Note: Descriptions are shown in the official language in which they were submitted.
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PHOSPHODIESTERASE 4 INHIBITORS
This application claims benefit of U.S. Provisional application Serial No.
60/262,651, filed January 22, 2001, U.S. provisional application Serial No.
60/267,196,
filed February 8, 2001, and U.S. Provisional application Serial No.
60/306,140, filed July
14, 2001.
FIELD OF THE INVENTION
The present invention relates generally to the field of phosphodiesterase 4
(PDE4)
enzyme inhibition. More specifically this invention relates to selective PDE4
inhibition
by novel compounds, e.g., N substituted aniline and diphenylamine analogs,
methods of
preparing such compounds, compositions containing such compounds, and methods
of
use thereof.
BACKGROUND OF THE INVENTION
The cyclic nucleotide specific phosphodiesterases (PDEs) represent a family of
enzymes that catalyze the hydrolysis of various. cyclic nucleoside
monophosphates
(including cAlVIP and cGMP). These cyclic nucleotides act as second messengers
within
cells, and as messengers, carry impulses from cell surface receptors having
bound various
hormones and neurotransmitters. PDEs act to regulate the level of cyclic
nucleotides within
cells and maintain cyclic nucleotide homeostasis by degrading such cyclic
mononucleotides
resulting in termination of their messenger role.
PDE enzymes can be grouped into eleven families according to their specificity
toward hydrolysis of ~cAMP or cGMP, their sensitivity to regulation by
calcium,
calmodulin or cGMP, and their selective inhibition by various compounds. For
example,
PDE 1 is stimulated by Ca2+/calmodulin. PDE 2 is cGMP-dependent, and is found
in the
heart and adrenals. PDE 3 is cGMP-dependent, and inhibition of this enzyme
creates
positive inotropic activity. PDE 4 is cAMP specific, and its inhibition causes
airway
relaxation, antiinflammatory and antidepressant activity. PDE 5 appears to be
important
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in regulating cGMP content in vascular smooth muscle, and therefore PDE 5
inhibitors
may have cardiovascular activity. Since the PDEs possess distinct biochemical
properties,
it is likely that they are subject to a variety of different forms of
regulation.
PDE4 is distinguished by various kinetic properties including low Michaelis
constant for cAMP and sensitivity to certain drugs. The PDE4 enzyme family
consists of
four genes, which produce 4 isoforms of the PDE4 enzyme designated PDE4A,
PDE4B,
PDE4C, and PDE4D [See: Wang et al., Expression, Purification, and
Characterization of
human CAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem.
Biophys. Res. Comm., 234, 320-324 (1997)] In addition, various splice variants
of each
PDE4 isoform have been identified.
PDE4 isoenzymes are localized in the cytosol of cells and are unassociated
with any
known membranous structures. PDE4 isoenzymes specifically inactivate cAMP by
catalyzing its hydrolysis to adenosine 5'-monophosphate (AMP). Regulation of
cAMP
activity is important in many biological processes, including inflammation and
memory.
Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and
ariflo are
powerful antiinflammatory agents and therefore may be useful in treating
diseases where
inflammation is problematic such as asthma or arthritis. Further, rolipram
improves the
cognitive performance of rats and mice in learning paradigms.
\ ~O \
I CI
O a ~~O O % N \
N
H O I iN
CI
rolipram piclamilast
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In addition to such compounds as rolipram, xanthine derivatives such as
pentoxifylline, denbufylline, and theophylline inhibit PDE4 and have received
considerable attention of late for their cognition enhancing effects. cAMP and
cGMP are
second messengers that mediate cellular responses to many different hormones
and
neurotransmitters. Thus, therapeutically significant effects may result from
PDE
inhibition and the resulting increase in intracellular cAMP or cGMP in key
cells, such as
those located in the nervous system and elsewhere in the body.
Rolipram, previously in development as an anti-depressant, selectively
inhibits
the PDE4 enzyme and has become a standard agent in the classification of PDE
enzyme
subtypes. Early work in the PDE4 field focused on depression and inflammation,
and has
subsequently been extended to include indications such as dementia. [see "The
PDE IV
Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, III, et al.,
Drugs of the
Future 1992, 17(9):799-807 for a general review). Further clinical
developments of
rolipram and other first-generation PDE4 inhibitors were terminated due to the
side effect
profile of these compounds. The primary side effect in primates is emesis,
while the
primary side effects in rodents are testicular degranulation, weakening of
vascular smooth
muscle, psychotrophic effects, increased gastric acid secretion and stomach
erosion.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds, e.g., novel N substituted
aniline and diphenylamine compounds, that inhibit PDE4 enzymes, and especially
have
improved side effect profiles, e.g., are relatively non-emetic, (e.g., as
compared to the
previously discussed prior art compounds). Preferably, the compounds
selectively inhibit
PDE4 enzymes. The compounds of this invention at the same time facilitate
entry into
cells, especially cells of the nervous system.
Still further, the present invention provides methods for synthesizing
compounds
with such activity and selectivity as well as methods of (and corresponding
pharmaceutical compositions for) treating a patient, e.g., mammals, including
humans,
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requiring PDE inhibition, especially PDE4 inhibition, for a disease state that
involves
elevated intracellular PDE 4 levels or decreased cAMP levels, e.g., involving
neurological syndromes, especially those states associated with memory
impairment,
most especially long term memory impairment, as where such memory impairment
is due
in part to catabolism of intracellular cAMP levels by PDE 4 enzymes, or where
such
memory impairment may be improved by effectively inhibiting PDE4 enzyme
activity.
In a preferred aspect, the compounds of the invention improve,such diseases by
inhibiting PDE4 enzymes at doses which do not induce emesis.
The present invention includes compounds of Formula I:
R'~O \
O ~ N~Rs
R2 R4
wherein
R' is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and
which is unsubstituted or substituted one or more times by halogen (e.g.,
CH3, CHF2, CF3, etc.);
RZ is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched
or unbranched and which is unsubstituted or substituted one or more times
by halogen, hydroxy, cyano, C1-a-alkoxy, oxo or combinations thereof,
and wherein optionally one or more -CHZCHZ- groups is replaced in each
case by -CH=CH- or -C=C- (e.g., CH3, CHFZ, CF3, methoxyethyl, etc.),
4
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cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is
unsubstituted or substituted one or more times by halogen, hydroxy, oxo,
cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon
atoms, or combinations thereof (e.g., cyclopentyl),
cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is
unsubstituted or substituted in the cycloalkyl portion and/or the alkyl
portion.one or more times by halogen, oxo, cyano, hydroxy, Cl-4-alkyl,
C,-4-alkoxy or combinations thereof (e.g., cyclopentylmethyl,
cyclopropylmethyl, etc.),
aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one
or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro,
methylenedioxy, ethylenedioxy,,cyano, or combinations thereof (e.g.,
methylphenyl, methoxyphenyl, chlorophenyl, etc.),
arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl
portion, which is branched or unbranched, has 1 to 5 carbon atoms, which
the arylalkyl radical is unsubstituted or is substituted in the aryl portion
one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro,
cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and
wherein in the alkyl portion one or more -CHzCHz- groups are each
optionally replaced by -CH=CH- or -C=C-, and one or more -CH2- groups
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are each optionally°replaced by -O- or -NH- and/or the alkyl portion is
optionally substituted by halogen, oxo, hydroxy, cyano, or combinations
thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl,
methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl,
chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl,
chlorophenoxyethyl, chlorophenylaminoethyl, etc.),
a partially unsaturated carbocyclic group having S to 14 carbon atoms,
which is unsubstituted or substituted one or more times by halogen, alkyl,
alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g.,
cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.),
a heterocyclic group, which is saturated, partially saturated or unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S
atom, which is unsubstituted or substituted one or more times by halogen,
hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or
combinations thereof (e.g., 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.),
or
a heterocycle-alkyl group; wherein the heterocyclic portion is saturated,
partially saturated or unsaturated, and has 5 to 10 ring atoms in which at
least 1 ring atom is a N, O or S atom, and the alkyl portion is branched or
unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is
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unsubstituted or substituted one or more times in the heterocyclic portion
by halogen, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl,
vitro, oxo, or combinations thereof, wherein in the alkyl portion one or
more -CHZCHZ- groups are each optionally replaced by -CH=CH- or
-C=C-, and one or more -CHZ- groups are each optionally replaced by -O-
or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo,
hydroxy, cyano, or combinations thereof (e.g., pyridylethyl,
pydridylpropyl, methylpiperazinylethyl, etc.);
R3 is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or
unbranched and which is unsubstituted or substituted one or more times
with halogen, cyano, C1-4-alkoxy, or combinations thereof (e.g., methyl,
ethyl, propyl, etc.),
a partially unsaturated carbocycle-alkyl group wherein the carbocyclic
portion has 5 to 14 carbon atoms and the alkyl portion which is branched
or unbranched has 1 to S carbon atoms, and which is unsubstituted or
substituted in the carbocyclic portion one or more times by halogen, alkyl,
alkoxy, vitro, cyano, oxo, or combinations thereof, and the alkyl portion is
optionally substituted by halogen, CI-4-alkoxy, cyano or combinations
thereof (e.g., cyclohexenylmethyl, etc.),
arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14
carbon atoms and the alkyl portion, which is branched or unbranched, has
1 to 5 carbon atoms,-arylalkyl radical is unsubstituted or substituted, in the
aryl portion, one or more times by halogen, trifluoromethyl, CF30, vitro,
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amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the
alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl,
phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl,
methylenedioxobenzyl, etc.), or
heteroarylalkyl group, wherein the heteroaryl portion may be partially or
fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a
N, O or S atom, the alkyl portion, which is branched or unbranched, has 1
to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted
one or more times in the heteroaryl portion by halogen, alkyl, alkoxy,
cyano, trifluoromethyl, CF30, nitro, oxo, amino, alkylamino,
dialkylamino, or combinations thereof and/or substituted in the alkyl
portion by halogen, cyano, or methyl or combinations thereof (e.g.,
pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl,
dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl,
isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl,
methylimidazolylmethyl, pyrrolylmethyl, etc.);
R4 is H,
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted
one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,
alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl,
OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg.,
hydroxymethyl), hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-
5-yl (eg., 2-(2-tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy,
alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl,
alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert-
butyldimethylsilyloxy), RS-L-, or combinations thereof (e.g., substituted
or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl,
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methylphenyl,_chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl,
methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl,
ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl,
nitrophenyl, aminophenyl, etc.), or
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom, which is unsubstituted or substituted one or more times by
halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,
ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl,
aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl),
hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl
(e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio,
alkylsulfmyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert-
butyldimethylsilyloxy), R5-L-, or combinations thereof (e.g., pyridyl,
thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl,
thiazolyl, etc.);
RS is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted
or substituted one or more times with halogen, C1-4-alkyl, Cl-4-alkoxy,
oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),
alkylamino or dialkylamino wherein each alkyl portion has independently
1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.),
a partially unsaturated carbocycle-alkyl group wherein the carbocyclic
portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon
atoms, which is unsubstituted or substituted, preferably in the carbocyclic
portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or
combinations thereof (e.g., cyclohexenylmethyl, etc.),
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cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is
unsubstituted or substituted one or more times by halogen, hydroxy, oxo,
cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof
(e.g., cyclopentyl),
cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is
unsubstituted or substituted in the cycloalkyl portion and/or the alkyl
portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy
or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl,
etc.),
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted
one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy,
nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino,
aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg.,
hydroxymethyl), hydroxamic acid, tetrazole-5-yl; hydroxyalkoxy,
carboxy, alkoxycarbonyl (e.g.; tert-butyloxycarbonyl, ethoxycarbonyl),
cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or
unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl,
fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl,
ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl,
dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),
arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14
carbon atoms and the alkyl portion, which is branched or unbranched, has
1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the
aryl portion, one or more times by halogen, trifluoromethyl, CF30, nitro,
amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted
in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl,
to
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phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl,
methylenedioxobenzyl, etc.),
a heterocyclic group, which is saturated, partially saturated or unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S
atom, which is unsubstituted or substituted one or more times by halogen,
alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,
ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl,
aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl),
hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl
(e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g.,
pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl,
imidazolyl, thiazolyl, etc.), or
a heterocycle-alkyl group, wherein the heterocyclic portion is saturated,
partially saturated or unsaturated, and has 5 to 10 ring atoms in which at
least 1 ring atom is a N, O or S atom, ahd the alkyl portion which is
branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl
group is unsubstituted or substituted one or more times in the heterocyclic
portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF30, nitro,
oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or
substituted in the alkyl portion by halogen, cyano, or methyl or
combinations thereof (e.g., pyridylmethyl, pyridylpropyl,
methylpridylmethyl, etc.);
L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms
wherein one or more -CHz- groups are each optionally replaced by -O-,
-S-, -NR6-, -SOzNH-, -NHSOZ-, -CO-, -NR6C0-, -CONR6-, -NHCONH-,
-OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g.,-O-,
CHZ-, -CO-, -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CHzCHZCHz-NH-
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CO-, -CHZ-CH2-O-, -SOz-NH-CHzCHz-O-, -O-CHZCHZ-O-, -CHZ-NH-
CO-, -CO-NH-CHZ-, -SOZ-NH-, -CHz-NH-S02-, -CHZCHzCHZ-SOZ-
NH-, etc.); and
R6 is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or
unbranched and which is unsubstituted or substituted one or more times
with halogen, C~-4-alkyl, C,-4-alkoxy, oxo, or combinations thereof (e.g.,
methyl, ethyl, propyl, etc.);
wherein at least one of R3 and R4 is other than H; and
pharmaceutically acceptable salts thereof.
According to a further aspect of the invention there is provided a genus of
novel
compounds according to the formulas II and III:
R~~O \ . R»O: \
II I III
O / N~Rs
Rz RH Rz H
wherein R', R2, R3, and R4 are as defined above. The compounds of this
subgenus of
formula I not only have PDE4 inhibitory activity, but also are useful as
intermediates for
preparing compounds of Formula I in which R3 and R4 are both other than H.
In addition, preferred compounds of formula I are those of the subformula IV
R~~~ \
/ ~ IV
02- N4 ~ B
R R iD
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wherein R', R2, and R4 are as defined in Formula I and one of A, B and D is N
and the others are C. Preferably, B is N. Also, R4 is preferably pyridyl or
phenyl which
in each case is substituted or unsubstituted.
The present invention also includes compounds of Formula I':
R~
Rs. I
X L
I 2,
R
wherein
R' ~ is methoxy, F, Cl, CHFz or CF3;
RZ' is
alkyl having 1 to 12 carbon atoms,
alkyl having 1 to 12 carbon atoms which is substituted one or more times
by halogen, oxo, cyano, or combinations thereof,
alkenyl having 2 to 12 carbon atoms,
alkenyl having 2 to 12 carbon atoms which is substituted one or more
times by halogen, oxo, cyano or combinations thereof,
alkynyl having 2 to 12 carbon atoms,
alkynyl having 2 to 12 carbon atoms which is substituted one or more
times by halogen, oxo, cyano or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms,
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cycloalkyl having 3 to 10 carbon atoms substituted one or more times by
halogen, oxo, alkyl, or combinations thereof,
cycloalkylalkyl having 4 to 12 carbon atoms,
cycloalkylalkyl having 4 to 12 carbon atoms which is substituted one or
more times by halogen, oxo, alkyl or combinations thereof,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms
which is substituted one or more times by halogen, alkyl, alkyloxy, nitro,
cyano, oxo, or combinations thereof,
arylalkyl having 7 to 26 carbon atoms
arylalkyl having 7 to 26 carbon atoms which is substituted one or more
times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or
combinations thereof,
heteroarylalkyl having S to 10 ring atoms in which at least 1 ring atom is a
heteroatom, or
substituted heteroarylalkyl having S to 10 ring atoms in which at least 1
ring, atom is a heteroatom and which is substituted one or more times in
the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano,
trifluoromethyl, nitro, amino, alkylamino, dialkylamino or combinations
thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or
combinations thereof;
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X is O or S;
R3' is aryl having 6 to 14 carbon atoms,
aryl having 6 to 14 carbon atoms which is substituted one or more times
by halogen, alkyl, hydroxy, alkoxy, vitro, methylenedioxy, ethylenedioxy,
amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy,
cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl,
phenoxy, heteroaryl which is unsubstituted or substituted by halogen,
alkyl or alkoxy, or combinations thereof,
heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom, or
substituted heteroaryl having S to 10 ring atoms in which at least 1 ring ,
atom is a heteroatom which is substituted one or more times by halogen,
aryl, alkyl, alkoxy, cyano, trifluoromethyl, vitro, oxo, amino, alkylamino,
dialkylamino or combinations 'thereof; t
L is -NH-, -NR4'-, -NHCHz-, -NR4'CHz-, or -CHZNR4'-; and 1
R4' is alkyl having 1 to 12 carbon atoms,
alkyl having 1 to 12 carbon atoms which is substituted one or more times
by halogen, oxo, cyano, or combinations thereof,
aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted
one or more times by halogen, alkyl, hydroxy, alkoxy, vitro,
methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino,
hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,
alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof,
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heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom,
substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring
atom is a heteroatom and which is substituted one or more times by
halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,
alkylamino, dialkylamino or combinations thereof,
arylalkyl having 7 to 16 carbon atoms,
arylalkyl having 7 to 16 carbon atoms which is substituted one or more
times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or
combinations thereof,
heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a
heteroatom, or
substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1
ring atom is a heteroatom and which is substituted one or more times in
the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or
combinations thereof and/or substituted in the alkyl portion by halogen,
oxo; cyano, or combinations thereof; and
pharmaceutically acceptable salts thereof.
The compounds of the present invention are effective in inhibiting, or
modulating
the activity of PDE4 in animals, e.g., mammals, especially humans. These
compounds
exhibit neurological activity, especially where such activity affects
cognition, including
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long term memory. These compounds will also be effective in treating diseases
where
decreased cAMP levels are involved. This includes but is not limited to
inflammatory
diseases. These compounds may also function as antidepressants, or be useful
in treating
cognitive and negative symptoms of schizophrenia.
Assays for determining PDE inhibiting activity as well as selectivity of PDE 4
inhibiting activity and selectivity of inhibiting PDE 4 isoenzymes are known
within the
art. See, e.g., US 6,136,821, the disclosure of which is incorporated herein
by reference.
According to a further aspect of the invention there~are provided compounds
useful as intermediates for the production of the PDE4 inhibitors described
herein (e.g.,
PDE4 inhibitors of Formula I) and/or useful for the synthesis of radio-labeled
analogs of
the PDE4 inhibitors with in this application.
Thus, there are provided intermediate compounds which correspond to
compounds of Formula I, wherein RZ, R3, and R4 are as previously defined for
Formula I,
but R' is H, tert-butyldimethylsilyl-, or a suitable phenolic protecting
group. Suitable
phenolic protecting groups are described, for 'example; in Greene, T.W. and
Wuts,
P.G.M., Protective Groups in Organic Synthesis, 3'd Edition, John Wiley &
Sons, 1999,
pp. 246-293. These intermediates are also useful for the synthesis of radio-
labeled
compounds, such as where R' is 3H3C-,'4CH3- or''CH3-, for example by removing
the
protecting group and reacting the resultant compound in which R' is H with
suitable
radio-labelled reagents. Such radio-labeled compounds are useful for
determining
compound tissue distribution in animals, in PET imaging studies, and for in
vivo, ex vivo,
and in vitro binding studies.
Also provided are intermediate compounds which correspond to compounds of
Formula I; wherein R', R3, and R4 are as previously defined for Formula I, but
RZ is H,
tert-butyldimethylsilyloxy-, or a suitable phenolic protecting group. Suitable
phenolic
protecting groups are described, for example, in Greene, T.W. and Wuts,
P.G.M.,
Protective Groups in Organic Synthesis, 3'd Edition, John Wiley & Sons, 1999,
pp. 246-
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293. Compounds in which RZ is H are useful as intermediates, for example, as
scaffolds
for parallel or combinatorial chemistry applications. Further, these compounds
are useful
for the introduction of radio-labels such as 3H,'4C, or 1'C.
As previously described, compounds according to formula II, wherein R', RZ and
R4 are as previously described are useful intermediates for the production of
compounds
according to formula I where in R3 is other than H.
Also, as previously described; compounds according to formula III, wherein Rl,
RZ and R3 are as previously. described are useful intermediates for the
production of
compounds according to formula I where in R4 is other than H.
Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F and Cl.
Alkyl, as a group or substituent per se or as part of a group or substituent
(e.g.,
alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), means a straight-
chain or
branched-chain aliphatic hydrocarbon radical having 1 to 12 carbon atoms,
preferably 1
to 8 carbon atoms, especially 1 to 4 carbon atoms. Suitable alkyl groups
include methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl,
octyl, nonyl,
decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups include 1-
, 2- or 3-
methylbutyl, 1,l-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-
methylpentyl,
1,l-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,
ethylmethylpropyl,
trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl,
dimethylbutyl, and the like.
Substituted alkyl groups are alkyl groups as described above which are
substituted
in one or more positions by halogens, oxo, hydroxyl, Ct_4-alkoxy and/or
cyano.. Halogens
are preferred substituents, especially F and Cl.
Alkoxy means alkyl-O- groups and alkoxyalkoxy means alkyl-O-alkyl-O- groups
in which the alkyl portions are in accordance with the previous discussion.
Suitable
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alkoxy and alkoxyalkoxy groups include methoxy, ethoxy, propoxy, butoxy,
pentoxy,
hexoxy, heptoxy, octoxy methoxymethoxy ethoxymethoxy, propoxymethoxy, and
methoxyethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly,
alkoxycarbonyl means alkyl -O-CO- in which the alkyl portion is in accordance
with the
previous discussion. Examples include methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, and tert-butoxycarbonyl.
Cycloalkyl means a monocyclic, bicyclic or tricyclic nonaromatic saturated
hydrocarbon radical having 3 to 10 carbon atoms, preferably 3 to 8 carbon
atoms,
especially 3 to 6 carbon atoms. Suitable cycloalkyl groups include
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, 1-
decalin,
adamant-1-yl, and adamant-2-yl. Other suitable cycloalkyl groups include
spiropentyl,
bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl,
bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl,
bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Preferred cycloalklyl groups are
cyclopropyl,
cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, for
example,
substituted by halogens and/or alkyl groups.
Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl
and
alkyl portions are in accordance with previous discussions. Suitable examples
include
cyclopropylmethyl and cyclopentylmethyl.
Aryl, as a group or substituent per se or as part of a group or substituent,
refers to
an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6
to 12
carbon atoms, especially 6 to 10 carbon atoms. Suitable aryl groups include
phenyl,
naphthyl and biphenyl. Substituted aryl groups include the above-described
aryl groups
which are substituted one or more times by, for example, halogen, alkyl,
hydroxy,
alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino,
hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, and phenoxy.
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Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkyl portions
are in
accordance with the previous descriptions. Suitable examples include benzyl, 1-
phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and napthylmethyl.
Heteroaryl refers to an aromatic heterocyclic group having one or two rings
and a
total number of 5 to 10 ring atoms wherein at least one of the ring atoms is a
heteroatom.
Preferably, the heteroaryl group contains 1 to 3, especially 1 or 2, hetero-
ring atoms
which are selected from N, O and S. Suitable heteroaryl groups include furyl,
thienyl,
pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, dithialyl, oxathialyl,
isoxazolyl,
oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl,
oxathiazolyl,
thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
oxazinyl, isoxazinyl,
oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl,
isothionaphthenyl, indolyl, isoindolyl, indazolyl, benzisoxazolyl,
benzoxazolyl,
benzthiazolyl, benzisothiaaolyl, purinyl, benzopyranyl, quinolinyl,
isoquinolinyl,
cinnolinyl, quinazolinyl, naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl, 3-
thienyl, 2-,
3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, and 1-, 3-, 4-, 5-, 6-
, 7- or 8-
isoquinolinyl.
Substituted heteroaryl refers to the heteroaryl groups described above which
are
substitued in one or more places by, for example, halogen, aryl, alkyl,
alkoxy,.carboxy,
methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and
dialkylamino.
Heterocycles include heteroaryl groups as described above as well as non-
aromatic cyclic groups containing at least one hetero-ring atom, preferably
selected from
N, S and O, for example, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl.
Heterocycle-alkyl refers to a heterocycle-alkyl-group wherein the heterocyclic
and alkyl portions are in accordance with the previous discussions. Suitable
examples are
pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and
isoquinolinylmethyl.
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Partially unsaturated carbocyclic structures are non-aromatic monocyclic or
bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to 10 carbon
atoms,
wherein the ring structures) contains at least one C=C bond. Suitable examples
are
cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthenyl and indan-2-
yl.
Alkenyl refers to straight-chain or branched-chain aliphatic radicals
containing 2
to 12 carbon atoms in which one or more -CHZ-CHZ- structures are each replaced
by -
CH=CH-. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-
butene, 2-
butene, 1-pentenyl, and 2-pentenyl.
Alkynyl refers to straight-chain or branched-chain aliphatic radicals
containing 2
to 1 ~ carbon atoms in which one or more -CHZ-CHZ- structures. are each
replaced by
-C=C-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl, and 2-
butynyl.
Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in which the
alkyl
portion can be substituted by halogen, alkyl, aryl and/or alkoxy, or amyl
radicals having
7 to 15 carbon atoms in which the aryl portion can be substituted by, for
example,
halogen, alkyl and/or alkoxy. Suitable acyl groups include formyl, acetyl,
propionyl,
butanoyl and benzoyl.
Substituted radicals preferably have 1 to 3 substituents, especially 1 to 2
substituents.
In the compounds of Formula I, R' is an alkyl group having preferably 1 to 4
carbon atoms which is optionally substituted by halogen, preferably fluorine
or chlorine.
In particular, R' is preferably methyl or difluoromethyl.
R2 is preferably cycloalkyl, particularly cyclopentyl.
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RZ is also preferably aryl or arylalkyl, particularly substituted or
unsubstituted
phenyl or phenylalkyl, such as phenyl, methylphenyl, methoxyphenyl,
chlorophenyl,
phenethyl, phenpropyl, phenbutyl, phenylethenyl, phenoxyethyl, phenoxypropyl,
phenoxybutyl, chlorophenylethyl, methoxyphenyl ethyl, chlorophenylethenyl,
chlorophenoxyethyl, chlorophenypropyl, methoxyphenpropyl, methoxyphenbutyl,
chlorophenbutyl, nitrophenbutyl, chlorophenylaminoethyl, and the like,
Rz is also preferably a partially unsaturated carbocyclic groups, which is
unsubstituted or substituted, particularly cyclohexenyl, cyclohexadienyl,
indan-2-yl.
R2 is also preferably an alkyl group having 1 to 8 carbon atoms, especially 1
to 4
carbon atoms, which is substituted or unsubstituted, e.g., methyl,
difluoromethyl,
trifluoromethyl, and methoxyethyl.
R2 is also preferably a heterocyclic or heterocycle--alkyl group, particularly
radicals in which the heterocycl.ic group has 5 to 6 ring atoms and 1 to 2
hetero-ring
atoms selected from N, O and S, e.g., tetrahydrofuranyl, pyrrolidinyl,
pyrrolyl,
pyridylmethyl, pyridylethyl, pyridylpropyl, piperazinylmethyl,
piperazinylethyl,
methylpiperazinylethyl and the like. ~ '
Preferred RZ include cyclopentyl, tetrahydrofuranyl, CHFZ, methoxyethyl,
cyclopropylmethyl, phenethyl, phenpropyl, phenyletheriyl, phenoxyethyl,
phenoxybutyl,
phenylaminoethyl, indan-2-yl, pyridylethyl, and pyridylpropyl.
R3 is preferably hydrogen, alkyl having 1 to 4 carbon atoms (e.g., methyl,
ethyl,
n-propyl, or n-butyl), arylalkyl (e.g., substituted or unsubstitituted benzyl,
phenethyl, and
phenpropyl), or a heteroarylalkyl group (e.g., substituted or unsubstituted
pyridylmethyl,
furanylmethyl, thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl,
thiazolylmethyl,
isoquinolinylmethyl and quinolinylmethyl). Preferred substituents for aryl and
heteroaryl
portions of R3 are F, Cl, CH3, CZHS, OCH3, and CN. '
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R4 is preferably aryl, or heteroaryl, especially phenyl, naphthyl, biphenyl,
furanyl,
pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, and isoquinolinyl, which in each
case is
unsubstituted or is substituted one or more times. Preferred substituents are
OH, F, Cl,
CF3, alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN,
vinyl,
CHZOH, CONHOH, CONH2, methylenedioxy, COOH, and combinations thereof.
In addition, when R4 is aryl, especially, phenyl, preferred substituents
include RS-
L-, e.g., RS-, R5-O-, R5-CO-, RS-NH-CO-, RS-SOZ-NH-, RS-SOz-NH-alkylene-O-,
NHz-
alkyl-NH-CO-, RS-alkylene-NH-CO-, alkyl-CO-NH-alkyl- as well as methyl, ethyl,
Cl, F,
CN, OCH3, CF3, amino, nitro,~ HOCHz and COOH.
When R4 is aryl substituted by RS-SOZ-NH- it is preferably a substituted
phenyl
group and RS is preferably methyl, ethyl, propyl or phenyl.
When R4 is aryl substituted by RS-SOZ-NH-alkylene-O- it is preferably a
substituted phenyl. In such cases, RS is preferably methyl, ethyl, propyl or
phenyl and
alkylene is preferably -CHz-, -CHZCHZ- or -CHZCHZCHZ-.
When R4 is aryl substituted by RS-L- it is preferably substituted phenyl. In
such
cases, preferred R5 groups include tetrazolyl, oxazinyl, piperazinyl,
methylpiperazinyl,
pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl, or
methylpiperadinyl,
and L is preferably a single bond, -O-, -CO-, -CHZ-, -CH2CHZ-, -CHZCHzCH2-, -
CHZ-O-
-CHZCHZ-O-, -CHZCHzCHz-O-, -CHz-NH-CHzCH2-O-, -CO-NH- or -NH-CO-.
In addition, preferred PDE4 inhibitors in accordance with the invention are
compounds described by subformulas Ia-Ih which correspond to formula I but
exhibit the
following preferred groups:
Ia R' is methyl or CHF2;
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Rz is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl,
cycloalkylalkyl, aryl, or heterocyclic, in each case substituted or
unsubstituted;
R3 is H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or
unsubstituted; and
R4 is aryl or heteroaryl; in each case
substituted or unsubstituted.
Ib R3 is heteroarylalkyl which is substituted or unsubstituted.
Ic R1 is methyl or CHF2; and
RZ is cyclopentyl, CHFZ, cyclopropylmethyl, pyridylethyl
(particularly 2-pyridylethyl), or tetrahydrofuranyl
(particularly (3R)-tetrahydrofuranyl).
Id R' is methyl or CHF2;
Rz is cyclopentyl;
R3 is heteroarylalkyl, in each case substituted or
unsubstituted; and '
R4 is substituted or unsubstituted aryl or heteroaryl.
Ie Rl is methyl;
RZ is cyclopentyl; and
R3 is heteroarylalkyl which is substituted or unsubstituted.
If Rl is methyl;
Rz is cyclopentyl;
R3 is heteroarylalkyl which is substituted or unsubstituted;
and
R4 is phenyl which is substituted or unsubstituted.
Ig Rl is methyl;
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Rz is cyclopentyl;
R3 is pyridylmethyl, phenethyl, benzyl, thienylmethyl,
pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl,
which in each case is substituted or unsustituted, or methyl,
ethyl, or propyl; and
R4 1S phenyl or phenyl substituted with 1 to 3 substituents.
Ih R' is methyl;
RZ is cyclopentyl;
R3 is pyridylmethyl, phenethyl, benzyl, thienylmethyl,
pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which
in each case is substituted or unsustituted, or rriethyl, ethyl,
or propyl; and
R4 is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl,
pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or
unsubstituted.
In addition, preferred PDE4 inhibitors in accordance with the invention are
compounds described by subformulas IIa-IId which correspond to formula II but
exhibit
the following preferred groups:
IIa R1 is methyl or CHFZ;
RZ is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl
(particularly 2-pyridylethyl), or tetrahydrofuranyl
(particularly (3R)-tetrahydrofuranyl); and
R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each
case is substituted or unsubstituted.
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IIb R1 is methyl or CHFZ;
RZ is cyclopentyl, CHFZ, cyclopropylmethyl, pyridylethyl
(particularly 2-pyridylethyl), or tetrahydrofuranyl
(particularly (3R)-tetrahydrofuranyl); and
R4 is phenyl which is unsubstituted or substituted by methyl, ethyl,
methoxy, Cl, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or
ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by
carboxy or alkoxycarbonyl.
IIc Rl is methyl;
R2 is cyclopentyl; and
R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each
case is substituted or unsubstituted.
IId R' is methyl;
R2 is cyclopentyl; and
R4 is phenyl which is unsubstituted or substituted by methyl, ethyl,
methoxy, Cl, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or
ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by
carboxy or alkoxycarbonyl.
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In addition, preferred PDE4 inhibitors in accordance with the invention are
compounds described by subformulas IIIa-IIId which correspond to formula III
but
exhibit the following preferred groups:
IIIa R' is methyl or CHFZ;
RZ is cyclopentyl, CHFZ, cyclopropylmethyl, pyridylethyl
(particularly 2-pyridylethyl), or tetrahydrofuranyl
(particularly (3R)-tetrahydrofuranyl); and
R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl,
thienylmethyl, pyridylmethyl, quinolinymethyl, isoquinolinylmethyl,
thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or
unsubstituted.
IIIb Rl is methyl or CHFZ;
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl);
and
R3 is pyrazinylmethyl, pyrimidinylmethyl or pyridylmethyl, which in each
is unsubstituted or substituted.
IIIc RI is methyl;
RZ is cyclopentyl; and
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R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl,
thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl,
quinolinymethyl, isoquinolinylmethyl, isoimidazolyl, thiazolylmethyl, or
pyrrolylmethyl, which in each case is substituted or unsubstituted.
IIId R' is methyl;
RZ is cyclopentyl; and
R3 is pyrazinylmethyl or pyridylmethyl, which in each is unsubstituted or
substituted.
In addition, preferred PDE4 inhibitors in accordance with the invention
are compounds described by subformulas Na-IVp which correspond to formula N
but
exhibit the following preferred groups:
Na R' is methyl or CHFz.
Nb Rl is methyl or CHFZ, and
B is N.
Nc Rl is methyl or CHF2, and
R2 is cyclopentyl, CHFZ, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl).
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IVd R' is methyl or CHFz,
B is N; and
RZ is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl).
IVe R' is methyl or CHFZ, and
R4 is 3-pyridyl or phenyl, which in each case is substituted or
unsubstituted.
IVf R' is methyl or CHFZ,
B is N, and
R4 is 3-pyridyl or phenyl, which in each case is substituted or
unsubstituted.
Ng R' is methyl or CHFZ,
RZ is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl_ (particularly ~2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and
R4 is 3-pyridyl or phenyl, which in each case is substituted or
unsubstituted.
IVh Rl is methyl or CHF2,
B is N,
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RZ is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and
R4 is 3-pyridyl or phenyl, which in each case is substituted or
unsubstituted.
IVi R1 is methyl or CHFZ, and
R4 is phenyl which is substituted in the 3- or 4- position.
IVj R1 is methyl or CHF2,
B is N, and
R4 is phenyl which is substituted in the 3- or 4- position.
IVk R' is methyl or CHFZ,
Rz is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and
R4 is phenyl which is substituted in the 3- or 4- position.
IVl R1 is methyl or CHFz,
B is N;
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RZ is cyclopentyl, CHFZ, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and
R4 is phenyl which is substituted in the 3- or 4- position.
IVm R' is methyl or CHFz, and
R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-
ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-
phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-
phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
IVn R' is methyl or CHFZ,
B is N, and
R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-
ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-
phenyl, 4-pyridyl, 4-COON-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-
phenyl, 4-tetrazol-S-yl-phenyl, or 4-hydroxymethyl-phenyl.
IVo Rl is methyl or CHF2,
RZ is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and
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R4 is 3-pyridyl, 3-COOH-phenyl, 3-C1-phenyl, 3-cyano-phenyl, 3-
ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-
phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-
phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
IVp Rl is methyl or CHFz,
B is N,
RZ is cyclopentyl, CHFz, cyclopropylmethyl, pyridylethyl (particularly 2-
pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and
R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-
ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-
phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-
ethylsulfonamido-phenyl, 4-tetrazol=S-yl-phenyl, or 4-hydroxymethyl-
phenyl.
Preferred aspects include pharmaceutical compositions comprising a compound of
this invention and a pharmaceutically acceptable carrier and, optionally,
another active
agent as discussed below; a method of inhibiting a PDE4 enzyme, especially an
isoenzyme, e.g., as determined by a conventional assay or one described
herein, either in
vitro or in vivo (in an animal, e.g., in an animal model, or in a mammal or in
a human); a
method of treating neurological syndrome, e.g., loss of memory, especially
long-term
memory, cognitive impairment or decline, memory impairment, etc. a method of
treating
a disease state modulated by PDE4 activity, in a mammal, e.g., a human, e.g.,
those
mentioned herein.
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The compounds of the present invention may be prepared conventionally. Some
of the processes which can be used are described below. All starting materials
are known
or can be conventionally prepared from known starting materials.
SCHEME 1
1a) R2Br, KZCO~, DMF .
1b) R20H, PPh3, DIAD, THF
1c) TBDMSCI, Imd., DMF
R1 ~O / 1d) RZB(OH)Z, Cu(OAC)z, R1 ~O / 2) HZ, ~~% Pd/C, EtOH
Et3N
HO - ~ NOz O ~ NOZ
R2
R1 ~O / 3) R3CH0, NaBHa, R1 i0 / 4) PdZdba3, NaOtBu, R1 ~O /
~pTsOH, MeOH I P(tBu)3, R4-I
O ~ N~R3 O \ N~R3
I I
R2 3 NHZ R2 4 H R2 5 R4
Starting nitrophenols of the type 1 are either commercially available (e.g.,
R1 =
CH3) or prepared by published procedures (e.g., Rl = CHFZ or both R1 and R2 =
CHF2,
see Mueller, Klaus-Helmut. Eur. Pat. Appl. (1994), 8 pp. CODEN: EPXXDW EP
626361A1; Touma, Toshihiko; Asai, Tomoyuki. Jpn. Kokai Tokkyo Koho (1999), 6
pp.
CODEN: JKXXAF JP 11071319 A2; Platonov, Andrew; Seavakov, Andrew;
Maiyorova, Helen; Chistokletov, Victor. Int. Symp. Wood. Pulping Chem., 1995,
8th, 3,
295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski, Joseph M.
PCT Int.
Appl. (1996), 12 pp. CODEN: PIXXD2 WO 9623754 A1 19960808). Aniline
intermediates 3 are produced in two steps; first, an addition reaction
provides
intermediate 2, followed by reduction of the nitro group. Intermediate nitro
compounds 2
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can be prepared by numerous published procedures, such as by Mitsunobu
reactions or
standard alkylation reactions. Compounds where R2 is aryl or heteroaryl can be
prepared
by copper catalyzed reactions with aryl or heteroaryl iodides under Ullman
conditions or
by coupling aryl-, vinyl-, or heteroaryl- boronic acids with phenol 2 in the
presence of a
copper catalyst (e.g., Cu(OAc)2) and base such as TEA. Mitsunobu reaction
between an
appropriately substituted nitrophenol and a primary or secondary alcohol using
an
azodicarboxylate (e.g., DEAD, DIAD), and a suitable phosphine (e.g., Ph3P,
Bu3P)
provides alkylated nitrophenols 2. Mitsunobu reactions are general performed
in aprotic
solvents such as dichloromethane or THF. Alternatively, alkylation can be
achieved by
the reaction between an appropriately substituted nitrophenol and an alkyl
halide in the
presence of abase (e.g., KZC03 or NaH) in a polar aprotic solvent (e.g., DMF
or
CH3CN).
Nitrocatechols 2 are subsequently reduced to the corresponding anilines 3 by
methods standard in the art such. as by hydrogenation using a suitable
catalyst (e.g., Pd on
carbon) in a polar protic solvent (e.g., MeOH or EtOH) under an atmosphere of
hydrogen. Alternatively, nitrocatechols 3 can be reduced by using a hydride
source (e.g.,
NaBH4) and a transition metal catalyst (e.g., NiCl2; Pd on carbon) or by using
metals
(e.g., Zn, Sn, Fe) in mineral acid solutions (e.g., HC1) to produce the
corresponding
anilines. Generally polar protic solvents such as ethanol or methanol are used
in these
reactions.
N Arylalkylanilines 4 are synthesized by standard methods in the art such as
by
reductive amination reaction, alkylation reaction, or by reduction of
corresponding
amides. For example, the reductive amination reaction of an aryl or arylalkyl
aldehyde
with appropriately substituted anilines in the presence of a borohydride
reducing agent
such as NaBH4 or NaBH3CN with an acid catalyst such as acetic acid or pTsOH
provides
desired N arylalkylanilines. These reactions generally take place in polar
protic solvents
such as methanol, ethanol, isopropanol, n-propanol and the like.
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N Arylalkylanilines 4 readily undergo N arylation by methods standard to the
art
including Ullman coupling reaction, metal-catalyzed coupling, or aromatic
nucleophilic
substitution reaction. For example, the metal catalyzed reaction between an N
benzylaniline and an aryl halide using a palladium catalyst, (e.g., Pd2dba3),
a bulky
electron rich phosphine ligand (e.g., tributylphosphine), and suitable base
(e.g., NaOtBu)
provides N Arylalkyldiphenylamines. Nickel and copper catalysts have been
employed
as well. Solvents useful in this reaction include non-polar aprotic solvents
such as
toluene, benzene, xylenes, tetrahydrofuran, and ether. When synthesizing
compounds of
the type 5 wherein R4 is an alkoxycarbonylphenyl, it is -advantageous that
amine 4 is
coupled with 1.1 equivalents of tert-butyl 3-iodobenzene and that 22 mol % of
(tBu)3P,
5.5 mol % of Pd2(dba)3 and 1.3 equivalents of tBuONa are used.
SCHEME 2
R1'O / R1'O
O ~ ~ N~R3 5) NaOH, EtOH R3
6)H O ~ ~ N~
I I
R2 / . , R2
' /
COZH
R5'O
7
Carboxylic ester intermediates 6 can be hydrolyzed under acidic or basic
conditions to give the corresponding carboxylic acids 7. For example, an ethyl
ester (RS
= Et) can be hydrolyzed using a mixture of aqueous base (e.g., NaOH, KOH) and
a water
miscible solvent (e.g., EtOH, THF). While t-Butyl esters (RS = t-butyl) can be
hydrolyzed using an aqueous acid (e.g., HCI, formic acid, TFA) in a water
miscible
organic solvent, if necessary.
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SCHEME 3
R1 ~O / R1 ~O /
,R3 7) H+, THF ~ I ,R3
4 N O N
R2 / R2 /
~ ~ ~
=N '=N
~N~N~ ~~N.NH
I JO
9
8
Coupling of protected tetrazole bromo or iodobenzenes (e.g., S-(3-iodophenyl)-
2-
(2-tetrahydropyran)tetrazole) with N substituted aniline derivatives 4 produce
THP-
protected tetrazoles 8. Hydrolysis of THP-protected tetrazoles 8 can be
accomplished by
using an aqueous acid, such as HCl in water and a miscible solvent such as THF
or EtOH
to provide tetrazoles 9. Further, THP tetrazoles 8 can also be oxidatively
cleaved using
reagents such as CAN and DDQ in halognenated hydrocarbon solvents such as
dichloromethane, chloroform, dichloroethane and the like to yield tetrazoles
9.
Alternatively, tetrazole analogs 9 can be prepared from the corresponding
nitrites
by treatment with azide ion (e.g., KN3, NaN3, etc.) and a proton source (e.g.,
NH4C1) in a
polar aprotic solvent such as DMF. They also may be prepared by treatment with
an
azide ion and a Lewis acid (e.g., ZnBr2) in water, using a water miscible co-
solvent such
as isopropanol if necessary. Another method of preparation is by treatment of
a nitrite
with tin or silicon azides (e.g., Me3SiN3, Bu3SnN3) in an aprotic organic
solvent such as
benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like.
SCHEME 4
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8A) R4-B(OH)Z, Cu(OAc)z,
Et3N, CHZCIZ
88) R4-I, NaOtBu, Toluene,
PdZ(dba)5, P(otol)~ O 9A) KN(TMS)2, R3-I,
R1'O ~ 8C) R4-Br, Pd(dppf)CIZ, R1' ~ THF, 0 C R~ ~0
dppf, NaOtBu, THF ~ / 9B) R3-CI, NaH, DMF ~ / R3
O NH 0 N'
O NHZ
R2 R2 R4 R2 R4
5
Diphenylamines 10 can be prepared by coupling appropriately substituted
anilines
3, such as 3-cyclopentyloxy-4-methoxyaniline, with arylboronic acids in the
presence of
a base such as triethylamine and a copper catalyst such as copper acetate (as
described by
Chan et al, Tetrahedron Lett., 39, 2933-2936 (1998)). In general, halogenated
solvents
such as dichloromethane, chloroform, dichloroethane, and the like as well as
nonpolar
aprotic solvents such as benzene, toluene, or xylene are utilized. Such
diphenylamines
(e.g., 10) can more preferably be synthesized by metal catalyzed amination
reactions.
For example, reaction of an appropriately substituted aniline 3 with an
arylhalide in the
presence of a base (e.g., K3POa, CsC03, or NaOtBu) and a palladium or nickel
catalyst,
for example Pd(dppf)C12, a ligand (e.g., dppf) and a base (e.g., NaOtBu)
(JACS. 1996,
118, 7217) or with Pdzdba3, a bulky electron rich phosphine such as P(tBu)3,
and a base
(e.g., NaOtBu) (J. Org. Chem. 1999, 64, 5575) provides the desired
diphenylamines 10.
Solvents most commonly utilized in this type of reaction include non-polar
aprotic
solvents such as benzene, toluene, tetrahydrofuran, ether, and the like.
Diphenylamines 10 can then be alkylated with various alkyl halides,or
arylalkyl
halides such as, but not limited to iodomethane, ethylbromide, benzylchloride,
3-
(chloromethyl)pyridine, 4-(chloromethyl)-2,6-dichloropyridine, and 4-
(bromomethyl)-
benzoic acid, or salts thereof, in the presence of a non-nucleophilic base
such as sodium
hydride, potassium hexamethyldisilazide or potassium diisopropylamide to
provide N
substituted diphenylamines 5. Solvents useful in this reaction include aprotic
solvents
such as benzene, toluene, tetrahydrofuran, ether, DMF, and the like.
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SCHEME 5
O R1 ~O
R1 ~ ~
10) pyBOP, DIPEA, NHR5R6 O \ N~R3
0 \ N'R3 CH2CI2 ~ R2
R2
\ I O
COzH R5-N
~Rs
11
Carboxylic acids 7 can be further manipulated to form carboxamides 11 using
methods standard in the art. For example, a carboxylic acid can be treated
with a suitable
primary or secondary amine, in the presence of a suitable coupling reagent
such as BOP,
pyBOP or DCC, and a base such as Et3N or DIEA to yield a carboxamide. These
reactions generally take place in non-polar aprotic solvents such as
dichloromethane,
chloroform, or dichloroethane.
Carboxylic esters 6 or acids 7 can be reduced using methods standard in the
art to
give the corresponding carboxaldehyde or hydroxymethyl analogs. For example,
an aryl
ethyl ester (e.g., structure 6, RS = ethyl) can be treated with an appropriate
reducing agent
(e.g., LAH, DIBAL, etc.)~in an aprotic solvent such as ether or THF, to
produce the
corresponding carboxaldehydes or hydroxymethyl analogs. Such aldehydes and
alcohols
can be further derivatised by methods standard in the art.
Similarly carboxamides (e.g., structure 11) and nitrites can be reduced using
methods standard in the art to provide the corresponding substituted amines or
aminomethyl analogs. For example, an aryl carboxamide 11 can be reduced with
an
appropriate reducing agent (e.g., LAH) in an aprotic solvent (e.g., benzene,
toluene,
ether, THF, etc.) to give the corresponding substituted aminomethyl analog.
Whereas
reduction of an aryl nitrite yields the corresponding primary aminomethyl
analog.
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SCHEME 6
R1'O ~ ' R1'O ~
\ ~ ,R3 11 ) 10% Pd/C, H2, \ ~ ~R3 12) RSSOZCI, or ReCOCI
O N EtOH ~ N Pyr., CHZCIZ
R2 R2 .
NOZ NHZ
13
12 p
R1' ~ R1 ~O
\ ~ ,R3 \ ~ ,R3
O N
O N
I
R2 R2
i I OR
\ \
NH NH
R5 O ~O R6---~
O
14 15
Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 by
methods standard in the art such as hydrogenation using a suitable catalyst
(e.g., Pd on
carbon) in a polar protic solvent (e.g., EtOH, MeOH, etc.). Nitrobenzenes 12
can also be
reduced using a hydride source (e.g., NaBH4) and a transition metal catalyst
(e.g., NiClz,
Pd on carbon) in polar protic solvents such as EtOH, to produce the
corresponding
anilines 13. These anilines can then befurther substituted by methods standard
in the art.
For example, anilines of the type 13 can be alkylated, acylated, or
sulfonylated to give the
corresponding N alkyl amines, carboxamides (e.g., structure 15) or
sulfonamides (e.g.,
structure 14) respectively. For example, a sulfonamide can be prepared from an
aniline
and an appropriate sulfonyl halide or sulfonic anhydride (e.g., MeSO2Cl,
EtSO2Cl,
BnSOzCI, PhSOZCI, etc.) in the presence of a base (e.g., Et3N, pyridine, DIEA,
etc.).
Suitable solvents for this reaction include non-polar aprotic solvents such as
dichloromethane, chloroform, ether, and the like.
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SCHEME 7
R1 ~O
,O
O \ ~ N~R3 17) TBAF, THF, 0 C R1 /
HO \ N~R3
i~ R4 I
R4
16 17
18A) R2-Br, K2C03, DMF R1 ~O
18B) DIAD, PPh3, Imd.,
R2-OH, THF O \ ~ N~R3
I I
R2 R4
Trialkylsilylethers of the type 16 are prepared as described in Scheme 1. The
tert-butyldimethylsilyl protected catechol intermediates 16 are readily
deprotected by
numerous literature methods (see Greerle, T.W. and Wuts, P.G.M., Protective
Groups in
Organic Synthesis, 3'd Edition, John Wiley & Sons, 1999, pp. 273-276.) such as
by using
a fluoride ion source (e.g., Bu4NF) in an aprotic solvent such as ether or
THF; or under
acidic conditions (e.g., KF, 48% HBr, DMF). The resultant phenol 17, which is
a very
useful synthetic intermediate, can then be alkylated by methods standard in
the art and in
a similar manner as described for the alkylation of nitrophenol 2 in Scheme 1.
For
example, by the Mitsunobu reaction, by reaction with an alkyl halide in the
presence of a
base, or by Ullman type aryl coupling or by reaction with vinyl-, aryl- or
heteroaryl-
boronic acids in the precence of a copper catalyst.
SCHEME 8
O
R1 ~ / ~ R1 ~O
O \ N~R3 21) NHR5R6, K2C03, O \ N~R3
I CH3CN I
R2 / R2 /
\ ~ _\
O~~ O~~RS
-r
19 - R6
18
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Haloalkoxy intermediates 18, prepared by alkylation of the corresponding
phenol,
can be alkylated by reactions with substituted amines, alcohols, or thiols in
the presence
of a base to provide analogs such as 19. For example, an alkyl halide can be
aminated
with an appropriate primary or secondary amine and a base such as KZC03, in a
polar
aprotic solvent such as THF, DMF, or CH3CN.
Many of these synthetic procedures are described more fully in the examples
below.
One of ordinary skill in the-art will recognize that some of the compounds of
Formulae (I) and (I') can exist in different geometrical isomeric forms. In
addition,
some of the compounds of the present invention possess one or more asymmetric
carbon
atoms and are thus capable of existing in the form of optical isomers, as well
as in the
form of racemic or nonracemic mixtures thereof, and in the form of
diastereomers and
diastereomeric mixtures inter alia. All of these compounds, including cis
isomers, traps
isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers,
and
substantially pure and pure enantiomers, are within the scope of the present
invention.
Substantially pure enantiomers contain no more than S% w/w of the
corresponding
opposite enantiomer, preferably no more than 2%, most preferably no more than
1%.
The optical isomers can be obtained by resolution of the racemic mixtures
according to conventional processes, for example, by the formation of
diastereoisomeric
salts using an optically active acid or.base or formation of covalent
diastereomers.
Examples of appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric,
ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can
be
separated into their individual diastereomers on the basis of their physical
and/or
chemical differences by methods known to those skilled in the art, for
example, by
chromatography or fractional crystallization. The optically active bases or
acids are then
liberated from the separated diastereomeric salts. A different process for
separation of
optical isomers involves the use of chiral chromatography (e.g., chiral HPLC
columns),
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with or without conventional derivation, optimally chosen to maximize the
separation of
the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel,
e.g.,
Chiracel OD and Chiracel OJ among many others, all routinely selectable.
Enzymatic
separations, with or without derivitization, are also useful. The optically
active
compounds of Formulae I and I' can likewise be obtained by chiral syntheses
utilizing
optically active starting materials.
The present invention also relates to useful forms of the compounds as
disclosed
herein, such as pharmaceutically acceptable salts and prodrugs of all the
compounds of
the present invention. Pharmaceutically acceptable salts include those
obtained by
reacting the main compound, functioning as a base, with an inorganic or
organic acid to
form a salt, for example, salts of hydrochloric acid, sulfuric acid,
phosphoric acid,
methane sulfonic acid, camphor sulfonic acid, oxalic acid, malefic acid,
succinic acid and
citric acid. Pharmaceutically acceptable salts also include those in which the
main
compound functions as an acid and is reacted with an appropriate base to form,
e.g.,
sodium, potassium, calcium, mangnesium, ammonium, and choline salts. Those
skilled
in the art will further recognize that acid addition salts of the claimed
compounds may be
prepared by reaction of the compounds with the appropriate inorganic or
organic acid via
any of a number of known methods. Alternatively, alkali and alkaline earth
metal salts
are prepared by reacting the compounds of the invention with the appropriate
base via a
variety of known methods.
The following are further examples of acid salts that can be obtained by
reaction
with inorganic or organic acids: acetates, adipates, alginates, citrates,
aspartates,
benzoates, benzenesulfonates, bisulfates, butyrates, camphorates,
digluconates,
cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates,
glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates,
hydrobromides,
hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,
methanesulfonates,
nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates,
persulfates, 3-
phenylpropionates, picrates, pivalates, propionates, succinates, tartrates,
thiocyanates,
tosylates, mesylates and undecanoates.
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Preferably, the salts formed are pharmaceutically acceptable for
administration to
mammals. However, pharmaceutically unacceptable salts of the compounds are
suitable
as intermediates, for example, for isolating the compound as a salt and then
converting
the salt back to the free base compound by treatment with an alkaline reagent.
The free
base can then, if desired, be converted to a pharmaceutically acceptable acid
addition salt.
The compounds of the invention can be administered alone or as an active
ingredient of a formulation. Thus, the present invention also includes
pharmaceutical
compositions of compounds of Formulae I or I' containing, for example, one or
more
pharmaceutically acceptable earners.
Numerous standard references are available that describe procedures for
preparing
various formulations suitable for administering the compounds according to the
invention. Examples of potential formulations and preparations are contained,
for
example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical
Association (current edition); Pharmaceutical Dosage Forms: Tablets
(Lieberman,
Lachman and Schwartz, editors) current edition, published by Marcel Dekker,
Inc., as
well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593
(current
edition).
In view of their high degree of PDE4 inhibition, the compounds of the present
invention can be administered to anyone requiring or desiring PDE4 inhibition,
and/or
enhancement of cognition. Administration may be accomplished according to
patient
needs, for example, orally, nasally, parenterally (subcutaneously,
intraveneously,
intramuscularly, intrasternally and by infusion), by inhalation, rectally,
vaginally,
topically, locally, transdermally, and by ocular administration.
Various solid oral dosage forms can be used for administering compounds of the
invention including such solid' forms as tablets, gelcaps, capsules, caplets,
granules,
lozenges and, bulk powders. The compounds of the present invention can be
administered
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alone or combined with various pharmaceutically acceptable carriers, diluents
(such as
sucrose, mannitol, lactose, starches) and excipients known in the art,
including but not
limited to suspending agents, solubilizers, buffering agents, binders,
disintegrants,
preservatives, colorants, flavorants, lubricants and the like. Time release
capsules, tablets
and gels are also advantageous in administering the compounds of the present
invention.
Various liquid oral dosage forms can also be used for administering compounds
of the invention, including aqueous and non-aqueous solutions, emulsions,
suspensions,
syrups, and elixirs. Such dosage forms can also contain suitable inert
diluents known in
the art such as water and suitable excipients known in the art such as
preservatives,
wetting agents, sweeteners, flavorants, as well as agents for emulsifying
and/or
suspending the compounds of the invention. The compounds of the present
invention
may be injected, for example, intravenously, in the form of an isotonic
sterile solution.
Other preparations are also possible.
Suppositories for rectal administration of the compounds of the present
invention
can be prepared by mixing the compound with a suitable excipient such as cocoa
butter,
salicylates and polyethylene glycols. Formulations for vaginal administration
can be in
the form of a pessary, tampon, cream, gel, paste, foam, or spray formula
containing, in
addition to the active ingredient, such suitable carriers as are known in the
art.
For topical administration the pharmaceutical composition can be in the form
of
creams, ointments, liniments, lotions, emulsions, suspensions, gels,
solutions, pastes,
powders, sprays, and drops suitable for administration to the skin, eye, ear
or nose.
Topical administration may also involve transdermal administration via means
such as
transdermal patches.
Aerosol formulations suitable for administering via inhalation also can be
made.
For example, for treatment of disorders of the respiratory tract, the
compounds according
to the invention can be administered by inhalation in the form of a powder
(e.g.,
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micronized) or in the form of atomized solutions or suspensions. The aerosol
formulation
can be placed into a pressurized acceptable propellant.
The compounds can be administered as the sole active agent or in combination
with other pharmaceutical agents such as other agents used in the treatment of
cognitive
impairment and/or in the treatment of psychosis, e.g., other PDE4 inhibitors,
calcium
channel blockers, chloinergic drugs, adenosine receptor modulators, amphakines
NMDA-
R modulators, mGluR modulators, and cholinesterase inhibitors (e.g.,
donepezil,
rivastigimine, and glanthanamine). In such combinations, each active
ingredient can be
administered either in accordance with their usual dosage range or a dose
below its usual
dosage range.
The present invention further includes methods of treatment that involve
inhibition of PDE4 enzymes. Thus, the present invention includes methods of
selective
inhibition of PDE4 enzymes in animals, e.g., mammals, especially humans,
wherein such
inhibition has a therapeutic effect, such as where such inhibition may relieve
conditions
involving neurological syndromes, such as the loss of memory, especially long-
term
memory. Such methods comprise administering to am animal in need thereof,
especially
a mammal, most especially a human, an inhibitory amount of a compound, alone
or as
part of a formulation, as disclosed herein.
The condition of memory impairment is manifested by impairment of the ability
to learn new information and/or the inability to recall previously learned
information.
Memory impairment is a primary symptom of dementia and can also be a symptom
associated with such diseases as Alzheimer's disease, schizophrenia,
Parkinson's disease,
Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV,
cardiovascular
disease, and head trauma as well as age-related cognitive decline.
Dementias are diseases that include memory loss and additional intellectual
impairment separate from memory. The present invention includes methods for
treating
patients suffering from memory impairment in all forms of dementia. Dementias
are
CA 02435847 2003-07-21
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classified according to their cause and include: neurodegenerative dementias
(e.g.,
Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease),
vascular (e.g.,
infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's,
bacterial
meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g.,
subdural
hematoma or traumatic brain in ur infectious (e.g., HIV), genetic (down
syndrome), f
J Y)
toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g.,
vitamin B 12 or
folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g.,
depression and
schizophrenia), and hydrocephalus.
The present invention includes methods for dealing with memory loss separate
from dementia, including mild cognitive impairment (MCI) and age-related
cognitive
decline. The present invention includes methods of treatment for memory
impairment as
a result of disease. In another application, the invention includes methods
for dealing
with memory loss resulting from the use of general anesthetics, chemotherapy,
radiation
treatment, post-surgical trauma, and therapeutic intervention.
The compounds may be used to treat psychiatric conditions including
schizophrenia, bipolar or manic depression, major depression, and drug
addiction and
morphine dependence. These compounds may enhance wakefulness. PDE4 inhibitors
can be used to raise cAMP levels and prevent neurons from undergoing
apoptosis. PDE4
inhibitors are also known to be anti-inflammatory. The combination of anti-
apoptotic
and anti-inflammatory properties make these compounds useful to treat
neurodegeneration resulting from any disease or injury, including stroke,
spinal cord
injury, neurogenesis, Alzheimer's disease, multiple sclerosis,
amylolaterosclerosis (ALS),
and multiple systems atrophy (MSA).
Thus, in accordance with a preferred embodiment, the present invention
includes
methods of treating patients suffering from memory impairment due to, for
example,
Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease,
Pick's
disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS
hypoxia,
cerebral senility, multiinfarct dementia and other neurological conditions
including acute
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neuronal diseases, as well as HN and cardiovascular diseases, comprising
administering
an effective amount of a compound according to Formula (I) or (I') or
pharmaceutically
acceptable salts thereof.
The compounds of the present invention can also be used in a method of
treating
patients suffering from disease states characterized by decreased NMDA
function, such
as schizophrenia. The compounds can also be used to treat psychosis
characterized by
elevated levels of PDE 4, for example, various forms of depression, such as
manic
depression, major depression, and depression associated with psychiatric and
neurological disorders.
As mentioned, the compounds of the invention also exhibit anti-inflammatory
activity. As a result, the inventive compounds are useful in the treatment of
a variety of
allergic and inflammatory diseases, particularly disease states characterized
by decreased
cyclic AMP levels and/or elevated phosphodiesterase 4 levels. Thus, in
accordance with
a further embodiment of the invention, there is provided a method of treating
allergic and
inflammatory disease states, comprising administering an effective amount of a
compound according to Formulae (I) or (I') or a pharmaceutically acceptable
salt thereof.
Such disease states include: asthma, chronic bronchitis, chronic obstructive
pulmonary
disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic
conjunctivitis,
vernal conjunctivitis, esoniophilic granuloma, psoriasis, inflammatory
arthritis,
rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease,
reperfusion injury
of the myocardium and brain, chronic glomerulonephritis, endotoxic shock,
adult
respiratory distress syndrome, cystic fibrosis, arterial restenosis,
artherosclerosis,
keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus,
pneumoconiosis, chronic obstructive airways disease, chronic obstructive
pulmonary
disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema,
lichen
simplex, sunburn, pruritis in the anogenital area, alopecia areata,
hypertrophic scars,
discoid lupus erythematosus, systemic lupus erythematosus, follicular and wide-
area
pyodermias, endogenous and exogenous acne, acne rosacea, Beghet's disease,
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anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia,
multiple
sclerosis, gastrointestinal diseases, autoimmune diseases and the like.
PDE4 inhibitors for, treating asthma, chronic bronchitis, psoriasis, allergic
rhinitis,
and other inflammatory diseases, and for inhibiting tumor necrosis factor are
known
within the art. See, e.g., WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517,
WO
94/14742, US 5,814,651, and US 5,935,9778. These references also describe
assays for
determining PDE4 inhibition activity, and methods for synthesizing such
compounds.
The entire disclosures of these documents are hereby incorporated by
reference.
PDE4 inhibitors may be used to prevent or ameliorate osteoporosis, as an
antibiotic, for treatment of cardiovascular disease by mobilizing cholesterol
from
atherosclerotic lesions, to treat rheumatoid arthritis (RA), for long-term
inhibition of
mesenchymal-cell proliferation after transplantation, for treatment of urinary
obstruction
secondary to benign prostatic hyperplasia, for suppression of chemotaxis and
reduction of
invasion of colon cancer cells, for treatment of B cell chronic lymphocytic
leukemia (B-
CLL), for inhibition of uterine contractions, to attenuate pulmonary vascular
ischemia-
reperfusion injury (IRI) , for corneal hydration , for inhibition of IL-2R
expression and
thereby abolishing HIV-1 DNA nuclear import into memory T cells, for
augmentation of
glucose-induced insulin secretion, in both the prevention and treatment of
colitis, and to
inhibit mast cell degranulation.
The compounds of the present invention can be administered as the sole active
agent or in combination with other pharmaceutical agents such as other agents
used in the
treatment of cognitive impairment and/or in the treatment of psychosis, e.g.,
other PDE4
inhibitors, calcium channel blockers, chloinergic drugs, adenosine receptor
modulators,
amphakines NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors
(e.g., donepezil, rivastigimine, and glanthanamine). In such combinations,
each active
ingredient can be administered either in accordance with their usual dosage
range or a
dose below their usual dosage range.
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The dosages of the compounds of the present invention depend upon a variety of
factors including the particular syndrome to be treated, the severity of the
symptoms, the
route of administration, the frequency of the dosage interval, the particular
compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile of the
compound, and
the presence of any deleterious side-effects, among other considerations.
The compounds of the invention are typically administered at dosage levels and
in
a mammal customary for PDE4 inhibitors such as those known compounds mentioned
above. For example, the compounds can be administered, in single or multiple
doses, by
oral administration at a dosage level of, for example, 0.01-100 mg/kg/day,
preferably 0:1-
70 mg/kg/day, especially 0.5-10 mg/kg/day. Unit dosage forms can contain, for
example,
0.1-50 mg of active compound. For intravenous administration, the compounds
can be
administered, in single or multiple dosages, at a dosage level of, for
example, 0.001-50
mg/kg/day, preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit
dosage
forms can contain, for example, 0.1-10 mg of active compound.
In carrying out the procedures of the present invention it is of course to be
understood that reference to particular buffers, media,'reagents, cells,
culture conditions
and the like are not intended to be limiting, but are to be read so as to
include all related
materials that one of ordinary skill in the art would recognize as being of
interest or value
in the particular context in which that discussion is presented. For example,
it is often
possible to substitute one buffer system or culture medium for another and
still achieve
similar, if not identical, results. Those of skill in the art will have
sufficient knowledge of
such systems and methodologies so as to be able, without undue
experimentation, to
make such substitutions as will optimally serve their purposes in using the
methods and
procedures disclosed herein.
The present invention will now be further described by way of the following
non-
limiting examples. In applying the disclosure of these examples, it should be
kept clearly
in mind that other and different embodiments of the methods disclosed
according to the
present, invention will no doubt suggest themselves to those of skill in the
relevant art.
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In the foregoing and in the following examples, all temperatures are set forth
uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and
percentages
are by weight.
The entire disclosures of all applications, patents and publications, cited
above
and below, are hereby incorporated by reference.
EXAMPLE 1A
1-Cyclopentyloxy-2-methoxy-5-nitrobenzene
To a suspension of 2-methoxy-5-nitrophenol (525g, 3.104 mol) and potassium
carbonate (643.5g, 4.66 mol) in dimethylformamide (1 L), under NZ protection,
was
added cyclopentyl bromide (499.2 mL, 4.66 inol). The suspension was heated to
100°C
for 6h. Potassium carbonate (85.8g, 0.62 mol) and cyclopentyl bromide (SO mL,
0.46
mol) were added. The suspension was heated to 100°C for 4h. TLC
indicated the
reaction was complete (9:1' DCM:MeOH). The reaction mixture was cooled to room
temperature and diluted with water (3L) and ether (3L). The layers were
separated and
the aqueous layer was re-extracted with ether (2L). The combined organic
layers were
washed with 1N NaOH (2L), water (2L), and brine (2L). The organic layer was
dried
over sodium sulfate, filtered, and evaporated. The resulting solid was
azeotroped with
toluene (2 x 300 mL) to obtain 736:7g (99.6% yield) as a yellow solid.
The following compounds were prepared in a similar manner as described above:
a) 1-Cyclopropylmethoxy-2-methoxy-S-nitrobenzene
b) 1-Cyclopentoxy-2-difluoromethoxy-5-nitrobenzene
so
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c) 1-Cyclopropylmethoxy-2-difluoromethoxy-5-nitrobenzene
EXAMPLE 1B
2-Methoxy-5-vitro-1-((3R)-tetrahydrofuryloxy)benzene
To a mixture of 2-Methoxy-5-nitrophenol ( 1.69 g, 10 mmol), triphenylphosphine
(5.24 g, 20 mmol) and 3-(R)-hydroxytetrahydrofuran (1.80 g, 20 mmol) in
anhydrous
tetrahydrofuran (40 mL) was added drop-wise, with stirring,
diisopropylazodicarboxylate
(4.0 mL, 20 mmol) and the mixture was allowed to stir at room temperature for
16 h.
The mixture was diluted with ether (150 mL) and washed with 2N NaOH (3 x 50
mL)
and brine (50 mL), (MgS04) and concentrated in vacuo. The crude residue was
purified
by flash column chromatography over silica gel (Biotage Flash 40M) eluting
with 20%
ethyl acetate in hexanes to give 1.05 g of product .
The following compounds were prepared in a similar manner as described above:
a) 2-Methoxy-5-vitro-1-(3-tetrahydrofuryloxy)benzene
b) 2-Methoxy-5-vitro-1-((3~-tetrahydrofuryloxy)benzene
c) 2-Difluoromethoxy-5-vitro-1-(3-tetrahydrofurylox'y)benzene
d) 2-Difluoromethoxy-S-vitro-1-((3R)-tetrahydrofuryloxy)benzene
e) 2-Difluoromethoxy-S-vitro-1-((3S~-tetrahydrofuryloxy)benzene
f) 2-Methoxy-5-vitro-1-(3-phenpropyloxy)benzene
g) 1-(2-Indanyloxy)-4-methoxy-5-nitrobenzene
EXAMPLE 1 C
1-(tent-Butyldimethylsilyl)oxy-2-methoxy-5-nitrobenzene
To a mixture of 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08
g, 15.9 mmol) in anhydrous DMF (40 mL) was added, with stirring, tert-
butyldimethylsilyl chloride (2.05 g, 13.6 mmol) and the mixture was allowed to
stir at
room temperature for 16 h. The solvent was removed in vacuo and the residue
was
dissolved in 40 mL of 50% ethyl acetate in hexanes and, filtered through 10 g
of silica gel.
The silica gel was washed with an'additional--200 mL of 50% ethyl acetate in
hexanes and
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the filtrates were combined and concentrated in vacuo to give 2.01 g of
product as a tan
crystalline solid. ~H NMR (CDC13) 8 7.89 (dd, 1H, J = 9.0 Hz, 2.8 Hz), 7.69
(d, 1H, J =
2.8 Hz), 6.88 (d, 1H, J = 9.0~, 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).
EXAMPLE 2
3-Cyclopentyloxy-4-methoxyaniline
To a suspension of 10% Pd on activated carbon (25g) in ethanol (4L), under NZ
protection, was added 1-cyclopentyloxy-2-methoxy-5-nitrobenzene (250g, 1.054
mol).
The reaction mixture was degassed under vacuum three times. The reaction
mixture was
stirred vigorously while hydrogen gas was allowed to flow over the reaction
mixture.
After 4h the reaction was complete by TLC ' (5:1 hex:EA). The reaction mixture
was
filtered through a pad of celite and the celite was rinsed with additional
ethanol. The
solvent was removed in-vacuo to obtain 208.38g (95% yield) of 3-cyclopentyloxy-
4-
methoxyaniline as a red liquid. 1H NMR (CDCl3) S 6.85 (d. J = 8.4Hz, 1H), 6.29
(s, 1H),
6.19 (dd, J = 2.8, 8.4, 1H), 4.69 (p, J = 4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs,
2H), 1.90-1.81
(m, 6H), 1.61-1.55 (m, 2H). .
a
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-difluoromethoxyaniline
b) 3-Cyclopropylmethoxy-2-methoxyaniline
c) 3-Cyclopropylmethoxy-4-difluoromethoxyaniline
d) 4-Methoxy-3-((3R)-tetrahydrofuryloxy)aniline
e) 4-Methoxy-3-(tetrahydrofuryloxy)aniline
f) 4-Methoxy-3-((35~-tetrahydrofuryloxy)aniline
g) 4-Difluoromethoxy-3-(3-tetrahydrofuryloxy)aniline
h) 4-Difluoromethoxy-3-((3R)-tetrahydrofuryloxy)aniline
i) 4-Difluoromethoxy-3-((3S~-tetrahydrofuryloxy)aniline
j) 3-(tert-Butyldimethylsilyl)oxy-4-methoxyaniline
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k) 4-Methoxy-3-(3-phenpropyloxy)aniline
I) 3-(2-Indanyloxy)-4-methoxyaniline
EXAMPLE 3
3-Cyclopentyl-4-methoxy-N (3-pyridylmethyl)aniline
To a mixture of 3-pyridinecarboxaldehyde (106.558, 0.995 mol) in methanol (SL)
was
added 3-cyclopentyloxy-4-methoxyaniline (208.388, 1.005 mol) and p-
toluenesulfonic
acid monohydrate (200 mg). The reaction mixture was stirred fox 4h. The flask
was then
cooled to 0°C and sodium borohydride (37.648, 2.3 mol) was added
portionwise over 4h.
0 The reaction mixture was allowed to warm to room temperature over 16h with
stirring.
TLC indicated the reaction was complete (1:3 hex:EA}. The solvent was
evaporated until
approximately O.SL of slurry remained. The slurry was diluted with water (1L)
and
extracted rVith ethyl acetate (2 x 2L). The combined organic layers were
washed with
brine (500 mL), dried over sodium sulfate, and concentrated to yield 3008
(100% yield)
5 of the desired product as a brown viscous liquid. 1H NMR (CDCl3) 8 8.61-8.48
(m, 2H),
7.69-7.67 (m, 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4 Hz, 1H), 6.23. (s, 1H),
6.13 (dd, J =
2.6, 8.6, 1H), 4.65 (bs, 1H), 4.27 (s, 2H), ,4.0 (bs, 1H), 3.73 (s, 3H), 1.88-
1.70 (m, 6H),
1.65-1.45 (m, 2Hj.
;0 The following compounds were prepared in a similar manner as described
above:
a) 3-Cyclopentyloxy-4-methoxy-N (3-thienylmethyl)amiline
b) 3-Cyclopentyloxy-4-methoxy-N (4-pyridylmethyl)aniline
c) 3-Cyclopentyloxy-N (2,6-dichloro-4-pyridylmethyl)- 4-methoxyaniline
!5 d) 3-Cyclopentyloxy-4-methoxy-N (2-quinolinylmethyl)aniline
e) 3-Cyclopentyloxy-4-methoxy-N (3-quinolinylmethyl)aniline
3-Cyclopentyloxy-4-methoxy-N (4-quinolinylmethyl)aniline
g} 3-Cyclopentyloxy-4-methoxy-N (2-pyrazinylmethyl)aniline
h) 4-Methoxy-N (3-pyridylmethyl)-3-(3-tetrahydrofuryloxy}aniline
.0 i) 4-Methoxy-N (3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)aniline
j) 4-Methoxy-N (3-pyridylmethyl)-3-((3S~-tetrahydrofuryloxy)aniline
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k) 3-Cyclopropylmethoxy-4-difluorornethoxy-N (3-pyridylmethyl)aniline
1) 3-Cyclopentyloxy-4-difluoromethoxy-N (3-pyridylmethyl)aniline
m) 4-Difluoromethoxy-N (3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)aniline
n) 4-Difluoromethoxy-N (3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)aniline
o) 3,4-Bis(difluoromethoxy)-N (3-pyridylmethyl)aniline
p) 3-tert-Butyldimethylsilyloxy-4-methoxy-N (3-pyridylmethyl)aniline
q) 3-Cyclopentyloxy-4-methoxy-N (2-pyridylmethyl)aniline
r) 3-Cyclopentyloxy-4-methoxy-N [1-(2-phenethyl)]aniline
s) N Benzyl-3-cyclopentyloxy-4-methoxyaniline
t) N [(Cyclohex-1-en-1-yl)methyl]-3-cyclopentyloxy-4-methoxyaniline
u) 3-Cyclopentyloxy-4-methoxy-N (3,4,5-trimethoxybenzyl)aniline
v) N [(Cyclohex-3-en-1-yl)methyl]-3-cyclopentyloxy-4-methoxyaniline
w) 3-Cyclopentyloxy-4-methoxy-N (2,4,6-trimethylbenzyl)aniline
x) 3-Cyclopentyloxy-4-methoxy-N (2-methylbenzyl)aniline
y) 3-Cyclopentyloxy-4-methoxy-N (2-trifluoromethylbenzyl)aniline
z) 3-Cylclopentyloxy-4-methoxy-N ((3,4-methylenedioxy)benzyl)aniline
aa) 3-Cyclopentyloxy-N (2-hydroxy-3-methoxylbenzyl)-4-methoxyaniline
bb) 3-Cyclopentyloxy-N (3-furylmethyl)-4-rriethoxyariiline
cc) 3-Cyclopentyloxy-4-methoxy-N (3-methylbenzyl)aniline
dd) 3-Cyclopentyloxy-4-methoxy-N (2-methoxybenzyl)aniline
ee) 3-Cyclopentyloxy-4-methoxy-N (3-chlorobenzyl)aniline
ff) 3-Cyclopentyloxy-4-methoxy-N (3-methoxybenzyl)aniline
gg) 3-Cyclopentyloxy-4-methoxy-N (2-chlorobenzyl)aniline
hh) 3-Cyclopentyloxy-4-methoxy-N (3-methylbenzyl)aniline
ii) 4-Methoxy-3-(3-phenpropyloxy)-N (4-pyridylmethyl)aniline
jj) N (2,6-Dichloro-4-pyridylmethyl)-3-(2-indanyloxy)-4-methoxyaniline
kk) 4-Methoxy-3-(3-phenpropyloxy)-N (2-pyridylmethyl)aniline
11) N (2,6-Dichloro-4-pyridylmethyl)-4-methoxy-3-(3-phenpropyloxy)aniline
mm) 4-Methoxy-3-(3-phenpropyloxy)-N (3-pyridylmethyl)aniline
nn) 3-Cyclopentyloxy-4-methoxy-N (2-thienylmethyl)aniline
oo) 3-(2-Indanyloxy)-4-methoxy-N (3-thienylmethyl)aniline
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pp) 4-Methoxy-3-(3-phenpropyloxy)-N (3-thienylmethyl)~niline
qq) 3-(2-Indanyloxy)-4-methoxy-N (2-pyridylmethyl)aniline
rr) 3-(2-Indanyloxy)-4-methoxy-N (3-pyridylmethyl)aniline
ss) 3-(2-Indanyloxy)-4-methoxy-N (4-pyridylmethyl)aniline
tt) 3-Cyclopentyloxy-4-methoxy-N (3-piperidinemethyl)aniline
uu) 3-Cyclopentyloxy-4-methoxy-N (3-(1-tert-
butyloxycarbonyl)piperidinemethyl)aniline
vv) 3-Cyclopentyloxy-4-methoxy-N (6-methyl-2-pyridylmethyl)aniline
ww) N (2-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline
xx)N (2-Chloro-5-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline
yy) 3-Cyclopentyloxy-4-methoxy-N (2-thiazolylmethyl)aniline
EXAMPLE 4
3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
To a 100 mL oven dried, argon flushed flask was added in the following order
0.59 g
(6.10 mmol) of NaOtBu, 360 mg of Pd2dba3, 20 mL of toluene, 0.14 mL of
P(tBu)3, and a
20 mL solution of 1.3 g (4.36 mmol) of N-(3-pyridylmethyl)-3-cyclopentyloxy-4-
methoxyaniline in toluene. With stirnng, f.1 g (15' mmol) of iodobenzene was
added
dropwise and the mixture was stirred for 18 hours. The reaction mixture was
diluted with
EtOAc and washed twice with H20 and extracted with 3 x 15 mL of 3N HCI. The
combined acid extracts were washed with 15 mL of EtOAc and then carefully
neutralized
with 6N NaOH to pH greater than 12. The basic solution was extracted with 2 x
15 mL
of EtOAc and the combined organic fractions were subsequently washed with 15
mL of
HZO and brine, dried (MgS04), and concentrated. The residue was purified by
chromatography over silica gel (Biotage Flash 40M) eluting with 25% EtOAc in
hexanes.
The material was further purified by crystallization from hexanes to give 550
mg of a
white solid.. 1H NMR (CDC13) 8 8.61 (s, 1H), 8.49 (d, 1H, J = 4.2 Hz), 7.67
(d, 1H, 7.9
Hz), 7.30-7.10 (m, 3H), 6.90-6.80 (m, 4H), 6.80-6.60 (m, 2H), 4.94 (s, 2H),
4.64 (p, 1H, J
= 4.1 Hz),3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
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a) 3-Cyclopentyloxy-4-methoxy-2'-methyl-N (3-pyridylmethyl)diphenylamine
b) 3-Cyclopentyloxy-4-methoxy-3'-methyl-N (3-pyridylmethyl)diphenylamine
c) 3-Cyclopentyloxy-4-methoxy-4'-methyl-N (3-pyridylmethyl)diphenylamine
d) 3-Cyclopentyloxy-4'-ethyl-4-methoxy-N (3-pyridylmethyl)diphenylamine
e) 3'-Chloro-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
4'-Chloro-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
g) 3-Cyclopentyloxy-2',4-dimethoxy-N (3-pyridylmethyl)diphenylamine
h) 3-Cyclopentyloxy-3',4-dimethoxy-N-(3-pyridylmethyl)diphenylamine
i) 3-Cyclopentyloxy-4,4'-dimethoxy-N (3-pyridylinethyl)diphenylamine
j) 3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-3'-
trifluoromethyldiphenylamine
k) 3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-4'-
trifluoromethyldiphenylamine
1) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-N (3-pyridylmethyl)diphenylamine
m) 3-Cyclopentyloxy-4'-fluoro-4-methoxy-N: (3-pyridylmethyl)diphenylamine.
n) 3-Cyclopentyloxy-4-methoxy-3'-phenyl-N (3-pyridylmethyl)diphenylamine
o) 3-Cyclopentyloxy-4-methoxy-4'-phenyl-N (3-pyridylmethyl)diphenylamine
p) 3'-Cyano-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
q) 4'-Cyano-3-cyclopentyloxy-4-methoxy-IV (3-pyridylmethyl)diphenylamine
r) Ethyl N (3-cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzoate
s) Ethyl N (3-cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-4-
aminobenzoate
t) 3.-Cyclopentyloxy-4-methoxy-3'-nitro-N-(3-pyridylmethyl)diphenylamine
u) 3-Cyclopentyloxy-4-methoxy-4'-nitro-N (3-pyridylmethyl)diphenylamine
v) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-1-naphthylamine
w) 3-Cyclopentyloxy-2',3'-dimethyl-4-methoxy-N (3-pyridylmethyl)diphenylamine
x) 3-Cyclopentyloxy-2',4'-dimethyl-4-methoxy-N (3-pyridylmethyl)diphenylamine
y) 3-Cyclopentyloxy-2',5'-dimethyl-4-methoxy-N (3-pyridylmethyl)diphenylamine
z) 3-Cyclopentyloxy-3',4'-dimethyl-4-methoxy-N (3-pyridylmethyl)diphenylamine
aa) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxy-N (3-pyridylmethyl)diphenylamine
bb) 3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-N (3-pyridylmethyl)diphenylamine
cc) 3-Cyclopentyloxy-3',5'-dichloro-4-methoxy-N (3-pyridylmethyl)diphenylamine
dd) 3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-
pyridylmethyl)diphenylamine
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ee) 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N (3-
pyridylmethyl)diphenylamine
ff) 4'-Chloro-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-3'-
trifluoromethyldiphenylamine
gg) 3-Cyclopentyloxy-4-methoxy-N (3-thienylmethyl)diphenylamine
hh)N (3-Cyclopentyloxy-4-methoxyphenyl)-N (3-thienylmethyl)-1-naphthylamine
ii) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxy-N (3-thienylmethyl)diphenylamine
jj) 3-Cyclopentyloxy-4-methoxy-4'-methyl-N (4-pyridylmethyl)diphenylamine
kk) 3-Cyclopentyloxy-N (2,6-dichloro-4-pyridylmethyl)-4-methoxy-3'-
methyldiphenylamine
11) 2'-Chloro-3-cyclopentyloxy-N (2,6-dichloro-4-pyridylmethyl)-4-
methoxydiphenylamine
mm) 3-Cyclopentyloxy-N (2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine
nn) 3-Cyclopentyloxy-4-methoxy-N (6-methyl-2-pyridylmethyl)diphenylamine
oo) 3-Cyclopentyloxy-4-methoxy-N (3-quinolinylmethyl)diphenylamine
pp) 3-Cyclopentyloxy-4-methoxy-N (4-quinolinylmethyl)diphenylamine
qq) 3-Cyclopentyloxy-4-methoxy-N (2-pyrazinylmethyl)diphenylamine
rr) 4-Methoxy-3'-methyl-N (3-pyridylmethyl)-3-(3-
tetrahydrofuryloxy)diphenylamine
ss) 4-Methoxy-4'-methyl-N (3-pyridylmethy~l)-3-(3-
tetrahydrofuryloxy)diphenylamine
tt) 4,4'-Dimethoxy-N (3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
uu) 3'-Chloro-4-methoxy-N (3-pyridylmethyl)-3-(3-
tetrahydrofuryloxy)diphenylamine
vv) 4-Methoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N (3-pyridylmethyl)-3-(3-
tetrahydrofuryloxy)diphenylamine
ww) 3'-Cyano-4-methoxy-N (3-pyridylmethyl)-3-((3R)-
tetrahydrofuryloxy)diphenylami~ne
xx) 3'-Cyano-4-methoxy-N (3-pyridylmethyl)-3-((3R)-
tetrahydrofuryloxy)diphenylamine
yy) 3-Cyclopropylmethoxy-4-difluoromethoxy-N (3-pyridylmethyl)diphenylamine
zz) 3-Cyclopentyloxy-4-difluoromethoxy-N (3-pyridylmethyl)diphenylamine
aaa) 4-Difluoromethoxy-N (3-pyridylmethyl)-3-(3-
tetrahydrofuryloxy)diphenylamine
bbb) 3,4-Bis(difluoromethoxy)-N (3-pyridylmethyl)diphenylamine
ccc) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-
tetrahydrofuryloxy)diphenylamine
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ddd) 3'-Cyano-4-difluoromethoxy-N (3-pyridylmethyl)-3-((3R)-
tetrahydrofuryloxy)diphenylamine
eee) 3'-Chloro-4-difluoromethoxy-N (3-pyridylmethyl)-3-((3R)-
tetrahydrofuryloxy)diphenylamine
fff) Ethyl N (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N (3-
pyridylmethyl)-3-
aminobenzoate
ggg) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-1-ylcarbonyl)-N (3-
pyridylmethyl)diphenylamine
hhh) 3-Cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N (3-
pyridylmethyl)diphenylamine
iii) 3'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylam.ine
jjj) 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
kkk) tert-Butyl N (3-cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzoate
111) Ethyl N (3-cyclopentyloxy-4-difluoromethoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzoate
mmm) Ethyl N (4-difluoromethoxy-3-(3-tetrahydrofuryloxy)phenyl)-N (3-
pyridylmethyl)-3-aminobenzoate
nnn) Ethyl N (3,4-Bis(difluoromethoxy)phenyl)-N (3-pyridylmethyl)-3-
aminobenzoate
ooo) Ethyl N (4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl)-N (3-pyridylmethyl)-
-3-
aminobenzoate
ppp) Ethyl N (3-cyclopropylmethoxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzoate
qqq) 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-
N
(3-pyridylmethyl)diphenylamine
m) 3-Cyclopentyloxy-4-methoxy-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N
(3-
pyridylmethyl)diphenylamine
sss) 4-Methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-S-yl)-N (3-
pyridylmethyl)-3-
((3R)-tetrahydrofuryloxy)diphenylamine
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ttt) 3-Cyclopropylmethoxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-
yl)-N
(3-pyridylmethyl)diphenylamine
uuu) 4-Difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N (3-
pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
vvv) 3-Cyclopropylmethoxy-4-difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H-
tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
www) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H-
tetrazol-5-
yl)-N (3-pyridylmethyl)diphenylamine
xxx) 3-Cyclopropylmethoxy-4-difluoromethoxy-3'-(2-(tetrahydropyran-2-yl)-2H-
tetrazol-5-yl)-N (3-pyridylmethyl)diphenylamine
yyy) Bis-(3.,4-difluoromethoxy)-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-
N (3-
pyridylmethyl)diphenylamine
zzz) 3-tert-Butyldimethylsilyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
aaaa) 3-tert-Butyldimethylsilyloxy-3'-chloro-4-methoxy-N (3-
pyridylmethyl)diphenylamine
bbbb) Ethyl N (3-tert-butyldimethylsilyloxy-4-methoxyphenyl)-N (3-
pyridylmethyl)-3-
aminobenzoate
cccc) 3-Cyclopentyloxy-2'-chloro-4-methoXy-N (3-pyridylmethyl)diphenylamine
dddd) 3-(2-indanyloxy)-4-methoxy-N (3-pyridylmethyl)diphenylamine
EXAMPLE 5
N (3-Cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-aminobenzoic acid
A solution of 6.5 g of ethyl N (3-cyclopentyloxy-4-methoxyphenyl)-N (3
pyridylmethyl)-3-aminobenzoate in SO mL of EtOH was treated with 10 mL of 6N
NaOH. The mixture was allowed to stand for 6 hours, concentrated, and diluted
with 50
mL of HZO. The aqueous mixture was extracted with 2 x 50 mL of ether,
acidified with
AcOH to pH 3, and extracted with 2 x 50 mL of EtOAc. The combined EtOAc
fractions
were washed with 25 mL of HZO and 25 mL of brine, dried (MgS04), and
concentrated.
The residue was purified by chromatography over Si02 (35 g RediSep~ column)
using a
linear gradient of EtOAc and hexanes as eluant (50% EtOAc to 70% EtOAc over 20
minutes) to provide 4.8 g of a yellow solid product after drying in vacuo for
12 h at 60°C.
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'H NMR (CDC13) 8 11.15 (bs, 1H), 8.70-8.55 (m, 2H), 7.77-6.71 (m, 9H), 4.99
(s, 2H),
4.65 (p, J = 3.8 Hz, 1H), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H):
The following compounds were prepared in a similar manner as described above:
a) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-4-aminobenzoic
acid
b) N (3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzoic acid
c) N [4-Difluoromethoxy-3-(3-tetrahydrofuryloxy)phenyl]-N (3-pyridylmethyl)-3-
aminobenzoic acid
d) N 3,4-Bis(difluoromethoxy)phenyl)-N (3-pyridylmethyl)-3-aminobenzoic acid -
e) N [4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N (3-pyridylmethyl)-3-
aminobenzoic acid
f) N (3-Cyclopropylmethoxy-4-methoxyphenyl)-N (3-pyridylmethyl)-4-aminobenzoic
acid
g) N (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzoic acid
h) N (3-Cyclopentyloxy-4-methoxyphenyl)-3-aminolienzoic acid
i) N [3-(4-Chlorophenyl)prop-1-yloxy-4-methoxyphenyl]-N (3-pyridylmethyl)-3-
aminobenzoic acid
j) N (3-Cyclopropylmethoxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-aminobenzoic
acid
k) N [3-(2-Indanyloxy)-4-methoxyphenyl]-N (3-pyridylmethyl)-3-aminobenzoic
acid
1) N [4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N (3-pyridylmethyl)-3-
aminobenzoic
acid
m) N [4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N (3-pyridylmethyl)-3-
aminobenzoic acid
n) N [3-(2-Methoxyethoxy)-4-methoxyphenyl]-N (3-pyridylmethyl)-3-aminobenzoic
acid
o) N [4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N (3-pyridylmethyl)-3-
aminobenzoic acid
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EXAMPLE 6
N (3-Cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-2-aminobenzoic acid
Tert-Butyl N (3-cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-2
aminobenzoate (60 mg, 0.13 mmol) was taken up in 2~mL 98% formic acid and
heated at
40 °C for 4 h. The formic acid was removed in vacuo and the residue was
loaded onto a
column of silica gel (RediSep, 4.2 g). The product was eluted with a linear
gradient from
40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 min to yield 16 mg of
product
as a brown solid. 1H NMR (CDC13) b 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H), 8.10
(d, 1H, J =
7.8); 7.67 (d, 1H, J = 7.8 Hz), 7.56 (m, 1H), 7.40-7.20 (m, 3H), 6.75 (d, 1H,
J = 8.7), 6.57
(d, 1H, J = 8.7), 6.47 (s, 1H), 4.72 (s, 2H), 4.54 (p, 1H, J = 4.3), 3.77 (s,
3H), 1.80-1.60
(m, 6H), 1.60-1.40 (m, 2H). .
The following compounds were prepared in a similar manner as described above:
a) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-aminobenzoic
acid
b) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-6-aminonicotinic
acid
EXAMPLE 7
3-Cyclopropylmethyloxy-4-difluoromethoxy-N (3-pyridylmethyl)-4'-
(2H-tetrazol-5-yl)diphenylamine
3-Cyclopropylmethoxy-4-difluoromethoxy-N (3-pyridylmethyl)-4'-[2-(2-
tetrahydropyranyl)-2H-tetrazol-5-yl]diphenylamine (1.5 g, 0.26 mmol) was
dissolved in
THF (5 mL) and 3 mL of 1N HC1 was added. After 6 h at room temperature, the
mixture
was neutralized to pH = 5 with saturated aqueous sodium bicarbonate and
extracted with
EtOAc (3 x 50 mL). The EtOAc extracts were combined, washed with brine (50
mL),
dried (MgS04), and concentrated in vacuo. The crude residue was loaded onto a
RediSep
column (10 g, silica gel) and the product was eluted using a linear gradient
from 0%
MeOH in EtOAc to 5% MeOH in EtOAc over 20 min to give 0.96 g of product as a
white
powder. 'H NMR (CD30D) b 8.55 (s, 1H), 8.43 (d, 1H, J = 4.9 Hz), 7.65 (d, 1H,
8.0 Hz),
7.21 (dd, 1H, J = 4.9 Hz, 8.0 Hz), 7.18 (d, 1H, J = 8.9 Hz), 7.10-6.90 (m,
3H), 6.87 (dd,
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1H, J = 8.6 Hz, 2.5 Hz); 6.75 (t, 1H, J = 75.5 Hz), 5.14 (s, 2H), 3.82 (d, 2H,
J = 6.9 Hz),
1.23 (m, 1H), 0.60 (m, 2H), 0.33 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-4'-(2H-tetrazol-5-
yl)diphenylamine
b) 3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-3'-(2H-tetrazol-5-
yl)diphenylamine
c) 4-Methoxy-N (3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5-
yl)diphenylamine
d) 3-Cyclopropylmethyloxy-4-methoxy-N (3-pyridylmethyl)-4'-(2H-tetrazol-5-
yl)diphenylamine
e) 4-Difluoromethoxy-N (3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-
tetrazol-
5-yl)diphenylamine
f) 3-Cyclopentyloxy-4-difluromethoxy-N (3-pyridylmethyl)-4'-(2H-tetrazol-5-
yl)diphenylamine
g) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N (f-pyridylmethyl)-3'-(2H-
tetrazol-5-
yl)diphenylamine
h) Bis-3,4-difluoromethoxy-N (3-pyridylmethyl)-4'-(2H-tetrazol-5-
yl)diphenylamine
EXAMPLE 8 (Method A)
3-Cyclopentyloxy-4-methoxydiphenylamine
Method A. (Ref. Chan, D.M.T.; Monaco, K.L.; Wang, R.P.; Winters, M.P.,
Tetrahedron Lett., 1998, 39, 2933-2936.). A slurry of 207 mg of 4-methoxy-3-
cyclopentyloxyaniline, 280 mg of phenylboronic acid, 182 mg of Cu(OAc)2, 280
~L of
Et3N and 4.0 mL of CHZCIz was stirred for 20 h at room temp. The black mixture
was
filtered through silica eluting with CHzCl2, concentrated, and purified by
chromatoghraphy over Si02 using EtOAc/Hexanes (15/85) as eluant to provide 75
mg of
the desired product. 1H NMR (CDC13) 8 7.26-7.20 (m, 2H), 6.94-6.63 (m, 6H),
5.50 (s,
1H), 4.71 (m, 1H), 3.82 (s, 3H), 1.89-1.54 (m, 8H).
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The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-3',4-dimethoxydiphenylamine .
b) 3'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine
c) 3-Cyclopentyloxy-4-methoxy-3'methyldiphenylamine
d) 3-Cyclopentyloxy-4'-fluoro-4-methoxydiphenylamine
e) 3-Cyclopentyloxy-4-methoxy-4'-vinyldiphenylamine
f) 3'-Cyano-3-cyclopentyloxy-4-methoxydiphenylamine
g) 4'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine
h) 3-Cyclopentyloxy-4,4'-dimethoxydiphenylamine
i) 3-Cyclopentyloxy-4-methoxy-2'-methyldiphenylamine
j) 3-Cyclopentyloxy-4-methoxy-4'-methyldiphenylamine
k) 2'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine
1) 3-Cyclopentyloxy-2',4-dimethoxydiphenylamine
m) 3-Cyclopentyloxy-4-methoxy-3'-trifluoromethyldiphenylamine
n) 3-Cyclopentyloxy-4-methoxy-4'-trifluoromethyldiphenylamine
o) 3-Cyclopentyloxy-2',5'-dimethyl-4-methbxydiph~nylamine
EXAMPLE 8 (Method B)
3-Cyclopentyloxy-4-methoxydiphenylamine
Method B (Angerw Chem. Int. Ed., 1995, 34(17), 1348-1351.) A mixture of 207
mg of 3-cyclopentyloxy-4-methoxyaniline, 204 mg of iodobenzene, 115 mg of
NaOtBu,
9 mg of Pd2(dba)3, 12 mg of P(o-tol)3 and' 7 mL of toluene was combined and
warmed
with stirring to 100 °C for 4h. The mixture was cooled to room temp,
diluted with 25 mL
of EtOAc and washed with 10 mL of HzO, 10 mL of brine, dried (MgS04) and
concentrated. The residue was purified by chromatography over SiOz using
EtOAc/hexanes (S/95) as eluant to provide 84 mg of the desired product.
The following compounds were prepared in a similar manner as described above:
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a) 3-Cyclopentyloxy-4-methoxy-2',4'-dimethyldiphenylamine
b) 3-Cyclopentyloxy-2',5'-dimethyl-4-methoxydiphenylamine
c) 3-Cyclopentyloxy-2',3'-dimethyl-4-methoxydiphenylamine
d) 3-Cyclopentyloxy-3',4'-dimethyl-4-methoxydiphenylamine
e) 3-Cyclopentyloxy-3',4'-methylenedioxydiphenylamine
f) 4'-tert-Butyl-3-cyclopentyloxy-4-methoxydiphenylamine
g) 3-Cyclopentyloxy-3',4'-dichloro-4-methoxydiphenylamine
h) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxydiphenylamine
EXAMPLE 8 (Method C)
3-Cyclopentyloxy-2',4,5'-trimethoxydiphenylamine
Method C. To a mixture of Pd(dppfJClz (0.025 mmol, 5mo1%), dppf (0.075 mmol,
3dppf/Pd) and NaOtBu (0.70 mmol, 1.4 equivalents) and 1.0 mL THF was added 1-
bromo-2,5-dimethoxybenzene (0.55 mmol, 1.1 equivalents) followed by 1.0 mL of
a
0.5M solution of 3-cyclopentyloxy-4-methoxyaniline in THF. The mixture was
heated to
60 °C for 3 hours and diluted with ether and washed with Hz0 and brine,
dried (MgS04),
and concentrated. The crude residue was purified by chromatography over silica
gel
(Biotage Flash 12) eluting with 15% EtOAc in hexanes:
The following compounds were prepared in a similar manner as described above:
a) N (3-Cyclopentyloxy-4-methoxyphenyl)-3-pyridylamine
b) 3-Cyclopentyloxy-2',4',4-trimethoxydiphenylamine
c) N (3-Cyclopentyloxy-4-methoxyphenyl)-2-pyridylamine
d) N (3-Cyclopentyloxy-4-methoxyphenyl)-8-quinolinylamine
e) N (3-Cyclopentyloxy-4-methoxyphenyl)-2-naphthylamine
f) N (3-Cyclopentyloxy-4-methoxyphenyl)-1-naphthylamine
g) 3-Cyclopentyloxy-4'-ethyl-4-methoxydiphenylamine
h) 3-Cyclopentyloxy-2'-fluoro-4-inethoxy-5'-methyldiphenylamine
i) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-4'-methyldiphenylamine
j) N (3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrimidinylamine
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k) 3-Cyclopentyloxy-3';5_'-dichloro-4-methoxydiphenylamine
1) 3-Cyclopentyloxy-2'-ethyl-4-methoxydiphenylamine
m) 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxydiphenylamine
n) N (3-Cyclopentyloxy-4-methoxyphenyl)-4-isoquinolinylamine
o) N (3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrazinylamine
p) N (3-Cyclopentyloxy-4-methoxyphenyl)-5-pyrimidinylamine
q) N (3-Cyclopentyloxy-4-methoxyphenyl)-1-isoquinolinylamine
r) N (3-Cyclopentyloxy-4-methoxyphenyl)-3-quinolinylamine
s) N (3-Cyclopentyloxy-4-methoxyphenyl)-4-pyridylamine
t) N (3-Cyclopentyloxy-4-difluoromethoxyphenyl)-3-pyridylamine
u) N (3-Cyclopropylmethyloxy-4-methoxyphenyl)-3-pyridylamine
v) N-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenyl)-3-pyridylamine
w) N (4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-3-pyridylamine
x) N (4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-3-pyridylamine
y) Ethyl N (3-cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoate
z) 3-Cyclopentyloxy-4'-(N,N dimethylamino)-4-methoxydiphenylamine
aa) N (3-Cyclopentyloxy-4-methoxyphenyl)-3-(6-methoxypyridyl)amine
bb) Methyl N (3-cyclopentyloxy-4-methoxyphenyl)-2=aminonicotinate
cc) tert-Butyl N (3-cyclopentyloxy-4-methoxyphenyl)-6-aminonicotinate
dd) 2'-Amino-3-cyclopentyloxy-4-methoxydiphenylamine
ee) 3-Cyclopentyloxy-4-methoxy-3'-(1-phthalimido)diphenylamine
ff) 3-Cyclopentyloxy-4-methoxy-3'-[2-(2-tetrahydropyranyl)-2H-tetrazol-5-
yl]diphenylamine
EXAMPLE 9 (Method A)
3-Cyclopentyloxy-4-methoxy- N methyldiphenylamine
To a solution of 3-cyclopentyloxy-4-methoxydiphenylamine (70 mg, 0.25 mmol)
in 3 mL of THF at 0 °C was added 0.55 mL of 0.5 M KN(TMS)2 in toluene.
The solution
was stirred at 0 °C for 0.5 h and 2.0 equivalents of iodomethane was
added and the
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reaction mixture was warmed to room temperature. Upon reaction completion as
indicated by TLC, 10 mL of EtOAc was added and the mixture was washed with 3
mL of
HzO, 3 mL of brine, dried (MgSOa) and concentrated. The crude residue was
purified by
column chromatography (Biotage flash 12) using S% EtOAc in hexanes as eluant.
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-N ethyl-4-methoxydiphenylamine
b) 3-Cyclopentyloxy-4-methoxy-N (1-propyl)diphenylamine
c) 3-Cyclopentyloxy-4-methoxy-N [1-(3-phenpropyl)]diphenylamine
d) N Benzyl-3-cyclopentyloxy-4-methoxydiphenylamine
e) 3-Cyclopentyloxy-4-methoxy-N (4-pyridylmethyl)diphenylamine
f) 3-Cyclopentyloxy-4-methoxy-N (2-pyridylmethyl)diphenylamine
g) 3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
h) 3-Cyclopentyloxy-4-methoxy-N [3-(3-pyridyl)-1-propyl]diphenylamine
i) N (3-Cyclopentyloxy-4-methoxyphenyl)-N ethyl-4-isoquinolinylamine
j) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-benzyl-4-isoqu'inolinylamine
k) N (3-Cyclopentyloxy-4-methoxyphenyl)-1V methyl-4-isoquinolinylamine
1) N (3-Cyclopentyloxy-4-methoxyphenyl)-N propyl-4-isoquinolinylamine
m) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (4-isoquinolinyl)-N (4-
pyridylmethyl)amine
n) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (4-isoquinolinyl)-N (3-
pyridylmethyl)amine
o) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-N (S-
pyrimidinyl)amine
p) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (2-pyrazinyl)-N (3-
pyridylmethyl)amine
q) N (3-Cyclopentyloxy-4-methoxyphenyl)-N (2-pyridyl)-N (3-pyridylmethyl)amine
r) N (3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N (3-pyridylmethyl)amine
s) N (3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-pyridyl)-N (3-pyridylmethyl)amine
t) tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-6-
aminonicotinate
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u) N (3-Cyclopropylmethoxy-4-methoxyphenyl)-N (3-pyridyl)-N-(3- -
pyridylmethyl)amine
v) N (4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N (3-pyridyl)-N (3-
pyridylmethyl)amine
w) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N (3-pyridyl)-N (3-
pyridylmethyl)amine
x) N (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N (3-pyridyl)-N (3-
pyridylmethyl)amine
y) N (4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N (3-pyridyl)-N-(3-
pyridylmethyl)amine .
z) N (4-Chloro-3-pyridylmethyl)-N (3-cyclopentyloxy-4-methoxyphenyl)-N (2-
pyridyl)amine ,
aa) N (3-cyclopentyloxy-4-methoxyphenyl)-N (4-methyl-3-pyridylmethyl)-N (2-
pyridyl)amine
bb) 3-Cyclopentyloxy-4-methoxy-N (2-thiazolylmethyl)diphenylamine
cc) N (2-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxydiphenylamine
dd) N (6-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxydiphenylamine
EXAMPLE 9 (Method B)
N 4-Chloro-3-pyridylmethyl)-N (3-cyclopentyl-4
methoxyphenyl)-N (2-pyridyl)amine
To a solution of (3-cyclopentyloxy-4-methoxyphenyl)-2-pyridylamine (30 mg,
0.10 mmol) and 4-chloropicolyl chloride hydrochloride (50 mg, 0.25 mmol) was
dissolved in DMF (1 mL) and sodium hydride (50 mg of a 60% mineral oil
dispersion,
1.3 mmol) was added in small portions. After stirring for 1 h at room
temperature, the
mixture was poured into 25 mL ice water. The mixture was extracted with EtOAc
(2 x
15 mL) and the EtOAc extracts were combined, washed with brine (15 mL), dried
(MgS04), and concentrated in vacuo. The crude residue was loaded onto a
RediSep
column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in
hexanes to give
20 mg of product as a yellow crystalline solid. 1H NMR (CDCI3) ~ 8.61 (s, 1H),
8.34 (d,
1H, J = 5.3 Hz), 8.17 (d, 1H, 5.0 Hz), 7.33 (m, 1.H), 7.25 (m, 1H), 6.83 (d,
1H, J = 8.5),
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6.75 (d, 1 H, J = 8.5), 6.71 (s; 1 H), 6.62 (m, 1 H), 6.42 (d, 1 H, J = 8.6),
5.31 (s, 2H), 4.63
(p, '1H, J = 4.12 Hz), 3.83 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3,4-Bis(difluoromethoxy)-N (4-chloro-3-pyridylmethyl)-3'-(2-
(tetrahydropyran-2-
yl)-2H-tetrazol-5-yl)diphenylamine
b) 3,4-Bis(difluoromethoxy)-N (4-methyl-3-pyridylmethyl)-3'-(2-
(tetrahydropyran-2-
yl)-2H-tetrazol-5-yl)diphenylamine
EXAMPLE 10
3-Cyclopentyloxy-4-methoxyanilino-N (3-pyridylmethyl)-N 3-(4-pyridyl)benzamide
To a solution of N (3-cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzoic acid (20 mg, 0.05 mmol) and pyBOP (40 mg. 0.08 mmol) in CHZC12 (2
mL) at room temperature was added diisopropylethylamine (20 L, 0.11 mmol).
After
stirring for 15 min, 4-aminopyridine (15 mg, 0.15 mmol) was added and the
mixture was
allowed to stir 16 h. The mixture was diluted with EtOAc (25 mL) and washed
with
water (2 x 15 mL) and brine (15 mL), dried (MgS04),'and concentrated in vacuo.
The
crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the
product was
eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in
hexanes over
15 min to give 22 mg of product. 1H NMR (CDCl3) 8 8.70-8.40 (m, 3H), 8.24 (s,
1H),
7.72 (d, 1H, 9.0 Hz), 7.68-7.55 (m, 2H), 7.30-7.20 (m, 1H), 6.88 (d, 2H, J =
8.5), 6.80-
6.65 (m, 3H), 4.98 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.86 (s, 3H), 1.86-1.70
(m, 6H),
1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-(3-Cyclopentyloxy-4-methoxyanilino)-N (3-pyridylmethyl)-N 3-[3-(N,N
dimethylamino)prop-1-yl]benzamide
b) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-1-ylcarbonyl)-N (3-
pyridylmethyl)diphenylamine
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c) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N (3-
pyridylmethyl)diphenylamine
d) 3-Cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N (3-
pyridylmethyl)-3-(3-tetrahydrofuranyloxy)-diphenylamine
EXAMPLE 11
The following compounds were prepared in a similar fashion as described in
Example
2:
a) 4'-Amino-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
b) 3'-Amino-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
c) 3'-Amino-3-cyclopropylmethoxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
d) 3'-Amino-4-methoxy-N (3-pyridylmethyl)-3-[(3R)-
tetrahydrofuryloxy]diphenylamine
EXAMPLE 12
3-Cyclopentyloxy-4'-methanesulfonyl~mino-4-methoxy-N
(3-pyridylmethyl)-diphenylamine
To a solution of 4'-amino-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-
diphenylamine (47 mg, 0.12 mmol) in CHzCl2 (2 mL) at room temperature was
added
pyridine (20 microliters, 0.24 mmol) followed by methanesulfonyl chloride (15
microliters, 0.18 mmol) and the mixture was allowed to stand at room
temperature for 16
h. The mixture was diluted with ether (50 mL) and washed with water (25 mL)
and brine
(25 mL), dried (MgS04), and concentrated. The crude residue was purified by
flash
column chromatography (4:2 g RediSep column, silica gel) eluting with a linear
gradient
from 45% EtOAc in hexanes to 60% EtOAc in hexanes over 20 min to yield 41 mg
of
product. ~H NMR (CDC13) 8 8.51 (s, 1H), 8.41 (d, 1H, J = 4.8 Hz), 7.56 (d, 1H,
7.9 Hz),
7.16 (m, 1H), 6.98 (d, 2H, J = 9.0 Hz), 6.80-6.60 (m, 6H), 4.82 (s, 2H), 4.56
(p, 1H, J =
4.0 Hz), 3.75 (s, 3H), 2.86 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).
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The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N (3-
pyridylmethyl)diphenylamine
b) 3-Cyclopentyloxy-4-methoxy-3'-(1-propanesulfonylamino)-N (3-
pyridylmethyl)diphenylamine
c) 3'-(1-Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
d) 3'-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
e) 3'-Acetaniido-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
f) 3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N (3-
pyridylmethyl)diphenylamine
g) 3-Cyclopentyloxy-4-methoxy-4'-(1-propanesulfonylamino)-N (3-
pyridylmethyl)diphenylamine
h) 3-Cyclopropylmethoxy-3'-ethanesulforiylamino-4-methoxy-N (3-
pyridylmethyl)diphenylamine
i) 4-Difluoromethoxy-3'-ethanesulfonylamirio-N (3-pyi-idylmethyl)-3-[(3R)-
tetrahydrofuryloxy]diphenylamine
EXAMPLE 13
3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N (3-pyridylmethyl)diphenylamine
To a solution of Ethyl N (3-cyclopentyloxy-4-methoxyphenyl)-N (3-
pyridylmethyl)-3-aminobenzoate (50 mg, 0.11 mmol) in THF (S mL) at 0 °C
was added
drop-wise, with stirnng, 2.5M diisobutylaluminum hydride in toluene (0.4 mL,
1.00
mmol). The mixture was stirred at 0 °C for 1 h and the excess
diisobutylaluminum
hydride was quenched by adding 5 drops of EtOAc to the mixture. The mixture W
as
concentrated and the residue was partitioned between CHZC12 (50 mL) and water
(50
mL). The layers were separated and the aqueous layer was extracted with CHZC12
(2 x 10
mL). The organic extracts were combined and washed with brine (50 mL), dried
(MgS04), and concentrated. The crude residue was purified by flash column
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chromatography (4.2 g RediSep column, silica gel) eluting with 300 mL 50%
EtOAc in
hexanes then 100% EtOAc to give 15 mg of product. 1H NMR (CDCl3)~8 8.51 (s,
1H),
8.40 (br, 1H), 7.58 (d, 1H, 7.9 Hz), 7.25-7.05 (m, 3H), 6.80-6.60 (m, SH),
4.85 (s, 2H),
4.56 (p, 1H, J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-
1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N (3-
pyridylmethyl)diphenylamine
EXAMPLE 14
3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-4'-(2H-tetrazol-5
yl)diphenylamine
To a solution of N (3-cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzonitrile (100 mg, 0.25 mmol) in DMF (3 mL) was added NaN3 (163 mg,
2.5
mmol) and NH4C1 (135 mg, 2.5 mmol) and the mixture was stirred at 120
°C for 6 h. The
mixture was cooled to room temperature, diluted with water (50 mL) and
extracted with
EtOAc (2 x 25 mL). . The EtOAc extracts were combined, washed with water (25
mL)
and brine (25 mL), dried (MgS04), and concentrated in vacuo. The residue was
loaded
onto a RediSep column (4.2 g, silica gel) and eluted with a linear gradient
from 50% to
75% EtOAc in hexanes to yield 12 mg of product. 'H NMR (CDC13) 8 12.50 (br,
1H),
8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, 1H, 7.8 Hz),
7.36 (m, 1H),
6.80-6.60 (m, SH), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-
1.70 (m, 7H),
1.65-1.45 (m, 2H).
EXAMPLE 15
3-Cyclopentyloxy-4-methoxy-4'-(4-methyl-1-piperazinylmethyl)-
N (3-pyridylmethyl)diphenylamine
To a solution of 3-cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-1-
ylcarbonyl)dipheylamine ( 100 mg, 0.20 mmol) in THF (5 mL) was carefully
added, with '
stirnng, lithium aluminum hydride (50 mg, 1.3 mmol). The mixture was stirred
for 15
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min and a few drops ofEtOAc was carefully added to quench the excess hydride.
Water
(SO mL) and CHZC12 (50 mL) were added and the mixtures were filtered through
Celite.
The CHZCIZ layer was separated, washed with brine (25 mL), dried (MgS04), and
concentrated in vacuo. The crude residue was purified on an ISCO RediSep
column.(4.2
g, silica) eluting with a gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc
to
yield 60 mg of product as a light yellow oil. 1H NMR (CDC13) 8 8.59 (s, 1H),
8.47 (d;
1H, J = 4.8 Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 (dd, 1H, J = 4.8 Hz, 7.9 Hz), 7.11
(d, 2H, J =
8.6 Hz), 6.82-6.73 (m, 3H), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J =
4.12 Hz),~
3.82 (s, 3H), 3.41 (s, 2H), 2.75-2.20 (m, 8H), 2.27 (s, 3H), 1.86-1.70 (m,
6H), 1.65-1.45
(m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-3'-(4-methyl-1-piperazinylmethyl)N (3-
pyridylmethyl)diphenylamine
EXAMPLE 16
3'-Aminomethyl-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
To a solution of N (3-cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzonitrile (50 mg, 0.12 mmol) in THF (5 mL) was carefully added, with
stirnng,
lithium aluminum hydride (20 mg, 0.52 mmol). The mixture was stirred for 4 h
and a
few drops of water were carefully added to quench the excess hydride. Water
(SO mL)
and CHzCIz (50 mL) were added and the mixtures were filtered through Celite.
The
CHzCIZ layer was separated, washed with brine (25 mL), dried (MgS04), and
concentrated in vacuo. The crude residue was purified on an ISCO RediSep
column (4.2
g, silica) eluting with 10% MeOH in EtOAc to yield 20 mg of product. 1H NMR
(CDCl3)
8 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-
6.65 (m, 6H),
4.94 (s, 2H), 4.63 (p, 1H, J = 4.1 Hz), 3.83 (s, 3H), 3.75 (m, 2H), 2.29 (br,
2H), 1.86-1.70
(m, 6H), 1.65-1.45 (m, 2H).
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EXAMPLE 17
3-Hydroxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
To a solution of 3-(tert-butyldimethylsiloxy)-N (3-pyridylmethyl)-4
methoxydiphenylamine (1.20 g, 2.85 mmol) in THF (40 mL) at 0 °C, was
added 1.0M
tetrabutylammonium fluoride in THF (10 mL, 10 mmol). The mixture was stirred
at 0 °C
for 30 min. Water (50 mL) was added and the mixture was extracted with ether
(3 x 25
mL). The ether extracts were combined and v~ashed with water (3 x 25 mL) and
brine
(25 mL), dried (MgSOa), and concentrated in vacuo. The residue was triturated
with
hexanes and collected by vacuum filtration to give 0.85 g of product. 1H NMR
(CDCl3) 8
8.58 (s, 1H), 8.46 (br, 1H), 7.67 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 3H), 6.90-
6.65 (rn, 5H),
6.64 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.53 (br, 1H), 4.92 (s, 2H), 3.86 (s, 3H).
The following compounds were prepared in a similar manner as described above:
a) 3'-Chloro-3-hydroxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
b) Ethyl lV (3-hydroxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-aminobenzoate
EXAMPLE 18 (Method B)
The following compounds were prepared in a similar manner as described in
Example
1B:
a) 3-[3-(4-Chlorophenyl)prop-1-yloxy]-4-methoxy-N (3-
pyridylmethyl)diphenylamine
b) 3-[2-(4-Chlorophenyl)ethoxy]-4-methoxy-N (3-pyridylmethyl)diphenylamine
c) 4-Methoxy-3-(4-phenoxybut-1-yl)oxy-N (3-pyridylmethyl)diphenylamine
d) 4-Methoxy-N (3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
e) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-1-yl]oxy-N (3-
pyridylmethyl)diphenylamine
f) 4-Methoxy-3-[3-(4-pyridyl)prop-1-yl]oxy-N (3-pyridylmethyl)diphenylamine
g) 4-Methoxy-3-[2-(4-methoxyphenyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
h) 4-Methoxy-3-(4-phenylbut-1-yl)oxy-N (3-pyridylmethyl)diphenylamine
i) 4-Methoxy-3-[4-(4-methoxyphenyl)but-1-yl]oxy-N (3-
pyridylmethyl)diphenylamine
j) 4-Methoxy-3-[4-(4-nitrophenyl)but-1-yl]oxy-N (3-pyridylmethyl)diphenylamine
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k) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N (3-pyridylmethyl)diphenylamine
1) 4-Methoxy-3-[2-(4-pyridyl)ethoxy]-N (3-pyridylmethyl)diphenylamine
m) 4-Methoxy-3-[3-(2-pyridyl)prop-1-yl]oxy-N (3-pyridylmethyl)diphenylamine
n) 4-Methoxy-3-(2-methoxyethoxy)-N (3-pyridylmethyl)diphenylamine
o) 3-Cyclopropylmethoxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
p) 4-Methoxy-3-(1-methylpyrrolidin-3-yl)oxy-N (3-pyridylmethyl)diphenylamine
q) 4-Methoxy-3-(1-methylpiperidin-4-yl)oxy-N (3-pyridylmethyl)diphenylamine
r) 4-Methoxy-N (3-pyridylmethyl)-3-[(3,5~-tetrahydrofuryloxy]diphenylamine
s) 4-Methoxy-N (3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine
t) 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N (3-
pyridylmethyl)diphenylamine
u) 3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N (3-
pyridylmethyl)diphenylamine
v) 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N (3-pyridylmethyl)diphenylamine
w) 3'-Chloro-4-methoxy-N (3-pyridylmethyl)-3-[(3R)-
tetrahydrofuryloxy]diphenylamine
x) 3-Cyclohexyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
y) 3-Cycloheptyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
z) 3-(2-Cyclopropylethoxy)-4-methoxy-N (3-pyridylmethyl)diphenylamine
aa) 3-Cyclopentylmethoxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
bb) Ethyl N [3-(4-chlorophenyl)prop-1-yloxy-4-methoxyphenyl]-N (3-
pyridylmethyl)-3-
aminobenzoate
cc) Ethyl N (3-cyclopropylmethoxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-
aminobenzoate
dd) Ethyl N (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N (3-pyridylmethyl)-
3-
aminobenzoate
ee) Ethyl N [3-(2-indanyloxy)-4-methoxyphenyl]-N (3-pyridylmethyl)-3-
aminobenzoate
ff) Ethyl N [4-methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N (3-pyridylmethyl)-3-
aminobenzoate
gg) Ethyl N [4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N (3-pyridylmethyl)-
3-
aminobenzoate
hh) Ethyl N [3-(2-methoxyethoxy)-4-methoxyphenyl]-N (3-pyridylmethyl)-3-
aminobenzoate
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ii) Ethyl N [4-methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N (3-pyridylmethyl)-3-
aminobenzoate
EXAMPLE 18 (Method C)
The following compounds were prepared in a similar manner as described in
Example
8A by coupling a phenol with a boronic acid rather than coupling an aniline
with a
boronic acid:
a) 4-Methoxy-3-(4-methoxyphenoxy)-N (3-pyridylmethyl)diphenylamine
b) 4-Methoxy-3-phenoxy-N (3-pyridylmethyl)diphenylamine
c) 4-Methoxy-3-(4-methylphenoxy)-N (3-pyridylmethyl)diphenylamine
d) 3-(4-Chlorophenoxy)-4-methoxy-N (3-pyridylmethyl)diphenylamine
e) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N (3-pyridylmethyl)diphenylamine
EXAMPLE 19
The following compounds were prepared in a similar manner as described in
Example
17:
a) 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
b) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
c) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
EXAMPLE 20 (Method A)
The following compounds were prepared in a similar manner as described in
Example
1A:
a) 3'-(2-Bromoethoxy)-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
EXAMPLE 20 (Method B)
The following compounds were prepared in a similar manner as described in
Example
1B:
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a) 3-Cyclopentyloxy-4'-(2-methoxyethoxy)-4-methoxy-N (3-
pyridylmethyl)diphenylamine
b) 3-Cyclopentyloxy-4'-(3-methyl-1-butoxy)-4-methoxy-N (3-
pyridylmethyl)diphenylamine
c) 3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-4'-[(3,5~-
tetrahydrofuranyloxy]-
diphenylamine
d) 3-Cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)-4'-[(3R)-
tetrahydrofuranyloxy]-
diphenylamine
e) 3-Cyclopentyloxy-4'-cyclopropylmethoxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
f) 4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
g) 4'-Cyclopentylethoxy-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
h) 3-Cyclopentyloxy-4-methoxy-4'-(1-methylpiperidin-4-yloxy)-N (3-
pyridylmethyl)diphenylamine
i) 3-Cyclopentyloxy-4-methoxy-4'-(1-methylpyrrolidin-3-yloxy)-N (3-
pyridylmethyl)diphenylamine
j) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-methylpyrrolidin-2-yl)ethoxy]-N (3-
pyridylmethyl)diphenylamine
k) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-pyrrolidinylethoxy)-N (3-
pyridylmethyl)diphenylamine
1) 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyl)methoxy)-N (3-
pyridylmethyl)diphenylamine
m) 3-Cyclopentyloxy-4-methoxy-4'-[3-(1-methylpiperidinyl)methoxy]-N (3-
pyridylmethyl)diphenylamine
n) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-methylpiperidinyl)methoxy]-N (3-
pyridylmethyl)diphenylamine
o) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N (3-
pyridylmethyl)diphenylamine
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p) 4'-[1-(3-Bromopropyl)oxy]-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
q) 3-Cyclopentyloxy-4-methoxy-4'-[2-(N phthalimido)ethoxy]-N (3-
pyridylmethyl)diphenylamine
EXAMPLE 21
3-Cyclopentyloxy-4-methoxy-3'-[2-(1-piperidinyl)ethoxy]-N (3-
pyridylmethyl)diphenylamine
To a solution of 3'-(2-bromoethoxy)-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine (17 mg, 0.03 mmol) in acetonitrile (1 mL) was
added
potassium carbonate (25 mg, 0.18 mmol) and piperidine (5 ~,L, 0.05 mmol) and
the
mixture was stirred at 60 °C for 4 h. The mixture was partitioned
between water (SO mL)
and EtOAc (50 mL). The layers were separated and the organic layer was washed
with
water (25 mL) and brine (25 mL), dried (MgS04), and concentrated in vacuo. The
residue was loaded on an ISCO RediSep column (4.2g, silica) and the column was
eluted
with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 11
mg
of product. 1H NMR (CDC13) 8 8.59 (s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H,
8.2 Hz),
7.26-7.20 (m, 1 H), 7.06 (t, 1 H, J = 8.6 Hz), 6.81 (d, 1 H, J = 9.2 Hz), 6.75-
6.68 (m, 2H),
6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p, 1H, J = 4.1 Hz), 4.00 (t, 2H, J =
6.2 Hz), 3.84 (s,
3H), 2.71 (t, 2H, J = 6.2 Hz), 2.47 (m, 4H), 1.90-1.70 (m, 6H), 1.86-1.70 (m,
6H), 1.65-
1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-3'-[2-(1-imidazolyl)ethoxy]-4-methoxy-N (3-
pyridylmethyl)diphenylamine
b) 3-Cyclopentyloxy-4-methoxy-3'-[2-(1-methylpiperazin-4-yl)ethoxy]-N (3-
pyridylmethyl)diphenylamine
c) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-methylpiperazin-4-yl)propoxy]-N (3-
pyridylmethyl)diphenylamine
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d) 3-Cyclopentyloxy-4-methoxy-4'-[3-(1-methylpiperazin-4-yl)propoxy]-N (3-
pyridylmethyl)diphenylamine
e) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-morpholin-4-ylethylamino)propoxy]-N (3-
pyridylmethyl)diphenylamine
f) 4-Methoxy-3-(2-phenoxyethoxy)-N (3-pyridylmethyl)diphenylamine
g) 3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-N (3-pyridylmethyl)diphenylamine
h) 4-Methoxy-3-(2-pyrrolidin-1-yl)ethoxy-N (3-pyridylmethyl)diphenylamine
i) 4-Methoxy-3-(2-(4-methylpiperazin-1-yl)ethoxy)-N (3-
pyridylmethyl)diphenylamine
j) 3-[2-(4-Chlorophenylamino)ethoxy]-4-methoxy-N (3-
pyridylmethyl)diphenylamine
EXAMPLE 22
4'-Aminoethoxy-3-cyclopentyloxy-4-methoxy-N (3-pyridylmethyl)diphenylamine
To a solution of N (3-pyridylmethyl)-3'-[2-(2-phthalimido)ethoxy]-3-
cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 mmol) in MeOH (5 mL) was
added hydrazine hydrate (1.0 mL, 20 mmol). After 6 h at room temperature,
EtOAc was
added (50 mL) and the precipitate was filtered off. The filtrate was washed
with water
(25 mL) and brine (25 mL), dried (MgSOa), and concentrated in vacuo. The
residue was
loaded on an ISCO RediSep column (10 g, silica). The column was washed with
10%
MeOH in EtOAc (200 mL) and the product was eluted with 50% MeOH in EtOAc to
yield 0.21 g. 1H NMR (CDC13) b 8.55 (s, 1H), 8.42 (d, 1H, J = 3.8 Hz), 7.62
(d, 1H, 7.7
Hz), 7.20-7.10 (m, 1 H), 6.91 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.0 Hz),
6.70 (d, 1 H, J
= 8.6 Hz), 6.50-6.35 (m, 2H), 4.82 (s, 2H), 4.54 (p, 1H, J = 4.1 Hz), 3.90 (t,
2H, J = 6.1
Hz), 3.74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 (m, 2H).
EXAMPLE 23
The following compounds were prepared in a similar manner as described in
Example
12:
a) 3-Cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
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b) 3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
c) 3-Cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonylamino)ethoxy]-N (3-
pyridylmethyl)diphenylamine
d) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-propanesulfonylamino)ethoxy]-N (3-
pyridylmethyl)diphenylamine
e) 4'-[2-(1-Butanesulfonylamino)ethoxy]-3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine
EXAMPLE 24
In Vitro Measurement of Type 4 Phosphodiesterase Inhibition Activity
Human PDE4 was obtained from baculovirus-infected Sf~ cells that expressed the
recombinant enzyme. The cDNA encoding hPDE-4D6 was subcloned into a
baculovirus
vector. Insect cells (Sf~) were infected with the baculovirus and cells were
cultured until
protein was expressed. The baculovirus-infected cells were lysed and the
lysate was used
as source of hPDE-4D6 enzyme. The enzyme was partially purified using a DEAE
ion
exchange chromatography. This procedure can be repeated using cDNA encoding
other
PDE-4 enzymes.
Assay:
Type 4 phosphodiesterases convert cyclic adenosine monophosphate (CAMP) to
5'-adenosine monophosphate (S'-AMP). Nucleotidase converts 5'-AMP to
adenosine.
Therefore the combined activity of PDE4 and nucleotidase converts CAMP to
adenosine.
Adenosine is readily separated from cAMP by neutral alumina columns.
Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this
assay;
consequently, PDE4 inhibitors cause a decrease in adenosine.
Cell lysates (40 u1) expressing hPDE-4D6 were combined with 50 u1 of assay mix
and 10 u1 of inhibitors and incubated for 12 min at room temperature. Final
concentrations of assay components were: 0. 4 ug enzyme, l OmM Tris-HCl (pH
7.5),
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IOmM MgCl2, 3 uM cAMP, 0.002 U 5'-nucleotidase, and 3 x 104 cpm of [3H]CAMP.
The reaction was stopped by adding 100 p,1 of boiling SmN HCI. An aliquot of
75 ~l of
reaction mixture was transferred from each well to alumina columns
(Multiplate;
Millipore). Labeled adenosine was eluted into an OptiPlate by spinning at 2000
rpm for
2 min; 150 p,1 per well of scintillation fluid was added to the OptiPlate. The
plate was
sealed, shaken for about 30 min, and cpm of [3H]adenosine was determined using
a
Wallac Triflux~.
All test compounds are dissolved in 100% DMSO and diluted into the assay such
that the final concentration of DMSO is 0.1 %. DMSO does not affect enzyme
activity at
this concentration.
A decrease in adenosine concentration is indicative of inhibition of PDE
activity..
pICSO values were determined by screening 6 to 12 concentrations of compound
ranging
from 0.1 nM to 10,000 nM and then plotting drug concentration versus 3H-
adenosine
concentration. Nonlinear regression software (Assay Explorer) was used to
estimate
pICSO values.
- EXAMPLE 25 (Method A)
Passive Avoidance in Rats, an in vivo Test for Learning and Memory
The test was performed as previously described (Zhang, H.-T., Crissman, A.M.,
Dorairaj, N.R., Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology,
2000,
23, 198-204.). The apparatus (Model E10-16SC, Coulbourn Instruments,
Allentown, PA)
consisted of a two-compartment chamber with an illuminated compartment
connected to
a darkened compartment by a guillotine door. The floor of the darkened
compartment
consisted of stainless steel rods through which an electric foot-shock could
be delivered
from a constant current source. All experimental groups were first habituated
to the
apparatus the day before the start of the experiment. During the training, the
rat (Male
Sprague-Dawley (Harlan) weighing 250 to 350 g) was placed in the illuminated
compartment facing away from the closed guillotine door for 1 minute before
the door
was raised. The latency for entering the darkened compartment was recorded.
After the
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rat entered the darkened compartment, the door was closed and a 0.5 mA
electric shock
was administered for 3 seconds. Twenty-four hours later, the rat was
administered 0.1
mg/kg MK-801 or saline, 30 minutes prior to the injection of saline or test
compound
(dosed from 0.1 to 2.5 mg/kg, i.p.), which was 30 minutes before the retention
test
started.. The rat was again placed in the illuminated compartment with the
guillotine door
open. The latency for entering the darkened compartment was recorded for up to
180
seconds, at which time the trial was terminated.
All data were analyzed by analyses of variance (ANOVA); individual
comparisons were made using Kewman-Keuls tests. Naive rats required less than
30
seconds, on average, to cross from the illuminated compartment to the darkened
compartment. However, 24 hours after the electric shock exposure, most rats
pretreated
with vehicle did not re-enter the darkened compartment; the average latency
was
increased up to 175 seconds (p < 0.001). Pretreatment with MK-801 (0.1 mg/kg)
markedly reduced this latency when compared to the vehicle (p<0.001 ). This
amnesic
effect of MK-801 is reversed in a statistically significant manner by actual
test
compounds in a dose-dependent fashion (e.g., 3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl) diphenylamine, Effective dose range = 0.5 to 2.5 mg/kg, i.p.;
and N (3-
cyclopentyloxy-4-methoxyphenyl)-N (3-pyridylmethyl)-3-aminobenzoic acid,
effective
dose range = 0.1 to 2.5 mg/kg, ip).
EXAMPLE 25 (Method B)
Radial arm maze task in Rats, an in vivo Test for Learning and Memory
The test was performed as previously described (Zhang, H.-T., Crissman, A.M.,
Dorairaj, N.R., Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology,
2000,
23, 198-204.). Five days after initial housing, rats (male Sprague-Dawley
(Harlan)
weighing 250 to 350 g) were placed in the eight-arm radial maze (each arm was
81
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60x 1 Ox 12 cm high; the maze was elevated 70 cm above the floor) for
acclimation for two
days. Rats were then placed individually in the center of the maze for 5
minutes with
food pellets placed close to the food wells, and then, the next day, in the
wells at the end
of the arms; 2 sessions a day were conducted. Next, four randomly selected
arms were
then baited with one pellet of food each. The rat was restricted to the center
platform (26
cm in diameter) for 15 seconds and then allowed to move freely throughout the
maze
until it collected all pellets of food or 10 minutes passed, whichever came
first. Four
parameters were recorded: 1) working memory errors, i.e., entries into baited
arms that
had already been visited during the same trial; 2) reference memory errors,
i.e., entries
into unbaited arms; 3) total arm entries; and 4) the test duration (seconds),
i.e., the time
spent in the collection of all the pellets in the maze. If the working memory
error was
zero and the average reference memory error was less than one in five
successive trials,
the rats began the drug tests. MK-801 or saline was injected 15 minutes prior
to vehicle
or test agent, which was given 45 minutes before the test. Experiments were
performed
in a lighted room, which contained several extra-maze visual cues.
All data were analyzed by analyses of variance (ANOVA); individual
comparisons were made using Kewman-Keuls tests. Compared to control, MK-801
(0.1
mg/kg, i.p.) increased the frequencies of both working and reference memory
errors
(p<0.01). This amnesic effect of MK-801 on working memory is reversed in a
statistically significant manner by the administration of actual test
compounds in a dose-
dependent fashion (e.g., 3-cyclopentyloxy-4-methoxy-N (3-
pyridylmethyl)diphenylamine, Effective dose = 2.5 mg/kg, i.p.; p<0.01)
The preceding examples can be repeated with similar success by substituting
the
generically or specifically described reactants and/or operating conditions of
this
invention for those used in the preceding examples.
While the invention has been illustrated with respect to the production and of
particular compounds, it is apparent that variations and modifications of the
invention can
be made without departing from the spirit or scope of the invention.
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