U.S. patent application number 11/045956 was filed with the patent office on 2005-08-25 for aminotetralin-derived urea modulators of vanilloid vr1 receptor.
Invention is credited to Codd, Ellen, Dax, Scott L., Jetter, Michele, McDonnell, Mark, McNally, James J., Youngman, Mark.
Application Number | 20050187291 11/045956 |
Document ID | / |
Family ID | 29550146 |
Filed Date | 2005-08-25 |
United States Patent
Application |
20050187291 |
Kind Code |
A1 |
Codd, Ellen ; et
al. |
August 25, 2005 |
Aminotetralin-derived urea modulators of vanilloid VR1 receptor
Abstract
This invention is directed to vanilloid receptor VR1 ligands.
More particularly, this invention relates to
.beta.-aminotetralin-derived ureas that are potent antagonists or
agonists of VR1 which are useful for the treatment and prevention
of inflammatory and other pain conditions in mammals.
Inventors: |
Codd, Ellen; (Blue Bell,
PA) ; Dax, Scott L.; (Landenberg, PA) ;
Jetter, Michele; (Norristown, PA) ; McDonnell,
Mark; (Lansdale, PA) ; McNally, James J.;
(Souderton, PA) ; Youngman, Mark; (Warminster,
PA) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
29550146 |
Appl. No.: |
11/045956 |
Filed: |
January 28, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11045956 |
Jan 28, 2005 |
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10438477 |
May 15, 2003 |
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60381575 |
May 17, 2002 |
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Current U.S.
Class: |
514/521 ;
514/563; 514/595 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 333/32 20130101; A61P 11/14 20180101; A61P 35/00 20180101;
C07D 213/40 20130101; C07D 217/24 20130101; C07C 275/26 20130101;
A61P 13/00 20180101; C07D 237/28 20130101; C07D 239/74 20130101;
C07D 401/12 20130101; A61P 1/04 20180101; C07D 217/22 20130101;
C07D 333/20 20130101; C07C 335/14 20130101; C07C 2602/10 20170501;
A61P 25/02 20180101; C07D 233/64 20130101; A61P 11/06 20180101;
A61P 25/06 20180101; C07C 2601/02 20170501; C07D 405/12 20130101;
C07D 471/04 20130101; A61P 19/02 20180101; A61P 39/02 20180101;
A61P 43/00 20180101; C07C 275/28 20130101; C07D 217/02 20130101;
A61P 25/00 20180101; C07D 409/12 20130101; C07C 275/32 20130101;
A61P 1/00 20180101; C07D 307/52 20130101; C07D 317/58 20130101;
A61P 17/04 20180101; A61P 25/04 20180101; C07D 215/38 20130101;
C07D 217/08 20130101; A61P 11/00 20180101 |
Class at
Publication: |
514/521 ;
514/563; 514/595 |
International
Class: |
A61K 031/277; A61K
031/195; A61K 031/17 |
Claims
1-96. (canceled)
97. A method for preventing or treating a chronic-pain causing
disease or condition, an acute-pain causing disease or condition,
or a pulmonary dysfunction comprising the step of administering to
a mammal in need of such treatment a therapeutically effective
amount of a compound of formula 1: 30wherein: R.sub.1 is a
substituent independently selected from the group consisting of
hydrogen; hydroxy; fluoro; and chloro; and C.sub.1-8alkanyloxy; n
is an integer from 1 to 3; m is an integer from 0 to 3; R.sub.2 is
independently selected from the group consisting of hydrogen;
hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl; C.sub.1-8alkylidenyl;
C.sub.1-8alkylidynyl; fluoro; chloro; C.sub.3-8cycloalkanyl; phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanylo-
xy, fluorinated alkanyl, cyano, nitro, amino,
C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8 alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino; L is a direct bond, C.sub.1-8alkandiyl,
C.sub.2-8alkendiyl, C.sub.1-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
R.sub.3 is selected from the group consisting of naphthyl
substituted with hydroxyl; quinolinyl optionally substituted with
one or more substituents selected from the group consisting of
methyl and chloro; quinolinyl-N-oxide; isoguinolinyl optionally
substituted with one or more substituents selected from the group
consisting of methyl and chloro and isoguinolinyl-N-oxide; R.sub.4
is selected from the group consisting of hydrogen and
C.sub.1-8alkanyl; R.sub.5 is selected from the group consisting of
hydrogen and C.sub.1-8alkanyl; X is selected from the group
consisting of O and S; and enantiomers, diastereomers, tautomers,
solvates, and pharmaceutically acceptable salts thereof.
98. The method according to claim 97 wherein said disease or
condition causes inflammatory pain, burning pain, itch, urinary
incontinence, or chronic obstructive pulmonary disease, said method
comprising the step of administering to a mammal in need of such
treatment a therapeutically effective amount of a compound, salt or
solvate of claim 1.
99. The method for preventing according to claim 97 wherein the
disease or condition selected from the group consisting of
osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine,
headache, toothache, burn, sunburn, snake bite (in particular,
venomous snake bite), spider bite, insect sting, neurogenic
bladder, benign prostatic hypertrophy, interstitial cystitis,
urinary tract infection, cough, asthma, chronic obstructive
pulmonary disease, rhinitis, contact dermatitis/hypersensitiv- ity,
itch, eczema, anxiety, panic disorders, inflammatory bowel
diseases, pharyngitis, mucositis, enteritis, cellulites, peripheral
neuropathy, bilateral peripheral neuropathy, diabetic neuropathy,
postherpetic neuralgia, trigeminal neuralgia, causalgia, sciatic
neuritis, mandibular joint neuralgia, peripheral neuritis,
polyneuritis, stump pain, phantom limb pain, bony fractures,
post-operative ileus, irritable bowel syndrome, Crohn's Disease,
ulcerative colitis, cholecystitis, pancreatitis, postmastectomy
pain syndrome, oral neuropathic pain, Charcot's pain, reflex
sympathetic dystrophy, Guillain-Barre syndrome, meralgia
paresthetica, burning-mouth syndrome, optic neuritis, postfebrile
neuritis, migrating neuritis, segmental neuritis, Gombault's
neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,
geniculate neuralgia, glossopharyngial neuralgia, migrainous
neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary
neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital
neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine
neuralgia, supraorbital neuralgia, vidian neuralgia, sinus
headache, tension headache, labor, childbirth, intestinal gas,
menstrual cramps, cancer, and trauma, said method comprising the
step of administering to a mammal in need of such treatment a
therapeutically effective amount of a compound, salt or solvate of
claim 1.
100. The method of claim 97 wherein said therapeutically effective
amount comprises a dose range of from about 0.001 mg to about 1,000
mg.
101. The method of claim 97 wherein said therapeutically effective
amount comprises a dose range of from about 0.1 mg to about 500
mg.
102. The method of claim 97 wherein said therapeutically effective
amount comprises a dose range of from about 1 mg to about 250
mg.
103-117. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This applicaiton claims priority to U.S. Provisional
Application No. 60/381,575, filed May 17, 2003.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] The research and development of the invention described
below was not federally sponsored.
BACKGROUND OF THE INVENTION
[0003] This invention is directed to novel vanilloid receptor VR1
ligands. More particularly, this invention relates to novel
.beta.-aminotetralin-derived ureas that are potent antagonists or
agonists of VR1 and exhibit activity in animal models of
hyperalgesia and colitis, and are useful for the treatment and
prevention of pain conditions in humans including arthritis, and
for the treatment of irritable-bowel syndrome and associated
conditions.
[0004] Noxious chemical, thermal and mechanical stimuli excite
peripheral nerve endings of small diameter sensory neurons
(nociceptors) in sensory ganglia (e.g., dorsal root, nodose and
trigeminal ganglIa) and initiate signals that are perceived as
pain. These neurons are crucial for the detection of harmful or
potentially harmful stimuli (heat) and tissue damage (local tissue
acidosis and/or stretch) that arise from changes in the
extracellular space during inflammatory or ischaemic conditions
(Wall, P. D., and Meizack, R., Textbook of Pain, 1994, New York:
Churchill Livingstone). Nociceptors transduce noxious stimuli into
membrane depolarization that triggers action potential, conducts
the action potential from the sensory sites to the synapses in the
CNS, and conversion of action potentials invokes a perception of
pain, discomfort, and appropriate mechanical/physical protective
reflexes. At the molecular level, nociception is carried out by ion
channels or receptors. Plant derived vanilloid compounds (capsaicin
and its ultrapotent analog, resiniferatoxin, etc.) are known to
selectively depolarize nociceptors and elicit sensations of burning
pain--the sensation that is typically obtained by hot chili
peppers. Therefore, capsaicin mimics the action of
physiological/endogenous stimuli that activates the "nociceptive
pathway". Recent advances in pain biology have identified receptors
for vanilloids, protons (i.e., acidic solutions), and for heat.
Because nociceptors are involved with unwanted pain and
inflammatory conditions in human beings and animals, modulation of
their nociceptive pathway is important in palliative and other
therapies.
[0005] Walpole and colleagues at Sandoz reported on the first
competitive antagonist of the sensory neuron excitants capsaicin
and resineriferatoxin (Walpole, C. S. J. et. al., J. Med. Chem.
1994, 37, 1942). Subsequently, capsazepine has been shown to be a
vanilloid receptor antagonist. Capsazepine, however, is not
aminotetralin-derived. Jee Woo Lee and colleagues at Pacific
Corporation disclosed thiocarbamic acid derived VR1 antagonists in
WO0216317A1 and vanilloid receptor modulators in WO0216318A1 and
WO0216319A1 but these applications do not disclose or describe
.alpha.-substituted .beta.-aminotetralins. Hutchinson and
colleagues at Neurogen describe a diaryl piperazinyl ureas and
related compounds as capsaicin receptor ligands in WO02082212A1 but
aminotetralins are not covered. Scientists at the Universidad
Miguel Hernandez in Alicante, the Universidad de Valencia and the
Consejo Superior de Investigaciones Cientificas (CSIC) in Barcelona
have used a combinatorial chemistry-based approach to discover
compounds that modulate the vanilloid VR1 receptor and have
disclosed two trialkylglycine-based compounds as noncompetitive VR1
channel blockers (Garcia-Martinez, C. et al. Proc Natl Acad Sci USA
2002, 99(4): 2374) but none are aminotetralin-derived.
[0006] U.S. Pat. Nos. 6,140,354 and 6,201,025 by Dax et. al. teach
the synthesis of N-acylated and N-alkylated .alpha.-substituted
.beta.-aminotetralins but do not describe the synthesis of ureido
.beta.-aminotetralins. U.S. Pat. No. 6,169,116 B1 by Swoboda
describes .beta.-aminotetralins and their pharmaceutical uses but
does not describe the synthesis of .alpha.-substituted
.beta.-aminotetralins and does not describe the synthesis of ureido
.beta.-aminotetralins. European patent application 0064964 by
Arvidsson teaches the synthesis of N-alkylated
.alpha.-alkyl-.beta.-aminotetralins in which the alkyl substituent
in the .alpha.-position is hydrogen or C.sub.1-6alkyl but does not
describe the synthesis of .beta.-aminotetralins substituted with
groups other than hydrogen or C.sub.1-6alkyl in .alpha.-position
nor describe the synthesis of ureido .beta.-aminotetralins.
[0007] Thus, there is a need for potent modulators of VR, and in
particular, for novel .beta.-aminotetralin-derived ureas that
exhibit potent binding affinity for the human and rat VR1 ion
channel. There is also a need for novel
.beta.-amino-tetralin-derived ureas that act as potent functional
antagonists and/or agonists of the human and rat VR1 ion channel.
Finally, there is a need for novel .beta.-aminotetralin-deri- ved
ureas that bind with high affinity to VR1 and also act as potent
functional antagonists of the human and rat VR1 ion channel.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to compositions comprising
a compound of Formula (I): 1
[0009] wherein:
[0010] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0011] n is an integer from 1 to 3;
[0012] m is an integer from 0 to 3;
[0013] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.2-8alkenyl; C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl;
fluoro; chloro; C.sub.3-8cycloalkanyl; phenyl optionally
substituted with one to three substituents independently selected
from the group consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanylo- xy, fluorinated
alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino, and
C.sub.1-8dialkanylamino; naphthyl optionally substituted with one
to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy, fluorinated
alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino, and
C.sub.1-8dialkanylamino; phenoxy optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
fluorinated alkanyl, cyano and nitro; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and halogen wherein
said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl or
imidazolyl; pyrrolidino; and piperidino;
[0014] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0015] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0016] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0017] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0018] X is selected from the group consisting of O and S; and
[0019] enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0020] Preferred embodiments of the present invention are those in
which: (1) R.sub.1 is a substituent independently selected from the
group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, and
C.sub.1-8alkanyloxy; (2) R.sub.1 is a substituent independently
selected from the group consisting of fluoro, chloro, bromo,
C.sub.1-8alkanyloxy, (3) R.sub.2 is independently selected from the
group consisting of hydrogen, C.sub.2-8alkenyl, C.sub.2-8alkenyl,
C.sub.1-8alkylidenyl, C.sub.1-8alkylidynyl, C.sub.3-8cycloalkanyl,
phenyl (optionally substituted with one to three substituents
independently selected from the group consisting of fluoro, chloro,
bromo, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanyloxy, and fluorinated alkanyl), naphthyl
(optionally substituted with one to three substituents
independently selected from the group consisting of fluoro, chloro,
bromo, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanyloxy, and fluorinated alkanyl), and a
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein the heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; (4) L is a direct bond or
C.sub.1-8alkanylene; and (5) R.sub.3 is selected from the group
consisting of naphthyl substituted with hydroxyl; quinolinyl
optionally substituted with one or more substituents selected from
the group consisting of methyl and chloro, quinolinyl-N-oxide,
isoquinolinyl optionally substituted with one or more substituents
selected from the group consisting of methyl and chloro and
isoquinolinyl-N-oxide.
[0021] Finally, the present invention is directed to pharamceutical
compositions containing compounds of Formula (I), as well as to
methods of treatment of diseases and conditions by administration
of these compositions, and also to pharmaceutical kits containing
them.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 shows the IC.sub.50 values of the competitive
vanilloid antagonist capsazepine for inhibition of calcium flux
induced by a number of different stimuli known to activate VR1.
[0023] FIG. 2 shows the IC.sub.50 values for inhibition by a
compound of the invention of the calcium flux induced by a number
of different stimuli known to activate VR1.
[0024] FIG. 3 shows inhibition by a compound of the invention of
capsaicin-induced contraction of guinea pig bronchial rings in an
isolated tissue assay.
[0025] FIG. 4 shows inhibition by another compound of the invention
of capsaicin-induced contraction of guinea pig bronchial rings in
an isolated tissue assay.
DETAILED DESCRIPTION OF THE INVENTION
[0026] As used herein, the following underlined terms are intended
to have the following meanings:
[0027] "C.sub.a-b" (where a and b are integers) refers to a radical
containing from a to b carbon atoms inclusive. For example,
C.sub.1-3 denotes a radical containing 1, 2 or 3 carbon atoms.
[0028] "Fluorinated alkyl" refers to a saturated branched or
straight chain hydrocarbon radical derived by removal of 1 hydrogen
atom from the parent alkane; the parent alkane contains from 1 to 6
carbon atoms with 1 or more hydrogen atoms substituted with
fluorine atoms up to and including substitution of all hydrogen
atoms with fluorine. Preferred fluorinated alkyls include
trifluoromethyl substituted alkyls and perfluorinated alkyls; more
preferred fluorinated alkyls include trifluoromethyl,
perfluoroethyl, 2,2,2-trifluoroethyl, perfluoropropyl,
3,3,3-trifluoroprop-1-yl, 3,3,3-trifluoroprop-2-yl,
1,1,1,3,3,3-hexafluoroprop-2-yl; a particularly preferred
fluorinated alkyl is trifluoromethyl.
[0029] "Fluorinated alkanyloxy" refers to a radical derived from a
fluorinated alkyl radical attached to an oxygen atom with the
oxygen atom having one open valence for attachment to a parent
structure.
[0030] "Alkyl:" refers to a saturated or unsaturated, branched,
straight-chain or cyclic monovalent hydrocarbon radical derived by
the removal of one hydrogen atom from a single carbon atom of a
parent alkane, alkene or alkyne. Typical alkyl groups include, but
are not limited to, methyl; ethyls such as ethanyl, ethenyl,
ethynyl; propyls such as propan-1-yl, propan-2-yl,
cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl,
cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,
prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,
2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,
but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl,
but-3-yn-1-yl, etc.; and the like. Where specific levels of
saturation are intended, the nomenclature "alkanyl", "alkenyl"
and/or "alkynyl" is used, as defined below. In preferred
embodiments, the alkyl groups are (C.sub.1-8) alkyl, with
(C.sub.1-3) being particularly preferred.]
[0031] "Alkanyl:" refers to a saturated branched, straight-chain or
cyclic monovalent hydrocarbon radical derived by the removal of one
hydrogen atom from a single carbon atom of a parent alkane. Typical
alkanyl groups include, but are not limited to, methanyl; ethanyl;
propanyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.;
butyanyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,
2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like. In
preferred embodiments, the alkanyl groups are (C.sub.1-8) alkanyl,
with (C.sub.1-3) being particularly preferred.
[0032] "Alkenyl:" refers to an unsaturated branched, straight-chain
or cyclic monovalent hydrocarbon radical having at least one
carbon-carbon double bond derived by the removal of one hydrogen
atom from a single carbon atom of a parent alkene. The radical may
be in either the cis or trans conformation about the double
bond(s). Typical alkenyl groups include, but are not limited to,
ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,
prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;
cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,
2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl,
but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,
cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,
etc.; and the like. In preferred embodiments, the alkenyl group is
(C.sub.2-8) alkenyl, with (C.sub.2-3) being particularly
preferred.
[0033] "Alkynyl:" refers to an unsaturated branched, straight-chain
or cyclic monovalent hydrocarbon radical having at least one
carbon-carbon triple bond derived by the removal of one hydrogen
atom from a single carbon atom of a parent alkyne. Typical alkynyl
groups include, but are not limited to, ethynyl; propynyls such as
prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as
but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In
preferred embodiments, the alkynyl group is (C.sub.2-8) alkynyl,
with (C.sub.2-3) being particularly preferred.
[0034] "Alkyldiyl:" refers to a saturated or unsaturated, branched,
straight-chain or cyclic divalent hydrocarbon radical derived by
the removal of one hydrogen atom from each of two different carbon
atoms of a parent alkane, alkene or alkyne, or by the removal of
two hydrogen atoms from a single carbon atom of a parent alkane,
alkene or alkyne. The two monovalent radical centers can form bonds
with the same or different atoms. Typical alkyldiyls include, but
are not limited to methandiyl; ethyldiyls such as ethan-1,1-diyl,
ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as
propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl,
cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl,
prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl,
cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,
-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,
butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,
butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,
cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,
but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,
but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,
2-methylprop-2-en-1,1-diyl, buta-1,3-dien-1,1-diyl,
buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl,
buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl,
cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,
cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,
but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.;
and the like. Where specific levels of saturation are intended, the
nomenclature alkandiyl, alkendiyl and/or alkyndiyl is used. In
preferred embodiments, the alkyldiyl group is (C.sub.1-8)
alkyldiyl, with (C.sub.1-8) being particularly preferred. Also
preferred are saturated acyclic alkandiyl radicals in which the
radical centers are at the terminal carbons, e.g., methandiyl;
ethan-1,2-diyl; propan-1,3-diyl; butan-1,4-diyl; and the like (also
referred to as alkylenos, as defined infra).
[0035] "Vic Alkyldiyl:" refers to a saturated or unsaturated,
branched, straight-chain or cyclic hydrocarbon radical having two
adjacent monovalent radical centers derived by the removal of one
hydrogen atom from each of two adjacent carbon atoms of a parent
alkane, alkene or alkyne. The two monovalent radical centers can
form bonds with the same or different atom(s). Typical vic
alkyldiyls include, but are not limited to vic ethyldiyls such as
ethan-1,2-diyl, ethen-1,2-diyl; vic propyldiyls such as
propan-1,2-diyl, cyclopropan-1,2-diyl, prop-1-en-1,2-diyl,
prop-2-en-1,2-diyl, cycloprop-1-en-1,2-diyl, etc.; vic butyldiyls
such as butan-1,2-diyl, 2-methyl-propan-1,2-diyl,
cyclobutan-1,2-diyl, but-1-en-1,2-diyl, cyclobut-1-en-1,2-diyl,
buta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl,
but-3-yn-1,2-diyl, etc.; and the like. Where specific levels of
saturation are intended, the nomenclature vic alkandiyl, vic
alkendiyl and/or vic alkyndiyl is used. In preferred embodiments,
the vic alkyldiyl group is (C.sub.2-8) vic alkyldiyl, with
(C.sub.2-3) being particularly preferred.
[0036] "Gem Alkyldiyl:" refers to a saturated or unsaturated,
branched, straight-chain or cyclic hydrocarbon radical having one
divalent radical center derived by the removal of two hydrogen
atoms from a single carbon atom of a parent alkane, alkene or
alkyne. The divalent radical center forms bonds with two different
atoms. Typical gem alkyldiyls include, but are not limited to gem
methanyldiyl; gem ethyldiyls such as ethan-1,1-diyl,ethen-1,I-diyl;
gem propyldiyls such as propan-1,1-diyl, propan-2,2-diyl,
cyclopropan-1,1-diyl, prop-1-en-1,1-diyl, cycloprop-2-en-1,1-diyl,
prop-2-yn-1,1-diyl, etc.; butyldiyls such as butan-1,1-diyl,
butan-2,2-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl,
but-1-en-1,1-diyl, 2-methyl-prop-1-en-1,1-diyl,
2-methyl-prop-2-en-1,1-diyl, cyclobut-2-en-1,1-diyl,
buta-1,3-dien-1,1-diyl, etc.; and the like. Where specific levels
of saturation are intended, the nomenclature gem alkandiyl, gem
alkendiyl and/or gem alkyndiyl is used. In preferred embodiments,
the gem alkyldiyl group is (C.sub.1-6) gem alkyldiyl, with
(C.sub.1-3) being particularly preferred.
[0037] "Alkyleno:" refers to a saturated or unsaturated,
straight-chain or branched acyclic bivalent hydrocarbon bridge
radical derived by the removal of one hydrogen atom from each of
the two terminal carbon atoms of an acyclic parent alkane, alkene
or alkyne. Typical alkyleno groups include, but are not limited to,
methano; ethylenos such as ethano, etheno, ethyno; propylenos such
as propano, propeno, prop-1,2-dieno, propyno, etc.; butylenos such
as butano, 2-methyl-propano, but-1-eno, but-2-eno,
2-methyl-prop-1-eno, 2-methanylidene-propano, but-1,3-dieno,
but-1-yno, but-2-yno, but-1,3-diyno, etc.; and the like. Where
specific levels of saturation are intended, the nomenclature
alkano, alkeno and/or alkyno is used. In preferred embodiments, the
alkyleno group is (C.sub.1-8) alkyleno, with (C.sub.1-3) being
particularly preferred. Also preferred are straight-chain saturated
alkano radicals, e.g., methano, ethano, propano, butano, and the
like.
[0038] "Alkylidene:" refers to a saturated or unsaturated,
branched, straight-chain or cyclic divalent hydrocarbon radical
derived by removal of two hydrogen atoms from the same carbon atom
of a parent alkane, alkene or alkyne. The divalent radical center
forms a double bond with a single atom. Typical alkylidene radicals
include, but are not limited to, methanylidene, ethylidenes such as
ethanylidene, ethenylidene; propylidenes such as propan-1-ylidene,
propan-2-ylidene, cyclopropan-1-ylidene, prop-1-en-1-ylidene,
prop-2-en-1-ylidene, cycloprop-2-en-1-ylidene, etc.; butylidenes
such as butan-1-ylidene, butan-2-ylidene,
2-methyl-propan-1-ylidene, cyclobutan-1-ylidene,
but-1-en-1-ylidene, but-2-en-1-ylidene, but-3-en-1-ylidene,
buta-1,3-dien-1-ylidene; cyclobut-2-en-1-ylidene, etc.; and the
like. Where specific levels of saturation are intended, the
nomenclature alkanylidene, alkenylidene and/or alkynylidene is
used. In preferred embodiments, the alkylidene group is (C.sub.1-8)
alkylidene, with (C.sub.1-3) being particularly preferred. Also
preferred are acyclic saturated alkanylidene radicals in which the
divalent radical is at a terminal carbon, e.g., methanylidene,
ethan-1-ylidene, propan-1-ylidene, butan-1-ylidene,
2-methyl-propan-1-ylidene, and the like.
[0039] "Alkylidyne:" refers to a saturated or unsaturated, branched
or straight-chain trivalent hydrocarbon radical derived by removal
of three hydrogen atoms from the same carbon atom of a parent
alkane, alkene or alkyne. The trivalent radical center forms a
triple bond with a single atom. Typical alkylidyne radicals
include, but are not limited to, methanylidyne; ethanylidyne;
propylidynes such as propan-1-ylidyne, prop-2-en-1-ylidyne,
prop-2-yn-1-ylidyne; butylidynes such as butan-1-ylidyne,
2-methyl-propan-1-ylidyne, but-2-en-1-ylidyne, but-3-en-1-ylidyne,
buta-2,3-dien-1-ylidyne, but-2-yn-1-ylidyne, but-3-yn-1-ylidyne,
etc.; and the like. Where specific levels of saturation are
intended, the nomenclature alkanylidyne, alkenylidyne and/or
alkynylidyne is used. In preferred embodiments, the alkylidyne
group is (C.sub.1-8) alkylidyne, with (C.sub.1-3) being
particularly preferred. Also preferred are saturated alkanylidyne
radicals, e.g., methanylidyne, ethanylidyne, propan-1-ylidyne,
butan-1-ylidyne, 2-methyl-propan-1-ylidyne, and the like.
[0040] "Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl.
Heteroalkylidene, Heteroalkylidyne, Heteroalkyldiyl, Vic
Heteralkyldiyl, Gem Heteroalkyldiyl, Heteroalkyleno and
Heteroalkyldiylidene:" refer to alkyl, alkanyl, alkenyl, alkynyl,
alkylidene, alkylidyne, alkyldiyl, vic alkyldiyl, gem alkyldiyl,
alkyleno and alkyldiylidene radicals, respectively, in which one or
more carbon atoms (and any necessary associated hydrogen atoms) are
independently replaced with the same or different heteroatoms
(including any necessary hydrogen or other atoms). Typical
heteroatoms to replace the carbon atom(s) include, but are not
limited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and
S. Thus, heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkynyl,
heteroalkylidene, heteroalkylidyne, heteroalkyldiyl, vic
heteroalkyldiyl, gem heteroalkyldiyl, heteroalkyleno and
heteroalkyldiylidene radicals can contain one or more of the same
or different heteroatomic groups, including, by way of example and
not limitation, epoxy (--O--), epidioxy (--O--O--), thioether
(--S--), epidithio (--SS--), epoxythio (--O--S--), epoxyimino
(--O--NR'--), imino (--NR'--), biimmino (--NR'--NR'--), azino
(.dbd.N--N.dbd.), azo (--N.dbd.N--), azoxy (--N--O--N--), azimino
(--NR'--N.dbd.N--), phosphano (--PH--), A.sup.4-sulfano
(--SH.sub.2--), sulfonyl (--S(O).sub.2--), and the like, where each
R' is independently hydrogen or (C.sub.1-C.sub.6) alkyl.
[0041] "Parent Aromatic Ring System:" refers to an unsaturated
cyclic or polycyclic ring system having a conjugated ff electron
system. Specifically included within the definition of "parent
aromatic ring system" are fused ring systems in which one or more
rings are aromatic and one or more rings are saturated or
unsaturated, such as, for example, indane, indene, phenalene, etc.
Typical parent aromatic ring systems include, but are not limited
to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,
azulene, benzene, chrysene, coronene, fluoranthene, fluorene,
hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane,
indene, naphthalene, octacene, octaphene, octalene, ovalene,
penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,
phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,
rubicene, triphenylene, trinaphthalene, and the like
[0042] "Aryl:" refers to a monovalent aromatic hydrocarbon radical
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Typical aryl groups include,
but are not limited to, radicals derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene, and the like. In preferred embodiments, the aryl
group is (C.sub.5-20) aryl, with (C.sub.5-10) being particularly
preferred. Particularly preferrec aryl groups are phenyl and
naphthyl groups.
[0043] "Arylalkyl:" refers to an acyclic alkyl group in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
carbon atom, is replaced with an aryl radical. Typical arylalkyl
groups include, but are not limited to, benzyl, 2-phenylethan-1-yl,
2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and
the like. Where specific alkyl moieties are intended, the
nomenclature arylalkanyl, arylakenyl and/or arylalkynyl is used.
[In preferred embodiments, the arylalkyl group is (C.sub.6-26)
arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the
arylalkyl group is (C.sub.1-6) and the aryl moiety is (C.sub.5-20).
In particularly preferred embodiments the arylalkyl group is
(C.sub.6-13), e.g., the alkanyl, alkenyl or alkynyl moiety of the
arylalkyl group is (C.sub.1-3) and the aryl moiety is (C.sub.5-10).
Even more preferred arylalkyl groups are phenylalkanyls.
[0044] "Alkanyloxy:" refers to a saturated branched, straight-chain
or cyclic monovalent hydrocarbon alcohol radical derived by the
removal of the hydrogen atom from the hydroxide oxygen of the
alcohol. Typical alkanyloxy groups include, but are not limited to,
methanyl; ethanyloxy; propanyloxy groups such as propan-1-yloxy
(CH.sub.3CH.sub.2CH.sub.2O--), propan-2-yloxy
((CH.sub.3).sub.2CHO--), cyclopropan-1-yloxy, etc.; butyanyloxy
groups such as butan-1-yloxy, butan-2-yloxy,
2-methyl-propan-1-yloxy, 2-methyl-propan-2-yloxy,
cyclobutan-1-yloxy, etc.; and the like. In preferred embodiments,
the alkanyloxy groups are (C.sub.1-8) alkanyloxy groups, with
(C.sub.1-3) being particularly preferred.
[0045] "Parent Heteroaromatic Ring System:" refers to a parent
aromatic ring system in which one or more carbon atoms are each
independently replaced with a heteroatom. Typical heteratoms to
replace the carbon atoms include, but are not limited to, N, P, O,
S, Si etc. Specifically included within the definition of "parent
heteroaromatic ring systems" are fused ring systems in which one or
more rings are aromatic and one or more rings are saturated or
unsaturated, such as, for example, arsindole, chromane, chromene,
indole, indoline, xanthene, etc. Typical parent heteroaromatic ring
systems include, but are not limited to, arsindole, carbazole,
.beta.-carboline, chromane, chromene, cinnoline, furan, imidazole,
indazole, indole, indoline, indolizine, isobenzofuran, isochromene,
isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,
naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,
phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,
tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,
and the like.
[0046] "Heteroaryl:" refers to a monovalent heteroaromatic radical
derived by the removal of one hydrogen atom from a single atom of a
parent heteroaromatic ring system. Typical heteroaryl groups
include, but are not limited to, radicals derived from acridine,
arsindole, carbazole, .beta.-carboline, chromane, chromene,
cinnoline, furan, imidazole, indazole, indole, indoline,
indolizine, isobenzofuran, isochromene, isoindole, isoindoline,
isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,
oxazole, perimidine, phenanthridine, phenanthroline, phenazine,
phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine,
quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,
thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.
In preferred embodiments, the heteroaryl group is a 5-20 membered
heteroaryl, with 5-10 membered heteroaryl being particularly
preferred. Specific preferred heteroaryls for the present invention
are quinoline, isoquinoline, pyridine, pyrimidine, furan, thiophene
and imidazole.
[0047] "Substituted:" refers to a radical in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s). Typical substituents include, but are not
limited to, --X, --R, --O.sup.-, .dbd.O, --OR, --O--OR, --SR,
--S.sup.-, .dbd.S, --NRR, .dbd.NR, --CX.sub.3, --CN, --OCN, --SCN,
--NCO, --NCS, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --NHOH,
--S(O).sub.2O.sup.-, --S(O).sub.2OH, --S(O).sub.2R,
--P(O)(O.sup.-).sub.2, --P(O)(OH).sub.2, --C(O)R, --C(O)X, --C(S)R,
--C(S)X, --C(O)OR, --C(O)O, --C(S)OR, --C(O)SR, --C(S)SR,
--C(O)NRR, --C(S)NRR and --C(NR)NRR, where each X is independently
a halogen (preferably --F, --Cl or --Br) and each R is
independently --H, alkyl, alkanyl, alkenyl, alkynyl, alkylidene,
alkylidyne, aryl, arylalkyl, arylheteroalkyl, heteroaryl,
heteroarylalkyl or heteroaryl-heteroalkyl, as defined herein.
Preferred substituents include hydroxy, halogen, C.sub.1-8alkyl,
C.sub.1-8alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,
C.sub.1-8alkylthio, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkanyloxy,
nitro, amino, C.sub.1-8alkylamino, C.sub.1-8dialkylamino,
C.sub.3-8cycloalkylamino, cyano, carboxy,
C.sub.1-7alkanyloxycarbonyl, C.sub.1-7alkylcarbonyloxy, formyl,
carbamoyl, phenyl, aroyl, carbamoyl, amidino,
(C.sub.1-8alkylamino)carbonyl, (arylamino)carbonyl and
aryl(C.sub.1-8alkyl)carbonyl.
[0048] "Aroyl" refers to arylacyl substituents.
[0049] "Acyl" refers to alkylcarbonyl substituents.
[0050] With reference to substituents, the term "independently"
means that when more than one of such substituent is possible, such
substituents may be the same or different from each other.
[0051] Throughout this disclosure, the terminal portion of the
designated side chain is described first, followed by the adjacent
functionality toward the point of attachment. Thus, for example, a
"phenylC.sub.1-6alkanylaminocarbonylC.sub.1-6alkyl" substituent
refers to a group of the formula 2
[0052] The present invention is directed to compositions comprising
a compound of Formula (I): 3
[0053] wherein R.sub.1 independently may be absent or an optionally
substituted substituent selected from alkyl, heteroalkyl, aryl
(preferably 5-10 membered aryl), arylalkyl, halogen, nitro, amino,
cyano, carboxy, carbamoyl, aroyl, amidino, and acyl; n is an
integer from 1 to 3; m is an integer from 0 to 3; R.sub.2 may be
absent or an optionally substituted substituent selected from
alkyl, heteroalkyl, aryl (preferably 5-10 membered aryl),
heteroaryl (preferably 5-10 membered heteroaryl), alkylidenyl,
heteroalkylidenyl, alkylidynyl, heteroalkylidynyl, arylalkyl,
halogen, nitro, amino, and cyano; L is a direct bond, alkyldiyl or
heteroalkyldiyl; R.sub.3 is aryl (preferably 5-10 membered aryl) or
heteroaryl (preferably 5-10 membered heteroaryl); R.sub.4 and
R.sub.5 are hydrogen, alkyl, o r heteroalkyl; X is O or S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0054] In particular, the present invention is directed to
compounds of Formula (I) wherein:
[0055] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0056] n is an integer from 1 to 3;
[0057] m is an integer from 0 to 3;
[0058] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0059] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0060] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0061] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0062] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0063] X is selected from the group consisting of O and S; and
[0064] enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0065] Preferred embodiments of the present invention are those in
which: (1) R.sub.1 is a substituent independently selected from the
group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, and
C.sub.1-8alkanyloxy; (2) R.sub.1 is a substituent independently
selected from the group consisting of fluoro, chloro, bromo,
C.sub.1-8alkanyloxy, (3) R.sub.2 is independently selected from the
group consisting of hydrogen, C.sub.2-8alkenyl,
C.sub.1-8alkylidenyl, C.sub.1-8alkylidynyl, C.sub.3-8cycloalkanyl,
phenyl (optionally substituted with one to three substituents
independently selected from the group consisting of fluoro, chloro,
bromo, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanyloxy, and fluorinated alkanyl), naphthyl
(optionally substituted with one to three substituents
independently selected from the group consisting of fluoro, chloro,
bromo, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanyloxy, and fluorinated alkanyl), and a
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein the heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; (4) L is a direct bond or
C.sub.1-8alkandiyl; (5) R.sub.3 is selected from the group
consisting of naphthyl substituted with hydroxyl; quinolinyl and
isoquinolinyl; and (6) any combination of (1) to (5) preceding.
Thus, preferred embodiments of the present invention are as
described below.
[0066] An embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein:
[0067] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; fluoro; chloro; and
C.sub.1-8alkanyloxy;
[0068] n is an integer from 1 to 3;
[0069] m is an integer from 0 to 3;
[0070] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0071] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0072] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0073] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0074] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0075] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0076] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein:
[0077] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0078] n is an integer from 1 to 3;
[0079] m is an integer from 0 to 3;
[0080] R.sub.2 is independently selected from the group consisting
of hydrogen; C.sub.2-8alkenyl; C.sub.1-8alkylidenyl;
C.sub.1-8alkylidynyl; C.sub.3-8cycloalkanyl; phenyl optionally
substituted with one to three substituents independently selected
from the group consisting of fluoro, chloro, bromo, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl; naphthyl optionally substituted with one to
three substituents independently selected from the group consisting
of fluoro, chloro, bromo, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy, fluorinated
alkanyl; and a heteroaryl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl;
[0081] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0082] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0083] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0084] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0085] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0086] Still another embodiment of the present invention is
directed to compositions comprising a compound of Formula (I)
wherein:
[0087] R, is a substituent independently selected from the group
consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0088] n is an integer from 1 to 3;
[0089] m is an integer from 0 to 3;
[0090] R.sub.2 is independently selected from the group consisting
of hydrogen; C.sub.2-8alkenyl; C.sub.1-8alkylidenyl;
C.sub.1-8alkylidynyl; C.sub.3-8cycloalkanyl; phenyl optionally
substituted with one to three substituents independently selected
from the group consisting of fluoro, chloro, bromo,
C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy and fluorinated
alkanyl; naphthyl optionally substituted with one to three
substituents independently selected from the group consisting of
fluoro, chloro, bromo, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanyloxy and fluorinated alkanyl; pyridyl;
pyrimidyl; furyl; thienyl and imidazolyl.
[0091] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0092] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0093] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0094] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0095] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0096] Furthermore, another embodiment of the present invention is
directed to compositions comprising a compound of Formula (I)
wherein:
[0097] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0098] n is an integer from 1 to 3;
[0099] m is an integer from 0 to 3;
[0100] R.sub.2 is independently selected from the group consisting
of C.sub.2-8alkenyl; C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of fluoro, chloro, bromo, and fluorinated alkanyl.
[0101] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0102] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0103] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0104] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0105] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0106] An embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein:
[0107] R.sub.1 is a substituent independently selected from the
group consisting of fluoro; chloro; C.sub.1-8alkanyloxy;
[0108] n is an integer from 1 to 3;
[0109] m is an integer from 0 to 3;
[0110] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0111] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0112] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0113] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0114] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0115] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0116] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein:
[0117] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0118] n is 1;
[0119] m is an integer from 0 to 3;
[0120] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0121] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0122] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0123] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0124] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0125] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0126] Still yet another embodiment of the present invention is
directed to compositions comprising a compound of Formula (I)
wherein:
[0127] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0128] n is an integer from 1 to 3;
[0129] m is an integer from 0 to 1;
[0130] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0131] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0132] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0133] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0134] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0135] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0136] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein:
[0137] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0138] n is an integer from 1 to 3;
[0139] m is 1;
[0140] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0141] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0142] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0143] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0144] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0145] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0146] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein:
[0147] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0148] n is an integer from 1 to 3;
[0149] m is an integer from 0 to 3;
[0150] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0151] L is a direct bond or C.sub.1-8alkandiyl;
[0152] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-18)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1alkanyl, halogen, nitro, amino
and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0153] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0154] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0155] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0156] Yet another embodiment of the present invention is directed
to compositions comprising a compound of Formula (I) wherein:
[0157] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0158] n is an integer from 1 to 3;
[0159] m is an integer from 0 to 3;
[0160] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0161] L is a direct bond;
[0162] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0163] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0164] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0165] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0166] Still yet another embodiment of the present invention is
directed to compositions comprising a compound of Formula (I)
wherein:
[0167] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0168] n is an integer from 1 to 3;
[0169] m is an integer from 0 to 3;
[0170] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0171] L is a direct bond, C: .sub.8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0172] R.sub.3 is selected from the group consisting of phenyl
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, fluoro, chloro,
bromo, C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro,
amino, di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, fluoro,
chloro, bromo, C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl,
nitro, amino, di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and
cyano; and heteroaryl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, fluoro and chloro, wherein said heteroaryl is
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0173] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0174] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0175] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0176] Furthermore, another embodiment of the present invention is
directed to compositions comprising a compound of Formula (I)
wherein:
[0177] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0178] n is an integer from 1 to 3;
[0179] m is an integer from 0 to 3;
[0180] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0181] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0182] R.sub.3 is selected from the group consisting of phenyl
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyloxy and hydroxy;
naphthyl substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyloxy and
hydroxy; and heteroaryl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl and chloro wherein said heteroaryl is
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl
and pyridyl-N-oxide;
[0183] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0184] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0185] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0186] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein
[0187] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0188] n is an integer from 1 to 3;
[0189] m is an integer from 0 to 3;
[0190] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0191] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0192] R.sub.3 is selected from the group consisting of naphthyl
substituted with hydroxyl; quinolinyl optionally substituted with
one or more substituents selected from the group consisting of
methyl and chloro, quinolinyl-N-oxide, isoquinolinyl optionally
substituted with one or more substituents selected from the group
consisting of methyl and chloro and isoquinolinyl-N-oxide;
[0193] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0194] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0195] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0196] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein:
[0197] R, is a substituent independently selected from the group
consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally independently substituted with one or more substituents
independently selected from the group consisting of halogen,
fluorinated alkanyl and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy
optionally independently substituted with one or more substituents
independently selected from the group consisting of halogen,
fluorinated alkanyl and C.sub.1-8alkanyloxy; fluorinated
alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio optionally
substituted with one or more substituents independently selected
from the group consisting of halogen, fluorinated alkanyl and
C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0198] n is an integer from 1 to 3;
[0199] m is an integer from 0 to 3;
[0200] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0201] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0202] R.sub.3 is 2-hydroxynaphth-8-yl, isoquinolin-5-yl and
isoquinolinyl-5-yl-N-oxide;
[0203] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0204] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0205] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0206] Yet another embodiment of the present invention is directed
to compositions comprising a compound of Formula (I) wherein:
[0207] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0208] n is an integer from 1 to 3;
[0209] m is an integer from 0 to 3;
[0210] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0211] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0212] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0213] R.sub.4 is hydrogen;
[0214] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0215] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0216] Still yet another embodiment of the present invention is
directed to compositions comprising a compound of Formula (I)
wherein:
[0217] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0218] n is an integer from 1 to 3;
[0219] m is an integer from 0 to 3;
[0220] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0221] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0222] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0223] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0224] R.sub.5 is hydrogen;
[0225] X is selected from the group consisting of O and S; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0226] Furthermore, another embodiment of the present invention is
directed to compositions comprising a compound of Formula (I)
wherein:
[0227] R.sub.1 is a substituent independently selected from the
group consisting of hydrogen; hydroxy; halogen; C.sub.1-8alkanyl
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.1-8alkanyloxy optionally substituted
with one or more substituents independently selected from the group
consisting of halogen, fluorinated alkanyl and C.sub.1-8alkanyloxy;
fluorinated alkanyloxy; fluorinated alkanyl; C.sub.1-8alkanylthio
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, fluorinated alkanyl
and C.sub.1-8alkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyloxy; nitro; amino; C.sub.1-8alkanylamino;
C.sub.1-8dialkanylamino; C.sub.3-8cycloalkanylamino; cyano;
carboxy; C.sub.1-7alkanyloxycarbonyl; C.sub.1-7alkanylcarbonyloxy;
formyl; carbamoyl; phenyl optionally substituted with one to three
substituents independently selected from the group consisting of
halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl;
amidino; (C.sub.1-8alkanylamino)carbonyl; (arylamino)carbonyl and
aryl(C.sub.1-8alkanyl)carbonyl;
[0228] n is an integer from 1 to 3;
[0229] m is an integer from 0 to 3;
[0230] R.sub.2 is independently selected from the group consisting
of hydrogen; hydroxy; C.sub.1-8alkanyl; C.sub.2-8alkenyl;
C.sub.1-8alkylidenyl; C.sub.1-8alkylidynyl; fluoro; chloro;
C.sub.3-8cycloalkanyl; phenyl optionally substituted with one to
three substituents independently selected from the group consisting
of halogen, hydroxy, C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
phenyl(C.sub.1-8)alkanylo- xy, fluorinated alkanyl, cyano, nitro,
amino, C.sub.1-8alkanylamino, and C.sub.1-8dialkanylamino; naphthyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, hydroxy,
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, phenyl(C.sub.1-8)alkanyloxy,
fluorinated alkanyl, cyano, nitro, amino, C.sub.1-8alkanylamino,
and C.sub.1-8dialkanylamino; phenoxy optionally substituted with
one to three substituents independently selected from the group
consisting of halogen, hydroxy, C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, fluorinated alkanyl, cyano and nitro; and
heteroaryl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and halogen wherein said heteroaryl is pyridyl,
pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and
piperidino;
[0231] L is a direct bond, C.sub.1-8alkandiyl, C.sub.2-8alkendiyl,
C.sub.2-8alkyndiyl, or C.sub.3-8cycloalkandiyl;
[0232] R.sub.3 is selected from the group consisting of phenyl
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl, halogen,
C.sub.1-8alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,
di(C.sub.1-8)alkanylamino, C.sub.1-8alkanylamino and cyano;
naphthyl optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, halogen, C.sub.1-8alkanyloxy, hydroxy,
fluorinated alkanyl, nitro, amino, di(C.sub.1-8)alkanylamino,
C.sub.1-8alkanylamino and cyano; and heteroaryl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, halogen, nitro,
amino and cyano wherein said heteroaryl is quinolinyl,
quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,
pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;
[0233] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0234] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-8alkanyl;
[0235] X is O; and enantiomers, diastereomers, tautomers, solvates,
and pharmaceutically acceptable salts thereof.
[0236] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (Ia): 4
[0237] the compound selected from the group consisting of:
[0238] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 3-Pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is
(3-OMe-4-OH)Ph, and X is S;
[0239] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is H, m is 0, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is S;
[0240] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is S;
[0241] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
3-Pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is
(3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S;
[0242] a compound of formula (Ia) wherein R, is H, R.sub.2 is
3-Pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0243] a compound of formula (Ia) wherein R, is 6-OMe, R.sub.2 is
3-Pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0244] a compound of formula (Ia) wherein R, is 6-OMe, R.sub.2 is
--CH.dbd.CH.sub.2, m is 1, L is --CH.sub.2--, R.sub.3 is
(3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S;
[0245] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is 4-Imidazolyl, m is 1, L is --CH.sub.2--, R.sub.3 is
(3-OMe-4-OH)Ph, and X is S;
[0246] a compound of formula (Ia) wherein R, is 6-OMe, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3,4-methylenedioxy)Ph,
and X is O;
[0247] a compound of formula (Ia) wherein R, is 6-OMe, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3,4-diOMe)Ph, and X is
O;
[0248] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (4-tBu)Ph, and X is
O;
[0249] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is (4-Cl)Ph, and
X is O;
[0250] a compound of formula (Ia) wherein R, is 6-OMe, R.sub.2 is
Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is (3,4-diOMe)Ph,
and X is O;
[0251] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
(3,4-methylenedioxy)Ph, and X is S;
[0252] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3,4-diOMe)Ph, and X
is S;
[0253] a compound of formula (Ia) wherein R, is 6-OMe, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (4-tBu)Ph, and X is
S;
[0254] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is (4-Cl)Ph, and
X is S;
[0255] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is (3,4-diOMe)Ph,
and X is S;
[0256] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is O;
[0257] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.dbd.CH--( ), R.sub.3 is (3-OMe-4-OH)Ph,
and X is O;
[0258] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
(3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S;
[0259] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X is
S;
[0260] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
(4-N(Me)(C.sub.5H.sub.11))Ph, and X is O;
[0261] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
(4-[N(Me)(cyclohexyl)])Ph, and X is O;
[0262] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3,4-diOMe)Ph, and X
is S;
[0263] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (4-CF.sub.3)Ph, and X
is O;
[0264] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3,4-diCl)Ph, and X is
O;
[0265] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is (3,4-diCl)Ph,
and X is O;
[0266] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (4-CF.sub.3)Ph, and X
is S;
[0267] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3,4-diCl)Ph, and X is
S;
[0268] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is (3,4-diCl)Ph,
and X is S;
[0269] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0270] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-quinolinyl, and X
is O;
[0271] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 8-(2-naphtholyl), and
X is O;
[0272] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X is
O;
[0273] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0274] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0275] a compound of formula (Ia) wherein R.sub.1 is 6-Br, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0276] a compound of formula (Ia) wherein R.sub.1 is 6,7-diOMe,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0277] a compound of formula (Ia) wherein R.sub.1 is 7-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0278] a compound of formula (Ia) wherein R.sub.1 is 5-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0279] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0280] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (3-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0281] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is 3-Pyridinyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0282] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (3-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0283] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is 3-Pyridinyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0284] a compound of formula (Ia) wherein R.sub.1 is 6,7-diOMe,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0285] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0286] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0287] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0288] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0289] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0290] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (3-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0291] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0292] a compound of formula (Ia) wherein R.sub.1 is 6-OH, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0293] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
--CH.dbd.CH.sub.2, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0294] a compound of formula (Ia) wherein R.sub.1 is 6-Br, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0295] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0296] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0297] a compound of formula (Ia) wherein R.sub.1 is 7-Cl, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0298] a compound of formula (Ia) wherein R.sub.1 is 8-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0299] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-CN)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0300] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-Br)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0301] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is CN, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0302] a compound of formula (Ia) wherein R.sub.1 is 6,7-diF,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0303] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 8-(2-naphtholyl), and
X is O;
[0304] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is --CH.dbd.CH.sub.2, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0305] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is --CH.dbd.CH.sub.2, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0306] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-OMe)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0307] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Cyclopropyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0308] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-OMe)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0309] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-OMe)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0310] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-Benzyloxy)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0311] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-Pyridinyl, and X is
O;
[0312] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 2-Thienyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0313] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2,6-diF)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0314] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is --CH.sub.2.dbd.CH.sub.2, m is 1, L is --CH.sub.2--, R.sub.3 is
(3-OMe-4-OH)Ph, and X is S;
[0315] a compound of formula (Ia) wherein R.sub.1 is 7-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is S;
[0316] a compound of formula (Ia) wherein R.sub.1 is 5-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is S;
[0317] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X is
S;
[0318] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
H, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X is
S;
[0319] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is H, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is S;
[0320] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Cyclopropyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0321] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
3-thienyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0322] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
2-thienyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0323] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
3-furyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe4-OH)Ph, and X
is S;
[0324] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
2-furyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and
X is S;
[0325] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
4-pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0326] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
3-pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0327] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0328] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2CH(Me)--, R.sub.3 is (3-OMe-4-OH)Ph, and
X is S;
[0329] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH(Me)CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and
X is S;
[0330] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is
(3-OMe-4-OCH.sub.2CH.sub.2NH.- sub.2)Ph, and X is S;
[0331] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2CH(Me)--, R.sub.3 is
(3-OMe-4-OCH.sub.2CH.sub.2NH.su- b.2)Ph, and X is S;
[0332] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH(Me)CH.sub.2--, R.sub.3 is
(3-OMe-4-OCH.sub.2CH.sub.2NH.su- b.2)Ph, and X is S;
[0333] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl, and X is
S;
[0334] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl, and X is
S;
[0335] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl, and X is
S;
[0336] a compound of formula (Ia) wherein R.sub.1 is 6,7-diF,
R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl,
and X is S;
[0337] a compound of formula (Ia) wherein R.sub.1 is 7-Cl, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl, and X is
S;
[0338] a compound of formula (Ia) wherein R.sub.1 is 5-Cl, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl, and X is
S;
[0339] a compound of formula (Ia) wherein R.sub.1 is 8-Cl, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl, and X is
S;
[0340] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-OMe)Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl,
and X is S;
[0341] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (3-OMe)Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl,
and X is S;
[0342] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-OMe)Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl,
and X is S;
[0343] a compound of formula (Ia) wherein R.sub.1 is 6,7-diOMe,
R.sub.2 is --CH.sub.2.dbd.CH.sub.2, m is 1, L is --CH.sub.2--,
R.sub.3 is 4-pyridinyl, and X is S;
[0344] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is cyclopropyl, m is 1, L is --CH.sub.2--, R.sub.3 is 4-pyridinyl,
and X is S;
[0345] a compound of formula (Ia) wherein R.sub.1 is 6-t-Bu,
R.sub.2 is (4-t-Bu)Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
4-pyridinyl, and X is S;
[0346] a compound of formula (Ia) wherein R.sub.1 is 6-CF.sub.3,
R.sub.2 is (4-CF.sub.3)Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
4-pyridinyl, and X is S;
[0347] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 3-pyridinyl, and X is
S;
[0348] a compound of formula (Ia) wherein R.sub.1 is 8-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 2-pyridinyl, and X is
S;
[0349] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is 4-pyridinyl, and
X is S;
[0350] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is 3-pyridinyl, and
X is S;
[0351] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2CH.sub.2--, R.sub.3 is 2-pyridinyl, and
X is S;
[0352] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (2-OMe-3-OH)-5-thienyl,
and X is S;
[0353] a compound of formula (Ia) wherein R.sub.1 is 6,7-diF,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0354] a compound of formula (Ia) wherein R.sub.1 is 8-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0355] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-OMe)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0356] a compound of formula (Ia) wherein R.sub.1 is 6,7-diOMe,
R.sub.2 is --CH.sub.2.dbd.CH.sub.2, m is 1, L is a direct bond,
R.sub.3 is 5-isoquinolinyl, and X is O;
[0357] a compound of formula (Ia) wherein R.sub.1 is 6-t-Bu,
R.sub.2 is (4-t-Bu)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0358] a compound of formula (Ia) wherein R.sub.1 is 6-CF.sub.3,
R.sub.2 is (4-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0359] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is (4-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0360] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is (3-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0361] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is (2-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0362] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
(4-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0363] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
(3-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0364] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
(2-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0365] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
(3-OMe-4-OH)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0366] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
(3-OH-4-OMe)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0367] a compound of formula (Ia) wherein R.sub.1 is 6-OMe-7-OH,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0368] a compound of formula (Ia) wherein R.sub.1 is 6-OH-7-OMe,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0369] a compound of formula (Ia) wherein R.sub.1 is 6-Me, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0370] a compound of formula (Ia) wherein R.sub.1 is
6-C(Me.sub.2)CH.sub.2Me, R.sub.2 is Ph, m is 1, L is a direct bond,
R.sub.3 is 5-isoquinolinyl, and X is O;
[0371] a compound of formula (Ia) wherein R.sub.1 is 6-NO.sub.2,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0372] a compound of formula (Ia) wherein R.sub.1 is 6-OSO.sub.3Me,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0373] a compound of formula (Ia) wherein R.sub.1 is
6-NHSO.sub.2Ph, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3
is 5-isoquinolinyl, and X is O;
[0374] a compound of formula (Ia) wherein R.sub.1 is 6-CO.sub.2H,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0375] a compound of formula (Ia) wherein R.sub.1 is
6-C(O)NH.sub.2, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3
is 5-isoquinolinyl, and X is O;
[0376] a compound of formula (Ia) wherein R.sub.1 is
6-C(O)NMe.sub.2, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3
is 5-isoquinolinyl, and X is O;
[0377] a compound of formula (Ia) wherein R.sub.1 is 6-C(O)NHMe,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0378] a compound of formula (Ia) wherein R.sub.1 is 6-CO.sub.2Ph,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0379] a compound of formula (Ia) wherein R.sub.1 is 6-cyclohexyl,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0380] a compound of formula (Ia) wherein R.sub.1 is 6-Ph, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0381] a compound of formula (Ia) wherein R.sub.1 is
6-NHC(O)(CH.sub.2).sub.4--CH.dbd.CH--CH(Me).sub.2, R.sub.2 is Ph, m
is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X is
O;
[0382] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
2-pyridinyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0383] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
3-pyridinyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0384] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
4-pyridinyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0385] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
3-thienyl, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl,
and X is O;
[0386] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
3-furyl, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl,
and X is O;
[0387] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
2-furyl, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl,
and X is O;
[0388] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-hydroxynaphth-8-yl,
and X is O;
[0389] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 1-hydroxynaphth-8-yl,
and X is O;
[0390] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 4-hydroxynaphth-8-yl,
and X is O;
[0391] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-hydroxynaphth-8-yl,
and X is O;
[0392] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
3-chloro-2-hydroxynaphth-8-yl, and X is O;
[0393] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
2,3-dihydroxynaphth-8-yl, and X is O;
[0394] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-quinolinyl, and X
is O;
[0395] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-cinnolinyl, and X
is O;
[0396] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-Me-5-quinolinyl,
and X is O;
[0397] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
4-(1,8-naphthyridinyl), and X is O;
[0398] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-quinazolinyl, and X
is O;
[0399] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 2-OH-5-quinolinyl,
and X is O;
[0400] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-OH-5-quinolinyl,
and X is O;
[0401] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-F-5-quinolinyl, and
X is O;
[0402] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-Cl-5-quinolinyl,
and X is O;
[0403] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
2-OH-3-Cl-5-quinolinyl, and X is O;
[0404] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is --CH.sub.2.dbd.CH.sub.2, m is 1, L is a direct bond, R.sub.3 is
5-quinolinyl, and X is O;
[0405] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is --CH.sub.2CH.sub.3, m is 1, L is a direct bond, R.sub.3 is
5-quinolinyl, and X is O;
[0406] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 8-Cl-5-quinolinyl,
and X is O;
[0407] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
2-naphthyl, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl,
and X is O;
[0408] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1,3-diMe-5-isoquinolinyl, and X is O;
[0409] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 8-Cl-5-isoquinolinyl,
and X is O;
[0410] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1,3-diMe-8-Cl-5-isoquinolinyl, and X is O;
[0411] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0412] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-quinolinyl, and X
is O;
[0413] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-quinolinyl, and X
is O;
[0414] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-quinolinyl, and X
is O;
[0415] a compound of formula (Ia) wherein R.sub.1 is 6-OH-7-OMe,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 3-quinolinyl,
and X is O;
[0416] a compound of formula (Ia) wherein R.sub.1 is 6,7-diOH,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 3-quinolinyl,
and X is O;
[0417] a compound of formula (Ia) wherein R.sub.1 is 6-OMe-7-OH,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 3-quinolinyl,
and X is O;
[0418] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is a direct bond, R.sub.3 is 3-quinolinyl, and X is
O;
[0419] a compound of formula (Ia) wherein R, is 6-F, R.sub.2 is Ph,
m is 1, L is a direct bond, R.sub.3 is 1-Cl-5-isoquinolinyl, and X
is O;
[0420] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 1-Me-5-isoquinolinyl,
and X is O;
[0421] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 3-Me-5-isoquinolinyl,
and X is O;
[0422] a compound of formula (Ia) wherein R.sub.1 is 6-Br, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 8-isoquinolinyl, and
X is O;
[0423] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 2-furyl, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl,
and X is O;
[0424] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0425] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 4-Cl-5-isoquinolinyl,
and X is O;
[0426] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl-N-oxide, and X is O;
[0427] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0428] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 3-furanyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0429] a compound of formula (Ia) wherein R.sub.1 is 6-OCH.sub.3,
R.sub.2 is 3-thienyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O
[0430] a compound of formula (Ia) wherein R.sub.1 is 6-OCH.sub.3,
R.sub.2 is 2,4 di-F Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0431] a compound of formula (Ia) wherein R.sub.1 is 6-OCH.sub.3,
R.sub.2 is 2,4 di-F Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0432] a compound of formula (Ia) wherein R.sub.1 is 6-OCH.sub.3,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0433] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0434] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0435] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl-N-oxide, and X is O;
[0436] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 4-Cl-5-isoquinolinyl,
and X is O;
[0437] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 4-Cl-5-isoquinolinyl,
and X is O;
[0438] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
3-methyl-5-isoquinolinyl, and X is O;
[0439] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1-methyl-5-isoquinolinyl, and X is O;
[0440] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 1-Cl-5-isoquinolinyl,
and X is O;
[0441] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl-N-oxide, and X is O;
[0442] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 4-CF.sub.3 Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0443] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1,3-diCl-5-isoquinolinyl, and X is O;
[0444] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1,3-diCl-5-isoquinolinyl, and X is O;
[0445] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 8-Cl-5-isoquinolinyl,
and X is O;
[0446] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1-piperidinyl-5-isoquinolinyl, and X is O;
[0447] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1-OCH.sub.3-5-isoquinolinyl, and X is O;
[0448] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 1-F-5-isoquinolinyl,
and X is O;
[0449] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1-N,N-dimethyl-5-isoquinolinyl, and X is O;
[0450] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is nil, m is nil, R.sub.3 is 1-CH.sub.3-5-isoquinolinyl, and X is
O;
[0451] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is nil, m is nil, R.sub.3 is 1-Cl-5-isoquinolinyl, and X is O;
[0452] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 3-CF.sub.3 Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0453] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 3-CF.sub.3 Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl-N-oxide, and X is O;
[0454] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 3-CF.sub.3 Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl-N-oxide, and X is O;
[0455] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is spiro-2-indanyl, L is a direct bond, R.sub.3 is 5-isoquinolinyl,
and X is O;
[0456] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 4-Cl,3-CF.sub.3 Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is 0; and
[0457] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is
1-CH.sub.3-5-isoquinolinyl, and X is O.
[0458] Preferred compounds of Formula (Ia) are selected from the
group consisting of:
[0459] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is S;
[0460] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
3-Pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph,
and X is S;
[0461] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is O;
[0462] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X is
S;
[0463] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3,4-diOMe)Ph, and X
is S;
[0464] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0465] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 8-(2-naphtholyl), and
X is O;
[0466] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X is
O;
[0467] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0468] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0469] a compound of formula (Ia) wherein R.sub.1 is 6-Br, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0470] a compound of formula (Ia) wherein R.sub.1 is 6,7-diOMe,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0471] a compound of formula (Ia) wherein R.sub.1 is 7-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0472] a compound of formula (Ia) wherein R.sub.1 is 5-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0473] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0474] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (3-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0475] a compound of formula (Ia) wherein R.sub.1 is 6,7-diOMe,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0476] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0477] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0478] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0479] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0480] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (3-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0481] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0482] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
--CH.dbd.CH.sub.2, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0483] a compound of formula (Ia) wherein R.sub.1 is 6-Br, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0484] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0485] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0486] a compound of formula (Ia) wherein R.sub.1 is 7-Cl, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0487] a compound of formula (Ia) wherein R.sub.1 is 8-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0488] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-CN)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0489] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-Br)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0490] a compound of formula (Ia) wherein R.sub.1 is 6,7-diF,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0491] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is --CH.dbd.CH.sub.2, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0492] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is --CH.dbd.CH.sub.2, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0493] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-OMe)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0494] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-OMe)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0495] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 2-Thienyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O.
[0496] More preferred compounds of Formula (Ia) are selected from
the group consisting of:
[0497] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0498] a compound of formula (Ia) wherein R.sub.1 is 6-Br, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0499] a compound of formula (Ia) wherein R.sub.1 is 5-Cl, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and
X is O;
[0500] a compound of formula (Ia) wherein R.sub.1 is H, R.sub.2 is
Ph, m is 1, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0501] a compound of formula (Ia) wherein R.sub.1 is 6-Br, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0502] a compound of formula (Ia) wherein R.sub.1 is 6-Cl, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0503] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0504] a compound of formula (Ia) wherein R.sub.1 is 7-Cl, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 5-isoquinolinyl, and X
is O;
[0505] a compound of formula (Ia) wherein R.sub.1 is 6,7-diF,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0506] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is --CH.dbd.CH.sub.2, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0507] a compound of formula (Ia) wherein R.sub.1 is 6-F, R.sub.2
is 2-Thienyl, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O.
[0508] Still other more preferred compounds of Formula (Ia) are
selected from the group consisting of:
[0509] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is (3-OMe-4-OH)Ph, and X
is S;
[0510] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (3-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0511] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-Cl)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0512] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (2-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0513] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (3-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0514] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-CF.sub.3)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0515] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-Br)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0516] a compound of formula (Ia) wherein R.sub.1 is 6-OMe, R.sub.2
is (4-OMe)Ph, m is 1, L is a direct bond, R.sub.3 is
5-isoquinolinyl, and X is O;
[0517] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts" (Ref. International
J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997 (Jan), 66, 1,
1). Other salts well known to those in the art may, however, be
useful in the preparation of compounds according to this invention
or of their pharmaceutically acceptable salts. Representative
organic or inorganic acids include, but are not limited to,
hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric,
phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic,
fumaric, malic, tartaric, citric, benzoic, mandelic,
methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic,
pamoic, 2-naphthalenesulfonic, p-toluenesulfonic,
cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic
acid. Representative organic or inorganic bases include, but are
not limited to, basic or cationic salts such as benzathine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
meglumine, procaine, aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc.
[0518] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0519] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are also
intended to be encompassed within the scope of this invention.
[0520] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography.
[0521] The compounds may be prepared in racemic form, or individual
enantiomers may be prepared either by enantiospecific synthesis or
by resolution. The compounds may, for example, be resolved into
their component enantiomers by standard techniques, such as the
formation of diastereomeric pairs by salt formation with an
optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid
and/or (+)-di-p-toluoyl-1-tartar- ic acid followed by fractional
crystallization and regeneration of the free base. The compounds
may also be resolved by formation of diastereomeric esters or
amides, followed by chromatographic separation and removal of the
chiral auxiliary. Alternatively, the compounds may be resolved
using a chiral HPLC column.
[0522] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the
art.
[0523] Even though the compounds of the present invention
(including their pharmaceutically, acceptable salts and
pharmaceutically acceptable solvates) can be administered alone,
they will generally be administered in admixture with a
pharmaceutical carrier, excipient or diluent selected with regard
to the intended route of administration and standard pharmaceutical
or veterinary practice. Thus, the present invention is directed to
pharmaceutical and veterinary compositions comprising compounds of
Formula (I) and one or more pharmaceutically acceptable carriers,
excipients or diluents.
[0524] By way of example, in the pharmaceutical and veterinary
compositions of the present invention, the compounds of the present
invention may be admixed with any suitable binder(s), lubricant(s),
suspending agent(s), coating agent(s), and/or solubilising
agent(s).
[0525] Tablets or capsules of the compounds may be administered
singly or two or more at a time, as appropriate. It is also
possible to administer the compounds in sustained release
formulations.
[0526] Alternatively, the compounds of the general Formula (I) can
be administered by inhalation or in the form of a suppository or
pessary, or they may be applied topically in the form of a lotion,
solution, cream, ointment or dusting powder. An alternative means
of transdermal administration is by use of a skin patch. For
example, they can be incorporated into a cream consisting of an
aqueous emulsion of polyethylene glycols or liquid paraffin. They
can also be incorporated, at a concentration of between 1 and 10%
by weight, into an ointment consisting of a white wax or white soft
paraffin base together with such stabilisers and preservatives as
may be required.
[0527] For some applications, preferably the compositions are
administered orally in the form of tablets containing excipients
such as starch or lactose, or in capsules or ovules either alone or
in admixture with excipients, or in the form of elixirs, solutions
or suspensions containing flavouring or coloring agents.
[0528] The compositions (as well as the compounds alone) can also
be injected parenterally, for example intracavernosally,
intravenously, intramuscularly or subcutaneously. In this case, the
compositions will comprise a suitable carrier or diluent.
[0529] For parenteral administration, the compositions are best
used in the form of a sterile aqueous solution which may contain
other substances, for example enough salts or monosaccharides to
make the solution isotonic with blood.
[0530] For buccal or sublingual administration the compositions may
be administered in the form of tablets or lozenges which can be
formulated in a conventional manner.
[0531] By way of further example, pharmaceutical and veterinary
compositions containing one or more of the compounds of the
invention described herein as the active ingredient can be prepared
by intimately mixing the compound or compounds with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending upon the desired route of administration (e.g.,
oral, parenteral). Thus for liquid oral preparations such as
suspensions, elixirs and solutions, suitable carriers and additives
include water, glycols, oils, alcohols, flavoring agents,
preservatives, stabilizers, coloring agents and the like; for solid
oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like. Solid oral preparations may also be coated with
substances such as sugars or be enteric-coated so as to modulate
the major site of absorption. For parenteral administration, the
carrier will usually consist of sterile water and other ingredients
may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous
carriers along with appropriate additives.
[0532] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those skilled in that art. To be administered in the form of a
transdermal delivery system, the dosage administration will, of
course, be continuous rather than intermittent throughout the
dosage regimen.
[0533] A therapeutically effective amount for use of the instant
compounds or a pharmaceutical composition thereof comprises a dose
range of from about 0.001 mg to about 1,000 mg, in particular from
about 0.1 mg to about 500 mg or, more particularly from about 1 mg
to about 250 mg of active ingredient per day for an average (70 kg)
human.
[0534] For oral administration, a pharmaceutical composition is
preferably provided in the form of tablets containing, 0.01, 0.05,
0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250
and 500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the subject to be treated.
[0535] It is also apparent to one skilled in the art that the
therapeutically effective dose for active compounds of the
invention or a pharmaceutical composition thereof will vary
according to the desired effect. Therefore, optimal dosages to be
administered may be readily determined and will vary with the
particular compound used, the mode of administration, the strength
of the preparation, and the advancement of the disease condition.
In addition, factors associated with the particular subject being
treated, including subject age, weight, diet and time of
administration, will result in the need to adjust the dose to an
appropriate therapeutic level. The above dosages are thus exemplary
of the average case. There can, of course, be individual instances
where higher or lower dosage ranges are merited, and such are
within the scope of this invention.
[0536] Compounds of this invention may be administered in any of
the foregoing compositions and dosage regimens or by means of those
compositions and dosage regimens established in the art whenever
use of the compounds of the invention as vanilloid receptor
modulators is required for a subject in need thereof.
[0537] The invention also provides a pharmaceutical or veterinary
pack or kit comprising one or more containers filled with one or
more of the ingredients of the pharmaceutical and veterinary
compositions of the invention. Optionally associated with such
container(s) can be a notice in the form prescribed by a
governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products, which notice reflects
approval by the agency of manufacture, use or sale for human
administration.
[0538] As modulators of the vanilloid VR1 ion channel, the
compounds of Formula (I) are useful in methods for treating or
preventing a disease or condition in a mammal which disease or
condition is affected by the modulation of one or more vanilloid
receptors. Such methods comprises administering to a mammal in need
of such treatment or prevention a therapeutically effective amount
of a compound, salt or solvate of Formula (I). In particular, the
compounds of Formula (I) are useful for in methods for preventing
or treating a chronic- or acute-pain causing diseases or conditions
and pulmonary dysfunction, and more particulalry, in treating
diseases or conditions that cause inflammatory pain, burning pain,
itch or urinary incontinence, and chronic obstructive pulmonary
disease.
[0539] By way of example only, the compounds of Formula (I) are
useful for treating diseases and conditions selected from the group
consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia,
migraine, headache, toothache, burn, sunburn, snake bite (in
particular, venomous snake bite), spider bite, insect sting,
neurogenic bladder, benign prostatic hypertrophy, interstitial
cystitis, urinary tract infection, cough, asthma, chronic
obstructive pulmonary disease, rhinitis, contact
dermatitis/hypersensitivity, itch, eczema, anxiety, panic
disorders, pharyngitis, mucositis, enteritis, cellulites,
peripheral neuropathy, bilateral peripheral neuropathy, diabetic
neuropathy, postherpetic neuralgia, trigeminal neuralgia,
causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral
neuritis, polyneuritis, stump pain, phantom limb pain, bony
fractures, post-operative ileus, irritable bowel syndrome,
inflammatory bowel diseases such as Crohn's Disease and ulcerative
colitis, cholecystitis, pancreatitis, postmastectomy pain syndrome,
oral neuropathic pain, Charcot's pain, reflex sympathetic
dystrophy, Guillain-Barre syndrome, meralgia paresthetica,
burning-mouth syndrome, optic neuritis, posifebrile neuritis,
migrating neuritis, segmental neuritis, Gombault's neuritis,
neuronitis, cervicobrachial neuralgia, cranial neuralgia,
geniculate neuralgia, glossopharyngial neuralgia, migrainous
neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary
neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital
neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine
neuralgia, supraorbital neuralgia, vidian neuralgia, sinus
headache, tension headache, labor, childbirth, intestinal gas,
menstruation, cancer, and trauma.
[0540] While the present invention comprises compositions
comprising one or more of the compounds of Formula (I), the present
invention also comprises compositoins comprising intermediates used
in the manufacture of compounds of Formula (I).
General Synthetic Methods
[0541] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and are illustrated in the schemes that follows.
Since the schemes are an illustration, the invention should not be
construed as being limited by the chemical reactions and conditions
expressed. The preparation of the various starting materials used
in the schemes is well within the skill of persons versed in the
art.
[0542] The ureas of formula (I) that comprise this invention are
synthesized using several distinct chemical methods. The general
transformations for constructing (3-aminotetralin-derived ureas
involve:
[0543] Preparation of suitably substituted .beta.-aminotetralin,
which is described in the general schemes below. Tetralone starting
materials were either purchased from commercial sources or were
prepared using the method reported by Sims (Sims, J. J. et. al.
Tetrahedron Lett. 1971, 951). Specifically, substituted
phenylacetic acids were separately reacted with ethylene gas and a
Lewis Acid such as aluminum trichloride to afford the desired
corresponding .beta.-tetralone.
[0544] An appropriately substituted .beta.-tetralone (II) is
reacted with an aryl or heteroaryl aldehyde in the presence of a
base such as piperidine, in an inert halohydrocarbon, ethereal or
hydrocarbon solvent, such as benzene, from ambient temperature to
reflux, to afford the corresponding
.alpha.-benzylidenyl-.beta.-tetralone or
.alpha.-heteroarylmethylidenyl-.beta.-tetralone (II). The
.beta.-tetralone (III) is dissolved in an inert hydrocarbon,
ethereal, ester or alcohol solvent, such as methanol, and reacted
with hydrogen gas at a pressure from ambient pressure to 100 p.s.i.
in the presence of a suitable catalyst such as palladium on carbon.
The reaction is performed at a temperature from ambient temperature
to reflux, to yield the desired
.alpha.-substituted-.beta.-tetralone (IV) (Scheme 1).
[0545] An alternative method for the preparation of
.alpha.-substituted-.beta.-tetralones (IV) involves the reaction of
an appropriately substituted .beta.-tetralone (II) with a base such
as pyrrolidine in an inert halohydrocarbon solvent such as
dichloromethane or hydrocarbon solvent such as benzene, under
Dean-Stark conditions (removal of water) or in an alcohol solvent
such as methanol, from ambient temperature to reflux, to afford
enamine (V). Alkylation of enamine (V) is accomplished by reaction
with a benzylic, heterocyclicalkanyl or an allylic halide in an
inert solvent such as acetonitrile, at a temperature from ambient
temperature to reflux, to afford the
.alpha.-substituted-.beta.-iminium salt (VI). Hydrolysis of the
salt (VI) to produce the desired
.alpha.-substituted-.beta.-tetralone product (IV) is accomplished
by reaction of (VI) with water and an inorganic or organic acid
such as hydrochloric or glacial acetic acid in an inert
hydrocarbon, ethereal, alcohol or halohydrocarbon solvent, or a
mixture thereof, such as methanol and dichloromethane (Scheme 1).
5
[0546] The .alpha.-substituted-.beta.-tetralones (IV) are converted
to the corresponding aminotetralins via reaction with an ammonium
salt such as ammonium acetate in the presence of a reducing agent
such as sodium cyanoborohydride, for example, in an inert
halohydrocarbon, hydrocarbon, ethereal or alcohol solvent such as
methanol to produce the cis-aminotetralin (VII). In some cases, the
trans-aminotetralin (VIII) is also formed as a minor product; both
sets of diastereomers are part of this invention. The
aminotetralins (VII) can also be isolated as acid addition salts by
treatment with an organic or an inorganic acid, such as
trifluoroacetic acid or hydrochloric acid, for example (Scheme 2).
6
[0547] Compounds in which m=0 are prepared from an appropriately
substituted aminotetralin (VII; m=0) starting from 1-tetralones
using the synthetic sequence shown in Scheme 2a. 7
[0548] Aminotetralin (VII) can be used in subsequent reactions as
the corresponding free base or as an acid addition salt. The use of
acid addition salts requires an additive, such as an organic base
like triethylamine or an inorganic base such as hydroxide, to
neutralize the acid and liberate the reactive nucleophilic amine
center. This common practice is well known to those skilled in the
art.
[0549] Aminotetralin VII is reacted with isocyanate or
isothiocyanate, in an appropriate inert solvent, with or without an
added base, to form ureas (IX) or thioureas (X), shown in Scheme 3.
8
[0550] In addition to isocyanates and isothiocyanates, other
carbamylating or thiocarbamylating agents may be used and this is
well known to those skilled in the art. Thus an appropriate amine,
such as an aminoisoquinoline, aminonaphthol or aminoquinoline, is
reacted with a chloroformate, such as phenyl chloroformate in an
inert solvent, with or without added base, to afford the
corresponding phenylcarbamates. Separately these carbamates are
reacted with aminotetralin (VI) in a polar solvent such as
dimethylsulfoxide, with or without added base, from room
temperature to approximately 150 C, to produce the
aminotetralin-derived ureas (IX) (Scheme 4). 9
[0551] The use of chlorothionoformates in the scheme above produces
the analogous aminotetralin-derived thioureas (X).
[0552] Isocyanates and isothiocyanates are also prepared by
reacting an amine with phosgene or thiophosgene in the presence of
a base. Benzylamines such as 4-alkanyloxy-3-methoxybenzylamine is
reacted with thiophosgene or a thiophosgene equivalent, in the
presence of a base, such as an organic amine, to produce the
corresponding thiocyanate. Subsequent reaction with aminotetralin
(VII) produces the corresponding aminotetralin-derived homovanillic
thioureas (Scheme 5). Protecting group manipulations may be used to
mask and subsequently liberate the phenolic OH group and this
practice is well known to those skilled in the art. 10
[0553] The use of (heteroaryl)alkanylamines, such as
pyridylmethylamine, produces the corresponding
aminotetralin-derived ureas in which R.sub.3=heteroaryl (Scheme 6).
Thiocarbamylation with aminotetralin, as described above, gives the
analogous thioureas. 11
[0554] minotetralin-derived ureas and thioureas with linking groups
(L) of varying length are produced via homologation of aryl- or
heteroaryl-carboxaldehydes or carboxylic acids. This practice is
well known in the literature and encompasses a wide variety of
chemical transformations, several of which are described below to
illustrate the strategy but are not intended to be inclusive.
[0555] Isoquinoline is reacted with
N-(hydroxymethyl)trifluoroacetamide in acid followed by reduction
to afford isoquinolin-5-yl-methylamine. Carbamylation using
aminotetralin as described above, produces aminotetralin-derived
ureas in which L=CH.sub.2 (methylene) (Scheme 7). 12
[0556] Aminonaphthalene is subjected to a Sandmeyer reaction,
namely diazotization followed by reaction with copper cyanide at
high temperature to produce the cyanonaphthalene. Reduction affords
naphthalen-2-yl-methylamine which is subjected to carbamylation
using aminotetralin (VII), as described above, to produce
aminotetralin-derived urea in which L CH.sub.2 (methylene) (Scheme
8). 13
[0557] Reaction of aryl- and heteroaryl-carboxaldehydes with
toluenesulfonyl methylisocyanide in the presence of base, with
subsequent hydrolysis affords the corresponding homologated
nitrile. Reduction produces the homologated amine which is
subjected to carbamylation with aminotetralin as described above to
yield aminotetralin-derived ureas in which L CH.sub.2CH.sub.2
(Scheme 9). 14
[0558] Heteroaryl- and aryl-carboxaldehydes are modified using
Wittig conditions to give the .alpha.,.beta.-unsaturated nitrile
which is reduced to the amine and subsequent carbamylated as
described above to yield aminotetralin-derived ureas in which
L=CH.sub.2CH.sub.2 CH.sub.2 (Scheme 10). 15
[0559] Homologation of heteroaryl- and aryl-carboxylic acids is
also accomplished using chemistry known as the Arndt-Eistert
synthesis, a procedure that converts carboxylic acids to the next
higher homolog using a three step synthesis. In the first
transformation, the carboxylic acid starting material is converted
to its acyl chloride, using thionyl chloride, oxalyl chloride or
another appropriate chlorinating agent. In the second step, the
acyl chloride is converted to a diazoketone via reaction with
diazomethane or a suitable equivalent. In the final transformation,
the diazoketone is oxidized to the homologous acid using an oxidant
such as silver oxide. The carboxylic acid group is then converted
to an isocyanate through the intermediacy of the acyl azide
(Curtius rearrangement) which is carried on to
aminotetralin-derived ureas and thioureas using the chemistry
described above. Alternatively, the carboxylic acid is reacted with
hydrazoic acid (or equivalent) under acid catalysis followed by
thermal decomposition to the amine (Schmidt reaction), which is
carried on to aminotetralin-derived ureas and thioureas using the
chemistry described above.
[0560] This chemistry and related variations are well known to
those skilled in the art.
[0561] Protecting group manipulations may be needed at various
stages of the syntheses depending upon substituents and functional
groups that are present on the reactants.
[0562] It is generally preferred that the respective product of
each process step be separated from other components of the
reaction mixture and subjected to purification before its use as a
starting material in a subsequent step. Separation techniques
typically include evaporation, extraction, precipitation and
filtration. Purification techniques typically include column
chromatography (Still, W. C. et. al., J. Org. Chem. 1978, 43,
2921), thin-layer chromatography, crystallization and distillation.
The structures of the final products, intermediates and starting
materials are confirmed by spectroscopic, spectrometric and
analytical methods including nuclear magnetic resonance (NMR), mass
spectrometry (MS) and liquid chromatography (HPLC). In the
descriptions for the preparation of compounds of this invention,
ethyl ether, tetrahydrofuran and dioxane are common examples of an
ethereal solvent; benzene, toluene, hexanes and cyclohexane are
typical hydrocarbon solvents and dichloromethane and dichloroethane
are representative halogenhydrocarbon solvents. In those cases
wherein the product is isolated as the acid addition salt the free
base may be obtained by techniques known to those skilled in the
art. In those cases in which the product is isolated as an acid
addition salt, the salt may contain one or more equivalents of the
acid.
[0563] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described above and are illustrated more particularly in the
schemes that follow. Since the schemes are illustrations, the
invention should not be construed as being limited by the chemical
reactions and conditions expressed. The preparation of the various
starting materials used in the schemes is well within the skill of
persons versed in the art.
EXAMPLE 1
1-(1-Benzyl-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-yl)-3-isoquinolin-5--
yl-urea
[0564] 16
[0565] Isoquinolin-5-yl-carbamic acid phenyl ester 1-1 (0.004 mole,
1.06 g) was dissolved in 15 mL of dimethylsulfoxide.
Diisopropylethyl amine (0.0044 mole, 0.57 g, 0.8 mL) was added
followed by addition of
1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine
hydrochloride 1-2 (0.0044 mole, 1.33 g). The reaction mixture was
stirred at room temperature for 16 hours. The reaction mixture was
then poured into 50 mL of water containing 10 mL of 1N sodium
hydroxide. The precipitated solid was collected by filtration. This
solid was chromatographed on silica gel eluting with methylene
chloride, 3% methanol. Subsequently the product was further
purified by recrystallization from ethyl acetate. The title
compound 33
(1-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-3--
isoquinolin-5-yl-urea) was obtained as an off-white solid (1.05 g,
0.0024 mole). MS (MH+): 438; .sup.1H NMR (CDCl.sub.3): .delta.
1.7-1.8 (m, 2H), 2.6-2.9 (m, 4H), 3.6 (s, 3H), 4.1 (m, 1H), 5.8 (d,
1H), 6.4-6.4 (m, 3H), 6.95 (d, 2H), 7.1 (m, 3H), 7.3 (t, 1H),
7.4-7.5 (m, 2H), 8.2 (d, 2H), 9.0 (s, 1H).
EXAMPLE 2
1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-3-isoquinolin-5-y-
l-urea
[0566] 17
[0567] Isoquinolin-5-yl-carbamic acid phenyl ester 2-1 (0.005 mole,
1.32 g) was dissolved in 15 mL of DMSO (dimethylsulfoxide) followed
by the addition of the aminotetralin
2-2,1-benzyl-6-fluoro-1,2,3,4-tetrahydro-na- phthalen-2-ylamine
(0.0044 mole, 1.12 g). The reaction mixture was then stirred at
room temperature for 16 hours. The reaction mixture was poured into
50 mL of water containing 10 mL of 1N NaOH (sodium hydroxide). The
precipitated solid was collected by filtration. This solid was
chromatographed on silica gel eluting with methylene chloride, 3%
methanol. Subsequently the product was further purified by
recrystallization from ethyl acetate. The title compound 38,
(1-(1-benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-
-yl-urea) was obtained as an off-white solid (1.25 g, 0.00295
mole). MS (MH+): 426; .sup.1H NMR (MeOH): 61.35 (m, 1H), 1.9 (m,
1H), 2.1-2.2 (m, 1H), 2.9-3.1 (m, 4H) 3.45 (m, 1H), 4.1-4.2 (m,
1H), 6.7 (t, 1H), 6.8-6.9 (m, 2H), 7.1-7.3 (m, 5H), 7.85 (t, 1H),
8.1 (d, 1H), 8.25 (d, 1H), 8.35 (d, 1H), 8.6 (d, 1H).
EXAMPLE 3
1-(1-cyclopropyl
methyl-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-3-iso-
quinolin-5-yl-urea
Compound 71
[0568]
1-Cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamin-
e hydrochloride (127 mg, 0.49 mmol), isoquinolin-5-yl-carbamic acid
phenyl ester (150 mg, 0.49 mmol), and diisopropylethylamine (193
mg, 1.47 mmol) were combined and stirred at ambient temperature in
DMSO (3 mL) overnight. The product was purified by directly
injecting the crude reaction onto a reverse phase prep-HPLC (10-90%
water:acetonitrile gradient). The appropriate fractions were
lyophilized to yield
1-(1-cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-iso-
quinolin-5-yl-urea 71 (68 mg, 0.14 mmol). MS (MH.sup.+) 390;
.sup.1H NMR (CD.sub.3OD) .delta. 0.08-0.87 (m, 2H), 1.60-1.65 (m,
2H), 2.03 (m, 1H), 2.97 (m, 2H), 3.14 (m, 1H), 4.36 (m, 1H), 6.87
(m, 2H), 7.27 (m, 1H), 7.93 (t, 1H, J=2.6 Hz), 8.14 (d, 1H, J=2.7
Hz), 8.32 (d, 1H, J=2.2 Hz), 8.47 (d, 1H, J=2.6 Hz), 8.53 (d, 1H,
J=2.2 Hz), 9.63 (s, 1H). HPLC R.sub.t=3.63 min (10-90%
water:acetonitrile gradient, 100% pure).
EXAMPLE 4
1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-3-isoquinolin-5-y-
lmethyl-urea
[0569] 18
[0570] Isoquinoline 4-1 (0.01 mole, 1.29 g) was dissolved in 50 mL
of concentrated H.sub.2SO.sub.4 (sulfuric acid) which had been
cooled to 0.degree. C. in an ice-water bath. The N-hydroxymethyl
trifluoroacetamide was then added in portions. The reaction mixture
was stirred at 0.degree. C. for 15 minutes and then allowed to warm
to room temperature and stirred for 16 hours. The clear light brown
reaction mixture was poured onto 200 g of ice then NH.sub.4OH
(ammonium hydroxide) was added until the reaction mixture was basic
to pH paper. The aqueous mixture was extracted with 100 mL of
CH.sub.2Cl.sub.2 (methylene chloride). The organic layer was
separated and washed with 2.times.100 mL of brine, dried over
Na.sub.2SO.sub.4 (sodium sulfate) and evaporated in vacuo. The
residue was chromatographed on silica gel eluting with 60/40
hexane/ethyl acetate to yield the trifluoroacetamide 4-2 product as
a white crystalline solid (0.008 mole, 2.03 g). MS (MH+): 255;
.sup.1H NMR (CDCl.sub.3): .delta. 5.0 (s, 2H), 7.6 (t, 1H), 7.8 (d,
1H), 7.95 (d, 1H), 8.1 (d, 1H), 8.5 (d, 1H), 9.2 (s, 1H).
[0571] The trifluoroacetamide 4-2 from step A (0.006 mole, 1.53 g)
was dissolved in 50 mL of methanol. Sodium borohydride (0.02 mole,
0.8 g) was then added and the reaction mixture was stirred at room
temperature for 2 hours. Thin layer chromatography (silica gel,
50/50 hexane/ethyl acetate) showed the reaction to be nearly
complete. An additional amount of sodium borohydride was added
(0.01 mole, 0.4 g) and stirring was continued for another 1 hour.
The reaction mixture was evaporated in vacuo. The residue was taken
up in 50 mL of CH.sub.2Cl.sub.2 and then washed with 2.times.50 mL
of brine, dried over Na.sub.2SO.sub.4 and evaporated in vacuo to
yield the amine product 4-3 as a clear oil (0.005 mole, 0.79 g). MS
(MH+): 159; .sup.1H NMR (CDCl.sub.3): .delta. 4.3 (s, 2H), 7.5 (t,
1H), 7.7 (d, 1H), 7.8 (d, 1H), 7.9 (d, 1H), 8.5 (d, 1H), 9.2 (s,
1H).
[0572] The amine 4-3 from step B (0.005 mole, 0.79 g) was dissolved
in 20 mL of tetrahydrofuran (THF). Pyridine (0.0055 mole, 0.44 g,
0.44 mL) was added followed by the careful addition of
phenylchloroformate (0.0055 mole, 0.86 g, 0.69 mL). The reaction
mixture immediately turned yellow and turbid. Stirring at room
temperature was continued for 2 hours. The reaction mixture was
evaporated in vacuo. The residue was taken up in 50 mL of
dichloromethane, washed with 2.times.100 mL saturated sodium
bicarbonate then 2.times.100 mL of water. The organic layer was
dried over sodium sulfate and evaporated in vacuo to give a thick
slightly yellow oil. This oil was triturated with diethylether and
then treated with 1M HCl/diethylether to give the carbamate
hydrochloride product 4-4 as an off-white solid. MS (MH+): 279;
.sup.1H NMR (MeOH): .delta. 4.6 (s, 2H), 6.8 (m, 1H), 7.1-7.4 (m,
4H), 7.9 (t, 2H), 8.1 (d, 1H), 8.5 (d, 1H), 8.8 (d, 1H), 9.8 (s,
1H).
[0573] The carbamate hydrochloride 4-4 from step C (0.0005 mole,
0.139 g) was dissolved in 2 mL of dimethylsulfoxide.
Diisopropylethyl amine (0.0011 mole, 0.142 g, 0.19 mL) was added
followed by addition of
1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine
hydrochloride (0.00055 mole, 0.297 g). The reaction mixture was
stirred at room temperature for 4 hours. The reaction mixture was
then poured into 20 mL of water containing 5 mL of 1N sodium
hydroxide and stirred at room temperature for 15 minutes. The
precipitated solid was collected by filtration. This cream colored
powder was recrystallized from ethyl acetate/hexane to afford the
title product 60, 1-(1-benzyl-fluoro-1,2,3,4-
-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-methyl urea as a
white chalky powder (0.000015 mole, 0.065 g). MS (MH+): 440;
.sup.1H NMR (CDCl.sub.3): .delta.1.8-2.0 (m, 2H), 2.8-3.0 (m, 4H),
4.1 (m 1H), 4.35 (d, 1H), 4.5 (m, 1H), 4.8 (d, 2H), 6.6-6.8 (m,
4H), 7.1-7.3 (m, 4H), 7.5 (t, 1H), 7.6 (d, 1H), 7.8 (d 1H), 7.9 (d,
1H), 8.6 (d, 1H), 9.2 (s, 1H).
EXAMPLE 5
1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-3-(7-hydroxy-naph-
thalen-1-yl)-urea
Compound 67
[0574] 8-Amino-naphthalen-2-ol (74 mg, 0.46 mmol) was added to a
solution of
1-benzyl-2-isocyanato-6-methoxy-1,2,3,4-tetrahydro-naphthalene (136
mg, 0.46 mmol) in acetonitrile (2 mL). The reaction was microwaved
for 5 min at 100.degree. C. The solvent was stripped off and the
residue chromatographed on a silica column using chloroform as
eluant to yield title compound 68 (95 mg, 45%) MS (MH.sup.+) 453;
.sup.1H NMR (CD.sub.3OD) .delta. 1.87 (m, 1H), 2.02 (m, 1H),
2.89-2.93 (m, 4H), 3.38 (m, 1H), 3.73 (s, 3H), 4.05 (m, 1H), 6.52
(d, 1H, J=3 Hz), 6.65 (m, 2H), 7.09 (d, 3H, J=2.4 Hz), 7.14 (d, 1H,
J=2.2 Hz), 7.21 (d, 2H, J=2.3 Hz), 7.26 (d, 2H, J=3.0 Hz),
7.52-7.58 (m, 2H), 7.72 (d, 1H, J=2.9 Hz). HPLC R.sub.t=4.73 min
(10-90% water:acetonitrile gradient, 100% pure).
EXAMPLE 6
1-(1-Benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(4-hydroxy-3-m-
ethoxy-benzyl)-thiourea
Compound 3
[0575] Sodium hydride (60% in oil, 2.81 g, 10 mmol) was added to a
solution of 4-hydroxy-3-methoxy-benzonitrile (10 g, 67 mmol) in DMF
(100 mL) at 0.degree. C. Mixture was allowed to stir at ambient
temperature for 30 min. Bromomethylmethyl ether (6.4 mL, 70 mmol)
was added to the resultant solution, and the solution was stirred
at rt for 2 h. The solution was poured into ice water (.about.400
mL). The product, 3-Methoxy-4-methoxymethoxy-benzonitrile, was
collected by filtration, washed generously with water, and allowed
to air dry to give the product as a colorless solid 11.75 g (91%).
The purity of the product was estimated to be (95% by HPLC and H
NMR, and the product was used without further purification in the
subsequent step). .sup.1H NMR (CDCl.sub.3): .delta. 3.51 (s, 3H),
3.91 (s, 3H), 5.23 (s, 2H), 7.12 (d, J=1.8 Hz, 1H), 7.20 (d, J=8.4
Hz, 1H) and 7.25 (d of d, J=8.4 & 1.8 Hz, 1H).
[0576] A solution of 3-methoxy-4-methoxymethoxy-benzonitrile (9.1
g, 47.1 mmol) in THF (75 mL) was slowly added, via an addition
funnel, to a solution of LAH in THF (1.0 M, 100 mL, 100 mmol)
cooled on an ice bath. The resultant solution was heated to reflux
for 4 h. The solution was cooled on an ice bath. Sequential
addition of water (3.5 mL), 15% aqueous sodium hydroxide (7 mL) and
water (10 mL) was carefully done via an addition funnel. The
inorganics were removed by filtration, and washed generously with
THF. The combined organic solutions were dried over sodium sulfate,
and the solvent was evaporated under vacuum to give the product,
5.3 g (57%). The product was used without purification in the
subsequent step. .sup.1H NMR (CDCl.sub.3): .delta. 1.58 (br s, 1H),
3.51 (s, 3H), 3.82 (s, 2H), 3.89 (s, 3H), 5.21 (s, 2H), 6.82 (d of
d, J=8.4 & 1.8 Hz, 1H), 6.90 (d, J=1.8 Hz) and 7.10 (d, J=8.1
Hz, 1H). MS: m/z 198 (M+H).sup.+.
[0577] A solution of 3-methoxy-4-methoxymethoxybenzylamine (5.3 g,
26.9 mmol) in ethyl acetate (50 mL) was added, via an addition
funnel) to a solution of thiophosgene (2.15 mL, 28.2 mmol) and
triethylamine (7.87 mL, 56.5 mmol) in ethyl acetate (30 mL) at
0.degree. C. The resultant solution was stirred at ambient
temperature overnight. The solution was washed with saturated
aqueous sodium bicarbonate and dried over sodium sulfate. The
solvent was evaporated in vacuo, and the residue was purified by
flash chromatography on silica gel eluted with ethyl
acetate/hexanes (1/9 to 3/7) to give the product,
4-isothiocyanatomethyl-- 2-methoxy-1-methoxymethoxy-benzene, as a
waxy tan solid, 4.9 g (76%). .sup.1H NMR (CDCl.sub.3): .delta. 3.51
(s, 3H), 3.91 (s, 3H), 4.64 (s, 2H), 5.23 (s, 2H), 6.83 (m, 2H) and
7.14 (d, J=8 Hz).
[0578] A solution of
cis-1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-- 2-ylamine
hydrochloride (0.306 g, 1.01 mmol), diisopropylethylamine (0.264
mL, 1.51 mmol) and
4-isothiocyanatomethyl-2-methoxy-1-methoxymethoxy-benz- ene (0.253
g, 1.06 mmol) in acetonitrile (10 mL) was stirred at ambient
temperature overnight. The solvent was evaporated in vacuo, and the
residue was purified by reverse phase preparative HPLC, on a C18
column eluted with a gradient of 40 to 90% acetonitrile in water
with 0.1% TFA, to give the product,
1-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen--
2-yl)-3-(3-methoxy-4-methoxymethoxy-benzyl)-thiourea, 0.21 g (41%).
.sup.1H NMR (CDCl.sub.3): .delta. 1.64 (br s, 1H), 1.85 (m, 1H),
2.04 (m, 1H), 2.63 (m, 1H), 2.82 (m, 2H), 2.98 (m, 1H), 3.33 (m,
1H), 3.49 (s, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 4.32 (br s, 2H),
5.19 (s, 2H), 5.7 (br s, 1H), 6.0 (br s, 1H), 6.64 (m, 3H), 6.80
(s, 1H), 6.91 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H) and 7.11 to
7.28 (m, 5H). MS: m/z 507 (M+H).sup.+.
[0579] A solution of
1-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-
-yl)-3-(3-methoxy-4-methoxymethoxy-benzyl)-thiourea (0.21 g, 0.42
mmol) in isopropanol/acetonitrile (10 mL/10 mL) was treated with
concentrated hydrochloric acid (1 mL) and stirred at ambient
temperature for 30 min. The solvent was evaporated under a stream
of nitrogen, and the residue was partitioned between
dichloromethane and water. The organic layer was collected and the
solvent was evaporated. The product was purified by flash
chromatography, on silica gel eluted with ethyl acetate/hexanes
(1/2) to give the title product, compound 3, as a colorless solid,
0.184 g (95%). .sup.1H NMR (CDCl.sub.3): .delta. 1.83 (m, 1H), 2.05
(m, 1H), 2.67 (m, 1H), 2.81 (m, 2H), 3.03 (br s, 1H), 3.78 (s, 3H),
3.84 (s, 3H), 4.25 (br s, 2H), 5.61 (s, 2H), 6.59 to 6.68(m, 3H),
6.74 (s, 1H), 6.80 (d, J=8 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H) and 7.12
to 7.29 (m, 5H). MS: m/z 463 (M+H).
EXAMPLE 7
1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(2-oxy-isoquino-
lin-5-yl)-urea
[0580] 19
[0581] The aminotetralin urea 1 (0.150 g, 0.00035 mol) was
dissolved in 5 mL of dichloromethane. The solid m-chloroperbenzoic
acid (0.066 g, 0.00039 mol) was added and the reaction mixture was
stirred at room temperature for 16 hours. Thin layer chromatography
(silica gel, CH.sub.2Cl.sub.2/5% MeOH) indicated the presence of
starting material. An additional portion of MCPBA was added (0.050
g) and stirring at room temperature was continued for another 4
hours. At the end of this period, the reaction was complete was
indicated by TLC. Saturated sodium bicarbonate (25 mL) was
cautiously added to the reaction mixture and the organic layer was
separated. The organic layer was washed with 25 mL of brine, dried
over Na.sub.2SO.sub.4 and evaporated in vacuo. The residue was
purified by flash chromatography on silica gel eluting with
CH.sub.2Cl.sub.2/4% MeOH. The product 2 was obtained as a light
brown powder (0.120 g, 0.00027 mol). .sup.1H NMR (CD.sub.3OD):
.delta. 1.8-2.1 (m, 2H), 2.9-3.1 (m, 4H), 3.6 (m, 1H), 4.2 (m, 1H),
6.6-6.9 (m, 3H), 7.1-7.3 (m, 5H), 7.6-7.8 (m, 2H), 8.0 (bd, 1H),
8.2 (bt, 2H), 8.9 (s, 1H); MS (M+): 442.
EXAMPLE 8
1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-chloro-isoqu-
inolin-5-yl)-urea
Compound 79
[0582] (1-Chloro-isoquinolin-5-yl)-carbamic acid phenyl ester (150
mgs, 0.5 mmol),
I-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine
hydrochloride (146 mgs, 0.5 mmol), and sodium bicarbonate (42 mgs,
0.5 mmol) were combined and stirred for one hour in DMSO (4 ml) at
ambient temperature. The product was purified by directly injecting
the crude reaction onto a reverse phase prep-HPLC (10-90%
water:acetonitrile gradient). The appropriate fractions were
lyophilized to yield
1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-chloro-isoq-
uinolin-5-yl)-urea (64 mgs, 28%) MS (MH.sup.+) 459; .sup.1H NMR
(CD.sub.3OD) .delta. 1.93-2.06 (m, 1H), 2.09-2.13 (m, 1H),
2.91-3.07 (m, 4H), 3.40-3.42 (m, 1H), 4.07-4.10 (s, 1H), 6.69-6.78
(m, 1H), 6.80-6.89 (m, 2H), 7.12-7.26 (m, 5H), 7.72 (t, 1H, J=8.2
Hz), 7.83 (d, 1H, J=6.1 Hz), 8.19 (d, 1H, J=8.6 Hz), 8.17-8.24 (m,
2H). HPLC R.sub.t=4.04 min (50-90% water:acetonitrile gradient,
100% pure).
EXAMPLE 9
1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-methyl-isoqu-
inolin-5-yl)-urea
[0583] 20
[0584] A. 1-Methyl-5-aminoisoquinoline (J. Med Chem., 1968,
11,700), (0.01 mole, 1.58 g) was dissolved in 20 mL of
tetrahydrofuran (THF). Pyridine (0.011 mole, 0.88 g, 0.88 mL) was
added followed by the careful addition of phenylchloroformate
(0.011 mole, 1.72 g, 1.4 mL). The reaction mixture immediately
turned yellow and turbid. Stirring at room temperature was
continued for 4 hours. The reaction mixture was evaporated in
vacuo. The residue was taken up in 50 mL of dichloromethane, washed
with 2.times.100 mL saturated sodium bicarbonate then 2.times.100
mL of water. The organic layer was dried over sodium sulfate and
evaporated in vacuo to give a thick dark yellow-brown oil. This oil
was triturated with diethylether to give the carbamate product I as
a yellowish-brown solid.
[0585] .sup.1H NMR (CDCl.sub.3): .delta. 3.0 (bs, 3H), 7.2 (m, 3H),
7.3-7.4 (m, 2H), 7.5-7.6 (m, 2H), 7.8 (bs, 1H), 8.2 (bs, 1H), 8.4
(bt, 1H). MS (MH+): 279 21
[0586] B. 1-Methyl-isoquinolin-5-yl-carbamic acid phenyl ester 1
obtained in step A (0.001 mole, 0.278 g) was dissolved in 5 mL of
dimethylsulfoxide. Diisopropylethyl amine (0.0011 mole, 0.14 g, 0.2
mL) was added followed by the addition of
1-benzyl-6-fluoro-1,2,3,4-tetrahydr- o-naphthalen-2-ylamine
hydrochloride 2 (0.0011 mole, 0.321 g). The reaction mixture was
stirred at room temperature for 16 hours. The reaction mixture was
then poured into 20 mL of water containing 5 mL of 1N sodium
hydroxide. The precipitated solid was collected by filtration. This
solid was chromatographed on silica gel eluting with a gradient of
methylene chloride/3-10% methanol. Subsequently the product was
further purified by recrystallization from ethyl acetate. The title
compound 3 was obtained as an off-white solid (0.272 g, 0.0006
mole).
[0587] .sup.1H NMR (CDCl.sub.3): .delta. 1.8-1.9 (m, 2H), 2.7-2.8
(m, 4H), 2.95 (s, 3H), 3.2-3.2 (m, 1H), 4.1-4.2 (m, 1H), 5.1 (d,
1H), 6.4-6.6 (m, 2H), 6.8 (d, 1H), 6.9 (s, 1H), 7.0 (d, 1H),
7.1-7.2 (m, 2H), 7.4-7.5 (m, 2H), 7.7 (d, 1H), 7.9 (d, 1H), 8.3 (d,
1H).
[0588] MS (MH+): 440
EXAMPLE 10
Spiro{indan-2,1'-(1',2',3',4'-tetrahydronaphthalene)-2'-yl}-3-isoquinolin--
5-yl-urea
[0589] 22
[0590] A. 6-Fluoro-3,4-dihydro-1H-naphthalen-2-one (2.472 g, 15.06
mmol) was dissolved in 75 mL THF and cooled on an ice bath with
stirring under nitrogen. o-Xylene dibromide (4.378 g, 16.59 mmol)
was added to the cooled tetralone solution. Separately potassium
tert-butoxide (3.73 g, 33.2 mmol) was slurried in a combination of
75 mL THF and 10 mL tBuOH. The KOtBu slurry was added to the
reaction mixture over a period of 15 minutes. The reaction was
stirred on the ice bath for one hour then at room temperature for
an additional hour after which time the entire reaction mixture was
filtered over a pad of celite. The filtrate was evaporated in vacuo
to give a residue which was taken up in 100 mL diethyl ether,
washed twice with 50 mL 1N HCl and once with 50 mL brine. The
organics were dried with MgSO.sub.4, filtered and evaporated in
vacuo to give the crude product which was purified by
chromatography over silica gel eluting with 0-10% EtOAc in hexanes.
Evaporation of the proper fractions yielded the product as an
off-white solid (3.09 g, 11.6 mmol). .sup.1H NMR (CDCl.sub.3):
.delta. 7.33-7.17 (m, 4H), 7.07 (q, 1H), 6.93 (dd, 1H), 6.82 (dt,
1H), 3.81 (d, 2H), 3.19 (m, 4H), 2.79 (t, 2H).
[0591] B. The spirotetralone from step A (3.06 g, 11.5 mmol) was
dissolved in 150 mL MeOH along with NH.sub.4OAc (13.57 g, 176.1
mmol) and NaCNBH.sub.3 (3.7 g, 59 mmol). The mixture was kept under
a nitrogen atmosphere and heated to reflux for 3 hours. The
reaction was concentrated in vacuo, mixed with 100 mL water and
basified with 25 mL 50% NaOH. The basified mixture was extracted
three times with 50 mL methylene chloride. The combined organics
were washed once with 50 ml brine, dried with Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give the crude free base. The
free base was then dissolved in diethyl ether, acidified with
ethereal HCl and evaporated in vacuo. The solid residue was
triturated with 50 mL hot EtOAc, filtered and dried to yield the
product HCl salt as a white powder (2.867 g, 9.44 mmol). MS:
M+H.sup.+=268.1; .sup.1H NMR (d6-DMSO): .delta. 8.22 (br s, 3H),
7.33 (d, 1H), 7.24 (m, 3H), 7.01 (d, 1H), 6.87 (d, 2H), 3.71 (m,
1H), 3.52 (d, 1H), 3.38 (d, 1H), 3.11 (d, 1H), 2.97 (m, 3H), 2.15
(m, 2H).
[0592] C. The spirotetralin salt from step B (0.304 g, 1.00 mmol)
was dissolved in 6 mL DMSO along with iPr.sub.2NEt (0.38 mL, 2.2
mmol) and 5-aminoisoquinoline phenylcarbamate (0.308 g, 1.02 mmol).
The reaction was stirred overnight then poured into 100 mL water.
The solid which formed was collected by filtration, rinsed with
water then triturated first with diethyl ether and finally with
hexanes to give the product urea as a tan powder (0.287 g, 0.66
mmol). MS: M+H.sup.+=438.4; .sup.1H NMR (d6-DMSO): .delta. 9.27 (s,
1H), 8.67 (s, 1H), 8.52 (d, 1H), 8.38 (d, 1H), 7.89 (d, 1H), 7.72
(d, 1H), 7.61 (t, 1H), 7.32 (d, 1H), 7.70 (m, 3H), 7.04 (dd, 1H),
7.00-6.76 (m, 3H), 4.26 (m, 1H), 3.39 (m, 2H), 3.19 (d, 1H),
3.05-2.88 (m, 3H), 2.18-1.92 (m, 2H).
EXAMPLE 11
Experimental Protocol for Resolution
[0593] 23
[0594] A.
6-F-.alpha.-(3-trifluoromethylbenzyl)-.beta.-aminotetralin (1.931
g, 5.97 mmol) was dissolved in 50 mL 1:1 iPrOH/MeOH.
(R)-(-)-O-Methyl mandelic acid (0.992 g, 5.97 mmol) was added and
the mixture was heated to reflux. An additional 170 mL 1:1
iPrOH/MeOH was added to bring the total volume of solvent to 220 mL
and make a clear solution. The solution was then allowed to sit and
cool overnight. The resulting crystalline material was collected by
filtration, rinsed with a small amount of 1:1 iPrOH/MeOH and dried.
This batch of crystals was re-crystallized as before from 125 mL
1:1 iPrOH/MeOH. After filtration and drying, 625 mg of the salt of
the aminotetralin with (R)-(-)-O-methyl mandelic acid (1.28 mmol)
were obtained.
[0595] B. The combined mother liquors, filtrates, and rinsates from
above were evaporated under vacuum. The residue was partitioned
between 200 mL Et.sub.2O and 100 mL 10% Na.sub.2CO.sub.3 solution.
The organics were separated, washed again with 100 mL 10%
Na.sub.2CO.sub.3 and then with 100 mL brine. The organics were
dried over Na.sub.2SO.sub.4, treated with charcoal, filtered and
evaporated in vacuo to give the recovered aminotetralin (1.399 g,
4.33 mmol). To this was added (S)-(+)--O-methyl mandelic acid
(0.719 g, 4.33 mmol) and 190 mL 1:1 iPrOH/MeOH and the mixture was
heated to reflux to give a clear solution. The solution was then
allowed to sit and cool overnight. The resulting crystalline
material was collected by filtration, rinsed with a small amount of
1:1 iPrOH/MeOH and dried. This batch of crystals was
re-crystallized as before from 140 mL 1:1 iPrOH/MeOH. After
filtration and drying, 759 mg of the salt of the aminotetralin with
(S)-(+)--O-methyl mandelic acid (1.55 mmol) were obtained.
[0596] C. Each of the mandelate salts thus prepared was separately
suspended in 100 mL Et.sub.2O, washed with 50 mL 10%
Na.sub.2CO.sub.3 then with 50 mL brine. The organics were then
dried with Na.sub.2SO.sub.4, filtered and evaporated in vacuo. The
residue was dissolved in MeOH and excess ethereal HCl was added.
The mixture was evaporated in vacuo and the resulting solids were
triturated with hexanes, filtered and dried under vacuum.
[0597] The HCl salt derived from the aminotetralin resolved with
(R)-(-)-O-methyl mandelic acid (0.422 g, 1.17 mmol):
[.alpha.].sub.D=-159.0.degree. (c=1, MeOH).
[0598] The HCl salt derived from the aminotetralin resolved with
(S)-(+)-O-methyl mandelic acid (0.506 g, 1.41 mmol):
[.alpha.].sub.D=+159.1.degree.(c=1, MeOH).
[0599] The .sup.1H NMR spectra of the hydrochloride salts were
identical: .sup.1H NMR (d6-DMSO): 8.64 (br s, 3H), 7.59 (d, 1H),
7.52 (t, 1H), 7.42 (m, 2H), 6.99 (dd, 1H), 6.63 (dt, 1H), 5.91 (dd,
1H), 3.59 (m, 1H), 3.34-3.19 (m, 2H), 3.08 (m, 1H), 2.92 (m, 1H),
2.59 (d, 1H), 2.08 (m, 2H). MS: M+H.sup.+=324.1.
[0600] D. Other resolutions were performed in a similar manner to
yield the results as shown in the table below.
1 [.alpha.].sub.D of the HCl Salts (c = 1, Racemic Amine Resolving
Acid Solvent MeOH) 24 25 1:1 iPrOH:MeOH
+159.1.degree./-159.0.degree. 26 27 iPrOH
+213.0.degree./-216.6.degree. 28 29 14-67:1 EtOH:H.sub.2O
+70.7.degree./-71.4.degree.
[0601] Using the procedures of the Examples above and the
appropriate reagents, starting materials and purification methods
known to those skilled in the art, other compounds of the present
invention may be prepared including, but not limited to:
2TABLE 1 Mass Spectral Data for Selected Compounds Parent Peak No.
Substituents on Formula (Ia) MW (calc) (obs) 3 R.sub.1 is 6-OMe,
R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 462.6 463.1
(3-OMe-4-OH)Ph, and X is S; (cis) 4 R.sub.1 is H, R.sub.2 is
3-Pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is 477.6 477.8
(3-OMe-4-(Methoxymethylen- eoxy)Ph, and X is S; (cis) 5 R.sub.1 is
H, R.sub.2 is 3-Pyridinyl, m is 1, L is --CH.sub.2--, R.sub.3 is
(3-OMe-4-OH)Ph, and X is S; (cis) 6 R.sub.1 is 6-OMe, R.sub.2 is
3-Pyridinyl, m is 1, L is --CH.sub.2--, 463.6 464.1 R.sub.3 is
(3-OMe-4-OH)Ph, and X is S; (cis) 7 R.sub.1 is 6-OMe, R.sub.2 is
--CH.dbd.CH.sub.2, m is 1, L is --CH.sub.2--, R.sub.3 456.6 457.1
is (3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S; (cis) 8 R.sub.1 is
6-OMe, R.sub.2 is 4-Imidazolyl, m is 1, L is --CH.sub.2--, 452.6
453.1 R.sub.3 is (3-OMe-4-OH)Ph, and X is S; 9 R.sub.1 is 6-OMe,
R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 444.5 445.1
(3,4-methylenedioxy)Ph, and X is O; 10 R.sub.1 is 6-OMe, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 460.6 461.1
(3,4-diOMe)Ph, and X is O; 11 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is
1, L is --CH.sub.2--, R.sub.3 is 456.6 457.2 (4-tBu)Ph, and X is O;
12 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is
--CH.sub.2CH.sub.2--, R.sub.3 is 449.0 449.1 (4-Cl)Ph, and X is O;
13 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is
--CH.sub.2CH.sub.2--, R3 is 474.6 475.1 (3,4-diOMe)Ph, and X is O;
14 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is --CH.sub.2--,
R.sub.3 is 460.6 461.1 (3,4-methylenedioxy)Ph, and X is S; 15
R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3
is 476.6 477.1 (3,4-diOMe)Ph, and X is S; 16 R.sub.1 is 6-OMe,
R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 472.7 473.1
(4-tBu)Ph, and X is S; 17 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1,
L is --CH.sub.2CH.sub.2--, R.sub.3 is 465.1 465.0 (4-Cl)Ph, and X
is S; 18 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is
--CH.sub.2CH.sub.2--, R.sub.3 is 490.7 491.1 (3,4-diOMe)Ph, and X
is S; 19 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is
--CH.sub.2--, R.sub.3 is 446.5 447.1 (3-OMe-4-OH)Ph, and X is O; 21
R.sub.1 is H, R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
476.6 476.7 (3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S; (cis) 23
R.sub.1 is H, R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
432.6 433.1 (3-OMe-4-OH)Ph, and X is S; (cis) 24 R.sub.1 is 6-OMe,
R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 499.7 500.3
(4-N(Me)(C.sub.5H.sub.11))Ph, and X is O; 25 R.sub.1 is 6-OMe,
R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 511.7 512.3
(4-[N(Me)(cyclohexyl)])Ph, and X is O; 26 R.sub.1 is 6-F, R.sub.2
is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 450.6 451.1
(3,4-diOMe)Ph, and X is S; (cis) 27 R.sub.1 is 6-OMe, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 468.5 469.3
(4-CF.sub.3)Ph, and X is O; 28 R.sub.1 is 6-OMe, R.sub.2 is Ph, m
is 1, L is --CH.sub.2--, R.sub.3 is 469.4 469.1 (3,4-diCl)Ph, and X
is O; 29 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is
--CH.sub.2CH.sub.2--, R.sub.3 is 483.4 483.7 (3,4-diCl)Ph, and X is
O; 30 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is --CH.sub.2--,
R.sub.3 is 484.6 485.6 (4-CF.sub.3)Ph, and X is S; 31 R.sub.1 is
6-OMe, R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 485.5
485.0 (3,4-diCl)Ph, and X is S; 32 R.sub.1 is 6-OMe, R.sub.2 is Ph,
m is 1, L is --CH.sub.2--CH.sub.2--, R.sub.3 is 499.5 499.0
(3,4-diCl)Ph, and X is S; 33 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is
1, L is a direct bond, 437.5 438.4 R.sub.3 is 5-isoquinolinyl, and
X is O; 34 R.sub.1 is 6-OMe, R.sub.2 is Ph, m is 1, L is a direct
bond, 437.5 438.7 R.sub.3 is 3-quinolinyl, and X is O; 35 R.sub.1
is 6-OMe, R.sub.2 is Ph, m is 1, L is a direct bond, 452.5 453.1
R.sub.3 is 8-(2-naphtholyl), and X is O; 36 R.sub.1 is H, R.sub.2
is H, m is 0, L is a direct bond, R.sub.3 is 317.4 359.1
5-isoquinolinyl, and X is O; (MeCN) 37 R.sub.1 is 6-F, R.sub.2 is
H, m is 0, L is a direct bond, R.sub.3 is 335.4 336.2
5-isoquinolinyl, and X is O; 38a R.sub.1 is 6-F, R.sub.2 is Ph, m
is 1, L is a direct bond, R.sub.3 is 425.5 426.3 5-isoquinolinyl,
and X is O; (racemate) 38b R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L
is a direct bond, R.sub.3 is 425.5 426 5-isoquinolinyl, and X is O;
(enantiomer 1) 38c R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is a
direct bond, R.sub.3 is 425.5 426 5-isoquinolinyl, and X is O;
(enantiomer 2) 39 R.sub.1 is 6-Br, R.sub.2 is Ph, m is 1, L is a
direct bond, R.sub.3 is 486.4 485.9 5-isoquinolinyl, and X is O;
(cis) 40 R.sub.1 is 6,7-diOMe, R.sub.2 is Ph, m is 1, L is a direct
467.6 468.2 bond, R.sub.3 is 5-isoquinolinyl, and X is O; (cis) 41
R.sub.1 is 7-Cl, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3
is 441.9 442.0 5-isoquinolinyl, and X is O; (cis) 42 R.sub.1 is
5-Cl, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 441.9
441.9 5-isoquinolinyl, and X is O; (cis) 43 R.sub.1 is H, R.sub.2
is Ph, m is 1, L is a direct bond, R.sub.3 is 407.5 408.2
5-isoquinolinyl, and X is O; 44 R.sub.1 is 6-OMe, R.sub.2 is
(3-Cl)Ph, m is 1, L is a direct 472.0 472.3 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (cis) 45 R.sub.1 is 6-OMe, R.sub.2 is
3-Pyridinyl, m is 1, L is a direct 438.5 439.0 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (cis) 46 R.sub.1 is 6-OMe, R.sub.2 is
(3-Cl)Ph, m is 1, L is a direct 472.0 471.9 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (trans) 47 R.sub.1 is 6-OMe, R.sub.2
is 3-Pyridinyl, m is 1, L is a direct 438.5 438.8 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (trans) 48 R.sub.1 is 6,7-diOMe,
R.sub.2 is Ph, m is 1, L is a direct 467.6 468.2 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (trans) 49 R.sub.1 is 6-OMe, R.sub.2
is (2-Cl)Ph, m is 1, L is a direct 472.0 473.3 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (cis) 50 R.sub.1 is 6-OMe, R.sub.2 is
(4-Cl)Ph, m is 1, L is a direct 472.0 472.3 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (cis) 51 R.sub.1 is 6-OMe, R.sub.2 is
H, m is 0, L is a direct bond, R.sub.3 347.4 348.6 is
5-isoquinolinyl, and X is O; 52 R.sub.1 is 6-OMe, R.sub.2 is
(2-Cl)Ph, m is 1, L is a direct 472.0 472.2 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (trans) 53 R.sub.1 is 6-OMe, R.sub.2
is (2-CF.sub.3)Ph, m is 1, L is a direct 505.5 506.4 bond, R.sub.3
is 5-isoquinolinyl, and X is O; 54 R.sub.1 is 6-OMe, R.sub.2 is
(3-CF.sub.3)Ph, m is 1, L is a direct 505.5 506.4 bond, R.sub.3 is
5-isoquinolinyl, and X is O; 55 R.sub.1 is 6-OMe, R.sub.2 is
(4-CF.sub.3)Ph, m is 1, L is a direct 505.5 506.3 bond, R.sub.3 is
5-isoquinolinyl, and X is O; 56 R.sub.1 is 6-OH, R.sub.2 is Ph, m
is 1, L is a direct bond, R.sub.3 423.5 424.2 is 5-isoquinolinyl,
and X is O; 57 R.sub.1 is H, R.sub.2 is --CH.dbd.CH.sub.2, m is 1,
L is a direct bond, 357.4 358.2 R.sub.3 is 5-isoquinolinyl, and X
is O; 58 R.sub.1 is 6-Br, R.sub.2 is H, m is 0, L is a direct bond,
R.sub.3 is 396.3 397.9 5-isoquinolinyl, and X is O; 59 R.sub.1 is
6-Cl, R.sub.2 is H, m is 0, L is a direct bond, R.sub.3 is 351.8
351.9 5-isoquinolinyl, and X is O; 60 R.sub.1 is 6-F, R.sub.2 is
Ph, m is 1, L is --CH.sub.2--, R.sub.3 is 439.5 440.2
5-isoquinolinyl, and X is O; 61 R.sub.1 is 7-Cl, R.sub.2 is H, m is
0, L is a direct bond, R.sub.3 is 351.8 351.9 5-isoquinolinyl, and
X is O; 62 R.sub.1 is 8-Cl, R.sub.2 is Ph, m is 1, L is a direct
bond, R.sub.3 is 441.9 441.9 5-isoquinolinyl, and X is O; 63
R.sub.1 is 6-OMe, R.sub.2 is (4-CN)Ph, m is 1, L is a direct 462.6
463.2 bond, R.sub.3 is 5-isoquinolinyl, and X is O; 64 R.sub.1 is
6-OMe, R.sub.2 is (4-Br)Ph, m is 1, L is a direct 516.4 517.9 bond,
R.sub.3 is 5-isoquinolinyl, and X is O; 65 R.sub.1 is 6-Cl, R.sub.2
is CN, m is 1, L is a direct bond, R.sub.3 390.0 390.9 is
5-isoquinolinyl, and X is O; (cis) 66 R.sub.1 is 6,7-diF, R.sub.2
is Ph, m is 1, L is a direct bond, 443.5 443.9 R.sub.3 is
5-isoquinolinyl, and X is O; 67 R.sub.1 is 6-F, R.sub.2 is Ph, m is
1, L is a direct bond, R.sub.3 is 440.5 441.1 8-(2-naphtholyl), and
X is O; 68 R.sub.1 is 6-OMe, R.sub.2 is --CH.dbd.CH.sub.2, m is 1,
L is a direct 387.5 388.4 bond, R.sub.3 is 5-isoquinolinyl, and X
is O; 69 R.sub.1 is 6-F, R.sub.2 is --CH.dbd.CH.sub.2, m is 1, L is
a direct 375.4 376.4 bond, R.sub.3 is 5-isoquinolinyl, and X is O;
70 R.sub.1 is 6-OMe, R.sub.2 is (4-OMe)Ph, m is 1, L is a direct
467.6 468.2 bond, R.sub.3 is 5-isoquinolinyl, and X is O; (trans)
71 R.sub.1 is 6-F, R.sub.2 is Cyclopropyl, m is 1, L is a direct
389.5 390.5 bond, R.sub.3 is 5-isoquinolinyl, and X is O; 72
R.sub.1 is 6-OMe, R.sub.2 is (4-OMe)Ph, m is 1, L is a direct 467.6
468.2 bond, R.sub.3 is 5-isoquinolinyl, and X is O; (cis) 73
R.sub.1 is 6-OMe, R.sub.2 is (2-OMe)Ph, m is 1, L is a direct 467.6
468.2 bond, R.sub.3 is 5-isoquinolinyl, and X is O; 74 R.sub.1 is
6-OMe, R.sub.2 is (4-Benzyloxy)Ph, m is 1, L is a 543.4 544.1
direct bond, R.sub.3 is 5-isoquinolinyl, and X is O; 75 R.sub.1 is
6-OMe, R.sub.2 is Ph, m is 1, L is --CH.sub.2--, R.sub.3 is
4-Pyridinyl, and X is O; 76 R.sub.1 is 6-F, R.sub.2 is 2-Thienyl, m
is 1, L is a direct 431.5 432.0 bond, R.sub.3 is 5-isoquinolinyl,
and X is O; 77 R.sub.1 is 6-OMe, R.sub.2 is (2,6-diF)Ph, m is 1, L
is a direct 473.5 474.4 bond, R.sub.3 is 5-isoquinolinyl, and X is
O; 81a R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is a direct bond,
R.sub.3 is 439.5 440 3-Me-5-isoquinolinyl, and X is O; (cis)
(enantiomer 1) 81b R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is a
direct bond, R.sub.3 is 439.5 440 3-Me-5-isoquinolinyl, and X is O;
(cis) (enantiomer 2) 85a R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L
is a direct bond, R.sub.3 is 441.5 442 5-isoquinolinyl-N-oxide, and
X is O; (cis) (enantiomer 1) 85b R.sub.1 is 6-F, R.sub.2 is Ph, m
is 1, L is a direct bond, R.sub.3 is 441.5 442
5-isoquinolinyl-N-oxide, and X is O; (cis) (enantiomer 2) 86
R.sub.1 is 6-Cl, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3
442 442 is 5-isoquinolinyl, and X is O; 87 R.sub.1 is 6-OCH.sub.3,
R.sub.2 is Ph, m is 1, L is a direct bond, 437.5 438.2 R.sub.3 is
5-isoquinolinyl, and X is O; (cis) (enantiomer 2) 88 R.sub.1 is
6-F, R.sub.2 is 3-furanyl, m is 1, L is a direct bond, 415.5 416.4
R.sub.3 is 5-isoquinolinyl, and X is O; (cis) 89 R.sub.1 is
6-OCH.sub.3, R.sub.2 is 3-thienyl, m is 1, L is a direct 443.6
444.4 bond, R.sub.3 is 5-isoquinolinyl, and X is O 90 R.sub.1 is
6-OCH.sub.3, R.sub.2 is 2,4 di-F Ph, m is 1, L is a direct 473.5
474.4 bond, R.sub.3 is 5-isoquinolinyl, and X is O; (cis) 91
R.sub.1 is 6-OCH.sub.3, R.sub.2 is 2,4 di-F Ph, m is 1, L is a
direct 473.5 474.5 bond, R.sub.3 is 5-isoquinolinyl, and X is O;
(trans) 92 R.sub.1 is 6-OCH.sub.3, R.sub.2 is Ph, m is 1, L is a
direct bond, R.sub.3 437.5 438.1 is 5-isoquinolinyl, and X is O;
(cis) (enantiomer 1) 93 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is
a direct bond, R.sub.3 is 425.5 426.4 5-isoquinolinyl, and X is O;
(cis) (enantiomer 1) 94 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is
a direct bond, R.sub.3 is 425.5 426.6 5-isoquinolinyl, and X is O;
(cis) (enantiomer 2) 95 R.sub.1 is 6-Cl, R.sub.2 is Ph, m is 1, L
is a direct bond, R.sub.3 is 442.0 442.5 5-isoquinolinyl, and X is
O; (cis) 96 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is a direct
bond, R.sub.3 is 441.5 442.7 5-isoquinolinyl-N-oxide, and X is O;
(cis) (enantiomer 1) 97 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is
a direct bond, R.sub.3 is 441.5 442.8 5-isoquinolinyl-N-oxide, and
X is O; (cis) (enantiomer 2) 98 R.sub.1 is 6-F, R.sub.2 is Ph, m is
1, L is a direct bond, R.sub.3 is 460.0 460 4-Cl-5-isoquinolinyl,
and X is O; (cis) 99 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is a
direct bond, R.sub.3 is 460.0 460 4-Cl-5-isoquinolinyl, and X is O;
(cis) 100 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is a direct
bond, R.sub.3 is 439.5 440.3 3-methyl-5-isoquinolinyl, and X is O;
(cis) (enantiomer 1) 101 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L
is a direct bond, R.sub.3 is 439.5 440.3 3-methyl-5-isoquinolinyl,
and X is O; (cis) (enantiomer 2) 102 R.sub.1 is 6-F, R.sub.2 is Ph,
m is 1, L is a direct bond, R.sub.3 is 439.5 440.5
1-methyl-5-isoquinolinyl, and X is O; (cis) (enantiomer 1) 103
R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3
is 439.5 440.5 1-methyl-5-isoquinolinyl, and X is O; (cis)
(enantiomer 2) 104 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1, L is a
direct bond, R.sub.3 is 459.96 459.6 1-Cl-5-isoquinolinyl, and X is
O; (cis) (enantiomer 1) 105 R.sub.1 is 6-F, R.sub.2 is Ph, m is 1,
L is a direct bond, R.sub.3 is 460.0 459.9 1-Cl-5-isoquinolinyl,
and X is O; (cis) (enantiomer 2) 106 R.sub.1 is 6-Cl, R.sub.2 is
Ph, m is 1, L is a direct bond, R.sub.3 is 457.9 459.0
5-isoquinolinyl-N-oxide, and X is O; (cis) 107 R.sub.1 is 6-F,
R.sub.2 is 4-CF.sub.3 Ph, m is 1, L is a direct bond, 493.5 494.5
R.sub.3 is 5-isoquinolinyl, and X is O; (cis) 108 R.sub.1 is 6-F,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 494.4 494
1,3-diCl-5-isoquinolinyl, and X is O; (cis) 109 R.sub.1 is 6-F,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 494.4 494
1,3-diCl-5-isoquinolinyl, and X is O; (cis) 110 R.sub.1 is 6-F,
R.sub.2 is 3-CF.sub.3 Ph, m is 1, L is a direct bond, 493.5 494.6
R.sub.3 is 5-isoquinolinyl, and X is O; (.+-.cis) 111 R.sub.1 is
6-F, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 460.0
460 8-Cl-5-isoquinolinyl, and X is O; (cis 112 R.sub.1 is 6-F,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 508.6 509
1-piperidinyl-5-isoquinolinyl, and X is O; (cis) 113 R.sub.1 is
6-F, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 455.5
456 1-OCH.sub.3-5-isoquinolinyl, and X is O; (cis) 114 R.sub.1 is
6-F, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 443.5
444 1-F-5-isoquinolinyl, and X is O; (cis) 115 R.sub.1 is 6-F,
R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3 is 468.6 469
1-N,N-dimethyl-5-isoquinolinyl, and X is O; (cis) 116 R.sub.1 is
6-Cl, R.sub.2 is nil, m is nil, R.sub.3 is 1-CH.sub.3- 365.9 366.0
5-isoquinolinyl, and X is O 117 R.sub.1 is 6-Cl, R.sub.2 is nil, m
is nil, R.sub.3 is 1-Cl- 386.3 386.1 5-isoquinolinyl, and X is O
118 R.sub.1 is 6-F, R.sub.2 is 3-CF.sub.3 Ph, m is 1, L is a direct
bond, 493.5 494.6 R.sub.3 is 5-isoquinolinyl, and X is O;
(cis)(enantiomer 1) 119 R.sub.1 is 6-F, R.sub.2 is 3-CF.sub.3 Ph, m
is 1, L is a direct bond, 493.5 494.6 R.sub.3 is 5-isoquinolinyl,
and X is O; (cis)(enantiomer 2) 120 R.sub.1 is 6-F, R.sub.2 is
3-CF.sub.3 Ph, m is 1, L is a direct bond, 509.5 510.2 R.sub.3 is
5-isoquinolinyl-N-oxide, and X is O; (cis) (enantiomer 1) 121
R.sub.1 is 6-F, R.sub.2 is 3-CF.sub.3 Ph, m is 1, L is a direct
bond, 509.5 510.2 R.sub.3 is 5-isoquinolinyl-N-oxide, and X is O;
(cis) (enantiomer 2) 122 R.sub.1 is 6-F, R.sub.2 is
spiro-2-indanyl, L is a direct bond, 437.5 438.4 R.sub.3 is
5-isoquinolinyl, and X is O 123 R.sub.1 is 6-F, R.sub.2 is 4-Cl,
3-CF.sub.3 Ph, m is 1, L is a direct 527.9 528.3 bond, R.sub.3 is
5-isoquinolinyl, and X is O; (cis) 124 R.sub.1 is 6-Cl, R.sub.2 is
Ph, m is 1, L is a direct bond, R.sub.3 is 442.0 442.2
1-CH.sub.3-5-isoquinolinyl, and X is O; (cis) (enantiomer 1) 125
R.sub.1 is 6-Cl, R.sub.2 is Ph, m is 1, L is a direct bond, R.sub.3
is 442.0 442.2 1-CH.sub.3-5-isoquinolinyl, and X is O; (cis)
(enantiomer 2) 126 R.sub.1 is 6-Cl, R.sub.2 is Ph, m is 1, L is a
direct bond, R.sub.3 is 442.0 442.2 1-CH.sub.3-5-isoquinolinyl, and
X is O; (trans) (enantiomer 1) 127 R.sub.1 is 6-Cl, R.sub.2 is Ph,
m is 1, L is a direct bond, R.sub.3 is 442.0 442.2
1-CH.sub.3-5-isoquinolin- yl, and X is O; (trans) (enantiomer
2)
BIOLOGICAL EXAMPLES
Example 1
[0602] Human or Rat VR.sub.1 Binding Assay
[0603] Compounds of the present invention were tested for their
ability to inhibit the binding of [3H] RTX to hVR1 receptors in a
[.sup.3H] RTX binding assay as previously described (Zhang, Sui-Po.
Improved ligand binding assays for vantiloid receptors. PCT Int.
Appl. (2002), 29 pp. CODEN: PIXXD2 WO 0233411 A1 20020425 AN
2002:315209; Grant, Elfrida R.; Dubin, Adrienne E.; Zhang, Sui-Po;
Zivin, Robert A.; Zhong, Zhong Simultaneous intracellular calcium
and sodium flux imaging in human vanilloid receptor 1 (VR1)--
transfected human embryonic kidney cells: a method to resolve ionic
dependence of VR1-mediated cell death. Journal of Pharmacology and
Experimental Therapeutics (2002), 300(1), 9-17.)
[0604] HEK293 cells were transfected with human VR1 vanilloid
receptors and washed with Hank's Balanced Salt Solution,
dissociated with cell dissociation buffer (Sigma), and then
centrifuged at 1000.times.g for 5 min. Cell pellets were
homogenized in cold 20 mM HEPES buffer, pH 7.4, containing 5.8 mM
NaCl, 320 mM sucrose, 2 mM MgCl.sub.2, 0.75 CaCl.sub.2 and 5 mM KCl
and centrifuged at 1000.times.g for 15 min. The resultant supernate
was then centrifuged at 40000.times.g for 15 min. The pelleted
membranes were kept in an -80.degree. C. freezer.
[0605] Approximately 120 .mu.g protein/ml from membranes were
incubated with indicated concentrations of [3H] RTX in 0.5 ml of
the HEPES buffer (pH 7.4) containing 0.25 mg/mL fatty acid-free
bovine serum albumin at 37.degree. C. for 60 min. The reaction
mixture was then cooled to 4.degree. C., 0.1 mg .alpha..sub.1-acid
glycoprotein added to each sample and incubated at 4.degree. C. for
15 min. The samples were centrifuged at 18500.times.g for 15 min.
The tip of the microcentrifuge tube containing the pellet was cut
off. Bound radioactivity was quantified by scintillation counting.
Non-specific binding was tested in the presence of 200 nM unlabeled
RTX.
[0606] Alternatively, a binding assay using rat tissue was used.
Rat spinal cord was homogenized twice with a Polytron and
centrifuged at 3000 rpm for 10 min in HEPES buffer containing 20 mM
HEPES, pH 7.4, NaCl 5.8 mM, sucrose 320 mM, MgCl.sub.2 2 mM,
CaCl.sub.2 0.75 mM and KCl 5 mM. The supernatant was then
centrifuged at 18,000 rpm for 20 min. The pellet was saved in a
tube and 10 ml assay buffer was added into the tube. The pellet and
buffer were mixed with a Polytron. The assay contained 120 .mu.g/ml
membrane protein and 0.3-0.6 nM [.sup.3H]-RTX (NEN, Boston) in a
total volume of 0.5 ml HEPES buffer. Following-incubation for 60
min at 37 C, the samples were cooled down on ice, and 100 mg of
.alpha.-acid glycoprotein were added into the samples. After
centrifugation at 13,000 rpm for 15 min, the supernatant was
aspirated and the tips of tubes were cut off and placed into 6 ml
vials. Data were calculated according to the equation: % inhibition
=(total binding-binding)*100/(total binding-non specific binding).
Ki value values were calculated using a Prism program.
Example 2
Human VR.sub.1 Functional Assay
[0607] The functional activity of the test compounds was determined
by measuring changes in intracellular calcium concentration using a
Ca.sup.++-sensitive fluorescent dye and FLIPR.TM. technology.
Increases in Ca.sup.++ concentration were readily detected upon
challenge with capsaicin.
[0608] HEK293 Cells expressing human VR1 were grown on
poly-D-lysine coated 96 well black-walled plates (BD 354640) and 2
days later loaded with Fluo-3/AM for 1 hour and subsequently tested
for agonist-induced increases in intracellular Ca.sup.2+ levels
using FLIPR technology. Cells were challenged with test compounds
(at varying concentrations) and intracellular Ca.sup.++ was
measured for 3 min prior to the addition of capsaicin to all wells
to achieve a final concentration of 0.015 .mu.M eliciting 80%
maximal response. EC.sub.50 or IC.sub.50 values were determined
from dose-response studies.
3TABLE 2 Vanilloid In vitro assay data Compound No. hVR1 K.sub.i
(nM) Rat VR1 Ki (nm) IC.sub.50 or EC.sub.50 (nM) 1 2530 NT 780 2
31600 NT NT 3 98.9 NT 12 4 NT NT 460 5 NT NT 120 6 >10000 NT 260
7 NT NT 2400 8 >10000 NT 10000 9 >10000 NT 3000 10 13000 NT
690 11 NT NT 10000 12 NT NT >30000 13 3600 NT >30000 14
>10000 NT 10000 15 3110 NT 440 16 NT NT >30000 17 NT NT
>30000 18 NT NT >30000 19 258 NT 92 20 5520 NT 10000 21 520
NT 520 23 98.2 NT 64 24 NT NT >30000 25 70900 NT 10000 26 28.2
NT 69 27 NT NT >30000 28 NT NT >30000 29 NT NT >30000 30
NT NT >30000 31 NT NT >30000 32 NT NT >30000 33 3.37 NT 25
34 NT NT >30000 35 9.64 NT 60 36 45.6 NT 41 37 24.9 NT 16 38a
1.76 NT 12 38b 0.72 NT NT 38c 3.59 NT NT 39 0.89 NT 14 40 29.6 NT
195 41 4.58 NT 86 42 1.94 NT 16 43 3.66 NT 20 44 1.96 NT 13 45 1540
NT 511 46 8.81 NT 540 47 1030 NT 3000 48 19.3 NT 230 49 2.66 NT 130
50 1.8 NT 80 51 24 NT 72 52 12.3 NT 250 53 0.48 NT 4.8 54 2.04 NT
5.1 55 1.55 NT 2.3 56 277 NT 200 57 15.4 NT 120 58 2.62 NT 13 59
2.6 NT 9 60 4.99 NT 14 61 3.42 NT 5.7 62 7.59 NT 22 63 16.5 NT 21
64 1.28 NT 22 65 NT NT 1000 66 1.82 NT 26 67 1.44 NT 390 68 21.3 NT
97 69 2.19 NT 100 70 5.55 NT 460 71 0.84 NT 350 72 7.52 NT 36 73
53.4 NT 110 74 11.3 NT 480 75 NT NT 730 76 3.81 NT 140 77 6.26 NT
490 79a 10.8 NT NT 79b 32.3 NT NT 80a 5.32 NT NT 80b 25.1 NT NT 81a
1.12 NT NT 81b 5.25 NT NT 82 103 NT NT 83 15.5 NT NT 84a 2700 NT NT
84b 2730 NT NT 85a 45.4 NT NT 85b 50.2 NT NT 86 1.7 NT NT 87 NT
53.7 NT 88 15.5 1270 NT 89 NT 1080 NT 90 NT 259 NT 91 NT 1480 NT 92
NT 7080 NT 93 3.59 517 NT 94 0.719 131 NT 95 1.7 217 NT 96 50.2 NT
NT 97 45.4 NT NT 98 2730 100000 NT 99 2700 100000 NT 100 5.25 781
NT 101 1.12 53.1 NT 102 25.1 100000 NT 103 5.32 101 NT 104 32.3
100000 NT 105 10.8 4922 NT 106 8.6 2840 NT 107 0.93 28.7 NT 108 186
NT NT 109 29.2 100000 NT 110 0.531 185 NT 111 NT 100000 NT 112 NT
100000 NT 113 NT 100000 NT 114 NT 100000 NT 115 NT 100000 NT 116 NT
100000 NT 117 NT 100000 NT 118 2.16 169 NT 119 0.5 152 NT 120 95.7
10000 NT 121 5.75 88.5 NT 122 73 1700 NT 123 NT NT NT 124 NT NT NT
125 NT NT NT 126 NT NT NT 127 NT NT NT
Example 3
Broadly Stimulated Recombinant Human VR1 and rat VR1 Functional
Assays
[0609] When nociceptors are exposed to tissue damaging stimuli, VR1
receptors are activated by a plethora of stimuli. In an effort to
identify potent and efficacious antagonists at human and rat VR1
that were active under conditions simulating aspects of in vivo
inflammation functional assays were developed using FLIPR to
determine antagonist activity against endogenous activators and
stimuli likely to be present in inflammation. Cell lines were
constructed that stably expressed recombinant rat VR1
(rVR1/HEK293). Cells were exposed to various stimuli at their
EC.sub.80, with the exception of the low pH and DTT stimuli.
[0610] Low pH (pH 5.9 (rat) or pH 6.5 (human). Cells were
challenged for 5 min with low pH solution which produced an
increase in intracellular Ca.sup.2+ which was subsequently reduced
by exposure to antagonists. After 3 min, other stimuli (a phorbol
ester to induce phosphorylation, capsaicin, anandamide, redox
agents) were applied to the cells to determine the potency of
antagonists to block those stimuli in an acidic environment. Cells
were maintained in low pH in all steps subsequent to the calcium
dye loading step.
[0611] Phoshorylation by PKC. Previous studies have suggested that
phorbol esters activate VR1 via PKC phosphorylation [Premkumar,
2000 #697; Vellani, 2001 #739]. These studies were corroborated and
further studies were performed to confirm that the phorbol ester
effect was not due to direct effects on the channel. The role of
PKC was shown pharmacologically: phorbol-12-myristate-13-acetate
(PMA) and other phorbol esters active at PKC (but not the inactive
4.alpha.-phorbol) caused an increase in intracellular Ca.sup.2+
that was mediated by VR1. The rank order potency for the panel of
phorbol esters was similar to their rank order potency to block
PKC. The PKC inhibitors bisindolylmaleimide (BIM) and staurosporin
blocked the PMA induced increase in Ca.sup.2+. The EC.sub.50 for
PMA at either rat or human recombinant VR1 was 90 nM. Cells were
challenged with 300 nM PMA (.about.EC.sub.80) after 3 min in the
indicated antagonist. The active phorbol ester effect was blocked
by RR and CPZ and required extracellular Ca.sup.2+. CPZ was more
potent at the recombinant human compared to the rat receptor.
[0612] Anandamide. Anandamide is a brain-derived cannabinoid ligand
that acts as a near full agonist at VR1 at low pM concentrations
[Smart, 2000 #507]. The EC.sub.50 of anandamide at recombinant rat
and human receptors was 5 .mu.M and 3 .mu.M, respectively. The
IC.sub.50 was determined near the EC.sub.80 of anandamide (10
.mu.M).
[0613] Reactive oxygen species: Disturbances in the regulatory
activities of free radicals may play a role in inflammation
[Winrow, 1993]. Reactive oxygen species (ROS) such as
H.sub.2O.sub.2 are formed in inflamed joints. H.sub.2O.sub.2
directly activates VR1: the increase in intracellular Ca.sup.2+ is
in part blocked by VR1 antagonists and the response is dependent on
extracellular Ca.sup.2+. The influx of Ca.sup.2+ through VR1 may
contribute to the known effects of ROS on signal transduction
(e.g., phosphorylation of proteins) and downstream regulation of
gene transcription. The EC.sub.80 for H.sub.2O.sub.2-induced
Ca.sup.+ flux in VR1/HEK cells was 0.015% H.sub.2O.sub.2 and this
concentration was used to determine the IC.sub.50 of VR1
antagonists.
[0614] Reducing agents: The reducing agent DTT also directly
activates VR1 [Vyklicky, 2002]. Cells were challenged with 5-10 mM
DTT to stimulate VR1 after 3 min incubation in compound.
[0615] Compound 33 potently blocked the activation of human
recombinant VR1 elicited by the agonists shown in Table 3. The
increase in intracellular Ca.sup.2+ caused by acidic solutions,
anandamide the PKC activator PMA, and H.sub.2O.sub.2 was completely
abolished by Compound 33 in a dose dependent manner after 3 min
incubation in antagonist (Table 3). The IC.sub.50 values obtained
in assays with low pH, anandamide and PMA stimuli were similar to
the IC.sub.50 values obtained against capsaicin-induced responses.
Thus, Compound 33 is a potent antagonist against a panel of
activators at the recombinant human receptor, with a more favorable
pharmacological profile than the two most well studied antagonists,
capsazepine and ruthenium red.
4TABLE 3 Antagonism of recombinant human VR1 activated by a panel
of stimuli in a Ca.sup.2+ influx in vitro assay (IC.sub.50 in nM)
H.sub.2O.sub.2 PKC reactive Low PKC phosphory- oxygen pH Anandamide
phosphory- lation at low species Compound (nM) (nM) lation (nM) pH
(nM) (nM) 33 23,40 41 70 39 Capsazepine 110 160 370 (CPZ) Ruthenium
500 500 Red (RR)
[0616] The reference compounds used in these studies were the
previously characterized VR1 antagonists capsazepine (CPZ) and
ruthenium red. CPZ, previously the most potent antagonist at human
VR1, shows similar potency (100-300 nM) at the human recombinant
receptor to inhibit Ca.sup.+ activity induced by these stimuli
(FIG. 1, left set of panels). For FIG. 1, human (left) and rat
(right) vanilloid 1 receptor expressed in HEK 293 cells was
stimulated by a number of different stimuli known to activate VR1.
FIG. 1 shows the IC.sub.50 values of the competitive vanilloid
antagonist capsazepine for inhibition of the calcium flux induced
by each of these activators. Note the similar potency of the
compound at the human receptor stimulated by various stimuli, but
the lower potency of the compound as an inhibitor of rat VR1.
[0617] In FIG. 2, the human (left) and rat (right) vanilloid 1
receptor expressed in HEK 293 cells was stimulated by a number of
different stimuli known to activate VR1. The IC.sub.50 values for
inhibition by example #33 of the calcium flux induced by each of
these activators is seen in FIG. 2.
[0618] CPZ has been shown to have significantly lower potency at
the rat receptor (recombinant and native receptors; [Mcintyre,
2001]). Since many of our animal models were in rat, we cloned the
rat VR1 and expressed it stably in HEK293 cells. We performed
assays similar to those described for the human recombinant
receptor with the exception that a lower pH was required in the
Ca.sup.2+ influx assay at the rat recombinant receptor.
[0619] As expected based on data from the literature, the CPZ
profile revealed low potency against heat-induced responses at the
recombinant rat receptor [Nagy, 1999]. With the exception of the
pore blocker RR, antagonists tended to have a lower potency at the
rat compared to the human recombinant receptor. Importantly,
Compound 33 potently and completely blocks rat recombinant VR1
activated by acidic solution, anandamide, and H.sub.2O.sub.2, and
PMA at acidic pH (Table 4).
5TABLE 4 Antagonism of recombinant rat VR1 activated by a panel of
stimuli in the Ca.sup.2+ influx in vitro assay (IC.sub.50 in nM)
Low Anand- PKC PKC pH amide phosphory- phosphorylation
H.sub.2O.sub.2 Compound (nM) (nM) lation (nM) at low pH (nM) (NM)
Cmpd 33 170 38 47 33 Capazepine 5000 1300 10000 10000 (CPZ)
Ruthenium 1860 300 Red (RR)
[0620] Compound 33 potently blocked the activation of rat
recombinant VR1 elicited by the agonists shown in Table 4. The
increase in intracellular Ca.sup.2+ caused by acidic solutions,
anandamide the PKC activator PMA at low pH, and H.sub.2O.sub.2 was
completely abolished by Compound 33 in a dose dependent manner
after 3 min incubation in antagonist (Table 4). The IC.sub.50
values obtained in assays with low pH, anandamide and PMA stimuli
were similar to the IC.sub.50 values obtained against
capsaicin-induced responses with the possible exception of the
blockade of the low pH response. Thus, Compound 33 is a potent
antagonist against a panel of activators at the recombinant rat
receptor, with a more favorable pharmacological profile than the
two most well studied antagonists, capsazepine and ruthenium
red.
EXAMPLE 4
Electrophysiologic Functional Assay Using Dissociated Rat DRG
Cells
[0621] Compounds 42, 95, 101, 105 and 106 were tested for their
activity on VR1 expressed endogenously on small rat dorsal root
ganglion (DRG) neurons. DRG neurons from normal rats were
dissociated (see methods in Chaplan et al., 2003) and whole cell
currents mediated by VR1 were recorded using the whole cell patch
clamp technique. The estimated potency of the compounds were
determined either 1) by measuring the shift in the
capsaicin-induced dose response in the presence of compound or 2)
by calculating the percent of capsaicin-induced current responses
in the presence of compound under conditions of limited
capsaicin-induced desensitization (i.e., using 0
Ca.sup.2+-containing saline solutions). Under these conditions,
repeated application of capsaicin produced similar current
responses when 3 min recovery/washout periods were allowed. Briefly
in the first method, if a cell was responsive to 300 nM capsaicin
(EC.sub.20), compound was applied to the cell at 100 or 300 or 1000
nM to determine if the compound had intrinsic agonist activity and
allow a 4-5 min incubation period prior to testing with capsaicin
in the presence of compound. After 4-5 min exposure to compound, 1
.mu.M capsaicin was applied in the presence of the same
concentration of compound and incubated another 2-3 min. This was
followed by application of 10 .mu.M CAP in the presence of
compound. Control cumulative capsaicin dose response curves (filled
squares) were obtained from a cell (the approximate EC.sub.50 in
this cumulative dose response assay was 1 .mu.M CAP; 10 .mu.M
causes a maximal response). Vehicle caused no shift in the
capsaicin concentration dependence (not shown). The ability of 1
and 10 .mu.M CAP to cause an increased current after exposure to a
compound of the invention was compared to controls.
[0622] In the second method, a nociceptor was challenged with 0.3
uM capsaicin while taking measurements of whole cell current using
voltage ramp protocols. After washout of the capsaicin, cells were
exposed to the compound for 4-5 min and subsequently challenged
with 1 uM capsaicin (approximately the ED80 at the native receptor
in this experiments) in the continued presence of compound. The
current elicited near -100 mV was measured during the first and
second capsaicin exposure. The percent of the response elicited by
0.3 .mu.capsaicin obtained during the exposure to 1 uM
capsaicin/compound was calculated. After washout, the cell was
challenged with 10 uM capsaicin in the presence of compound and
subsequently washed again and challenged with capsaicin without
compound.
6TABLE 5 VR1 antagonists inhibit capsaicin-induced currents in
dissociated rat DRG neurons % of the initial CAP % of the initial
CAP Compound response in response in concentration presence of 1 uM
presence of 10 uM Compound (uM) CAP CAP 42 0.3 0 95 0.03 78 1073
0.1 21 200 0.1 4 12 101 0.03 14 54 0.1 0 0 105 1 0 23 8 160 106 1 2
11 vehicle 330 115 180 171 204
[0623] All compounds inhibited the response to 1 uM capsaicin. The
inhibition was dose dependent (compounds 95 and 101). The response
to 10 uM capsaicin in the presence of compound was larger than the
response to 1 uM capsaicin/compound with the exception of the cell
challenged with 0.1 uM 101 which revealed no capsaicin induced
current until the compound was washed out and capsaicin alone was
applied to the cell. These results indicate that Compounds 95 and
101 appeared to shift the capsaicin dose response to the right in a
dose dependent manner. PKB' values could not be determined because
it is not known whether the blockade could not be surmounted by
higher concentrations of capsaicin. Tested compounds had no
detectable, reproducible effect on whole cell voltage-activated
currents in the DRG neurons studied.
Example 5
Carrageenan Paw-Induced Thermal Hyperalgesia
[0624] Each rat was placed on a heated surface (51.degree. C.) in
order to measure the time necessary to elicit a response, and an
initial (baseline) response time to a thermal stimuli was recorded
for each animal. A response is defined as any shaking, licking, or
tucking of the treated paw or jumping. Animals not treated with a
test compound respond in approximately 20 seconds. The maximal
exposure time permitted is 60 seconds to prevent tissue damage.
Rats were injected with an irritant (e.g., 1% carrageenan solution
in 0.9% saline) subcutaneously into the sub-plantar tissue of the
left hind paw to stimulate an acute inflammatory reaction.
[0625] Two hours later, the response time of the animal to the
thermal stimulus was evaluated and compared to the animal's
baseline response time. This shorter response time was recorded as
percent hyperalgesia (% H). A cut-off value for % H (usually 75%)
was used during analysis to ensure that the animals were
hyperalgesic. Animals were then dosed with test drug or
vehicle.
[0626] At some time(s) later (typically 45 and 90 minutes), the
response time of the animal to the thermal stimulus was again
evaluated. For each time point, a percent reversal of hyperalgesia
(% R) was calculated using the following formula: % R=(Drug
Latency-Carrageenan latency)/(Baseline latency-Carrageenan
latency). ED.sub.50 values were calculated from % R obtained at
several drug doses.
7 CgHP ED.sub.50 Cmpd No (mg/kg, po) 33 0.276 57 0.354 4 0.804 17
19.958
[0627]
8TABLE 6 Percent Recovery at 1 mg/ml or ED.sub.50 value (mg/kg,
p.o.), each at 90 min. Compound % Recovery ED.sub.50 (mg/kg, p.o.)
106 0.027 105 0.394 107 0.92 110 64.3 120 83.0 121 80.1 124 55.2
125 63.9 126 46.0 127 41.3
Example 6
Evaluation of Action on Isolated Guinea Pig Bronchial Rings
[0628] Aminotetralin VR1 antagonists were tested for their potency
to block capsaicin-induced guinea pig bronchial ring contraction in
a standard in vitro organ bath assay [Tucker, 2001]. Two mm rings
of bronchial tissue obtained from male guinea pigs (325 g) were
suspended in normal Krebs solution between two wire hooks under an
initial loading tension of 1 gram. The saline was maintained in a
5% CO.sub.2 and 95% O.sub.2 atmosphere at 37.degree. C. in the
presence of indomethacin (5 .mu.M). A sub-maximal dose of
5-Methylfurmethide (5Mef, 1 .mu.M) was added to each tissue to
determine responsiveness using an isometric force transducer. After
washout, tissues were exposed to compounds or vehicle for 30 min,
treated with thiorphan (10 .mu.M, 5% Na.sub.2CO.sub.3), and primed
using KCl in increasing linear concentrations from 1 mM at 1 mM
intervals until a slight increase in muscle tone was induced
(.about.1% of 5Mef response). A concentration-response curve was
then constructed using capsaicin (10 nM-10 .mu.M) increasing in 0.5
log unit increments. The dose response curve was calculated as %
max of the 5-Mef response and estimated pA.sub.2 were determined
[Tucker, 2001]).
[0629] Both Compound 38a (FIG. 3) and Compound 105 (FIG. 4)
inhibited capsaicin-evoked bronchial ring contraction with an
estimated pA.sub.2 of 8.0 and 6.2, respectively (Table 7). The
potent antagonism of capsaicin-induced bronchial ring contraction
indicated that these compounds may be effective inhibitors of cough
and bronchial spasm mediated by VR1.
[0630] In FIG. 3, inhibition of capsaicin-induced contraction of
guinea pig bronchial rings is shown for an isolated tissue assay.
The closed symbols represent the capsaicin-only
concentration-response relationship, whereas the open symbols
represent the capsaicin plus example number 105
concentration-response. The inhibition appears as a shift to the
right of the concentration-response curve, resulting in a pA.sub.2
(.+-.SEM) value of 6.2.+-.0.11.
[0631] In FIG. 4, inhibition of capsaicin-induced contraction of
guinea pig bronchial rings is shown for an isolated tissue assay.
The closed symbols represent the capsaicin-only
concentration-response relationship, whereas the open symbols
represent the capsaicin plus example number 38a
concentration-response. The inhibition appears as a shift to the
right of the concentration-response curve, resulting in a pA.sub.2
(+SEM) value of 8.0.+-.0.02.
9TABLE 7 VR1 antagonist blocked capsaicin-induced guinea pig
bronchial ring contraction in a competitive manner. Compound
Estimated pA.sub.2 33 8.0 +/- 0.02 105 (1000 nM) 6.2 +/- 0.11
Example 7
Antitussive efficacy of VR1 Antagonists
[0632] The antitussive activity of intraperitoneally (IP)
administered compound is assessed at a single dose level against
capsaicin-induced cough responses as compared to positive and
vehicle controls. Thirty-six male Dunkin-Hartley guinea pigs
(295-590 g, mean=425 g) are randomly allocated to one of three
groups (n=12 guinea pigs per group). The blinding code is not
revealed to the experimenter until coughs from all animals are
tallied. Guinea pigs are dosed IP at -60 min with vehicle (15%
Solutol in 5% dextrose solution); the positive control codeine (25
mg/kg), or test compound (20 mg/kg in 15% Solutol in 5% dextrose
solution). Individual guinea pigs are placed in an exposure chamber
with an airflow of 3 L/min at -10 min to acclimatize. At .+-.0 min,
cough responses are induced by exposure to capsaicin aerosol (15
.mu.M) generated by an ultrasonic nebulizer at a nebulization rate
of 0.6 ml/min for 4 min. Coughs are counted throughout the 4 min
capsaicin exposure and for a further 11 min. The mean.+-.SEM number
of capsaicin-induced cough responses recorded in vehicle
pre-treated guinea pigs was 3.0.+-.0.5. This level of response was
reduced significantly to 0.58.+-.0.15 coughs in codeine pre-treated
guinea pigs (P<0.001) and is reduced in compound pre-treated
guinea pigs. ANOVA statistical analysis was used to determine the
level of significance.
[0633] The antitussive properties of test compounds are assessed in
a citric acid-induced cough model as compared to positive and
vehicle controls. Evaluation of a given compound in this paradigm
is as follows: Six male Dunkin-Hartley guinea pigs (approximately
300-600 g) are randomly assigned to each treatment group. Guinea
pigs are intra-peritoneally (IP) injected with vehicle, test
compound, or positive control (codeine 25 mg/kg) 60 minutes prior
to citric acid exposure. Individual guinea pigs are placed in an
exposure chamber with an airflow of 3 L/min at -10 min to
acclimatize. At .+-.0 min, cough responses are induced by exposure
to nebulized citric acid. Coughs elicited during the 10-minute
aerosol of citric acid and additional 5-minute observation period
are recorded and analysed for onset of cough, and cough number and
frequency. To eliminate bias, pre-treatments are randomised and the
experiments are done blinded. The blinding code is not revealed to
the experimenter until coughs from all animals are tallied.
Example 8
Rodent Colitis Model
[0634] 5% Dextran Sulfate Sodium administered in the drinking water
of mice or rats for 7 days results in an acute colitis with some
morphological changes that are similar to human ulcerative colitis.
Among those changes are colon shortening, accumulation of
neutrophils and other inflammatory cells, decreases in colon
weight, decreases in body weight, tissue damage in the colon, and
loss of stool consistency.
[0635] Each animal is dosed daily in the morning and late afternoon
for BID dosing. Treatment with vehicle or test compound begins on
day 0, immediately after initial body weights are taken, and ends
on day 6. Water bottles are removed and replaced by graduated water
bottles containing 5% DSS in indicated groups. Tap water remains on
control groups only. Sufficient DSS drinking water is placed in
graduated water bottles and refilled each day to monitor daily
output. Animals are weighed daily from day 0 to 7, and animal
condition and the consistency of stools recorded. Following
sacrifice of the animal on day 7, the colon is surgically removed
from the distal rectum (anus) to the cecal-colonic juncture and the
colon length and weight measured. Colon slices may be obtained for
histological evaluation. An active drug should decrease or
eliminate disruption of the epithelium and colonic folds, dense
inflammatory cell infiltrates, mucosal sloughing, etc. In life
observations include monitoring for signs of gross toxicity and/or
behavioral changes, gross evaluation of the skin and fur, motor
activity and any behavioral patterns with special attention to
tremors, convulsions and diarrhea. Water consumption and body
weights are measured daily. Scores include ratings for colon weight
loss, stool consistency, colon damage, and colon shortening, and
are used to assemble a Disease Activity Score. An increase in
myeloperoxidase activity occurs in this model and is evaluated
separately.
Example 9
Uterine Pain Assessment
[0636] Female adult virgin Sprague Dawley rats (190-290 g) are
used. Rats are anesthetized with pentobarbital (50 mg/kg IP). One
uterine horn is approached via a small ventral midline laparotomy
and tightly ligated at its caudal end near the cervix with 3.0 silk
suture to prevent leakage of mustard oil through the cervix and
vagina. Using a 22 G needle 0.1-0.2 ml of 10% mustard oil (Aldrich
Chemical Co., Milwaukee Wis. USA; dissolved in mineral oil) or an
equivalent volume of saline in sham control rats, are injected into
the uterine lumen. The abdominal incision is then closed and the
rats allowed to recover from anesthesia. Rats are then transferred
to individual Plexiglas cages in a quiet environment (12/12 h
light-dark cycle) with food and water ad libitum for nonstop
videotape recording for the duration of the experiment. Compounds
or vehicle is administered by the intended route before
(therapeutic) or after (prophylactic) acquisition of hyperalgesia.
The recording system consists of a camera connected to a videotape
recorder with a wide range of recording and reading speeds to allow
for detailed analysis of the movements of the rats. During the dark
phase an infrared light is used to permit continuous filming.
Animal behavior is analyzed post-hoc using a scoring system to
count abnormal behaviors. Six characteristic abnormal behaviors are
expected in uterine inflammation rats: (1) hunching (2) hump-backed
position (3) repeated licking of the lower abdomen/ipsilateral
flank (4) repeated waves of contraction of the ipsilateral oblique
musculature with inward turning of the ipsilateral hind limb (5)
stretching of the body (6) squashing of the lower abdomen against
the cage floor. The effect of administered compounds on the
intensity and frequency of pain related behaviors is quantitatively
assessed.
Example 10
Models of Itch, Contact Dermatitis, Eczema and Other Manifestations
of Dermal Allergy, Hypersensitivity and/or Inflammation
[0637] Vanilloid receptor modulators are tested in an animal model
of contact dermatitis or itch, according to previously documented
and validated methods, including but not limited to those described
by Saint-Mezard et al. (2003), Gonzalez et al. (2001), Wille et al.
(1998), Weisshaar et al. (1999) and Thomsen et al. (2002). In
models of contact dermatitis, testing is conducted in mouse, guinea
pig or human in response to a single (primary allergic dermatitis)
or repeated (sensitized allergic dermatitis) topical or
photomechanical exposure of the skin to one or more haptensselected
from 12-myristate-13 acetate, picryl chloride, oxazolone,
capsaicin, arachidonic acid, lactic acid, trans-retinoic acid or
sodium lauryl sulfate. For increased sensitivity, animals are
sensitized by pre-exposure to certain agents selected from
dinitrochlorobenzene, para-phenylenediamine or oxazolone. For
prophylactic or therapeutic testing, a vanilloid receptor modulator
or vehicle control is administered to the test subjects by the
enteral or parenteral route prior to or following hapten challenge.
Significant differences in skin inflammation (erythema, edema,
hyperthermia, etc.) for the test compound-treated subjects compared
with vehicle-treated subjects demonstrate anti-allergy activity.
The following additional dependent measures are also collected and
compared: skin and/or lymph node levels of CF8+ T cells,
interleukin-1 alpha and beta, tumor necrosis factor alpha,
interferon gamma, nitric oxide, inducible nitric oxide synthase and
keratinocyte apoptosis, Fas expression and/or inflammatory mediator
secretion.
[0638] In models of itch, testing is conducted in mouse, rat,
guinea pig or human in response to the sub- or intra-dermal
injection or iontophoresis of pruritogens select4ed from serotonin,
compound 48/80, leukotriene B4, arachidonic acid, prostaglandin E2,
histamine, substance P, neurokinin A, neurokinin B, trypsin,
hydroxyethylstarch or platelet-activating factor singly or in
combination with mosquito bite or injection of salivary gland
extract therefrom. In some cases, animals are inflamed by
pre-exposure to certain agents, including but not limited to sodium
lauryl sulfate. For prophylactic or therapeutic testing, a
vanilloid receptor modulator or vehicle control is administered to
the test subjects by the enteral or parenteral route prior to or
following pruritogen challenge. Cumulative scratching behavior
and/or number of scratches per unit time are measured. Significant
differences in scratching behavior for the test compound-treated
subjects compared with vehicle-treated subjects demonstrate
anti-pruritic activity. The following additional dependent measures
are collected and compared: skin inflammation (erythema, edema,
hyperthermia, etc.), surface area of the wheal and flare,
hyperalgesia, allodynia, plasma protein extravasation, inflammatory
mediator release and serum immunoglobulin levels.
Example 11
Models of Rhinitis and Other Manifestations of Nasal
Hypersensitivity and/or Inflammation
[0639] Vanilloid receptor modulators are tested in an animal model
of rhinitis, according to previously documented and validated
methods, including but not limited to those described by Hirayama
et al. (2003), Tiniakov et al. (2003) and Magyar et al. (2002).
Testing is conducted in mouse, guinea pig, dog or human in response
to intranasal challenge with one or more irritants selected from
bradykinin, histamine, pollens, dextran sulfate, 2,4-tolylene
diisocyanate, Bordetella bronchiseptica, Pasteurella multodica or
acetic acid. For increased sensitivity, animals may be sensitized
by pre-exposure to ragweed or ovalbumin. For prophylactic or
therapeutic testing, a vanilloid receptor modulator or vehicle
control is administered to the test subjects by the enteral or
parenteral route prior to or following irritant challenge. The
relevant dependent measures collected are plasma extravasation of
the nasal mucosa, nasal eosinophilia or neutrophilia, nasal mucosal
or nasal cavity lavage fluid levels of IL-5, interferon gamma,
histamine or IgE, serum immunoglobulin levels, rhinorrhea,
cumulative time spent sneezing or number of sneezes per unit time,
nasal airway volume, peak inspiratory flow and resistance,
intranasal pressure and nasal lesions. Significant differences in
one or more of these measures for the test compound-treated
subjects compared with vehicle-treated subjects demonstrate
anti-rhinitis activity.
Example 12
Models of Anxiety, Panic Disorder and Other Non-Adaptive Stressful
or Phobic Responses
[0640] Vanilloid receptor modulators are tested in an animal model
of anxiety, according to previously documented and validated
methods, including but not limited to those reviewed by Imaizumi
and Onodera (2000). Testing is conducted in mouse or rat and
consists of methods to measure avoidance of aversive environmental
stimuli selected from the Geller-type or Vogel-type anticonflict
tests, the light/dark test, the hole-board test, the elevated
plus-maze and the elevated T-maze. Prior to environmental exposure
the test subject receives the prophylactic administration one or
more times of a vanilloid receptor modulator, or vehicle control,
by the enteral or parenteral route. The cumulative time or number
of times spent engaged in the aversive behavior is measured.
Significant differences in one or more of these measures for the
test compound-treated subjects compared with vehicle-treated
subjects are taken as evidence of anxiolytic activity.
* * * * *