in the present application with
conventional antipsychotic drugs could also provide an enhanced therapeutic
effect
for the treatment of schizophrenic disorders, as described above for manic
disorders.
As used here, schizophrenic disorders include paranoid, disorganized,
catatonic,
undifferentiated and residual schizophrenia, schizophreniform disorder,
schizoaffective disorder, delusional disorder, brief psychotic disorder and
psychotic
disorder not specified. Examples of suitable antipsychotic drugs for
combination with
the compounds in the present application include the antipsychotics mentioned
above,
as well as dopamine receptor antagonists, muscarinic receptor agonists, 5HT2A
receptor antagonists and 5HT2A/dopamine receptor antagonists or partial
agonists
(e.g., olanzepine, aripiprazole, risperidone, ziprasidone).
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DOSAGE FORMS
[0099] The compounds of the present invention can be administered in oral
dosage form The dosage form for said pharmaceutical composition includes such
oral
dosage forms as granules, powders, tablets, capsules, syrups, emulsions,
suspensions,
etc. and such non-oral dosage forms as injections (e.g., subcutaneous,
intravenous,
intramuscular and intraperitoneal injections), drip infusions, external
application
forms (e.g., nasal spray preparations, transdermal preparations, ointments,
etc.), and
suppositories (e.g., rectal and vaginal suppositories).
[00100] These dosage forms can be manufactured by the per se known technique
conventionally used in pharmaceutical procedures. The specific manufacturing
procedures are as follows.
[00101] To manufacture an oral dosage form, an excipient (e.g., lactose,
sucrose,
starch, mannitol, etc.), a disintegrator (e.g., calcium carbonate,
carboxymethylcellulose calcium, etc.), a binder (e.g., a-starch, gum arabic,
carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.),
and a
lubricant (e.g., talc, magnesium stearate, polyethylene glyco16000, etc.), for
instance,
are added to the active component or components and the resulting composition
is
compressed. Where necessary, the compressed product is coated, by the per se
known technique, for masking the taste or for enteric dissolution or sustained
release.
The coating material that can be used includes, for instance, ethylcellulose,
hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate, and Eudragit (Rohm & Haas, Germany,
methacrylic-acrylic copolymer).
[00102] Injections can be manufactured typically by the following procedure.
The
active component or components are dissolved, suspended or emulsified in an
aqueous vehicle (e.g., distilled water, physiological saline, Ringer's
solution, etc.) or
an oily vehicle (e.g., vegetable oil such as olive oil, sesame oil, cottonseed
oil, corn
oil, etc. or propylene glycol) together with a dispersant, e.g., Tween 80
(Atlas
Powder, U.S.A.), HCO 60 (Nikko Chemicals), polyethylene glycol,
carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g., methyl p-
hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol,
phenol,
etc.), an isotonizing agent (e.g., sodium chloride, glycerol, sorbitol,
glucose, inverted
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sugar, etc.) and other additives. If desired, a solubilizer (e.g., sodium
salicylate,
sodium acetate, etc.), a stabilizer (e.g., human serum albumin), a soothing
agent (e.g.,
benzalkonium chloride, procaine hydrochloride, etc.) and other additives can
also be
added.
[00103] A dosage form for external application can be manufactured by
processing
the active component or components into a solid, semi-solid or liquid
composition.
To manufacture a solid composition, for instance, the active component or
components, either as they are or in admixture with an excipient (e.g.,
lactose,
mannitol, starch, microcrystalline cellulose, sucrose, etc.), a thickener
(e.g., natural
gums, cellulose derivatives, acrylic polymers, etc.), etc., are processed into
powders.
The liquid composition can be manufactured in substantially the same manner as
the
injections mentioned above. The semi-solid composition is preferably provided
in a
hydrous or oily gel form or an ointment form. These compositions may
optionally
contain a pH control agent (e.g., carbonic acid, phosphoric acid, citric acid,
hydrochloric acid, sodium hydroxide, etc.), and a preservative (e.g., p-
hydroxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), among
other
additives.
[00104] Suppositories can be manufactured by processing the active component
or
components into an oily or aqueous composition, whether solid, semi-solid or
liquid.
The oleaginous base that can be used includes, for instance, higher fatty acid
glycerides [e.g., cacao butter, Witepsols (Dinamit-Nobel), etc.], medium-chain
fatty
acids [e.g., Migriols (Dinamit-Nobel), etc.], vegetable oils (e.g., sesame
oil, soybean
oil, cotton-seed oil, etc.), etc. The water-soluble base includes, for
instance,
polyethylene glycols propylene glycol, etc. The hydrophilic base includes, for
instance, natural gums, cellulose derivatives, vinyl polymers, and acrylic
polymers,
etc.
DOSAGES
[00105] The dosage of the pharmaceutical composition of the present invention
may be appropriately determined with reference to the dosages recommended for
the
respective active components and can be selected appropriately according to
the
recipient, the recipient's age and body weight, current clinical status,
administration
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time, dosage form, method of administration, and combination of the active
components, among other factors. For example, the dosage of the compound of
Formula I of the invention for a human adult can be selected from the clinical
oral
dose range of 0.01 to 30 mg/kg body weight (preferably 0.05 to 10 mg/kg body
weight, more preferably 0.05 to 5 mg/kg body weight) or the clinical
parenteral dose
range of 0.005 to 10 mg/kg body weight (preferably 0.01 to 10 mg/kg body
weight,
more preferably 0.01 to 1 mg/kg body weight) or 1 to 1000 mg/day. The other
active
component or components having different modes of action for use in
combination
can also be used in dose ranges selected by referring to the respective
recommended
clinical dose ranges. Administration is generally carried out in a single
dose/day or in
divided doses, for example, 2 to 4 times a day.
ABBREVIATIONS
[00106] The following abbreviations may be employed herein:
Ph = phenyl
Bn = benzyl
t-Bu = tertiary butyl
Me = methyl
Et = ethyl
TMS = trimethylsilyl
TBS = tert-butyldimethylsilyl
Et20 = diethyl ether
EtOAc = ethyl acetate
MeOH = methanol
EtOH = ethanol
i-PrOH = isopropanol
HOAc or AcOH = acetic acid
i-Pr2NEt = diisopropylethylamine
Et3N = triethylamine
DMAP = 4-dimethylaminopyridine
NaBH4 = sodium borohydride
n-BuLi = n-butyllithium
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Pd/C = palladium on carbon
KOH = potassium hydroxide
NaOH = sodium hydroxide
LiOH = lithium hydroxide
K2CO3 = potassium carbonate
NaHCO3 = sodium bicarbonate
Ar = argon
N2 = nitrogen
min = minute(s)
h or hr = hour(s)
L = liter
mL = milliliter
L = microliter
g = gram(s)
mg = milligram(s)
mol moles
mmo1= millimole(s)
meq = milliequivalent
RT = room temperature
sat or sat'd = saturated
aq. = aqueous
TLC = thin layer chromatography
HPLC = high performance liquid chromatography
LC/MS = high performance liquid chromatography/mass spectrometry
MS or Mass Spec = mass spectrometry
NMR = nuclear magnetic resonance
mp = melting point
EXAMPLES
[00107] The following examples are provided to illustrate various preferred
embodiments of the invention, and should not be construed as limiting the
scope
thereo
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GENERAL EXPERIMENTAL INFORMATION SECTION
[00108] In the following examples, nomenclature conforms to either IUPAC or
CAS guidelines; was generated using (or is consistent with) the Autonom
module
(version 2.1) distributed with ChemDraw Ultra 6.0 ; or are taken from vendor
literature.
brine = saturated aqueous sodium chloride
DIC = diisopropylcarbodiimide
DMF = N,N-dimethylformamide
HOBT = Hydroxybenzotriazole
PyBOP = benzotriazo-l-yl-oxy-trispyrrolidinophosphonium hexafluoroborate
TFA = trifluoroacetic acid
THF = tetrahydrofuranyl
WSC = 1- [3 -(dimethylamino)propyl] -3 -ethylcarbodiimide hydrochloride
Analytical Chromatography Methods
[00109] HPLC: column:
Method 1: Phenom-Luna (ODS) S-5, 4.6 mm x 50 mm; flow-5.0 mL/min.;
detection at 220 nm; solvent- A = 10% methanol/water + 0.2% phosphoric acid, B
=
90% methanol/water + 0.2% phosphoric acid; gradient-linear, 0% B to 100% B
over
4 min and 100% B for 1 min.
Method 2: YMC Combiscreen S-5, 4.6 mm x 50 mm; flow-4.0 mL/min.;
detection at 220 nm; solvent- A = 10% methanol/water + 0.2% phosphoric acid, B
90% methanol/water + 0.2% phosphoric acid; gradient-linear, 0% B to 100% B
over
4 min and 100% B for 1 min.
LC MS: column-Phen-Luna (S5 ODS column) 4.6 mm x 30 mm; detection at
220 nm; flow-4 mL/min; solvent- A = 10% methanol/water + 0.1% TFA, B = 90%
methanol/water + 0.1% TFA; linear gradient, 0% B to 100% B over 2 min and 100%
B for 1 min.
Preparative HPLC Chromatography Method
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[00110] Phenomenex Luna C18, S5, 21 x 100 mm; flow-20 mL/min, detection at
220 nm; solvent- A = 10% methanol/water + 0.1% TFA, B = 90% methanol/water +
0.1% TFA; gradient-linear, 10% B to 90% B over 20 min.
General Experimental Procedures for Preparation of
3-(Arylthio)-1-(aryl)pyrazin-2(1H)-one
Preparation of 1-Aryl pyrazine-2,3(1H,4H)-dione
Part A
O-
o r__I
I \ ~ O NH \ O
HZN / O /~ I /
O N O
H
[00111] Ethyl oxalyl chloride (7.8 g, 6.8 mL, 57 mmol) was added to a mixture
of
3,4-dimethoxyaniline (4.4 g, 29 mmol) and K2C03 (14 g, 140 mmol) in EtOAc (44
mL) and water (12 mL) at 0 C. After stirring at 0 C for 10 min, water (18 mL)
was
added; whereupon the mixture was transferred to a separatory funnel and
extracted
with EtOAc (2 x 40 mL). The combined EtOAc were filtered through Na2SO4 and
evaporated to about 30 mL. After addition of 2,2-dimethoxyethylamine (3.8 g,
3.9
mL, 36 mmol), the reaction was stirred at ambient temperature overnight. The
resultant white solid was filtered and then washed with hexane to afford N1-
(2,2-
dimethoxyethyl)-N2-(3,4-dimethoxyphenyl)oxalamide as a light purple-grey solid
(6.3 g, 71% yield). HPLC 33% 2.47 min and 63% at 2.79 min. LC MS 1.37 min
(M+1 = 281 and 335). H-NMR (CDC13) 9.15 (broad s, 1H), 7.76 (broad s, 1H),
7.41
(d, J = 2.4 Hz, 1H), 7.06 (dd, J = 2.4, 8.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H),
4.45 (t, J
= 5.5 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.52 (t, J = 5.5 Hz, 2H), 3.42 (s,
6 H).
Part B
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O-
rlO- O ~ O\
O NH O O
~N O
HN /
O N O ~
H
[00112] After addition of trifluoroacetic acid (0.12 mL, 1.7 mmol) to a
mixture of
the aryl oxalamide prepared in Part A (0.50 g, 1.6 mmol) in acetic acid (1.0
mL), the
resulting solution was heated to 125 C for 20 min using a microwave. Following
evaporation of the solvent, the residue was triturated with EtOAc to afford 1-
(3,4-
dimethoxyphenyl)pyrazine-2,3(1H,4H)-dione as a white solid (1.1 g, 92% yield).
HPLC 1.83 min. LC MS 1.20 min (M+1 = 249). H-NMR (CD3OD) 7.06 (m, 2H),
6.97 (m, 1H), 6.56 (d, J = 5.7 Hz, 1H), 6.45 (d, J = 5.7 Hz, 1H), 3.89 (s,
3H), 3.85 (s,
3H).
Preparation of Desired Substituted 3-thio-l-aryl-pyrazin-2(1H)-one
Method 1
Part C
0 ~
0 0 a
O I/ / Ci ~
O N O
~t"~ N
[00113] Thionyl chloride (0.28 g, 0.17 mL, 2.4 mmol) was slowly added to a
stirred solution of the 1-aryl pyrazine-2,3(1H,4H)-dione prepared in Part B
(0.54 g,
2.2 mmol) in EtOAc (0.88 mL) and DMF (0.44 mL) at 45 C. After stirring at 55
to
60 C for 2 h, the reaction was transferred to a separatory funnel, diluted
with EtOAc
and 2N KHCO3 and extracted with EtOAc (2 x). The combined organic layers were
washed with 2N KHCO3 and water; whereupon, the combined aqueous layers were
extracted with CH2C12. All of the organic layers were combined prior to drying
over
MgS04 to afford 3-chloro-l-(3,4-dimethoxyphenyl)pyrazin-2(1H)-one (0.34 g, 59%
yield). HPLC 2.33 min. LC MS 1.00 min (M+1 = 267/269). The chloropyrazinone
was used in the subsequent steps without further purification.
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Part D
o J:::~O ci I~ ci` ~ SY _N N O
INII' NI~
[00114] 4-Chlorobenzylmercaptan (71 mg, 0.059 mL, 0.45 mmol) was added to a
stirred THF (1.0 mL) suspension of sodium hydride (60% oil dispersion, 18 mg,
0.45
mmol), that had been previously washed with hexane 3x. The reaction was
stirred at
ambient temperature for 20 min until it became a solid mass; whereupon, the
chloropyrazinone prepared in Part C (100 mg, 0.38 mmol) in THF (5 mL) was
added
resulting in gas evolution. After stirring at ambient temperature for 40 min,
the
reaction was diluted with CH2C12/H20, extracted with CH2C12 (2 x) and dried
over
MgSO4 to afford 220 mg of crude product after evaporation of the solvent. The
desired was purified by chromatography on silica gel (12 g) employing gradient
elution (0 - 100% EtOAc/hexane over 12 min) to elute the desired 3-(4-
chlorobenzylthio)-1-(3,4-dimethoxyphenyl)pyrazin-2(1H)-one (130 mg, 89%
yield).
Method 2
[00115] A solution of the 1-aryl pyrazine-2,3(1H,4H)-dione prepared in Part B
(67
mg, 0.27 mmol), diisopropylethyl amine (0.15 mL, 0.81 mmol), pyBOP (0.23 g,
0.46
mmol), and dimethylaminopyridine (13 mg) in DMF (1.2 mL) was stirred at
ambient
temperature for 15 min. After addition of 2-pyridylethyl mercaptan (28 mg,
0.40
mmol), the reaction was stirred at ambient temperature for 2.5 h prior to
quenching
by addition of H20 and extraction with EtOAc. The EtOAc extracts were washed
with water (2 x), brine, dried over MgSO4 and concentrated to yield 204 mg of
crude
product. Chromatography on silica employing a gradient elution with
hexane/EtOAc
afforded the desired product 1-(3,4-dimethoxyphenyl)-3-(2-(pyrazin-2-
yl)ethylthio)pyrazin-2(1H)-one (17 mg, 17% yield).
Method 2a
[00116] The same procedure was employed as that described in Method 2 except
that the reaction was run for 18 hr.
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Method 3
[00117] Following preparation of the oxalamide as described in Part A, ring
closure can be effected by prolonged thermal heating in TFA/HOAc at 78 C for
ld.
In the case of 3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)aniline which contained
a
basic amine, the reaction was brought to pH 6 to 7 with saturated NaHCO3 and
then
evaporated in vacuo. The residue was absorbed on silica gel and purified by
flash
chromatography (5 to 15% 2N NH3 in MeOH/CHzCIz) to afford the desired 1-aryl
pyrazine-2,3(1H,4H)-dione in 36% yield. This material was subsequently
converted
to final product following the procedure described in Method 2.
Method 4
[00118] If the oxalamide as described in Part A contained a primary or
secondary
alcohol, prolonged thermal heating in TFA/HOAc at 78 C for 1 day not only
effected
ring closure but also converted the alcohol moiety to an acetate. The
resulting 1-aryl
pyrazine-2,3(1H,4H)-dione was converted to the desired 3-thio substituted-l-
arylpyrazin-2-one employing Method 1. Following workup and purification as
described in Method 1, the acetylated product was converted to the desired 3-
thio
substituted-l-arylpyrazin-2-one (19 mg, 0.041 mmol) bearing a free hydroxyl by
dissolution in MeOH (1.0 mL) and H20 (0.1 mL) and stirring at ambient
temperature
for lh after addition of potassium carbonate (30 mg). The reaction was then
diluted
with CH2C12/H20 prior to extraction with CH2C12 (2 x). After drying the
combined
organic layers over MgSO4, concentration afforded the desired final product
(16 mg,
93% yield).
Method 5
[00119] For weakly nucleophilic thiols more forcing conditions were required
effect PyBOP mediated conversion of the 1-aryl pyrazine-2,3(1H,4H)-dione to a
3-
thio substituted-l-arylpyrazin-2-ones. Accordingly, a DMF solution (0.4 mL)
containing the 1-aryl pyrazine-2,3(1H,4H)-dione prepared in Part B (92 mg,
0.30
mmol), PyBOP (0.27 g, 0.53 mmol) and diisopropylethylamine (0.16 mL, 0.9 mmol)
was stirred for 3 h before addition of a DMF solution prepared by stirring 5-
methoxybenzo[d]thiazole-2-thiol (296 mg, 1.502 mmol) with NaH (60.1 mg, 1.502
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mmol, rinsed with hexane 2x) in DMF (0.2 mL) at ambient temperature for 10
min.
After stirring at ambient temperature for 7 days, the reaction mixture was
diluted with
EtOAc and washed sequentially with water (2 x) and brine prior to drying over
MgSO4. After evaporation of the solvent, CH2C12 (10 mL) was added to the 0.30
g of
crude product. Filtration to remove any residual solids followed by
evaporation of
the filtrate afforded 0.10 g crude product. Final purification required flash
chromatography on 12 g silica gel using gradient elution (0 to 100%
EtOAc/CHzC1z )
followed by preparatory HPLC (YMC S5 ODS 20x100 mm, 20 mL/min, 30 to 100%
B in A over 10 min,.Solvent A = 10% MeOH/H20 - 0.1% TFA, Solvent B = 90%
MeOH/H20 - 0.1% TFA) to afford pure desired product ( 6.3 mg, 4% yield).
Method 6
General Experimental Procedures for Preparation of 1-(4-(2-Hydroxy-2-
methylpropoxy)-3-methylphenyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-
2(1H)-one
O ~ O v _OH
S ~ ~
" N
F3C, ~ N
Part A. N1-(2,2-Dimethoxyethyl)-N2-(4-methoxybenzyl)oxalamide
OII "O
NHy Q ~NHZ THF/EtOAc, DIEA_ N X _N~O/
p I~ CI/IJ~LI/O O O reflux I/ H_ IXOI
I I
O
O
[00120] To a mixture of (4-methoxyphenyl)methanamine (9.90 g, 72.2 mmol) in
THF (40 mL) was slowly added ethyl 2-chloro-2-oxoacetate (10.84 g, 79 mmol).
After stirring the reaction at RT for 15 min, a solution of 2,2-
dimethoxyethanamine
(9.10 g, 87 mmol) and N,N-diisopropylethylamine (37.8 mL, 217 mmol) in EtOAc
(40.0 mL) was added. The reaction was heated at reflux for 18 hours;
whereupon,
after cooling to RT, saturated NaHCO3 (50 ml) was added and the mixture
extracted
with EtOAc (50 ml). The EtOAc layer was dried over NazSO4 and concentrated.
The
crude product was purified by silica gel chromatography employing a solvent
gradient
(CH2C12 to 5 % MeOH/ CH2C12) to elute N1-(2,2-dimethoxyethyl)-N2-(4-
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methoxybenzyl)oxalamide (7.50 g, 25.3 mmol, 35.1 % yield) as white solid. 1H
NMR (400 MHz, chloroform-d) b ppm 9.07 (1 H, s), 7.69 (1 H, t, J=5.65 Hz),
7.59 (1
H, d, J=8.78 Hz), 6.74 (1 H, d, J=8.78 Hz), 4.46 (1 H, t, J=5.40 Hz), 3.79 (2
H, s),
3.53 (2 H, t), 3.44 (6 H, s), 2.23 (6 H, d, J=5.27 Hz), 1.37 (6 H, s).
Part B. 3-Hydroxy-l-(4-methoxybenzyl)pyrazin-2(1H)-one
O 1~1O O
~ H NO
/ HOAc/TFA HO~N
H
0 NJ
O O
[00121] A solution ofNl-(2,2-dimethoxyethyl)-N2-(4-methoxybenzyl)oxalamide
(7.5 g, 25.3 mmol) and TFA (2.340 mL, 30.4 mmol) in AcOH (160 mL) was stirred
at
135 C in a seal tube for 1.5 hours. After cooling to RT and removal of the
volatiles
under vacuum, ethyl ether (150 ml) and sat. aq. NaHCO3 solution (150 ml) were
added. The resulting precipitate was collected by filtration, washed with H20
(50 ml)
and ether (50 ml) prior to drying under high vacuum to yield 3-hydroxy-l-(4-
methoxybenzyl)pyrazin-2(1H)-one (5.30 g, 21.68 mmol, 86 % yield) as brown
solid.
1H NMR (400 MHz, DMSO-d6) b ppm 11.17 (1 H, br. s.), 7.18 (2 H, d), 6.81 (2 H,
d), 6.46 (1 H, d, J=5.77 Hz), 6.23 (1 H, br. s.), 4.74 (2 H, s), 3.24 (1 H,
s).
Part C. 1-(4-Methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-
one
0 0II
HO NN 0/ F~O I/ SH PyBOP, o S N' N O
[00122] A mixture of 3-hydroxy-l-(4-methoxybenzyl)pyrazin-2(1H)-one (2.0 g,
8.61 mmol), PyBOP (7.84 g, 15.07 mmol) and N,N-diisopropylethylamine (4.51 mL,
25.8 mmol) in DMF (40 mL) was stirred at RT under N2 for 3 hours whereupon 4-
(trifluoromethoxy)benzenethiol (2.007 g, 10.33 mmol) was added. After having
stirred for 18 additional hours, the reaction was diluted with saturated aq.
NaHCO3
(65 ml) and was then extracted with EtOAc (60 ml). The EtOAc layer was dried
over
Na2SO4 and concentrated. The crude product was purified by silica gel
chromatography employing a solvent gradient (hexane to 75 % EtOAc/hexane) to
elute 1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one
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(2.76 g, 6.42 mmol, 74.6 % yield) as white solid. 1H NMR (400 MHz, chloroform-
d)
6 ppm7.58(2H,d,J=8.78Hz),7.21-7.35(4H,m),7.02(1H,d,J=4.52Hz),6.90
(2 H, d, J=8.78 Hz), 6.85 (1 H, d, J=4.27 Hz), 5.03 (2 H, s), 3.81 (3 H, s).
Part D. 3-(4-(Trifluoromethoxy)phenylthio)pyrazin-2(1H)-one
0 0
F F I~ S Y N TFA, reflux F F I~ S Y NH
F~O' 0 FOj\% NI\%
[00123] A solution of 1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)-
pyrazin-2(1H)-one (2.76 g, 6.76 mmol) in TFA (25 mL) was stirred at reflux for
2
days. Since LC-MS analysis revealed that 28 % SM remained, the reaction was
stirred for 7 days. After removal of the TFA under vacuum, the crude product
was
purified by silica gel chromatography employing a solvent gradient (hexane to
100 %
EtOAc to elute 3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (1.60 g,
5.27
mmol, 78 % yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) b ppm
7.61
(2 H, d, J=9.03 Hz), 7.29 (2 H, d, J=7.78 Hz), 7.24 (1 H, d, J=4.02 Hz), 7.07
(1 H, d).
Part E. 1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(4-
(trifluoromethoxy)p henylthio)pyrazin-2(1H)-one
OII ~ OII ~ I O v OH
H
110
\ S 7 ~HH O OH Cul, K3PO4, diioixane \ S J
~
F3C,0 I~ HJ Br HH F3CI0 I/ YH
H
[00124] A mixture of 3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (100
mg, 0.347 mmol), 1-(4-bromo-2-methylphenoxy)-2-methylpropan-2-ol (90 mg, 0.347
mmol), N1,N2-dimethylethane-1,2-diamine (92 mg, 1.041 mmol), copper(1) iodide
(19.82 mg, 0.104 mmol) and K3PO4 (221 mg, 1.041 mmol) in dioxane (1.0 mL) was
stirred at 115 C in a sealed tube for 2 hours. After removal of the
precipitate by
filtration, the filtrate was concentrated. The crude product was purified by
silica gel
chromatography employing a solvent gradient (hexane to 100 % EtOAc) to elute 1-
(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(4-
(trifluoromethoxy)phenylthio)-pyrazin-2(1H)-one (18.65 mg, 0.040 mmol, 11.52 %
yield) as off-white solid. 1H NMR (500 MHz, methanol-d3) b ppm 7.62 - 7.68 (2
H,
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WO 2009/009501 PCT/US2008/069361
m), 7.37 (2 H, d, J=7.97 Hz), 7.21 - 7.28 (3 H, m), 7.16 (1 H, d, J=4.40 Hz),
7.02 (1
H, d, J=8.25 Hz), 3.84 (2 H, s), 2.31 (3 H, s), 1.36 (6 H, s).
Method 7
General Experimental Procedures for Preparation of 3-(4-Chlorophenethoxy)-1-
(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one
O O v OH
O I /
I \ " N
CI N
Part A. 2-(4-Chlorophenethoxy)-3-methoxypyrazine
\o \O
,OH CI ~ IN NaHMDS, THF O` IY~ N
CI / NCI Nv
[00125] To a mixture of 2-(4-chlorophenyl)ethanol (1.246 g, 7.96 mmol) in THF
was added 1.0 M sodium bis(trimethylsilyl)amide in THF (6.92 mL, 6.92 mmol).
After stirring at RT under nitrogen for 18 hours, the reaction was diluted
with a
solution of saturated NaHCO3 (65 ml) and extracted with EtOAc 720 ml). The
ethyl
acetate layer was dried over NazSO4 and concentrated. The crude product was
purified by silica gel chromatography employing a solvent gradient (hexane to
30 %
ethyl acetate) to elute 2-(4-chlorophenethoxy)-3-methoxypyrazine (1.25 g, 4.72
mmol, 68.3 % yield) as clear oil. 1H NMR (500 MHz, CDC13) b ppm 7.61 - 7.64 (1
H, m), 7.59 - 7.61 (1 H, m), 7.26 - 7.30 (2 H, m), 7.20 - 7.24 (2 H, m), 7.15
(1 H, d,
J=8.52 Hz), 4.49 - 4.63 (2 H, m), 4.02 (3 H, s), 3.12 (2 H, t, J=7.29 Hz).
Part B. 3-(4-Chlorophenethoxy)pyrazin-2(1H)-one
O1.1 O
~ NSH ~I\ ON NaHCO3, DMA, 135 C ` I O I ` N
~S CI~ % INI~% CI~ I II
[00126] A mixture of benzo[d]thiazole-2-thiol (1.264 g, 7.56 mmol), 2-(4-
chlorophenethoxy)-3-methoxypyrazine (1.00 g, 3.78 mmol) and NaHCO3 (1.587 g,
18.89 mmol) in DMA (10 mL) was stirred at 135 C for 6 hours. After cooling to
RT,
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the mixture was diluted with a solution of saturated NaHCO3 (55 ml) and was
then
extracted with EtOAc (60 ml). The EtOAc layer was dried over Na2SO4 and
concentrated. The crude product was purified by silica gel chromatography
employing a solvent gradient (hexane to 100 % EtOAc) to elute 3-(4-
chlorophenethoxy)pyrazin-2(1H)-one (477 mg, 1.808 mmol, 47.9 % yield) as off-
white solid. 1H NMR (400 MHz, chloroform-d) b ppm 7.27 - 7.31 (2 H, m), 7.19 -
7.25 (2 H, m), 6.95 (1 H, d, J=4.27 Hz), 6.89 (1 H, d, J=4.52 Hz), 4.54 (2 H,
t, J=7.53
Hz), 3.14 (2 H, t, J=7.40 Hz).
Part C. 3-(4-Chlorophenethoxy)-1-(4-(2-hydroxy-2-
methylpropoxy)phenyl)pyrazin-2(1 H)-one
OII O
N II I\ Ov OH
OY `+ I \ Ov OH
" INIV
CI" `~ INIV Br~ ci
[00127] A mixture of 3-(4-chlorophenethoxy)pyrazin-2(1H)-one (25 mg, 0.100
mmol), K3PO4 (63.5 mg, 0.299 mmol), copper (1) iodide (18.99 mg, 0.100 mmol),
1-
(4-bromophenoxy)-2-methylpropan-2-ol and N,N'-dimethylethylenediamine (0.032
mL, 0.299 mmol) in dioxane (1.0 mL) was stirred at 110 C for 60 min. After
removal of the precipitate by filtration, the filtrate was concentrated. The
crude
product was purified by silica gel chromatography employing a solvent gradient
(CH2C12 to 10 % MeOH/ CH2C12) to elute 3-(4-chlorophenethoxy)-1-(4-(2-hydroxy-
2-methylpropoxy)phenyl)pyrazin-2(1H)-one (31.82 mg, 0.073 mmol, 73.1 % yield)
as
white solid. 1H NMR (500 MHz, chloroform-d) b ppm 7.32 (2 H, d), 7.23 - 7.29
(4
H, m), 7.02 (2 H, d), 6.84 (2 H, s), 4.51 (2 H, t, J=7.29 Hz), 3.83 (2 H, s),
3.13 (2 H, t,
J=7.15 Hz), 1.36 (6 H, s).
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ti cc
"C
N N~ N N n
Z Z - cy
cn
n n x o II ~ M ~~ v M p
cocoM
"o N ~ - ~ - - -
c-I
m c-I c-i
N m o N
cc CC
cc
ti
ti N Lr) ~p N' ~
M l~
o~r ti o00o oocn
co~ Ncocy~ vo~~ cy M~ cy c~c~
II ~~~" o v M cc r-~ ~N N
Lr)
01 M p
+ M V V "C
M
--i
a O O N O
V V V V
p GO
"O
rl /'
fi Z
N v U U U _
=n~~
0 0 O O O O
F' - -
M =~ U z z z
0 o
~ a o 0 = p 0 ~
o
/ \ M= 0 oh, 0H, N
Z~ O.V / \ LV
_ ~X ao a\ ~ a W y --N M V
CA 02692671 2010-01-05
WO 2009/009501 PCT/US2008/069361
II M N r ti Ln O~
ti ^ ,~ = N V '"~ N N 01 .~ .~ .~ O
ti N V I I N ^ ~' M V N N ^ =--~ =--~ =--~ ~ ~' ~.`~i
ctm N ~~ N ~~ Nv,~~m N T Mr II NV~ N^ti NM 00 0~ NCC M
C15
N~ 7~ 7~~
Nj ^ ti M~^y ti N N M ti N --~ V N . c~C c~C c~C --i V ti^õi N
Ln Ln cn m Vo ~ `!) ~n M m '!? ~ cn =--~ =--~ =--~ ti N Ln M
omo -M z o r o ti~7 01 M n õ ti r. o~ - - --N~ =~
cn v ~ C15
N
Lr) M M Lr) ~ti ..
Q Nco~ No~ II v~ o~ II `n ~ ~ o nvM~ N~
co
i+ M M
M M Lr) Lr)
--i
M O GO Lr)
~ N M M M
~..i
O
N N N N
y 2 S = I
Z~ U
o 0 0 0 0 0 0 0
~o - - - -
U z z z z
o o
0 0 = o 0
=
O O
N N O' J O' J
/ \ ^ ~ - - -
(L (6
Z~\\ ~. Z~ Z~
`' Q \\ ~
^ \/)
Z Xy / O O O
v 0 L O Q~ z a z 4 j. U X U X
if
E
Z \ ~ ~
Ni0
- .~ JJ 7 7
O GO
CA 02692671 2010-01-05
WO 2009/009501 PCT/US2008/069361
N Lr) ti N "C II "C
"o No~
cc m~ ~"~y Vp '~" M v
Lr)
II N~ ~M r NM ^~O 1~~~ ~II cc
u~ coM
C M~ II Dj M M V C-n
N M~ ti N V l~ ~ y=--~
+
Z cc N N N~vx ox`^ ox N ~~~~
)
~Q x~x N x~ II ~~ ~~x x~~x II `rLr)
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CA 02692671 2010-01-05
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CA 02692671 2010-01-05
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CA 02692671 2010-01-05
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CA 02692671 2010-01-05
WO 2009/009501 PCT/US2008/069361
[00128] Prodrugs were prepared of selected secondary and tertiary alcohols to
improve solubility and exposure. Standard conditions, employed to generate
amino
acid esters of all but the glycine ester of the tertiary alcohols, are
exemplified in
Example 193. Preparation of the glycine ester of the tertiary alcohols is
exemplified
in Example 202. Preparation of a phosphate ester prodrug is exemplified by
Example
204.
EXAMPLE 193
1-(2-Methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-
yl)phenoxy)-2-methylpropan-2-y12-aminoacetate
O
O OOJ~NH2
S`
N O
INI
F
F
Part A. 1-(2-Methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-
yl)phenoxy)-2-methylpropan-2-y12-(tert-butoxycarbonylamino)acetate
O OO~Ny O
~
S` ~ 0
I ~ ~! N O
F / INI
F
F
[00129] To a stirred suspension of the alcohol prepared in Example 36 (3.0 g,
6.4
mmol), 4-pyrrolidinopyridine (0.95 g, 6.4 mmol) and BOC-glycine (3.4 g, 19
mmol)
in CH2C12 (60 mL) at 42 C was added N,N'-diisopropylcarbodiimide 3.0 mL, 19
mmol) over 3.5 h. After stirring at reflux for 2.5 h, HPLC analysis showed 25%
alcohol still remained. More BOC-glycine (3.4 g, 19 mmol) was added followed
by
additional N,N'-diisopropylcarbodiimide (3.0 mL, 19 mmol) which was slowly
added
over 3.5 h; whereupon, HPLC analysis showed < 5% alcohol remained. The
reaction
was allowed to cool to RT prior to addition of hydrazine monohydrate (18 mL,
370
mmol). After stirring for 5 minutes, the reaction mixture was cooled to 0 C
and
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filtered. The filtrates were sequentially washed with cold 1M HC1(3x20 mL) and
cold
2% NaHCO3 (3x20 mL) prior to drying over MgSO4 and concentrating under vacuum
to afford 5.6 g of crude product. Chromatography (silica ge1230-400 mesh,
gradient
elution: 0 to 60% EtOAc/hexane over 47 min) of the residue afforded the
desired
ester (3.9 g, 88% yield). HPLC 4.42 min. LC MS (M+1 = 624), H-NMR (CDC13)
7.72 (m, 4H), 7.12 (d, J = 4.4 Hz, 1H), 7.02 (d, J = 4.4 Hz, 1H), 7.00 (d, J =
8.3 Hz,
1H), 6.99 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 2.5 and 8.3 Hz, 1H), 4.21 (s,
2H), 3.87 (s,
3H), 3.78 (m, 2H), 1.61 (s, 6H), 1.45 (s, 9H).
Part B. 1-(2-Methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-
yl)phenoxy)-2-methylpropan-2-y12-aminoacetate
O
O 11-~z OO~NH2
I ~ N O
F / INI
F
F
[00130] The BOC'd glycinate ester described in Part A (3.9 g, 6.2 mmol) was
treated with 1:2 TFA/ CH2C12 (145 mL) at RT for 25 min. After removal of the
volatiles under vacuum, the residual TFA was removed by co-evaporation with
CH2C12 (3x8 mL) and drying under vacuum for 20 min. Following dissolution in
CH2C12 (70 mL), the solution was washed with cold 5% NaHCO3 (3x30 mL) dried
over MgS04 and concentrated to yield 3.3 g of crude product. Purification by
flash
chromatography (120 g silica gel, 0 to 5% MeOH/CH2C12 over 24 min) afforded
the
desired free amine (2.5 g, 77% yield). ). HPLC 3.72 min. LC MS 2.18 min (M+1 =
524), H-NMR (CDC13) 7.75 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.14
(d, J =
4.4 Hz, 1H), 7.02 (d, J = 4.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.99 (d, J =
2.4 Hz,
1H), 6.92 (dd, J = 2.4 and 8.5 Hz, 1H), 4.24 (s, 2H), 3.89 (s, 3H), 3.36 (m,
2H), 1.63
(s, 6H), 1.54 (broad s, 2H).
EXAMPLES 194 TO 201
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WO 2009/009501 PCT/US2008/069361
[00131] Examples 194 to 201 were prepared in a similar manner to Example 193
using the appropriate alcohol and BOC glycine followed by TFA removal of the
BOC
group.
TABLE 4
Glycine Prodrug Esters
Example No. Glycine ester of HPLC LC MS iH-NMR
Example No. (Met 1) (CDC13)
194 38 3.86 540 7.55 (d, J = 9.3 Hz, 2H), 7.27 (d, J = 9.3 Hz,
2H), 7.18 (d, J = 4.4 Hz, 1H), 7.06 (d, J =
4.4 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.99
(d, J = 8.2 Hz, 1H), 6.86 (dd, J = 2.2 and 8.2
Hz, 1H), 4.15 (s, 2H), 3.76 (s, 3H), 3.17 (s,
2H,1.50 s,6H.
195 32 3.59 470 7.47 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.7 Hz,
2H), 7.11 (d, J = 4.4 Hz, 1H), 6.98 (d, J =
2.3 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.95
(d, J = 4.4 Hz, 1H), 6.88 (dd, J = 2.3 and
8.5 Hz, 1H), 4.20 (s, 2H), 3.86 (s, 3H), 3.33
(s, 2H), 2.40 (s, 3H), 1.50 (s, 6H).
196 50 3.78 484 7.34 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz,
2H), 7.05 (d, J = 4.4 Hz, 1H), 6.92 (d, J =
2.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.87
(d, J = 4.4 Hz, 1H), 6.83 (dd, J = 2.2 and
8.2 Hz, 1H), 4.14 (s, 2H), 3.79 (s, 3H), 3.27
(s, 2H), 2.63 (q, H = 7.7 Hz, 2H), 1.54 (s,
6H,1.19 t,J=7.7Hz,3H.
197 65 482 7.25-7.09 (m, 8H), 6.87 (d, J = 4.4 Hz, 1H),
6.80 (d, J = 9.4 Hz, 1H), 4.09 (s, 2H), 3.30
(2, 2H), 3.23 (dd, J = 7.2, 9.8 Hz, 2H), 2.94
(dd, J = 7.2 and 8.2 Hz, 2H), 2.58 (q, J = 7.6
Hz, 2H), 1.55 (s, 6H), 1.13 (t, J = 7.6 Hz,
3H).
198 87 524 1H NMR (400 MHz, chloroform-d) 8 ppm
8.40 (2 H, br. s.), 7.59 (2 H, d, J=8.78 Hz),
7.28 (2 H, d, J=8.03 Hz), 7.09 - 7.23 (3 H,
m), 6.97 (2 H, d, J=4.27 Hz), 4.22 (2 H, br.
s.), 3.79 (2 H, br. s.), 2.27 (3 H, s), 1.62 (6
H, s
199 88 544 1H NMR (500 MHz, methanol-d3) 8 ppm
7.65 (2 H, d, J=9.07 Hz), 7.61 (1 H, d,
J=2.47 Hz), 7.34 - 7.43 (3 H, m), 7.23 - 7.29
(2 H, m), 7.16 (1 H, d, J=4.40 Hz), 4.38 (2
H, s), 3.75 (2 H, s), 1.68 (6 H, s)
200 123 486 1H NMR (500 MHz, methanol-d3) 8 ppm
7.38 (1 H, d, J=4.40 Hz), 7.29 (2 H, dd,
J=8.52, 5.50 Hz), 7.19 - 7.25 (3 H, m), 6.98
- 7.05 (3 H, m), 4.29 (2 H, s), 3.74 (2 H, s),
3.31 - 3.35 (2 H, m), 2.98 (2 H, t, J=7.56
Hz), 2.28 (3 H, s), 1.67 (6 H, s)
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Example No. Glycine ester of HPLC LC MS iH-NMR
Example No. Metl CDC13
201 113 468 1H NMR (500 MHz, methanol-d3) 8 ppm
7.39 (1 H, d, J=4.40 Hz), 7.25 - 7.31 (4 H,
m), 7.17 - 7.25 (4 H, m), 7.03 (1 H, d,
J=8.25 Hz), 4.28 (2 H, s), 3.74 (2 H, s), 3.24
- 3.39 (2 H, m), 2.91 - 3.04 (2 H, m), 2.28 (3
H, s), 1.67 (6 H, s)
[00132] If desired the amino acid prodrug esters may be converted to the
corresponding HC1 salt. For example, the HC1 salt of Example 197 was prepared
by
dissolving the compound (0.655 mg, 1.36mmoles) in CH2C12 (10 mL) and MeOH (1
mL) and cooling to -30 C. 1N HC1 in ether (2.3 mL, 1.7 eq) was added with
stirring.
Evaporation in vacuo afforded the desired salt. (0.71 g). LC MS was identical
to the
free base. H-NMR (CD3OD) 7.30 (d, J = 4.4 Hz, 1H), 7.20 (m, 4H), 7.13 (m, 4H),
6.93 (d, J = 8.5 Hz, 1H), 4.19 (s, 2H), 3.64 (s, 2H), 3.23 (dd, J = 7.4, 15.4
Hz, 2H),
2.90 (dd, J = 8.0 and 15.4 Hz, 2H), 2.62 (q, J = 7.5 Hz, 2H), 1.59 (s, 6H),
1.14 (t, J
7.5 Hz, 3H).
EXAMPLE 202
1-(2-Methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-
yl)phenoxy)propan-2-y12-amino-3-methylbutanoate
O O NHZ
~ O
S ` _~N ~ I
Y
INI~%
F3C
[00133] To a stirred mixture of the alcohol described in Example 71 (0.882 g,
1.949 mmol), 4- dimethylaminopyridine (0.714 g, 5.85 mmol) and N-(t-
butoxycarbonyl)-L-valine (1.271 g, 5.85 mmol) in 18 mL of CH2C12 at rt was
added
WSC (1.121 g, 5.85 mmol). After stirring at ambient temperature for 30 min,
the
reaction mixture was transferred to a separatory funnel, washed with cold 5%
H2SO4
(3x), 5% Na2CO3 (2x), and water and dried over MgS04. Evaporation of the
solvent
afforded 1.03 g of crude product as the BOC amine. The crude product was
dissolved
in a 1:2 mixture of TFA/CH2C12 (18 mL). After stirring for 15 min the solvent
was
evaporated in vacuo. The residue was transferred to a separatory funnel with
CH2C12,
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washed with cold 5% Na2CO3 (2x), and dried over MgSO4 to afford crude 790 mg
of
product after evaporation of the solvent. The product was purified by flash
chromatography (80 g silica gel, gradient elution: 1 to 8 % MeOH/CH2C12 over
24
min) to afforded the desired valine ester as a free base (0.69 g, 64% yield).
[00134] HPLC (Method 1) 3.84 min. LC MS 2.26 min (M+1 = 552), H-NMR
(CDC13) 7.74 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 4.4
Hz, 1H),
7.02 (d, J = 4.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H),
6.91 (dd, J
= 2.4 and 8.5 Hz, 1H), 5.34 (m, 1H), 4.12 (m, 2H), 3.86 (d, 3H), 3.30 (t, J =
5.2 Hz,
1H), 2.05 (m, 1H), 1.40 (d, J = 6.4 Hz), 0.98 (m, 3H), 0.92 (m, 3H).
[00135] The HC1 salt of Example 176 was prepared by dissolving the compound in
CH2C12 (9 mL). After cooling the solution to -30 C, 1N HC1 in ether (2.85 mL,
1.7
eq) was added with stirring. The yellow precipitate was collected and dried to
afford
the HC1 salt (0.74 g).
[00136] LC MS was identical to the free base. H-NMR (CDC13) 7.74 (d, J = 8.7
Hz, 2H), 7.79 (m, 4H), 7.33 (d, J = 4.4 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H),
7.15 (d, J
2.4 Hz, 1H), 7.02 (dd, J = 2.4 and 8.5 Hz, 1H), 5.51 (m, 1H), 4.24 (m, 2H),
3.86 (d,
3H), 3.33 (s, 1H), 2.30 (m, 1H), 1.41 (d, J = 6.4 Hz), 1.12 (m, 6H).
EXAMPLE 203
(2S)-1,1,1-Trifluoro-3-(2-methoxy-4-(2-oxo-3-(4-
(trifluoromethyl)phenylthio)pyrazin-1(2H)-yl)phenoxy)propan-2-y12-amino-3-
methylbutanoate
)//,, N H2
OO
O OF
F
S~ N O F
I "
F N
F
[00137] In an analogous fashion to that described in Example 202, the valine
ester
of the alcohol described in Example 74 was prepared.
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[00138] LC MS at t= 2.35 min. (m+1 = 606 ) Phenomenex S5 C18 4.6X30 mm
column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min
with 1 min hold at the end of the gradient.
[00139] iH NMR (500 MHz, CDC13) b ppm 0.97 (dd, J=35.13, 6.92 Hz, 6 H), 1.97
- 2.20 (m, 1 H), 3.42 (d, J=4.78 Hz, 1 H), 3.86 (s, 4 H), 4.26 - 4.36 (m, 1
H), 4.44 (dd,
J=11.08, 3.53 Hz, 1 H), 5.73 - 5.87 (m, 1 H), 6.91 (dd, J=8.56, 2.27 Hz, 1 H),
6.97 -
7.06 (m, 2 H), 7.13 (d, J=4.53 Hz, 1 H), 7.58 (s, 1 H), 7.66 - 7.77 (m, 4 H).
EXAMPLE 204
Sodium 3,3-difluoro-l-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)-
phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate
0
P\ONa
O ONa
O ~ I Ov \ ~F
S` ~ "\/~ ~ \F
JI _N O
F3C\ NII~
O
Part A. Dibenzy13,3-difluoro-l-((2-methoxy-4-(2-oxo-3-(4-
(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl
phosphate
0
~` OBz
OH N 0 " OBzI
"P~BzI \ S O tIN O~F ~H\ S~N \ I O~~ Bzl F3C~0 I ~ DCE F3C O ~/ N J
[00140] To a mixture of dibenzyl diisopropylphosphoramidite (135 mg, 0.390
mmol), 1-(4-((3,3-difluoro-l-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)-3-(4-
(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (Example 75) (69 mg, 0.130
mmol)
and 1H-1,2,4-triazole (27.0 mg, 0.390 mmol) in DCE (20 mL) was stirred at
reflux
for 6 hours. The mixture was cooled to RT. 30 % hydrogen peroxide in water (10
ml) was slowly added and the mixture was stirred at RT for 30 min. The mixture
was
diluted with a solution of aqueous 10 % sodium thiosulfate ( 40 ml) and was
extracted
with DCM (50 ml). The DCM layer was dried over sodium sulfate and
concentrated.
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The crude product was purified by ISCO silica gel Column (40 g) and the
product
was eluted with hexane to 100 % ethyl acetate in 10 min. Yield dibenzy13,3-
difluoro-l-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-
1(2H)-
yl)phenoxy)methyl)cyclobutyl phosphate (79 mg, 0.100 mmol, 77 % yield) as off-
white solid. 1H NMR (400 MHz, chloroform-d) b ppm 7.57 - 7.66 (2 H, m), 7.27 -
7.39 (12 H, m), 7.13 (1 H, d, J=4.53 Hz), 6.81 - 7.00 (4 H, m), 4.97 - 5.14 (4
H, m),
4.29 (2 H, s), 3.75 (3 H, s), 2.93 - 3.20 (4 H, m).
Part B. Sodium 3,3-difluoro-l-((2-methoxy-4-(2-oxo-3-(4-
(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl
phosphate
~-OBzI ~~ONa
O' 'OBzI O'~ONa
O N / I ~F TFA, RT 0 / I Ol/\ \/F
\ S~ \ O/ F S~N \ O/ ~~F
F3C 0 I/ N J F3C 0 I/ N J
[00141] To a solution of dibenzy13,3-difluoro-l-((2-methoxy-4-(2-oxo-3-(4-
(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl
phosphate (79 mg, 0.100 mmol) in TFA (2 mL) was stirred at RT for 3.5 hours.
The
mixture was concentrated. The crude product was purified by prep-HPLC
(Phenomenex, Luna 5 micron 25 x 250 mm, flow rate = 30 ml/min., gradient = 20%
A to 100%B in 10 min., A =90%H20/10% MeOH/0.1% TFA, B = 10%H20/90%
MeOH/0.1% TFA). Yield 46 mg, 0.075 mmol. as yellow gum. The yellow gum in
ACN (2 ml) was added 0.5 N aqueous sodium bicarbonate (302 l, 0.151 mmol.),
the
mixture was diluted with water (5 ml). The solution was then lyopholized.
Yield
sodium 3,3-difluoro-l-((2-methoxy-4-(2-oxo-3-(4-
(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl
phosphate (51.08 mg, 0.078 mmol, 78 % yield) as off-white powder. MS
(M+H=61 1). 1H NMR (400 MHz, MeOD) b ppm 7.54 - 7.63 (2 H, m), 7.19 - 7.33 (3
H, m), 7.02 - 7.17 (3 H, m), 6.91 (1 H, dd, J=8.44, 2.39 Hz), 4.28 (2 H, s),
3.80 (3 H,
s), 3.13 - 3.32 (2 H, m), 2.75 - 2.90 (2 H, m).
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EXAMPLE 205
Sodium 1-(2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-
1(2H)-yl)phenoxy)-2-methylpropan-2-yl phosphate
0
~P\OH
O OH
O
/ O
S " N \ I O
NJ
F3CO
[00142] In an analogous fashion to that described in Example 204, the
phosphate
prodrug of the alcohol described in Example 38 was prepared. MS (M-H=561). 1H
NMR (400 MHz, MeOD) b ppm 7.57 (2 H, d, J=8.56 Hz), 7.28 (2 H, d, J=8.31 Hz),
7.20 (1 H, d, J=4.28 Hz), 6.97 - 7.12 (3 H, m), 6.88 (1 H, dd, J=8.56, 2.27
Hz), 4.00
(2 H, s), 3.78 (3 H, s), 1.48 (6 H, s).
[00143] The following experimental descriptions exemplify the preparation of
specific compounds as set out in Examples 27, 95, 110, 113, and 124.
EXAMPLE 27
O \ O v OH
S`
Y N OMe
iN INI ~ I /
J
1-(4-(2-Hydroxy-2-methylp rop oxy)-3-m ethoxyp henyl)-3-(2-(pyridin-2-yl)-
ethylthio)pyrazin-2 (1H)-one
[00144] Following the procedures described in parts A-D of example 134, 2-
methoxy-4-nitrophenol was converted to 1-(4-(2-hydroxy-2-methylpropoxy)-3-
methoxyphenyl)pyrazine-2,3(1H,4H)-dione. A solution of 1-(4-(2-hydroxy-2-
methylpropoxy)-3-methoxyphenyl)pyrazine-2,3(1H,4H)-dione prepared in Part ?
(2.28 g, 7.44 mmol), EtN(iPr)2 (3.9 mL, 22.3 mmol), PyBOP (6.78 g, 13.0 mmol)
in
DMF (35 mL) was stirred at ambient temperature for 1.5 h. After addition of 2-
pyridylethyl mercaptan (1.24 g, 8.93 mmol), the reaction was stirred at
ambient
temperature. After stirring overnight the reaction mixture was partially
concentrated
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under reduced pressure, quenching by addition of aq. NaHCO3 and extracted with
EtOAc. The EtOAc extracts were washed with brine, dried over MgSO4 and
concentrated. Chromatography on silica employing a gradient elution with 2.5-
10%
methanol/methylene chloride, followed by chromatography on silica eluting with
EtOAc, and trituration with EtOAc/Hexanes afforded the desired product 1-(4-(2-
hydroxy-2-methylpropoxy)-3-methoxyphenyl)-3-(2-(pyridin-2-yl)ethylthio)pyrazin-
2(1H)-one (2.15g, 68% yield).
EXAMPLE 95
O ~ O OH
NI /
I \ "
iN NJ
CF3
1-(4-(2-Hydroxy-2-methylprop oxy)-3-methylphenyl)-3-(5-
(trifluoromethyl)pyridin-2-ylthio)pyrazin-2(1 H)-one
Part A. 2-Methyl-l-(2-methyl-4-nitrophenoxy)propan-2-ol
Ov 'OH
OH
I\ KZC03, ACN/HZO, 150 C 02N / \ 15 OZN
[00145] A mixture of 2-methyl-4-nitrophenol (5.50 g, 35.9 mmol), 2,2-
dimethyloxirane (7.77 g, 108 mmol), K2C03 (4.96 g, 35.9 mmol) and NaH2PO4
(4.31
g, 35.9 mmol) in MeCN (50 mL) and H20 (8.82 mL) was stirred at 140 C in a
steel
bomb for 6 hours. After cooling to RT, the reaction was diluted with aq.
saturated
NaHCO3 (80 ml) prior to extraction with EtOAc (100 ml). The EtOAc layer was
dried over Na2SO4 and concentrated. The crude product was purified by silica
gel
chromatography employing a solvent gradient (hexane to 60 % ethyl acetate) to
elute
2-methyl-l-(2-methyl-4-nitrophenoxy)propan-2-ol (7.3 g, 32.4 mmol, 90 % yield)
as
yellow oil. MS (M+1 = 226). 1H NMR (500 MHz, chloroform-d) b ppm 8.00 - 8.15
(2 H, m), 6.86 (1 H, d, J=8.80 Hz), 3.90 (2 H, s), 2.33 (3 H, s), 1.40 (6 H,
s).
Part B. 1-(4-Amino-2-methylphenoxy)-2-methylpropan-2-ol
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~ O~OH Pd/C, H2, MeOH ~ O" OH
OZNJ / I /
HZN
[00146] A mixture of 2-methyl-l-(2-methyl-4-nitrophenoxy)propan-2-ol (7.30 g,
32.4 mmol) and 10 % Pd/C (0.345 g, 3.24 mmol) in MeOH (150 mL) was
hydrogenated at 1 atm of H2 for 18 hours. After removal of the Pd/C by
filtration, the
solution was concentrated to yield 1-(4-amino-2-methylphenoxy)-2-methylpropan-
2-
ol (6.10 g, 29.7 mmol, 92 % yield) as clear gum which was carried forward
without
further purification.
Part C. N1-(2,2-Dimethoxyethyl)-N2-(4-(2-hydroxy-2-methylpropoxy)-3-
methylphenyl)oxalamide
I~ O~OH O\
1 ~NHp THF/EtOAc, DIEA HO~O O Ho
' ~N
HpN ~ cl x0 O O reflux N
IOI H O
[00147] Slow addition of a solution of ethyl 2-chloro-2-oxoacetate (4.69 g,
34.4
mmol) in THF (30 ml) to a solution of 1-(4-amino-2-methylphenoxy)-2-
methylpropan-2-ol (6.10 g, 31.2 mmol) in THF (100 mL) resulted in formation of
a
precipitate as the reaction stirred at RT for 30 min. At which time a solution
of Et3N
(13.06 mL, 94 mmol) and 2,2-dimethoxyethanamine (3.94 g, 37.5 mmol) in EtOAc
(100 mL) was added prior to heating the mixture at reflux for 25 hours. After
cooling and concentration under vacuum, the residue, following dilution with
CH2C12,
was extracted with aqueous 0.5 N HC1(2 x 150 ml). The CH2C12 layer was dried
over sodium sulfate and concentrated to yield N1-(2,2-dimethoxyethyl)-N2-(4-(2-
hydroxy-2-methylpropoxy)-3-methylphenyl)-oxalamide (11.40 g, 30.6 mmol, 98 %
yield) as white solid which was carried forward without further purification.
Part D. 3-Hydroxy-l-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-
2(1H)-one
~O ~ o~
HO I O N~ TFA/HOAc HO O OH
H O II N
O N J
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[00148] A solution of N1-(2,2-dimethoxyethyl)-N2-(4-(2-hydroxy-2-
methylpropoxy)-3-methylphenyl)oxalamide (11.4 g, 32.2 mmol) and TFA (2.97 mL,
38.6 mmol) in AcOH (120 mL) was stirred at 135 C in a seal tube for 60 min.
After
cooling and concentration under vacuum, addition of CH2C12 (300 ml) produced a
precipitate which was collected by filtration and was washed with CH2C12 (150
ml) to
yield 3-hydroxy-l-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-2(1H)-
one (7.19 g, 23.53 mmol, 73.1 % yield) as brown solid. MS (M+1 = 226). 1H NMR
(500 MHz, methanol-d3) b ppm 7.13 - 7.26 (2 H, m), 6.98 (1 H, d, J=8.52 Hz),
6.50 (1
H, d, J=5.77 Hz), 6.41 (1 H, d, J=6.05 Hz), 3.82 (2 H, s), 2.29 (3 H, s), 1.35
(6 H, s).
Part E. 1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(5-
(trifluoromethyl)-pyridin-2-ylthio)pyrazin-2 (1H)-one
`\x/ O ~/ O v OH
Ov
OII / OH ~ 1 I1
HO` XN ~ I F ~ SH PyBOP, DIEA N SY `N\~/\
IY /J F N
NV F F
F
[00149] A mixture of 3-hydroxy-l-(4-(2-hydroxy-2-methylpropoxy)-3-
methylphenyl)pyrazin-2(1H)-one (100 mg, 0.344 mmol), PyBOP (314 mg, 0.603
mmol) and EtN(iPr)2 (0.180 mL, 1.033 mmol) in DMF (6 mL) was stirred at RT for
3
hours prior to addition of 5-(trifluoromethyl)pyridine-2-thiol (74.1 mg, 0.413
mmol).
After stirring for 3 days, The reaction was diluted with aq. saturated NaHCO3
(15 ml)
prior to extraction with EtOAc (20 ml). The EtOAc layer was dried over NazSO4
and
concentrated. The crude product was purified by prep-HPLC (Phenomenex, Luna 5
micron 30 x 250 mm, flow rate = 30 ml/min., gradient = 20% A to 100%B in 30
min.,
A=90%Hz0/10% MeOH/0.1% TFA, B = 10%Hz0/90% MeOH/0.1% TFA). After
concentration, the residue in EtOAc (30 ml) was converted to the free base by
washing with aq. saturated NaHCO3 (30 ml). The EtOAc layer was dried over
NazSO4 and concentrated. To yield 1-(4-(2-hydroxy-2-methylpropoxy)-3-
methylphenyl)-3-(5-(trifluoromethyl)pyridin-2-ylthio)pyrazin-2(1H)-one (22.76
mg,
14%) as off-white solid. MS (M+1 = 452). 1H NMR (500 MHz, chloroform-d) b
ppm 8.88 (1 H, s), 7.89 - 7.99 (2 H, m), 7.16 - 7.24 (3 H, m), 7.07 (1 H, d,
J=4.40
Hz), 6.90 (1 H, d, J=8.52 Hz), 3.84 (2 H, s), 2.30 (3 H, s), 1.39 (6 H, s).
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EXAMPLE 110
O O v _OH
S I /
I \ " N
iN NJ
1-(4-(2-Hydroxy-2-methylp rop oxy)-3-methylp henyl)-3-(2-(pyridin-2-
yl)ethylthio)pyrazin-2 (1H)-one
0 O~ O ~ I O v 'OH
}I~I OH Cul, K3PO4, dioxane N S ~
S_7 -NH I~ ~ /II ~ ~J
N J Br NN N~%
~/ H
[00150] A mixture of 3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one (100 mg,
0.429 mmol), which was prepared by the procedure described in Method 7 except
for
substitution of 2-(2-pyridylethylthiol) for 2-(4-chlorophenethanol), 1-(4-
bromo-2-
methylphenoxy)-2-methylpropan-2-ol (133 mg, 0.514 mmol), N1,N2-dimethylethane-
1,2-diamine (113 mg, 1.286 mmol), K3PO4 (0.106 mL, 1.286 mmol) and copper(1)
iodide (82 mg, 0.429 mmol) in dioxane (1.0 mL) was stirred at 115 C for 90
min.
The reaction mixture, after cooling to RT, was filtered and the filtrate was
concentrated. The crude product was purified by silica gel chromatography
employing a solvent gradient (hexane to 100 % ethyl acetate) to yield 1-(4-(2-
hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(2-(pyridin-2-yl)ethylthio)pyrazin-
2(1H)-one (140 mg, 0.340 mmol, 79 % yield) as white solid. MS (M+H 412). 1H
NMR (400 MHz, MeOD) b ppm 8.67 (1 H, d), 8.48 (1 H, td, J=7.91, 1.51 Hz), 8.02
(1H,d,J=8.28Hz),7.81-7.95(1H,m),7.07-7.29(4H,m),6.93(1H,d,J=8.78
Hz), 3.76 (2 H, s), 3.35 - 3.57 (4 H, m), 2.22 (3 H, s), 1.27 (6 H, s).
EXAMPLE 113
O O v OH
s
" N
N
1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(phenethylthio)pyrazin-
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2(1H)-one
0 0 ~ I Ov -OH
~ NH v _ \ OOH S~ N\/\
" J N" /1
N~
Br ~
[00151] A mixture of 3-(phenethylthio)pyrazin-2(1H)-one (25 mg, 0.108 mmol),
which was prepared by the procedure described in Method 7 except for
substitution
of 2-phenethylthiol for 2-(4-chlorophenethanol), 1-(4-bromo-2-methylphenoxy)-2-
methylpropan-2-ol (33.5 mg, 0.129 mmol), copper iodide (20.50 mg, 0.108 mmol),
K3PO4 (70 mg, 0.323 mmol) and N,N'-dimethylethylenediamine (28.5 mg, 0.323
mmol) in dioxane (1.0 ml) was stirred at 115 C for 2 hours. The reaction
mixture,
after cooling to RT, was filtered and the filtrate was concentrated. The crude
product
was purified by silica gel chromatography employing a solvent gradient (hexane
to
100 % ethyl acetate) to elute to yield 1-(4-(2-hydroxy-2-methylpropoxy)-3-
methylphenyl)-3-(phenethylthio)-pyrazin-2(1H)-one (26.74 mg, 0.062 mmol, 57.5
%
yield) as off-white solid. MS (M+1 = 411). 1H NMR (500 MHz, methanol-d3) b
ppm 7.38 (1 H, d, J=4.40 Hz), 7.25 - 7.32 (4 H, m), 7.16 - 7.24 (4 H, m), 7.00
(1 H, d,
J=8.25 Hz), 3.83 (1 H, s), 3.24 - 3.39 (2 H, m), 2.90 - 3.05 (2 H, m), 2.29 (3
H, s),
1.35 (6 H, s).
RADIOLIGAND BINDING ASSAY FOR ASSESSMENT OF MCHR1
ACTIVITY
Assay and Biological Evaluation
[00152] Compounds of Formula I were initially characterized in an in vitro
binding
assay to determine their Ki or ability to antagonize binding of a peptide
agonist to the
human melanin concentrating hormone receptor (MCHR1).
Radioligand Binding Assay for Assessment of MCHR1 Activity
[00153] Membranes from stably transfected HEK-293 cells expressing a mutated
(E4Q, A5T) hMCHR1 receptor were prepared by dounce homogenization and
differential centrifugation. Binding experiments were carried out with 0.5 -
1.0 ug of
membrane protein incubated in a total of 0.2 ml in 25 mM HEPES (pH 7.4) with
10
mM MgC1z, 2 mM EGTA, and 0.1% BSA (Binding Buffer) for 90 min. For
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competition binding assays, reactions were carried out in the presence of with
0.06 -
0.1 nM [Phe13 [125 I]Tyr19]-MCH and increasing concentrations of unlabeled
test
molecules. Reactions were terminated by rapid vacuum filtration over 96 well-
GFC
Unifilter plates pre-coated with 0.075 ml binding buffer containing 1% BSA,
and
washed 3 times with 0.4 ml of Phospho-buffered Saline (pH 7.4) containing
0.01%
TX-100. Filters were dried; 0.05 ml microscint 20 was added to each well and
radioactivity was subsequently quantified by scintillation counting on a
TopCountTM
microplate scintillation counter (Packard). Inhibitory constants were
determined by
nonlinear least squares analysis using a four parameter logistic equation.
Biological Data
[00154] The following representative in vitro biological data was measured in
a
binding assay for the compounds from the Examples herein above:
Example Ki nM
113 8
124 9
65 10
110 17
125 17
131 18
38 20
181 21
67 28
36 33
95 41
155 45
69 49
71 62
27 63
151 64
141 78
172 85
59 125
170 132
10 141
46 232
178 290
3 576
169 1294
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Example Ki (nM)
39 1580
157 1730
49 3043
19 3127
28 3153
40 3218
50 4664
EVALUATION OF PRODRUGS
[00155] The relative ability of the prodrug to enhance exposure
(bioavailability)
was assessed in an eight hour PK study using cannulated Sprague Dawley (CD,
Charles River Breeding Laboratory) rats. The compounds (parent and prodrug
esters)
were administered p.o. at 2.0 ml/kg as a suspension in 0.5% methyl cellulose,
0.1%
Tween 80 in water at 10 mg/kg p.o. Blood samples were taken at 1, 2, 4 and 8
hr.
After determination of parent concentration, an AUC was calculated for the
eight
hour study.
Assessment of In Vivo MCHR1 Activity
[00156] Male Sprague Dawley (CD, Charles River Breeding Laboratory) rats
weighing approximately 240 grams were placed in individual plastic cages with
AlphaDri bedding. The room was maintained at 72 F and 50% humidity, and a
12/12 light dark cycle with lights out at 1600 hours. The rats were
conditioned for 5
days prior to the start of the study to having a choice of foods. A normal
chow
(Harlan Teklad, 2018) that contains 18% protein, 5% fat and 73% carbohydrate
and a
high fat high sugar diet (Research Diets (D2327) that contains 20% protein,
40% fat
and 40% carbohydrate where the carbohydrate is entirely sucrose and the fat is
soybean and coconut oil. Studies have revealed that rats exhibit a high
preference for
the high fat/high sucrose diet (80% preference). Body weight and consumption
of
both kinds of food as well as water intake were measured daily. Water was
available
ad lib throughout the study. Food consumption is presented as daily caloric
consumption which is the sum of grams of chow multiplied by the Kcal per gram
(3.5) plus grams of high fat high sugar multiplied by Kcal per gram (4.59).
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[00157] Baseline body weight was measured prior to drug treatment on day 0 of
the study. Baseline food consumption was the average of the 3 days prior to
the first
drug treatment. Drug was administered daily p.o. at 2.0 ml/kg at 1500 hours
beginning on day 0 and continuing daily through day 4 as a suspension in 0.5%
methyl cellulose, 0.1% Tween 80 in water at 3.0, 10 and 30 mg/kg p.o. All data
were
evaluated using ANOVA and Fishers PLSD statistics.
Biological Data
Example Dose Weight Reduction
m k versus Vehicle
193 3 0.7%
2.1%
30 3.4%
194 3 0.9%
10 2.7%
30 7.4%
202 30 2.2%
27 45 4.1%
113 45 4.2%
10 [00158] While the invention has been described according to several
embodiments,
various modifications thereto, in addition to those described herein, may
become
apparent to those skilled in the art from the foregoing description. Such
modifications are also intended to fall within the scope of the appended
claims.
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