U.S. patent application number 11/133751 was filed with the patent office on 2005-11-17 for preparation and use of imidazole derivatives for treatment of obesity.
This patent application is currently assigned to Bayer Pharmaceuticals Corporation. Invention is credited to Achebe, Furahi, Choi, Soongyu, Kluender, Harold C.E., O'Connor, Stephen J., Smith, Roger A., Su, Ning, Wang, Gan, Wirtz, Stephan-Nicholas, Wong, Wai C., Ying, Shihong.
Application Number | 20050256167 11/133751 |
Document ID | / |
Family ID | 23263739 |
Filed Date | 2005-11-17 |
United States Patent
Application |
20050256167 |
Kind Code |
A1 |
Smith, Roger A. ; et
al. |
November 17, 2005 |
Preparation and use of imidazole derivatives for treatment of
obesity
Abstract
This invention relates to substituted imidazole derivatives
which have been found to suppress appetite and induce weight loss.
The invention also provides methods for synthesis of the compounds,
pharmaceutical compositions comprising the compounds, and methods
of using such compositions for inducing weight loss and treating
obesity and obesity-related disorders.
Inventors: |
Smith, Roger A.; (Madison,
CT) ; O'Connor, Stephen J.; (Guilford, CT) ;
Wirtz, Stephan-Nicholas; (Wuppertal, DE) ; Wong, Wai
C.; (Hamden, CT) ; Choi, Soongyu; (Trumbull,
CT) ; Kluender, Harold C.E.; (Trumbull, CT) ;
Su, Ning; (Hamden, CT) ; Wang, Gan;
(Wallingford, CT) ; Achebe, Furahi; (West Haven,
CT) ; Ying, Shihong; (Orange, CT) |
Correspondence
Address: |
JEFFREY M. GREENMAN
BAYER PHARMACEUTICALS CORPORATION
400 MORGAN LANE
WEST HAVEN
CT
06516
US
|
Assignee: |
Bayer Pharmaceuticals
Corporation
West Haven
CT
|
Family ID: |
23263739 |
Appl. No.: |
11/133751 |
Filed: |
May 20, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11133751 |
May 20, 2005 |
|
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10255049 |
Sep 24, 2002 |
|
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60324473 |
Sep 24, 2001 |
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Current U.S.
Class: |
514/326 ;
514/341; 514/396; 546/210; 546/272.7; 548/333.5 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
3/06 20180101; C07D 403/12 20130101; C07D 405/14 20130101; A61P
25/30 20180101; A61P 35/00 20180101; C07D 409/14 20130101; A61P
3/00 20180101; C07D 409/06 20130101; A61P 9/12 20180101; A61P 15/00
20180101; A61P 25/28 20180101; A61P 9/10 20180101; A61P 3/10
20180101; C07D 233/90 20130101; A61P 19/02 20180101; A61P 11/00
20180101; C07D 401/06 20130101; A61P 9/00 20180101; C07D 401/14
20130101; C07D 401/12 20130101; A61P 25/00 20180101 |
Class at
Publication: |
514/326 ;
514/341; 514/396; 546/210; 546/272.7; 548/333.5 |
International
Class: |
A61K 031/454; A61K
031/4439; C07D 043/02; A61K 031/4172 |
Claims
1-118. (canceled)
119. A method of treating obesity-related disorders comprising the
step of administering to a patient in need thereof a
pharmaceutically effective amount of
1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidinyl)-5-ethyl-
-1H-imidazole-4-carboxamide, or pharmaceutical salts and esters
thereof.
120. The method of claim 119, wherein said obesity-related
disorders include dyslipidernia, hypertriglyceridemia,
hypertension, diabetes, Syndrome X, atherosclerotic disease,
cardiovascular disease, cerebrovascular disease, peripheral vessel
disease, cholesterol gallstones, cancer, menstrual abnormalities,
infertility, polycystic ovaries, osteoarthritis, and sleep
apnea.
121. A method of regulating appetite and food intake comprising the
step of administering to a patient in need thereof a
pharmaceutically effective amount of
1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidiny-
l)-5-ethyl-1H-imidazole-4-carboxamide, or pharmaceutical salts and
esters thereof.
122. A method of treating bulimia comprising the step of
administering to a patient in need thereof a pharmaceutically
effective amount of 1-(4-chlorophenyl)-2-(2-
chlorophenyl)-N-(1-piperidinyl)-5-ethyl-1H-imida-
zole-4-carboxamide, or pharmaceutical salts and esters thereof.
123. A method of treating obesity and obesity-related disorders
comprising the step of administering to a patient in need thereof a
pharmaceutically effective amount of
1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidiny-
l)-5-ethyl-1H-imidazole4-carboxamide, or pharmaceutical salts and
esters thereof, in combination with one or more agents that
modulate digestion and/or metabolism.
124. The method of claim 123, wherein said obesity-related
disorders include dyslipidemia, hypertriglyceridemia, hypertension,
diabetes, Syndrome X, atherosclerotic disease, cardiovascular
disease, cerebrovascular disease, peripheral vessel disease,
cholesterol gallstones, cancer, menstrual abnormalities,
infertility, polycystic ovaries, osteoarthritis, and sleep
apnea.
125. The method of claim 123, wherein said agents that modulate
digestion and/or metabolism are selected from the group consisting
of agents that modulate thernogenesis, lipolysis, gut motility, fat
absorption, and satiety.
126. The method of claim 124, wherein said agents that modulate
digestion and/or metabolism are selected from the group consisting
of agents that modulate thermogenesis, lipolysis, gut motility, fat
absorption, and satiety.
127. The method of claim 123, wherein said agent that modulates
digestion and/or metabolism is a .beta..sub.3-adrenoreceptor
agent.
128. The method of claim 124, wherein said agent that modulates
digestion and/or metabolism is a .beta..sub.3-adrenoreceptor
agent.
129. A method of treating obesity and obesity-related disorders
comprising the step of administering to a patient in need thereof a
pharmaceutically effective amount of
1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidiny-
l)-5-ethyl-1H-imidazole-4-carboxarnide, or pharmaceutical salts and
esters thereof, in combination with one or more agents selected
from the group consisting of HMG CoA reductase inhibitor, bile acid
binding agent, fibric acid derivative, and agent that regulates
hypertension.
130. The method of claim 129, wherein said obesity-related
disorders include dyslipidemia, hypertriglyceridemia, hypertension,
diabetes, Syndrome X, atherosclerotic disease, cardiovascular
disease, cerebrovascular disease, peripheral vessel disease,
cholesterol gallstones, cancer, menstrual abnormalities,
infertility, polycystic ovaries, osteoarthritis, and sleep apnea.
Description
[0001] This application claims benefit of U.S. Provisional
Application Ser. No. 60/324,473, filed Sep. 24, 2001, the contents
of which are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the field of pharmaceuticals, in
particular to the field of obesity treatment. More specifically, it
relates to certain imidazole compounds which are useful in the
treatment of obesity and obesity-related disorders, and as
weight-loss and weight-control agents.
BACKGROUND OF THE INVENTION
[0003] Obesity, which is defined as an excess of body fat relative
to lean body mass, is a well-established risk factor for a number
of potentially life-threatening diseases such as atherosclerosis,
hypertension, diabetes, stroke, pulmonary embolism, sleep apnea,
and cancer. Furthermore, it complicates numerous chronic conditions
such as respiratory diseases, osteoarthritis, osteoporosis, gall
bladder disease, and dyslipidemias. The enormity of this problem is
best reflected in the fact that death rates escalate with
increasing body weight. More than 50% of all-cause mortality is
attributable to obesity-related conditions once the body mass index
(BMI) exceeds 30 kg/m.sup.2, as seen in 35 million Americans (Lee,
JAMA 268:2045-2049, 1992). By contributing to greater than 300,000
deaths per year, obesity ranks second only to tobacco smoking as
the most common cause of potentially preventable death (McGinnis,
JAMA 270:2207-2212, 1993). Accompanying the devastating medical
consequences of this problem is the severe financial burden placed
on the health care system in the United States. It is estimated
that 30-50% of the middle-age population may be considered as obese
(Kuczmarski et al., JAMA 272:205-211, 1994). The economic impact of
obesity and its associated illnesses from medical expenses and loss
of income are reported to be in excess of $68 billion/a year
(Colditz, Am. J. Clin. Nutr. 55:503S-507S, 1992). This figure does
not include the greater than $30 billion per year spent on weight
loss foods, products, and programs (Wolf, Pharmacoeconomics.
5:34-37, 1994).
[0004] The accumulation or maintenance of body fat bears a direct
relationship to caloric intake. Comprehensive treatment programs,
therefore, focused on behavior modifications to reduce caloric
intake and increase physical activity using a myriad of systems.
These methods have limited efficacy and are associated with
recidivism rates exceeding 95% (NIH Technology Assessment
Conference Panel, Ann. Intern. Med. 119:764-770, 1993).
[0005] Obesity has also been treated by administering specific
agents, for example, anorectic agents, to obese subjects. However,
anorectic agents such as dextroamphetamine, the combination of the
non-amphetamine drugs phentermine and fenfluramine (Phen-Fen), and
dexfenfluramine (Redux) alone, are associated with serious side
effects. Indigestible materials such as olestra (OLEAN.RTM.,
mineral oil or neopentyl esters (see U.S. Pat. No. 2,962,419)) have
been proposed as substitutes for dietary fat. Garcinia acid and
derivatives thereof have been described as treating obesity by
interfering with fatty acid synthesis. Swellable crosslinked vinyl
pyridine resins have been described as appetite suppressants via
the mechanism of providing non-nutritive bulk (see, e.g., U.S. Pat.
No. 2,923,662).
[0006] Surgical interventions, such as gastric partitioning
procedures, jejunoileal bypass, and vagotomy, have also been
developed to treat severe obesity (Greenway, Endo. Metab. Clin. N.
Amer. 25:1005-1027, 1996). Although these surgical procedures are
somewhat more effective in the long run, the acute risk benefit
ratio has reserved these invasive procedures for morbidly obese
patients according to the National Health Institutes (NIH)
consensus conference on obesity surgery (BML>40 kg/m.sup.2) (NIH
Conference, Ann. Intern. Med. 115:956-961, 1991). Therefore, this
approach is not an alternative for the majority of overweight
patients unless and until they become profoundly obese and are
suffering the attendant complications.
[0007] Thus, new methods and compositions that promote weight-loss
are urgently needed.
SUMMARY OF THE INVENTION
[0008] The present invention provides substituted imidazole
derivatives which have been found to suppress appetite and induce
weight loss in laboratory animals. The invention also provides
methods for synthesis of the compounds, pharmaceutical compositions
comprising the compounds, and methods of using such compositions
for inducing weight loss and treating obesity and obesity-related
disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0009] The invention relates to substituted imidazole derivatives
that have utility in the treatment of obesity, said derivatives
having Formula I 1
[0010] wherein
[0011] R.sup.1 and R.sup.2 are identical or different and are
selected from a phenyl group optionally substituted with one or
more halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
trifluoromethyl, cyano, nitro, (C.sub.1-C.sub.6)alkyl sulfonyl,
(C.sub.1-C.sub.6)alkyl sulfonyl-amino, (C.sub.1-C.sub.6)alkyl
carbonyl-amino, (C.sub.1-C.sub.6)alkyl amino-carbonyl-amino, or
phenyl,
[0012] (C.sub.2-C.sub.6)alkyl,
[0013] cyclohexyl optionally substituted with
(C.sub.1-C.sub.6)alkyl, (C.sub.1C.sub.6)alkoxy, trifluoromethyl,
cyano, or with one or more fluorine,
[0014] 1-naphthyl or 2-naphthyl optionally substituted with
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
trifluoromethyl, or cyano,
[0015] benzyl optionally substituted on the phenyl ring with one or
more halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)atkoxy,
trifluoromethyl, or cyano,
[0016] a 5- to 10-membered saturated or unsaturated heterocyclic
radical optionally substituted with fluorine,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, trifluoromethyl,
or cyano, and
[0017] a 5- to 10-membered aromatic monocyclic or bicyclic
heterocyclic radical optionally substituted with one or more
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
trifluoromethyl, cyano, nitro, or phenyl;
[0018] R.sup.3 is hydrogen, (C.sub.1-C.sub.6)alkyl, benzyl, chloro,
or bromo; 2
[0019] X is
[0020] where R.sup.4 is hydrogen or (C.sub.1-C.sub.6)alkyl;
[0021] R.sup.5 is selected from
[0022] (C.sub.2-C.sub.9)alkyl or (C.sub.7-C.sub.11)bicycloalkyl,
each of which may optionally be substituted with one or more
phenyl, hydroxy, benzyloxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-amino, bis[(C.sub.1-C.sub.3)alkyl]-amino,
1-piperidinyl, 1-pyrrolidinyl, 2,3-dihydro-1,4-benzodioxin-2-yl,
hydroxy-substituted (C.sub.1-C.sub.6)alkyl, or fluorine,
[0023] benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl,
each of which may optionally be substituted on one of the alkyl
carbons with hydroxy, benzyloxy, or hydroxy (C.sub.1-C.sub.6)alkyl,
and optionally substituted on the phenyl ring with one or more
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
trifluoromethyl, cyano, hydroxy, benzyloxy, or nitro,
[0024] piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, each of
which may optionally be substituted on the nitrogen atom of the
piperidine or pyrrolidine ring with (C.sub.1-C.sub.6)alkyl,
hydroxy-substituted (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.3)alkoxy-substituted (C.sub.1-C.sub.3)alkyl, benzyl,
or phenyl optionally substituted with one or more of
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, trifluoromethyl,
cyano, hydroxy, benzyloxy, nitro, or halogen,
[0025] --NR.sup.6R.sup.7
[0026] where R.sup.6 is hydrogen or (C.sub.1-C.sub.6)alkyl;
[0027] R.sup.7 is (C.sub.1-C.sub.9)alkyl; or phenyl optionally
substituted with one or more of (C.sub.1-C.sub.6)alkyl,
hydroxy-substituted (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.3)alkoxy-substituted (C.sub.1-C.sub.3)alkyl, phenyl,
hydroxy, benzyloxy, (C.sub.1-C.sub.6)alkoxy, trifluoromethyl,
cyano, nitro, or a halogen atom, or
[0028] R.sup.6 and R.sup.7, taken together with the nitrogen atom
to which they are attached, form a 5- to 10-membered saturated or
unsaturated heterocyclic ring which is optionally substituted by
one or more (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy-substituted (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy-substituted (C.sub.1-C.sub.3)alkyl, benzyl,
phenyl, hydroxy, benzyloxy, or fluorine;
[0029] or
[0030] R.sup.4 and R.sup.5, taken together with the nitrogen atom
to which they are attached, form a 5- to 10-membered saturated or
unsaturated heterocyclic radical optionally substituted with one or
more of fluorine, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-a- mino, bis[(C.sub.1-C.sub.3)alkyl]-amino,
trifluoromethyl, hydroxy, hydroxy-substituted
(C.sub.1-C.sub.6)alkyl, phenyl-substituted (C.sub.1-C.sub.6)alkyl,
cyano, a 5- to 10-membered aromatic monocyclic or bicyclic
heterocyclic radical, or phenyl optionally substituted with one or
more (C.sub.1-C.sub.6)alkyl, hydroxy, benzyloxy,
(C.sub.1-C.sub.6)alkoxy, trifluoromethyl, cyano, nitro, or
halogen;
[0031] or
[0032] X is 3
[0033] where R.sup.10 is (C.sub.1-C.sub.9)alkyl optionally
substituted with one or more phenyl, hydroxy, benzyloxy,
(C.sub.1-C.sub.6)alkoxy, or a fluorine atom, or
[0034] phenyl, benzocyclohexyl or benzocyclopentyl optionally
substituted on the phenyl ring with one or more of a phenyl,
hydroxy, benzyloxy, (C.sub.1-C.sub.6)alkoxy, or halogen;
[0035] and pharmaceutical salts and esters thereof.
[0036] Another embodiment of the invention consists of imidazole
derivatives having Formula I wherein
[0037] R.sup.1 and R.sup.2 are identical or different and are
selected from
[0038] a phenyl group optionally substituted with one or more
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
trifluoromethyl, cyano, nitro, (C.sub.1-C.sub.6)alkyl
carbonyl-amino, (C.sub.1-C.sub.6)alkyl amino-carbonyl-amino, or
phenyl,
[0039] (C.sub.2-C.sub.6)alkyl,
[0040] cyclohexyl optionally substituted with
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, trifluoromethyl,
cyano, or with one or more fluorine,
[0041] 1- or 2-naphthyl optionally substituted with halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)atkoxy, trifluoromethyl,
or cyano,
[0042] benzyl optionally substituted on the phenyl ring with one or
more halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
trifluoromethyl, or cyano,
[0043] a 5- to 10-membered saturated or unsaturated heterocyclic
radical optionally substituted with fluorine,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, trifluoromethyl,
or cyano, and
[0044] a 5- to 10-membered aromatic monocyclic or bicyclic
heterocyclic radical optionally substituted with one or more
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
trifluoromethyl, cyano, nitro, or phenyl, with the proviso that
R.sup.2 is not an unsubstituted 4-pyridyl or an unsubstituted
4-pyrimidinyl group;
[0045] R.sup.3 is hydrogen, (C.sub.1-C.sub.6)alkyl, benzyl, chloro,
or bromo;
[0046] X is 4
[0047] where R.sup.4 is hydrogen or (C.sub.1-C.sub.6)alkyl;
[0048] R.sup.5 is phenyl substituted with one or more
(C.sub.1-C.sub.6)alkyl, hydroxy (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, phenyl, hydroxy, benzyloxy,
trifluoromethyl, or halogen, or
[0049] a 5- to 10-membered aromatic monocyclic or bicyclic
heterocyclic radical optionally substituted with one or more
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, or
trifluoromethyl;
[0050] or
[0051] X is 5
[0052] where R.sup.8 is a hydrogen or (C.sub.1-C.sub.6)alkyl;
[0053] R.sup.9 is a (C.sub.1-C.sub.9)alkyl or
(C.sub.7-C.sub.11)bicycloalk- yl group, each of which is optionally
substituted with one or more of phenyl, hydroxy, benzyloxy,
(C.sub.1-C.sub.6)alkoxy, or fluorine,
[0054] benzyl in which the phenyl ring is optionally substituted
with one or more of (C.sub.1-C.sub.6)alkyl, hydroxy, benzyloxy,
(C.sub.1-C.sub.6)alkoxy, trifluoromethyl, cyano, nitro, or halogen,
or
[0055] phenyl, benzocyclohexyl or benzocyclopentyl optionally
substituted on the phenyl ring with one or more of a phenyl,
hydroxy, benzyloxy, (C.sub.1-C.sub.6)alkoxy, or halogen;
[0056] or
[0057] R.sup.8 and R.sup.9, together with the nitrogen atom to
which they are attached, form a 5- to 10-membered saturated or
unsaturated heterocyclic radical optionally substituted with one or
more of (C.sub.1-C.sub.6)alkyl, benzyl, hydroxy, benzyloxy,
(C.sub.1-C.sub.6)alkoxy, halogen, a 5- to 10-membered saturated or
unsaturated heterocyclic radical; or phenyl optionally substituted
with one or more of (C.sub.1-C.sub.6)alkyl, hydroxy, benzyloxy,
(C.sub.1-C.sub.6)alkoxy, trifluoromethyl, cyano, nitro, or
halogen;
[0058] or
[0059] X is 6
[0060] where R.sup.11 is (C.sub.2-C.sub.9)alkyl optionally
substituted with one or more phenyl, hydroxy, benzyloxy,
(C.sub.1-C.sub.6)alkoxy, or fluorine,
[0061] phenyl in which the phenyl ring is optionally substituted
with one or more of (C.sub.1-C.sub.6)alkyl, hydroxy, benzyloxy,
(C.sub.1-C.sub.6)alkoxy, trifluoromethyl, cyano, nitro, or
halogen,
[0062] benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl,
each of which may be optionally substituted on one of the alkyl
carbons with hydroxy, benzyloxy, or hydroxy (C.sub.1-C.sub.6)alkyl,
and optionally substituted on the phenyl ring with halogen,
[0063] (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
trifluoromethyl, cyano, hydroxy, benzyloxy or nitro, or
[0064] a 5- to 10-membered aromatic monocyclic or bicyclic
heterocyclic radical;
[0065] and pharmaceutical salts and esters thereof.
[0066] The terms identified above have the following meaning
throughout:
[0067] "Halogen" means fluorine, chlorine, bromine or iodine.
[0068] The terms "(C.sub.1-C.sub.3)alkyl",
"(C.sub.1-C.sub.6)alkyl", "(C.sub.2-C.sub.6)alkyl",
"(C.sub.1-C.sub.9)alkyl", and "(C.sub.2-C.sub.9)alkyl" mean
C.sub.1-C.sub.3, C.sub.1-C.sub.6, C.sub.2-C.sub.6, C.sub.1-C.sub.9,
and C.sub.2-C.sub.9 linear or branched alkyl groups, respectively,
that may also include a cyclic alkyl radical as part of the alkyl
group. For example, this includes groups such as cyclopropyl,
cyclohexyl, cyclopropyl-methyl, and cycloheptyl-methyl groups. The
preferred alkyl groups are methyl, ethyl, propyl, and isopropyl
groups.
[0069] "(C.sub.1-C.sub.3)alkoxy" and "(C.sub.1-C.sub.6)alkoxy" mean
(C.sub.1-C.sub.3)alkyl-oxy and (C.sub.1-C.sub.6)alkyl-oxy,
respectively.
[0070] "(C.sub.7-C.sub.11)bicycloalkyl" means a C.sub.7-C.sub.11
bicyclic alkyl group, such as octahydro-2-pentalenyl,
bicyclo[2.2.1]hept-2-yl, and bicyclo[3.2.1]oct-8-yl, that is
optionally substituted with one or more methyl groups.
[0071] The term "5- to 10-membered saturated or unsaturated
heterocyclic radical" means a fused or bridged, mono-, bi-, or
tri-cyclic, non-aromatic heterocyclic radical which may contain one
to three of the heteroatoms nitrogen, oxygen, or sulfur. These
radicals include the following radicals, for example,
pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, azepan-1-yl,
morpholin4-yl, hexahydrocyclopenta[c]pyrrol-- 2(1H)-yl, and
thiomorpholin4-yl.
[0072] The term "5- to 10-membered aromatic monocyclic or bicyclic
heterocyclic radical" means a 5- or 6-membered aromatic
heterocyclic radical or a fused bicyclic aromatic heterocyclic
radical, which may contain one to three of the heteroatoms
nitrogen, oxygen, or sulfur. These radicals include the following
radicals, for example, furyl, thienyl, isoxazolyl, pyridyl,
pyrimidinyl, benzofuranyl, and benzothienyl.
[0073] When any moiety is described as being substituted, it can
have one or more of the indicated substituents that can be located
at any available position on the moiety. When there are two or more
substituents on any moiety, each term shall be defined
independently of any other in each occurrence.
[0074] Representative salts of the compounds of Formula I include
the conventional non-toxic salts and the quaternary ammonium salts
which are formed, for example, from inorganic or organic acids or
bases by means well known in the art. For example, such acid
addition salts include acetate, adipate, alginate, ascorbate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
citrate, camphorate, camphorsulfonate, cinnamate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate,
mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
[0075] Base salts include alkali metal salts such as potassium and
sodium salts, alkaline earth metal salts such as calcium and
magnesium salts, and ammonium salts with organic bases such as
dicyclohexylamine salts and N-methyl-D-glucamine. Additionally,
basic nitrogen containing groups may be quaternized with such
agents as lower alkyl halides such as methyl, ethyl, propyl, and
butyl chlorides, bromides and iodides; dialkyl sulfates like
dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long
chain halides such as decyl, lauryl, myristyl and strearyl
chlorides, bromides and iodides, aralkyl halides like benzyl and
phenethyl bromides and others.
[0076] The esters in the present invention are non-toxic,
pharmaceutically acceptable ester derivatives of the alcohols of
Formula I. This includes ester derivatives prepared from acetic,
benzoic, mandelic, stearic, lactic, salicylic, hydroxynaphthoic,
glucoheptonic, and gluconic acid. The alcohol compounds of Formula
I may be esterified by a variety of conventional procedures
including reacting the appropriate anhydride, carboxylic acid, or
acid chloride with the alcohol group of the Formula I compound. The
appropriate anhydride is reacted with the alcohol in the presence
of an acylation catalyst such as 1,8-bis[dimethylamino]naphthale-
ne or DMAP (N,N-dimethylaminopyridine). An appropriate carboxylic
acid may be reacted with the alcohol in the presence of a
dehydrating agent such as dicyclohexylcarbodiimide,
1-[3-dimethylaminopropyl]-3-ethylcarbodiimid- e or other water
soluble dehydrating agents which are used to drive the reaction by
the removal of water, and optionally, an acylation catalyst.
Esterification may also be reached using the appropriate carboxylic
acid in the presence of trifluoroacetic anhydride and optionally,
pyridine, or in the presence of N,N-carbonyldiimidazole with
pyridine. Reaction of an acid chloride with the alcohol may be
carried out with an acylation catalyst such as DMAP or pyridine.
One skilled in the art would readily know how to successfully carry
out these as well as other methods of esterification of alcohols.
Sensitive or reactive groups on the compound of Formula I may need
to be protected during any of the above methods for forming esters,
and protecting groups may be added and removed by conventional
methods well known in the art.
[0077] It will be appreciated that diastereomers and enantiomers of
the exemplified structures will often be possible, and that pure
isomers represent preferred embodiments. It is intended that pure
stereoisomers, and mixtures thereof, are within the scope of the
invention.
[0078] The compounds of this invention may, either by nature of
asymmetric centers or by restricted rotation, be present in the
form of isomers. Any isomer may be present in the (R)--, (S)--, or
(R,S) configuration, preferably in the (R)-- or (S)-configuration,
whichever is most active.
[0079] All isomers, whether separated, pure, partially pure, or in
racemic mixture, of the compounds of this invention are encompassed
within the scope of this invention. The purification of said
isomers and the separation of said isomeric mixtures may be
accomplished by standard techniques known in the art.
[0080] Geometric isomers by nature of substituents about a double
bond or a ring may be present in cis (=Z-) or trans (=E-) form, and
both isomeric forms are encompassed within the scope of this
invention.
[0081] The particular process to be utilized in the preparation of
the compounds of this invention depends upon the specific compound
desired. Such factors as the selection of the specific moieties and
the specific substituents on the various moieties, all play a role
in the path to be followed in the preparation of the specific
compounds of this invention. These factors are readily recognized
by one of ordinary skill in the art.
[0082] For synthesis of any particular compound, one skilled in the
art will recognize that the use of protecting groups may be
required for the synthesis of compounds containing certain
substituents. A description of suitable protecting groups and
appropriate methods of adding and removing such groups may be found
in: Protective Groups in Organic Synthesis, Second Edition, T. W.
Greene, John Wiley and Sons, New York, 1991.
[0083] In the Reaction Schemes below, one skilled in the art will
recognize that reagents and solvents actually used may be selected
from several reagents and solvents well known in the art to be
effective equivalents. When specific reagents or solvents are shown
in a Reaction Scheme, therefore, they are meant to be illustrative
examples of conditions desirable for the execution of that
particular Reaction Scheme. Abbreviations not identified in
accompanying text are listed later in this disclosure under
"Abbreviations and Acronyms."
[0084] Another object of this invention is to provide methods of
making the compounds of the invention. The compounds may be
prepared from readily available materials by the methods outlined
in Reaction Schemes 1 and 2 below, and by obvious modifications
thereto.
[0085] The present invention relates to the use of the compounds of
this invention for the treatment of bulimia and obesity including
associated dyslipidemia and other obesity- and overweight-related
complications such as, for example, cholesterol gallstones, cancer
(e.g., colon, rectum, prostate, breast, ovary, endometrium, cervix,
gallbladder, and bile duct), menstrual abnormalities, infertility,
polycystic ovaries, osteoarthritis, and sleep apnea, as well as for
a number of other pharmaceutical uses associated therewith, such as
the regulation of appetite and food intake, dyslipidemia,
hypertriglyceridemia, Syndrome X, type II diabetes
(non-insulin-dependent diabetes), atherosclerotic diseases such as
heart failure, hyperlipiderira, hypercholesteremia, low HDL levels,
hypertension, cardiovascular disease (including atherosclerosis,
coronary heart disease, coronary artery disease, and hypertension),
cerebrovascular disease and peripheral vessel disease. The
compounds of this invention may also be useful for treating
physiological disorders related to, for example, regulation of
insulin sensitivity, inflammatory response, plasma triglycerides,
HDL, LDL and cholesterol levels and the like.
[0086] The compounds of Formula I of this invention are expected to
be valuable as therapeutic agents. Accordingly, an embodiment of
this invention includes a method of treating the various conditions
identified above in a patient (including mammals) which comprises
administering to said patient a composition containing an amount of
the compound of Formula I that is effective in treating the target
condition.
[0087] Compounds of Formula I may be administered alone or in
combination with one or more additional therapeutic agents.
Combination therapy includes administration of a single
pharmaceutical dosage formulation which contains a compound of
Formula I and one or more additional therapeutic agents, as well as
administration of the compound of Formula I and each additional
therapeutic agents in its own separate pharmaceutical dosage
formulation. For example, a compound of Formula I and a therapeutic
agent may be administered to the patient together in a single oral
dosage composition such as a tablet or capsule, or each agent may
be administered in separate oral dosage formulations.
[0088] Where separate dosage formulations are used, the compound of
Formula I and one or more additional therapeutic agents may be
administered at essentially the same time (e.g., concurrently) or
at separately staggered times (e.g., sequentially).
[0089] For example, the compounds of Formula I may be used in
combination with other therapies and drugs useful for the treatment
of obesity, for example, in combination with
.beta..sub.3-adrenoreceptor agonists such as CL-316,243, or in
combination with a drug compound that modulates digestion and/or
metabolism such as drugs that modulate thermogenesis, lipolysis,
gut motility, fat absorption, and satiety.
[0090] In addition, the compounds of Formula I may be administered
in combination with one or more of the following hypoglycemic
agents for the treatment of diabetes or diabetes-related disorders:
insulin; biguanidines such as metformin or buformin; sulfonylureas
such as acetohexamide, chloropropamide, tolazamide, tolbutamide,
glyburide, glipizide, glyclazide; or any other insulin secretagogue
such as, for example, repaglinide and nateglinide; or
.alpha.-glycosidase inhibitors such as acarbose, voglibose, or
miglitol. Also, the compounds of Formula I may be used in
combination with HMG Co-A reductase inhibitors (statins), bile acid
binding resin, or fibric acid derivatives to improve the lipid
profile of subjects with dyslipidemia. Compounds of Formula I may
also be used in combination with agents that regulate hypertension
(e.g., inhibitors of angiotension converting enzyme (ACE),
.beta.-blockers, calcium channel blockers).
[0091] Furthermore, compounds of the present invention were
determined, following oral dosing in rodents, to be present in
significant concentrations in the brain. Therefore, the compounds
of this invention may have utility for the treatment of any of
various CNS (central nervous system) or psychological disorders,
such as the treatment of substance or behavioral addiction, and the
treatment of disorders associated with the use of psychotropic
substances. Likewise, the compounds of this invention may have
utility for the management and treatment of cognition and memory
disorders.
[0092] The compounds of Formula I may also be utilized, in free
base form or in compositions, as well as in research and
diagnostics or as analytical reference standards, and the like,
which are well known in the art. Therefore, the present invention
includes compositions which are comprised of an inert carrier and
an effective amount of a compound of Formula I, or a salt, or ester
thereof. An inert carrier is any material which does not interact
with the compound to be carried and which lends support, means of
conveyance, bulk, traceable material, and the like to the compound
to be carried. An effective amount of the compound is that amount
which produces a result or exerts an influence on the particular
procedure being performed.
[0093] It is anticipated that prodrug forms of the compounds of
this invention will prove useful in certain circumstances, and such
compounds are also intended to fall within the scope of the
invention. Prodrug forms may have advantages over the parent
compounds exemplified herein, in that they are better absorbed,
better distributed, more readily penetrate the central nervous
system, are more slowly metabolized or cleared, etc. Prodrug forms
may also have formulation advantages in terms of crystallinity or
water solubility. For example, compounds of the invention having
one or more hydroxyl groups may be converted to esters or
carbonates bearing one or more carboxyl, hydroxyl or amino groups,
which are hydrolyzed at physiological pH values or are cleaved by
endogenous esterases or lipases in vivo. See for example U.S. Pat.
Nos. 4,942,184; 4,960,790; 5,817,840; and 5,824,701 (all of which
are incorporated herein by reference in their entirety), and
references therein.
[0094] An object of this invention is to provide a method of
inducing weight loss in an individual by administration of a
compound of the invention. The method of the invention comprises
administering to an individual a therapeutically effective amount
of at least one compound of the invention, or a prodrug thereof,
which is sufficient to induce weight loss. The invention further
comprises a method of preventing weight gain in an individual by
administering an amount of at least one compound of the invention,
or a prodrug thereof, which is sufficient to prevent weight
gain.
[0095] General Preparation of Compounds of Formula I
[0096] Compounds of Formula I are prepared by a variety of
methodologies. The selection of the particular method to be used
depends upon such factors as the availability of appropriate
starting materials, compatibility of functional groups with the
reagents used, and the ultimate structural features present in the
final compound being prepared. It will be understood by those
skilled in the art that more than one method may, in some cases, be
useful for the preparation of individual compound examples of
Formula I.
[0097] In general, the compounds of Formula I are prepared from the
intermediate compound of Formula VI by the methods outlined in
Reaction Scheme 2; the compound of formula VI is prepared by the
methods outlined in Reaction Scheme 1, by one of the two paths as
shown. For the compounds of Formulas Ia-d and II-XmIII, unless
specifically defined otherwise, R, R.sup.1--R.sup.11, and X are as
defined above for Formula I. 7
[0098] Preparation of Intermediates of Formula VI (Reaction Scheme
1)
[0099] In Path 1, an imidamide of Formula IV is prepared by
reaction of an amine of Formula III with a nitrile of Formula II.
This reaction is either conducted using a strong base such as a
Grignard reagent (e.g., EtMgBr) in a neutral solvent (e.g., THF) at
room temperature, or with a Lewis Acid (e.g., AlCl.sub.3) in an
inert solvent (e.g., toluene) with heating. The product, imidamide
IV, is then allowed to react with a 3-bromopyruvate of Formula V by
mixing together in an inert solvent (e.g., toluene or THF), with
optional heating, to give the imidazole intermediate of Formula VI.
This reaction may be further facilitated by the addition of a base
(e.g., propyl amine, sodium carbonate, and the like) to remove
excess HBr produced as a side product. Alternatively, the
conversion of IV to VI may be accomplished in a stepwise manner,
i.e., first carrying out the reaction of IV with V and isolation of
the crude product, and then heating the residue with the
R.sup.1NH.sub.2 compound in acetic acid complete the cyclization to
imidazole VI.
[0100] In path 2, ketoesters of Formula VII are converted to an
oxime compound of Formula VIII, by reaction with sodium nitrite in
a protic solvent, typically acetic acid/water, while cooling. The
product VIII is then heated with an amine of formula
R.sup.1NH.sub.2 in a polar solvent such as acetonitrile, to provide
the imidazole of Formula IX. Finally, N-substitution may be carried
out by treatment of IX with a base and a compound of formula
R.sup.2Y, where Y is a leaving group such as halogen, mesylate, or
tosylate. For this pathway, when the R.sup.2 is aryl, it is
generally an activated (electrophilic) haloarene such as
4-halonitrobenzene or a 2- or 4-halopyridine, capable of undergoing
nucleophilic aromatic substitution reactions.
[0101] The compounds of Formula VI, in which R' is H, may be made
from the compounds of Formula VI in which R' is alkyl, by ester
hydrolysis methods well known in the art. 8
[0102] Preparation of Compounds of Formula I (Reaction Scheme
2)
[0103] The compounds of Formula VI, prepared as shown in Reaction
Scheme 1, may then be used for the preparation of the compounds of
Formula I. To illustrate the methods which are useful for the
preparation of the Formula I compounds, synthetic routes are shown
for the more specific compounds of Formula Ia, Ib, Ic, and Id.
These four structures represent the variants of the Formula I
compounds when X.dbd.--C(.dbd.O)NR.sup.4R.s- up.5,
--CH.sub.2NR.sup.8R.sup.9, --C(.dbd.O)NHSO.sub.2R.sup.10, and
--C(.dbd.O)R.sup.11, respectively.
[0104] The synthetic methods for the preparation of each of these
variants of the Formula I compounds are illustrated in Reaction
Scheme 2.
[0105] In one such method, compounds of Formula VI, in which
R'.dbd.H, the carboxylic acid group is first activated as an acid
halide (e.g., using SOCl.sub.2 or TFFH) and subsequently treated
with a compound of formula R.sup.4R.sup.5NH, usually with base
present such as triethyl amine or PS-DIEA (polystyrene
bound-diisopropylethylamine). Alternatively, the acid may be
activated as a carbodiimide adduct (e.g., with
1-(3-dimethylaminopropyl, triethylarine, and
1-hydroxy-7-azabenzotriazole- )-3-ethylcarbodiimide hydrochloride)
or as a hexafluorophenyl ester (prepared from hexafluorophenol and
EDCl). Following activation, a compound represented as
R.sup.4R.sup.5NH is added to complete the reaction to the Formula
Ia compound. One-pot variations of this conversion may also be
carried out, for example, by mixing a coupling reagent such as HATU
and the R.sup.4R.sup.5NH compound at the same time.
[0106] Compounds of Formula Ia may also be prepared from compounds
of Formula VI where R'=alkyl by heating together the
R.sup.4R.sup.5NH compound and trimethylaluninum.
[0107] Compounds of Formula Ia may also be prepared as shown, from
an ester of Formula VI where R.sup.3 is H, by first halogenating
the imidazole by standard means (e.g., NBS or SO.sub.2Cl.sub.2) to
give the haloimidazole of Formula X. While this intermediate may be
used to prepare Formula VI intermediates where R.sup.3.noteq.H,
using such methods as Pd-catalyzed organotin coupling reactions
(e.g., when R.sup.3 is methyl), Formula X compounds may also be
converted to the amides of Formula XI under the same conditions
described above for conversion of Formula VI compounds to Formula
IA. The resulting amide of Formula XI may then be converted to a
Formula Ia compound, where R.sup.3.noteq.H, by Pd-catalyzed
organotin coupling reactions.
[0108] Formula Ib compounds may be prepared from Formula VI
compounds in the presence of an amino compound of Formula
R.sup.8R.sup.9NH under reductive conditions. When R.sup.8 is
hydrogen, a Formula VI compound where R'=alkyl, is first partially
reduced to the aldehyde with, for example, diisobutylaluminum
hydride (DIBAH), the R.sup.8R.sup.9NH compound is added to form an
imine intermediate in situ, which is then reduced with sodium
borohydride. When R.sub.8.noteq.H, the reductive alkylation may be
accomplished in one step with the R.sup.8R.sup.9NH compound and
lithium aluminum hydride by using the procedure described by Khanna
et al., (Synthesis 607-608, 1975).
[0109] The acylsulfonamides of Formula Ic may be prepared by
reaction of the Formula VI compound (where R'.dbd.H) with a
sulfonamide of Formula R.sup.10SO.sub.2NH.sub.2, facilitated by a
coupling agent such as, for example, a N,N'-dialkyl carbodiimide
such as N,N'-dicyclohexyl carbodiimide and a base such as, for
example, DMAP.
[0110] Formula Id compounds may be prepared by conversion of an
acid chloride represented by Formula XII, prepared as described
above from VI (where R'.dbd.H) and SOCl.sub.2, to an amide of
Formula XIII, which is then allowed to undergo reaction with a
organometallic reagent such as, for example, an alkyl or aryl
Grignard reagent of Formula R.sup.11MgBr, prepared by standard
methods. The resulting product is the ketone of Formula Id. This
Formula Id ketone may also be prepared by similar reaction of aryl-
or alkllithium reagents, such as, for example, R.sup.11Li, with
Formula XIII, or certain Formula Ia amides where R.sup.4R.sup.5NH
is 4-piperidone.
[0111] Conversion of the substituted compounds of Formula Ia, Ib,
Ic, and Id to differently substituted Formula I compounds may be
carried out using standard functional group conversion chemistry.
For example, keto substituents may be reduced with reagents such as
Na.sub.2BH.sub.4, to the corresponding hydroxy substituted
compounds. Other such examples are 1) the conversion of nitrophenyl
substituent to the corresponding aminophenyl substituent, and 2)
O-- or N-alkylation or acylation of OH or NH substituents to give
the corresponding O-- or N-alkyl or O-- or N-acyl substituted
compounds.
EXPERIMENTAL EXAMPLES
[0112] The following specific preparative examples are included as
illustrations of preparation of specific compounds of the
invention, and are not to be construed as limiting the scope of the
invention in any way.
[0113] NMR Methods:
[0114] Proton (.sup.1H) nuclear magnetic resonance (NMR) spectra
were measured with a General Electric GN-Omega 300 (300 MHz)
spectrometer with either Me.sub.4Si (.delta. 0.00) or residual
protonated solvent (CHCl.sub.3 .delta. 7.26; MeOH .delta. 3.30;
DMSO .delta. 2.49) as reference standard. Carbon (.sup.13C) NMR
spectra were measured with a General Electric GN-Omega 300 (75 MHz)
spectrometer with solvent (CDCl.sub.3 .delta. 77.0; d.sub.3-MeOD;
.delta. 49.0; d.sub.6-DMSO .delta. 39.5) as reference standard.
[0115] LC-MS Instrumentation:
[0116] (a) a Gilson HPLC system equipped with two Gilson 306 pumps,
a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro
C-18 column (2.times.23 mm, 120 A), and a Micromass LCZ single
quadrupole mass spectrometer with z-spray electrospray ionization.
Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD
(Evaporative Light Scattering Detector) data was also acquired as
an analog channel.
[0117] (b) a Hewlett-Packard 1100 HPLC equipped with a quaternary
pump, a variable wavelength detector set at 254 nm, a YMC pro C-18
column (2.times.23 mm, 120A), and a Finnigan LCQ ion trap mass
spectrometer with electrospray ionization. Spectra were scanned
from 120-1200 amu using a variable ion time according to the number
of ions in the source.
[0118] HPLC conditions. In the Examples and Tables provided below,
LC-MS data are given with retention times (RT) determined by using
one of the following methods:
[0119] Method 1. Eluents were A: 2% acetonitrile in water with
0.02% TFA, and B: 2% water in acetonitrile with 0.02% TFA. Elution
conditions consisted of a flow rate of 1.0 mL/min with an initial
hold at 10% B for 0.5 minutes, followed by gradient elution from
10% B to 95% B over 3.5 minutes, followed by a final hold at 95% B
for 0.5 minutes. Total run time was 6.5 minutes.
[0120] Method 2. Eluents as above; elution at a flow rate of 1.5
mL/min with an initial hold at 10% B for 0.5 minutes, followed by
gradient elution from 10% B to 90% B over 3.5 minutes, followed by
a final hold at 90% B for 0.5 minutes. Total run time was 4.8
minutes.
[0121] Abbreviations and Acronyms
[0122] When the following abbreviations are used herein, they have
the following meaning:
[0123] BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
[0124] CD.sub.3OD methanol-d.sub.4
[0125] Celite.RTM. diatomaceous earth filter agent, .RTM.Celite
Corp.
[0126] DMAP 4-(N,N-dimethylamino)pyidine
[0127] DMF N,N-dimethylformamide
[0128] DMSO dimethylsulfoxide
[0129] EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
[0130] ELSD evaporative light scattering detector
[0131] EtOAc ethyl acetate
[0132] EtOH ethanol (100%)
[0133] Et.sub.2O diethyl ether
[0134] Et.sub.3N triethylamine
[0135] h hour(s)
[0136] HATU O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethyluronium
hexafluorophosphate
[0137] HPLC high performance liquid chromatography
[0138] LC-MS liquid chromatography-mass spectroscopy
[0139] min minute(s)
[0140] m/z mass-to-charge ratio
[0141] MeCN acetonitrile
[0142] Ms methanesulfonyl
[0143] NBS N-bromosuccinimide
[0144] NMM 4-methylmorpholine
[0145] OMs methanesulfonyl-oxy
[0146] OTs 4-toluenesulfonyl-oxy
[0147] PS-DIEA Polystyrene-bound diisopropylethylamine
[0148] Rf retention factor (TLC)
[0149] RT retention time (HPLC)
[0150] rt room temperature
[0151] THF tetrahydrofuran
[0152] TFA trifluoroacetic acid
[0153] TFFH Fluoro-N,N,N,N',N'-tetramethylformamidinium
hexafluorophosphate
[0154] TLC thin layer chromatography
[0155] Ts 4-toluenesulfonyl
Example 1
Preparation of
2,4-dichloro-N-(4-chlorophenyl)benzenecarboximidamide
[0156] 9
[0157] Under argon, 4-chloroaniline (6.67 g, 52.5 mmol) was slowly
added to EtMgBr (52 mL, 1 M in THF, 52 mmol) portion wise. After
the solution was stirred for 0.5 h, 2,4-dichlorobenzonitrile (9.03
g, 52.5 mmol) was added. The resulting solution was stirred at rt
overnight. The reaction mixture was carefully quenched with water
and extracted with ethyl acetate. The organic layer was dried over
MgSO.sub.4, filtered, and concentrated. Crude product (16.26 g,)
was obtained as a sticky brown foam which was used without
purification for the next step. LC-MS m/z 299.3 (MH.sup.+),
retention time 1.75 min (MDLC 1); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 4.92 (2H, br), 7.09-7.51 (7H, m).
Example 2
Preparation of N-(4-chlorophenyl)-3-methylbutanimidamide
[0158] 10
[0159] To a solution of 3-methylbutanenitrile (250 mg, 3.0 mmol)
and AlCl.sub.3 (400 mg, 3.0 mmol) in toluene (6 mL) was added
4-chloroaniline (383 mg, 3.0 mmol). The resulting solution was
stirred at reflux for 2 h, diluted with water, and extracted with
EtOAc. The aqueous layer was neutralized with saturated NaHCO.sub.3
solution and extracted with EtOAc. The combined extracts were dried
over MgSO.sub.4, filtered, and concentrated. The crude product (364
mg, 58% yield) was used for the next step without purification.
Example 3
Preparation of ethyl
1-(4-fluorophenyl)-2-(2-chlorophenyl)-1H-imidazole-4--
carboxylate
[0160] 11
[0161] To a solution of crude
2-chloro-N-(4-fluorophenyl)benzenecarboximid- amide (6.8 g, 27
mmol) in toluene (100 mL), ethyl bromopyruvate (3.5 mL, 27 mmol)
was added. The resulting solution was heated at 115.degree. C. for
90 minutes. The reaction mixture was cooled to rt. Propylamine (2.2
mL, 27 mmol) was added. The reaction mixture was diluted with ethyl
acetate and washed with saturated NaCl solution. The organic layer
was dried over MgSO.sub.4, filtered, and concentrated. The residue
was purified by flash chromatography over silica gel (30% ethyl
acetate in hexane) to give the product (3.4 g, 37% overall yield
from 4-fluoroaniline) as a light yellow solid: LC-MS m/z 345.2
(MH.sup.+), retention time 2.78 min (method 1); Rf=0.20 (30% EtOAc
in hexane). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.38-1.43
(3H, t, J=6.9 Hz), 4.39-4.46 (2H, q, J=3.9 Hz), 6.98-7.52 (8H, m),
7.89 (1H, s).
Example 4
Preparation of ethyl
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-
e-4-carboxylate
[0162] 12
[0163] To a solution of crude
2,4-dichloro-N-(4-chlorophenyl)benzenecarbox- imidamide (10.3 g,
34.6 mmol) in toluene (100 mL), ethyl bromopyruvate (4.3 mL, 34.6
mmol) and Na.sub.2CO.sub.3 (7.3 g, 41.6 mmol) were added. The
resulting solution was heated at reflux for 3 h. The reaction
mixture was cooled to rt. The solid was filtered off and the
solvent was evaporated. The residue was purified by flash
chromatography over silica gel (40% ethyl acetate in hexane) to
give the product (7.5 g, 52% overall yield from 4-chroloaniline) as
a light yellow solid: LC-MS m/z 395 (MH.sup.+), retention time 3.91
min (method 1); mp 143-144.degree. C.; Rf=0.63 (50% EtOAc in
hexane). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.39-1.43 (3H,
t, J=7.2 Hz), 4.39-4.46 (2H, q, J=6.9 Hz), 7.04-7.08 (2H, m),
7.25-7.50 (5H, m), 7.89 (1H, s).
Example 5
Preparation of ethyl
2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imid-
azole-4-carboxylate
[0164] 13
[0165] A solution of
2-dichloro-N-(4-chlorophenyl)benzenecarboximidamnide (10 g, 37.7
mmol) in THF (100 mL) was treated with K.sub.2CO.sub.3 (5.2 g, 37.7
mmol) followed by the slow addition of ethyl
3-bromo-2-oxopentanoate (10.1 g, 45 mmol) over 3 h. The reaction
mixture was stirred at rt overnight. The solid was then filtered
off and the solvent was evaporated. The residue (20 g, 37.7 mmol)
was dissolved in acetic acid (100 mL) and heated at reflux for 1 h.
The reaction mixture was cooled to rt, diluted with water (200 mL),
and extracted with ethyl acetate. The organic layer was washed with
water. The aqueous layer was neutralized with saturated
NaHCO.sub.3, and extracted with ethyl acetate. The combined
extracts were dried over MgSO.sub.4, filtered, and concentrated.
The residue was purified by flash chromatography over silica gel
(40% ethyl acetate in hexane) to give the product (8.5 g, 40%
overall yield from 4-chroloaniline) as a light yellow solid: LC-MS
m/z 389 (MH.sup.+), retention time 3.31 min (method 1); Rf=0.28
(40% EtOAc in hexane). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.05-1.10 (3H, t, J=7.5 Hz), 1.40-1.44 (3H, t, J=7.2 Hz), 2.85-2.92
(2H, q, J=4.2 Hz), 4.39-4.46 (2H, q, J=7.2 Hz), 7.09-7.41(8H,
m).
Example 6
Preparation of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-N-(1-piperidi-
nyl-1H-imidazole-4-carboxamide
[0166] 14
[0167] To a solution of 1-aminopiperidine (2.48 mL, 23 mmol) in
CH.sub.2Cl.sub.2(15 mL) was added trimethylaluminum (11.5 mL, 2 M
in hexane, 23 mmol). After the mixture was stirred for 0.5 h, a
solution of ethyl
2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carbox-
ylate (3.0 g, 7.7 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added. The
reaction mixture was heated at reflux for 2 h and cooled to rt.
Water was slowly added dropwise to the reaction mixture at
0.degree. C. until no more gas bubbled out. The mixture was dried
over Mg.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by flash chromatography over silica gel (40% then 60%
ethyl acetate in hexane) to give the product (2.4 g, 64 % yield) as
a white solid: LC-MS m/z 443 (MH.sup.+), retention time 2.95 min
(method 1); mp 208-209 .degree. C.; Rf=0.74 (EtOAc). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 0.98-1.03 (3H, t, 7.8 Hz), 1.35-1.37
(2H, m), 1.58-1.70 (4H, m), 2.77-2.88 (6H, m), 6.70-7.30 (8H, m),
7.84 (1H, s).
Example 7
Preparation of
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5H-imidazole-4-ca-
rboxylic acid
[0168] 15
[0169] To a solution of ethyl
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-
-imidazole4-carboxylate (1.1 g, 2.79 mmol) in MeOH (20 mL), a
solution of KOH (2.2 g, 39 mmol) in H.sub.2O (20 mL) was added. The
mixture was heated at 90.degree. C. for 3 h. The reaction mixture
was cooled to rt and the MeOH was evaporated. HCl (1N) was added
until a white precipitate formed. The solid was filtered off, and
dried under vacuum. The product (1.0 g, 98% yield) was obtained as
a white solid: LC-MS m/z 367 (MH.sup.+), retention time is 3.43 min
(method 1); mp 150-151 .degree. C.; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.24-7.65 (7H, m), 8.26 (1H, s).
Example 8
Preparation of
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(4-morpholinyl)-
-1H-imidazole-4-carboxamide
[0170] 16
[0171] To a solution of
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5H-imida-
zole-4-carboxylic acid (50 mg, 0.137 mmol) in CH.sub.2Cl.sub.2 (5
mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(58 mg, 0.164 mmol), 1-hydroxy-7-azabenzotriazole (40 mg, 0.164
mmol), and triethylamine (1.5 mL) were added. After the mixture was
stirred for 15 minutes, 4-morpholinamine (0.164 mmol) was added.
The reaction mixture was stirred at rt overnight, and washed with
water. The organic layer was dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by HPLC (YMC-packed PRO C18
15.times.200 mm column, 10-90% CH.sub.3CN in H.sub.2O/TFA, 20
mL/min.) to give the product (10 mg, 16% yield) as a yellow oil:
LC-MS m/z 451 (MH.sup.+), retention time 3.03 min (method 1);
Rf=0.57 (50% EtOAc in hexane); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 2.97-3.00 (4H, t, J=4.5 Hz), 3.83-3.86 (4H, t, J=4.2 Hz),
7.04-7.39 (8H, m), 7.92 (1H, s).
Example 9
Preparation of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(3-pyridinyl)-1H-im-
idazole-4-carboxamide
[0172] 17
[0173]
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic
acid (403 mg, 1.2 mmol) was dissolved in dichloromethane (5 mL) and
treated with
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) (459 mg, 1.56 mmol) and
N-methylmorpholine (NMM) (182 mg, 1.8 mmol). The mixture was
stirred under argon for 15 minutes before 3-aminopyridine (349 mg,
3.6 mmol) was added. Stirring at rt was continued overnight. The
reaction mixture was then adsorbed onto silica gel and
chromatographed (2-3% MeOH in CH.sub.2Cl.sub.2) to afford
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(3-pyridinyl)-1H-imidazole-4-carb-
oxamide (266 mg, 54% yield): LC-MS nz/z 409.3, retention time 2.43
min (method 1).
Example 10
Preparation of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N'-[2-(trifluoromethy-
l)phenyl]-1H-imidazole-4-carbohydrazide
[0174] 18
[0175] In a 20-mL screw-cap vial, 100 mg (0.3 mmol)
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic
acid, 87 mg (0.33 mmol) TFFH (Advanced Chemtech, Louisville, Ky.),
and 5.0 equiv. PS-DIEA (Argonaut Technologies Inc., San Carlos,
Calif.) (loading level: 3.50 mmol/g, 429 mg, 1.5 mmol) were heated
in 8 mL 1,2-dichloroethane at 35.degree. C. overnight. The
formation of acyl fluoride was monitored by LC-MS. To the mixture,
1.1 equiv. (58 mg, 0.33 mmol) 2-(trifluoromethyl)phenyl hydrazine
was added and the reaction continued overnight. The mixture was
filtered through a filter tube (polypropylene frit), and the
filtrate was evaporated under reduced pressure. The crude product
was redissolved in 1 mL MeOH and purified by preparative HPLC to
give 41.8 mg of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N'-[2-(trifluoromet-
hyl)phenyl]-1H-imidazole-4-carbohydrazide as the trifluoroacetate
salt (light yellow solid, 23% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.70 (s, 1 H), 7.85 (s, 1 H), 7.45 (m, 2 H),
7.20-7.38 (m, 6 H), 7.12 (d, 1 H), 7.00 (d, 2 H), 6.88 (t, 1 H),
6.60 (s, 1 H); LC-MS m/z 491.2 (MH.sup.30), retention time 4.02 min
(method 2).
[0176] The free base form of the product was obtained by dissolving
the TFA salt in dichloromethane, washing with saturated aqueous
sodium carbonate solution and water, followed by drying the organic
phase with magnesium sulfate, and evaporation of the organic phase
under reduced pressure. The hydrochloride salt form of the product
was obtained by treating the free base in dichloromethane with 1.0
M hydrogen chloride in diethyl ether until no more precipitate was
formed, followed by evaporation of solvent under reduced
pressure.
Example 11
Preparation of
1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]-
carbonyl}-4-[4-(trifluoromethyl)phenyl]piperazine
[0177] 19
[0178] In a 20-mL screw-cap vial, 100 mg (0.3 mmol)
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic
acid, 87 mg (0.33 mmol) TFFH, and 5.0 equiv. PS-DIEA (loading
level: 3.50 mmol/g, 429 mg, 1.5 mmol) were heated in 8 mL
1,2-dichloroethane at 35.degree. C. overnight. The formation of
acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv.
(76 mg, 0.33 mmol) 1-(4-trifluormethylphenyl)-piperaz- ine was
added and the reaction continued overnight. The mixture was
filtered through a filter tube (polypropylene frit), and the
filtrate was evaporated under reduced pressure. The crude product
was redissolved in 1 mL MeOH and purified by preparative HPLC to
give 45.9 mg of
1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-[4-
-(trifluoromethyl)phenyl]piperazine as the trifluoroacetate salt
(yellow oil, 23% yield). .sup.1H NMR (400 MHz, CD.sub.3COCD.sub.3)
.delta. 7.95 (s, 1 H), 7.60 (m, 1 H), 7.30-7.50 (m, 7 H), 7.25 (d,
2 H), 7.05 (d, 2 H), 4.5 (bs, 2 H), 3.80 (bs, 2 H), 3.35 (m, 4 H);
LC-MS m/z 545.3 (MH.sup.+), retention time 4.21 min (method 2).
Example 12
2-(2,4-dichlorophenyl)-N-(trans-2-hydroxycyclohexyl)-1-(4-methoxyphenyl)-1-
H-imidazole-4-carboxamide
[0179] 20
[0180] In a 20-mL screw-cap vial, 182 mg (0.5 mmol)
2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic
acid, 145 mg (0.55 mmol) TFFH, and 5.0 equiv. PS-DIEA (loading
level: 3.50 mmol/g, 716 mg, 2.5 mmol) were heated in 10 mL
1,2-dichloroethane at 35.degree. C. overnight. The formation of
acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv.
(84 mg, 0.55 mmol) trans-2-aminocyclohexanol hydrochloride was
added and the reaction continued overnight. The mixture was
filtered through a filter tube (polypropylene frit), and the
filtrate was evaporated under reduced pressure. The crude product
was redissolved in 1 mL MeOH and purified by preparative HPLC to
give 53 mg of 2-(2,4-dichlorophenyl)-N-(trans-2-hydro-
xycyclohexyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide (amber
oil, 23% yield). .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2) .delta.
7.90 (s, 1 H), 7.30-7.50 (m, 4 H), 7.10 (d, 2 H), 6.90 (d, 2 H),
3.85 (s, 3 H), 3.80 (m, 1 H), 3.50 (m, 1 H), 3.25 (bs, 1 H), 2.0
(m, 2 H), 1.75 (m, 2 H), 1.30-1.50 (m, 4 H); LC-MS m/z 460.2
(MH.sup.+), retention time 3.31 min (method 2).
Example 13
Preparation of
1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]-
carbonyl}-4-piperidinone
[0181] 21
[0182] Step 1. Thionyl chloride (0.66 mL, 9 mmol) was added to a
solution of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic
acid (1 g, 3 mmol) in toluene (10 mL). The mixture was refluxed
under argon for 1.5 h and concentrated to provide
2-(2-chlorophenyl)-1-(4-chloropheny- l)-1H-imidazole-4-carbonyl
chloride, which was used in the next step without purification.
.sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) .delta. 8.40 (s, 1H),
7.69-7.09 (m, 8H).
[0183] Step 2. Triethylamine (1.46 mL, 10.45 mmol) was added to a
suspension of 4-piperidinone trifluoroacetate (0.76 g, 3.58 mmol)
in CH.sub.2Cl.sub.2 (10 mL) and a solution of
2-(2-chlorophenyl)-1-(4-chloro- phenyl)-1H-imidazole-4-carbonyl
chloride in CH.sub.2Cl.sub.2 (5 mL) was added. The mixture was
stirred at rt under argon for 17 h, diluted with CH.sub.2Cl.sub.2
(50 mL), washed with water (2.times.50 mL), dried over MgSO.sub.4,
and concentrated to give 1-{[2-(2-chlorophenyl)-1-(4-chloroph-
enyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinone as a yellow solid
(0.96 g, 77%). MS (Electrospray) 414 (MH.sup.+), .sup.1H NMR (300
MHz, CD.sub.2Cl.sub.2) .delta. 7.80 (s, 1H), 7.37-7.20 (m, 6H),
7.06-7.00 (m, 6H), 4.47 (br, 2H), 3.92 (br, 2H), 2.46 (t, 4H).
Example 14
5-Butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidinyl)-1H-imidazo-
le-4-carboxamnide
[0184] 22
[0185] Step 1. To a solution of
5-butyl-2-(2-chlorophenyl)-1-(4-chlorophen-
yl)-1H-imidazole-4-carboxylic acid (438 mg, 1.12 mmol) in dry
toluene (3 mL), at rt was added thionyl chloride (401 .mu.L, 3.4
mmol). The solution was stirred overnight at rt, and then heated at
110.degree. C. for 5 h. The resulting reaction was cooled to rt,
and the solvents evaporated, to give
5-butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbony-
l chloride (455 mg, 100%), which was used in the next step without
purification. LC-MS m/z 407 (MH.sup.+), retention time 3.62 min
(method 2).
[0186] Step 2. To a solution of
5-butyl-2-(2-chlorophenyl)-1-(4-chlorophen-
yl)-1H-imidazole-4-carbonyl chloride (227 mg, 0.56 mmol) in
CH.sub.2Cl.sub.2 (5 mL), were added 1-aminopiperidine (113 mg, 1.12
mmol) and Et.sub.3N (234 .mu.L, 1.68 mmol). The solution was
stirred overnight at rt, and then the solvents were evaporated
under reduced pressure. The residue was purified by preparative
reversed-phase HPLC, using 20 to 100% MeCN in water as gradient, to
provide 125 mg (48%) of
5-butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidinyl)-1H-imidaz-
ole-4-carboxamide as a white powder. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.49-7.27 (m, 8 H), 2.93 (t, 2 H), 2.82 (bs, 4
H), 1.77-1.71 (m, 4 H), 1.46-1.37 (m, 4 H), 1.25-1.20 (2 H), 0.79
(t, 3 H). LC-MS m/z 471.33 (MH.sup.+), retention time 2.88 min
(method 2).
Example 15
Preparation of
N-exo-bicyclo[2.2.1]hept-2-yl-2-(2-chlorophenyl)-1-(4-chlor-
ophenyl)-1H-imidazole-4-carboxamide
[0187] 23
[0188] Step 1.
2-(2-Chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbox- ylic
acid (1.5 g, 4.5 mmol) was dissolved in dichloromethane (40 mL).
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI,
946 mg, 4.95 mmol) and triethylamine (500 mg, 4.95 mmol) were added
followed by pentafluorophenol (815 mg, 4.37 mmol). The mixture was
stirred at rt under argon for one hour before it was washed with 5%
HCl, sodium bicarbonate solution, and then brine. The organic layer
was dried (MgSO.sub.4), filtered, and concentrated to give the
crude product (1.26 g) which was chromatographed over silica gel
(20% EtOAc in hexanes) to afford pentafluorophenyl
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazo- le-4-carboxylate
(0.73 g, 32% yield): LC-MS m/z 499.0 (MH.sup.+), retention time
3.93 min (method 1).
[0189] Step 2. The pentafluorophenol ester (60 mg, 0.12 mmol) and
exo-norbomylamine (40 mg, 0.36 mmol) were dissolved in
dichloromethane (2 mL), treated with triethylamine (49 mg, 0.48
mmol), and stirred at rt overnight. The mixture was then washed
with 5% aqueous HCl, sodium bicarbonate solution and brine, dried
(MgSO.sub.4), filtered, and concentrated. Pure
N-exo-bicyclo[2.2.1]hept-2-yl-2-(2-chlorophenyl)-1-(4--
chlorophenyl)-1H-imidazole-4-carboxamide was thus obtained (30 mg,
59% yield): LC-MS mnz 426.1 (MH.sup.+), retention time 3.49 min
(method 1).
Example 16
Preparation of
N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]-
carbonyl}4-(trifluoromethyl)benzenesulfonamide
[0190] 24
[0191] In a 20-mL screw-cap vial, 250 mg (0.75 mmol)
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic
acid, 18.3 mg DMAP (0.15 mmol), 1.25 g PS-Carbodiimide (1.5 mmol)
(polystyrene-supported cyclohexylcarbodimide ,Argonaut Technologies
Inc., San Carlos, Calif.), 169 mg
.alpha.,.alpha.,.alpha.-trifluoro-p-toluenesu- lfonamide (0.75
mmol), and 12 mL dichloromethane were added, and the reaction
mixture was mixed by orbital shaking at rt overnight. The reaction
mixture was filtered through a filter tube (polypropylene frit),
and the filtrate was evaporated under reduced pressure. The crude
product was redissolved in 2 mL MeOH and purified by preparative
HPLC to give 39.3 mg of
N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]car-
bonyl}-4-(trifluoromethyl)benzenesulfonamide (beige solid, 10%
yield). .sup.1H NMR (400 MHz, CD3COCD3) .delta. 8.25 (d, 2 H), 7.85
(s, 1 H), 7.75 (s, 2H), 7.20-7.40 (m, 6 H), 6.95 (t, 2 H); LC-MS
m/z 540 (MH.sup.+), retention time 3.36 min (method 2).
Example 17
Preparation of
1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]-
carbonyl}-4-(4-fluorophenyl)-4-piperidinol
[0192] 25
[0193] A solution of
1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-
4-yl]carbonyl}-4-piperidinone (0.1 g, 0.24 mmol, prepared as
described in Example 13) in THF (4 mL) was added dropwise to a
solution of 4-fluorophenylmagnesium bromide (0.6 mL, 0.60 mL) at
-78.degree. C. The mixture was stirred at -78.degree. C. for 2 h
then allowed to warm up to 30.degree. C. Saturated NH.sub.4Cl (3
mL) was added slowly followed by water (3 mL). The mixture was
extracted with ethyl acetate (3.times.20 mL) and dried over
MgSO.sub.4. The product (0.056 g, 46%) was isolated by column (50%
ethyl acetate in hexane). MS (Electrospray) 510.1 (M).sup.+;
.sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) .delta. 7.81 (s, 1H),
7.50-7.24 (m, 8H), 7.10-6.98 (m, 4H), 5.33-5.17 (m, 1H), 4.74-4.57
(m, 1H), 3.68 (t, 1H), 3.31 (t, 1H), 2.15 (br, 2H), 1.83 (d,
2H).
Example 18
Preparation of
1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]-
carbonyl}-4-(2-furyl)-4-piperidinol
[0194] 26
[0195] BuLi (0.875 mL, 1.40 mmol, 1 M solution in THF) was added
slowly to a solution of furan (0.106 mL, 1.45 mmol) in THF (2 mL)
at -78.degree. C., and the mixture was stirred at -78.degree. C.
for 1 h. A solution of
1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-pi-
peridinone (0.3 g, 0.68 mmol) in THF (1 mL) was added slowly. The
mixture was stirred at -78.degree. C. for 2 h and saturated
NH.sub.4Cl (3 mL) and water added. The mixture was extracted with
ethyl acetate (3.times.20 mL) and dried over MgSO.sub.4. The
product (0.142 g, 61%) was isolated by column (ethyl acetate). MS
(Electrospray) 482 (M).sup.+; .sup.1H NMR (300 MHz,
CD.sub.2Cl.sub.2) .delta..7.85 (s, 1H), 7.51-7.31 (m, 7H),
7.10-6.98 (m, 4H), 7.17-7.10 (m, 2H), 6.39 (s, 1H), 6.29 (s, 1H),
4.68 (br, 1H), 4.28 (br, 1H), 3.94 (br, 1H), 3.57 (br, 1H),
2.26-1.91 (m, 4H).
Example 19
Preparation of t-butyl 2-hydroxyimino-3-oxobutanoate
[0196] 27
[0197] t-Butyl acetoacetate (5.0 g, 31.6 mmol) was dissolved in
acetic acid (4.5 mL), cooled by an ice water bath, and treated with
sodium nitrite (2.45 g, 35.5 mmol) in water (5.5 mL) while the
internal temperature was kept at <10.degree. C. (see, e.g., U.S.
Pat. No. 4,743,586). After the addition was complete, the mixture
was stirred at rt for 30 minutes before water (16 mL) was added.
After 2 h, extraction with ether (3.times.25 mL), which was washed
with water (10 mL), sodium bicarbonate solution (3.times.10 mL),
and water (20 mL), gave t-butyl 2-hydroxyimino-3-oxobutanoate as a
white solid (5.52 g, 93%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.61 (s, 1H), 2.39 (s, 3H), 1.58 (s, 9H).
Example 20
Preparation of t-Butyl
2-(2-chlorophenyl)-5-methyl-1H-imidazole-4-carboxyl- ate
[0198] 28
[0199] t-Butyl 2-hydroxyimino-3-oxobutanoate (0.50 g, 2.67 mmol)
was mixed with 2-chlorobenzylamine (0.34 mL, 2.82 mmol) in
anhydrous acetonitrile (10 mL), and heated at reflux for 3 h. Upon
cooling, the suspension was filtered, and the filtered material was
washed with a small amount of acetonitrile to afford a white solid
(0.379 g). The filtrate was concentrated and the residue
chromatographed over silica gel (25% EtOAc in hexane) to give
.tau.-butyl 2-(2-chlorophenyl)-5-methyl-1H-imidazole-4-
-carboxylate as a yellow foam (0.262 g, 82% combined yield):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.43 (br, 1H), 8.29 (mn,
1H), 7.38 (m, 3H), 2.52 (s, 3H), 1.60 (s, 9H).
Example 21
Preparation of t-Butyl
2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-im-
idazole-4-carboxylate
[0200] 29
[0201] t-Butyl 2-(2-chlorophenyl)-5-methylimidazole-4-carboxylate
(70 mg, 0.24 mmol) was mixed with 4-fluoro-1-nitrobenzene (27
.mu.L, 0.25 mmol) and potassium carbonate (66 mg, 0.48 mmol) in dry
DMF and heated at 120.degree. C. for 4 h. The mixture was diluted
with water and filtered to give a yellow solid which was
chromatographed over silica gel (40% EtOAc in hexane) to afford a
yellow solid (72 mg, 73%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.20 (m, 2H), 7.51 (m, 1H), 7.25 (m, 5H), 2.45 (s, 3H),
1.66 (s, 9H).
Example 22
Preparation of
2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-imidazole--
4-carboxylic acid
[0202] 30
[0203] t-Butyl
2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-imidazole--
4-carboxylate (69 mg, 0.17 mmol) was dissolved in dry
dichloromethane (2 mL) and treated dropwise with trifluoroacetic
acid (2 mL). After stirring at rt for 2 h, the solution was
concentrated to give
2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-imidazole-4-carboxylic
acid as a yellow foam, which was used without purification in the
preparation of Example 23.
Example 23
Preparation of
N-cyclohexyl-2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)--
1H-imidazole-4-carboxamide
[0204] 31
[0205] The carboxylic acid obtained from Example 22 was dissolved
in dry dichloromethane (3 mL), cooled by an ice water bath, and
treated with 1-(3-dimethylamino)propyl-3-ethylcarbodiimide
hydrochloride (39 mg, 0.20 mmol) and dimethylaminopyridine (46 mg,
0.38 mmol). The mixture was stirred at rt for 1 h before
cyclohexylamine (23 .mu.L, 0.20 mmol) was added. The solution was
stirred overnight, diluted with dichloromethane, washed with water
and ammonium chloride solution, dried (sodium sulfate), and
filtered. The filtrate was concentrated to afford a yellow oil (70
mg) which was chromatographed over silica gel (35% EtOAc in hexane)
to give
N-cyclohexyl-2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-imidaz-
ole-4-carboxamide as a yellow solid (50 mg, 67%): mp
217-220.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.20
(d, 2H), 7.41 (m, 1H), 7.25 (m, 5H), 7.12 (m, 1H), 3.95 (m, 1H),
2.55 (s, 3H), 2.00 (m, 2H), 1.75 (m, 2H), 1.61 (m, 1H), 1.30 (m,
5H); LC-MS m/z 439.2 (MH.sup.+), retention time 3.41 min (method
1).
Example 24
Preparation of tert-butyl
1-(4-chlorobenzyl)-2-(2-chlorophenyl)-5-methyl-1-
H-imidazole-4-carboxylate
[0206] 32
[0207] t-Butyl 2-(2-chlorophenyl)-5-methylimidazole-4-carboxylate
(70 mg, 0.24 mmol) was mixed with 4-chlorobenzyl bromide (50 mg,
0.24 mmol) and potassium carbonate (66 mg, 0.48 mmol) in dry
acetonitrile (3 mL) and heated at reflux overnight. The next day,
additional 4-chlorobenzyl bromide (10 mg, 0.05 mmol) was added, and
the reaction mixture was again heated at reflux overnight. The next
day, water was added to the cooled mixture, which was subsequently
extracted with EtOAc. The extract was washed with aqueous NaCl,
dried (NaSO.sub.4), filtered, and concentrated to give a colorless
oil (113 mg). It was chromatographed over silica gel (25% EtOAc in
hexane) to afford tert-butyl 1-(4-chlorobenzyl)-2-(2-chloro-
phenyl)-5-methyl-1H-imidazole-4-carboxylate as a white foam (61 mg,
61% yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.48 (d, 1H),
7.40 (m, 1H), 7.27 (m, 2H), 7.17 (d, 2H), 6.78 (d, 2H), 5.33 (br,
2H), 2.55 (s, 3H), 1.50 (s, 9H); LC-MS m/z 417.1 (MH.sup.+),
retention time 3.23 min (method 1).
Example 25
Preparation of ethyl
5-bromo-1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)-1H--
imidazole-4-carboxylate
[0208] 33
[0209] Ethyl
1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)-1H-imidazole-4-carb-
oxylate (1.23 g, 3.47 mmol) was dissolved in EtOH (15 mL) and
treated with N-bromosuccinirnide (1.25 g, 7.02 mmol). The solution
was stirred at rt for 3 h. Water was added. Extraction with
dichloromethane, which was then washed with NaCl solution, gave an
orange solid (1.94 g). Purification by chromatography over silica
gel (20% EtOAc in hexane) afforded a light tan solid (1.028 g,
68%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.35 (d, 2H), 7.03
(d, 2H), 7.00 (m, 1H), 6.86 (m, 2H), 4.44 (q, 2H), 2.26 (s, 3H),
2.10 (s, 3H), 1.43 (t, 3H); LC-MS m/z 433.1 (MH.sup.+), retention
time 3.84 min (method 1).
Example 26
Preparation of ethyl
1-(4-chlorophenyl)-5-methyl-2-(2,4-dimethylnhenyl)-1H-
-imidazole-4-carboxylate
[0210] 34
[0211] Ethyl
5-bromo-1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)-1H-imidazol-
e-4-carboxylate (430 mg, 0.99 mmol) was dissolved in dry DMF (5 mL)
in a pressure tube and treated with tetramethyltin (1.3 mL, 9.38
mmol), palladium acetate (9 mg, 0.04 mmol), and
tri-(o-tolyl)phosphine (26 mg, 0.085 mmol). The mixture was heated
at 110.degree. C. for 15 minutes. After the mixture was cooled to
rt, water was added (25 mL). The mixture was extracted with
dichloromethane (2.times.25 mL), and the organic phase was washed
with water, dried (Na.sub.2SO.sub.4), filtered, and concentrated,
to give a light brown oil (436 mg). Purification by chromatography
over silica gel (33% EtOAc in hexane) afforded ethyl
1-(4-chlorophenyl)-5-methyl-2-(2,4-dimethylphenyl)-1H-imidazole-4-carboxy-
late as a white foam (338 mg, 93% yield): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.30 (d, 2H), 7.00 (m, 3H), 6.85 (m, 2H), 4.41
(q, 2H), 2.42 (s, 3H), 2.23 (s, 3H), 2.06 (s, 3H), 1.41 (t,
3H).
Example 27
Preparation of
5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidi-
nyl)-1H-imidazole-4-carboxamide
[0212] 35
[0213] Step 1. A solution of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imid- azole-4-carboxylic
acid (50 mg, 0.15 mmol) and N-bromosuccinimide (88 mg, 0.49 mmol)
in dimethylformamide (5 mL) was stirred at 75.degree. C. for 3
days. The solution was purified by preparative HPLC to give
5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic
acid as a white solid (30.7 mg, 50%). LC-MS m/z 411.2 (MH.sup.+),
retention time 2.70 min (method 2).
[0214] Step 2. As described previously for Example 14,
5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic
acid was converted to
5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1--
piperidinyl)-1H-imidazole-4-carboxamide. LC-MS m/z 493.0
(MH.sup.+), retention time 2.63 min (method 2). .sup.1H NMR
(CD.sub.2Cl.sub.2, 400 MHz) .delta. 7.29 (m, 6H, Ph), 7.05 (m, 2H,
Ph), 3.68 (m, 3H, piperidine), 3.36 (m, 2H, piperidine), 1.88 (m,
3H, piperidine), 1.57 (m, 2H, piperidine).
Example 28
Ethyl
5-chloro-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbox-
ylate
[0215] 36
[0216] To a solution of ethyl
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imi- dazole-4-carboxylate
(270 mg, 0.75 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added
SO.sub.2Cl.sub.2 (1.6 mL, 20 mmol). The mixture was heated at
reflux overnight, and diluted with water. The organic layer was
dried over MgSO.sub.4, filtered, and concentrated. The residue was
purified by flash chromatography over silica gel (33% EtOAc in
hexane) to give ethyl
5-chloro-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate
(60 mg) in 20% yield as a white solid: LC-MS m/z 395.0 (MH.sup.+),
retention time 3.45 min (method 1). This intermediate, which is an
example of Formula X in Scheme 2, was converted into
5-chloro-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidinyl)-1H-imida-
zole-4-carboxamide (Table entry 21).
Example 29
Preparation of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N-methyl-1H-
-imidazole-4-carboxamide
[0217] 37
[0218] A solution of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-- carbonyl
chloride (4.71 g, 13.4 mmol, prepared by the method described in
Example 13, step 1) in 10 mL dichloromethane was added to a
solution of N,O-dimethylhydroxyamine hydrochloride (1.44 g, 14.7
mmol) and triethylamine (5.6 mL, 40.2 mmol) in 60 mL
dichloromethane in an ice water bath under argon with stirring. The
bath was removed upon completion of addition. Stirring was
continued for 1 h. Water was added and the mixture was extracted
with ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated down under reduced pressure. The
crude product was purified on silica gel, eluting with ethyl
acetate to yield
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N-methyl-1H-imid-
azole-4-carboxamide as an off-white solid (4.20 g, 83%):
R.sub.f=0.22 (ethyl acetate).
Example 30
Preparation of
[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl](4--
fluorophenyl)-methanone
[0219] 38
[0220] To a solution of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N--
methyl-1H-imidazole-4-carboxamide (50.0 mg, 0.133 mmol) in 1.5 mL
THF was added a 1.0 M solution of 4-fluorophenylmagnesium bromide
(0.27 mL, 0.27 mmol) under argon at rt with stirring. The resultant
mixture was stirred for 30 minutes and a saturated aqueous solution
of NH.sub.4Cl was added. The mixture was extracted with ethyl
acetate. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated down in vacuo. The crude product was purified on HPLC
to give [2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-im-
idazol-4-yl](4-fluorophenyl)-methanone as a solid (38.0 mg, 69%):
R.sub.f=0.58 (1:1 ethyl acetate/hexanes).
Example 31
Preparation of
[2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazol--
4-yl](2-thienyl)-methanone
[0221] 39
[0222] To a solution of 2-bromothiophene (0.22 g, 1.36 mmol) in 2
mL THF was added 0.84 mL of a 1.6 M solution of BuLi in hexane
under argon at -78.degree. C. with stirring. The stirring was
continued for 1 h. To this was added a solution of
1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-
-1H-imidazol-4-yl]carbonyl}-4-piperidinone in 2 mL THF. The
resultant mixture was stirred and gradually allowed to warm up to
rt overnight. The reaction was quenched with saturated aqueous
NH.sub.4Cl and the mixture was extracted with ethyl acetate. The
organic layer was concentrated and the crude product was purified
by HPLC to yield [2-(2-chlorophenyl)-1-(4--
chlorophenyl)-5-ethyl-1H-imidazol-4-yl](2-thienyl)-methanone as a
solid (60 mg, 31%): R.sub.f=0.13 (1:5 ethyl acetate/hexanes).
Example 32
Preparation of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbox-
aldehyde
[0223] 40
[0224] To a solution of ethyl
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imi- dazole-4-carboxylate
(200 mg, 0.51 mmol) in toluene (10 mL) at -78.degree. C. was added
DIBAH (2.0 mL) in toluene dropwise. The resulting solution was
stirred at rt, quenched with 1N HCl (0.5 mL). The organic layer was
washed with 1N HCl (5 mL), dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography (50%
EtOAc in hexane) to give the product (62 mg, 38% yield). LC-MS m/z
317.0 (MH.sup.+), retention time: 2.75 min (method 1).
Example 33
Preparation of
N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]-
methyl}-N-cyclohexylamine
[0225] 41
[0226] To a solution of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-
-4-carboxaldehyde (62 mg, 0.20 mmol) in methanol (7 mL) was added
cyclohexylamine (58 .mu.L, 0.5 mmol). The mixture was stirred
overnight, and cooled to 4.degree. C. NaBH.sub.4 (40 mg, 1.1 mmol)
was added. The mixture was stirred at rt for 1 h, and concentrated.
The residue was dissolved in CH.sub.2Cl.sub.2, washed with brine,
dried over MgSO.sub.4, filtered, and concentrated. The residue was
purified by preparative TLC (50% EtOAc in hexane) to give
N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1-
H-imidazol-4-yl]methyl}-N-cyclohexylamine (65 mg, 81% yield): LC-MS
m/z (400.7 MH.sup.+), retention time 2.32 min (method 1).
Example 34
Preparation of
1-{[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-
-yl]methyl}-4-(4-methylphenyl)piperazine
[0227] 42
[0228] To a suspension of lithium aluminum hydride (21 mg, 0.54
mmol) in THF (2 mL), 1-(4-methylphenyl)piperazine hydrochloride (32
mg, 0.13 mmol) was added. After 10 minutes, a solution of ethyl
2-(2,4-dichlorophenyl)-1-
-(4-chlorophenyl)-1H-imidazole-4-carboxylate (39 mg, 0.1 mmol) in
THF (2 mL) was added dropwise. The reaction mixture was stirred for
10 minutes, and diluted by water. The organic layer was dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
HPLC (YMC-packed Pro C18 20.times.150 mm column, 10-90% CH.sub.3CN
in H.sub.2O/mFA, 25 mL/min) to give the product
1-{[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-
-1H-imidazol-4-yl]methyl}-4-(4-methylphenyl)-piperazine (1.4 mg, 2%
yield): LC-MS m/z 511.1 (MH.sup.+), retention time 2.94 min (method
1). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.29 (3H, s),
3.42-3.49 (8H, br), 4.39(2H, s), 6.85-7.41 (11H, m), 7.54 (1H,
s).
[0229] Other Procedures
[0230] In certain cases, the products and intermediates prepared by
the experimental methods described in Examples 1-34 were converted
into additional products, by applying the appropriate additional
chemical steps. These additional examples are described below.
Example 35
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-[(1R,2R)-2-hydroxycyclohexyl]--
1H-imidazole-4-carboxamide
[0231] 43
[0232] To a solution of N-[(1R,
2R)-2-(benzyloxy)cyclohexyl]-1-(4-chloroph-
enyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide (Table
entry 278, prepared according to the procedures described in
Examples 13 and 14) (100 mg, 0.18 mmol) in CH.sub.2Cl.sub.2 (2 mL),
TMSI (iodotrimethylsilane) (60 .mu.L, 0.42 mmol) was added. The
mixture was stirred at rt overnight, and diluted with water. The
organic layer was dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by preparative TLC (EtOAc)
to afford 1-(4-chlorophenyl)-2-(2,4-d-
ichlorophenyl)-N-[(1R,2R)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxamide
(56 mg, 67% yield) as a yellow solid: LC-MS m/z 464.3 (MH.sup.+),
retention time 3.19 min (method 1); Rf=0.67 (EtOAc); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.16-1.30 (4H, m), 1.66-1.69 (2H, m),
1.98-2.02 (2H, m), 3.37-3.39 (1H, m), 3.70-3.80 (1H, m), 3.99-4.06
(1H, m), 6.96-7.37 (8H, m), 7.78 (1H, s).
Example 36
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-[(1S,
2S)-2-hydroxycyclopentyl- ]-1H-imidazole-4-carboxamide
[0233] 44
[0234] To a solution of N-[(1S,
2S)-2-(benzyloxy)cyclopentyl]-1-(4-chlorop-
henyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide (Table
entry 282, prepared according to the procedures described in
Examples 13 and 14) (119 mg, 0.22 mmol) in CH.sub.2Cl.sub.2 (4 mL),
TMSI (0.2 mL, 1.4 mmol) was added. The mixture was stirred at rt
overnight, and diluted by water. The organic layer was dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
preparative TLC (EtOAc) to afford
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-[(1S,
2S)-2-hydroxycyclopenty- l]-1H-imidazole-4-carboxamide (80 mg, 82%
yield) as a white foam: LC-MS m/z 450.0 (MH.sup.+), retention time
3.24 min (method 1); Rf =0.45 (50% EtOAc in hexane); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.22-2.24 (6H, m), 3.97-4.15 (2H, m),
7.03-7.42 (7H, m), 7.86 (1H, s).
Example 37
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperidinyl)-1H-imidazole-4-car-
boxamide
[0235] 45
[0236] To a solution of ethyl
4-({[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1-
H-imidazol-4-yl]carbonyl}amino)-1-piperidinecarboxylate (Table
entry 221) (0.595 g, 1.221 mmol) in CH.sub.2Cl.sub.2 (10 mL) was
added TMSI (0.176 mL, 2.7 mmol). The mixture was heated at reflux
for 3 h, diluted by methanol, and concentrated. The residue was
dissolved in methanol and NaOMe (0.62 mmol) was added. The mixture
was concentrated and purified by flash chromatography (2M NH.sub.3
in methanol : EtOAc=15:85) to afford the product
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperidinyl)-1H-im-
idazole-4-carboxamide (180 mg, 36% yield): LC-MS m/z 415.3
(MH.sup.+), retention time 2.22 min (method 1); Rf=0.25 (1:1
EtOAc/2M NH.sub.3 in MeOH). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 1.35-1.51 (2H, m), 1.91-2.15 (3H, br), 2.63-2.78 (2H, m),
3.03-3.09 (2H, m), 3.97-4.15 (1H, m), 6.96-7.52 (8H, m), 7.81 (1H,
s).
Example 38
2-(2-Chlorophenyl)-1-(4-chlorophenyl)-N-[1-(2-pyridinyl)4-piperidinyl]-1H--
imidazole-4-carboxamide
[0237] 46
[0238] A flask was charged with
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-
-piperidinyl)-1H-imidazole-4-carboxamide (Example 37) (100 mg, 0.24
mmol), 2-bromopyridine (0.55 mg, 0.22 mmol), Pd.sub.2(dba).sub.3
(38 mg, 0.24 mmol), BINAP (1.18 mg, 0.0019 mmol), NaOtBu (33.6 mg,
0.35 mmol), and toluene (2 mL). The reaction mixture was heated at
reflux overnight, cooled to rt, and diluted with CH.sub.2Cl.sub.2.
The solid was filtered off. The solvent was evaporated. The residue
was purified by flash chromatography (33% EtOAc in hexane) to give
the product
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[1-(2-pyridinyl)-4-piperidinyl]-1-
H-imidazole-4-carboxamide (55 mg, 47% yield): LC-MS m/z 492.1
(MH.sup.+), retention time 2.47 min (method 1); Rf=0.33 (50% EtOAc
in hexane).
Example 39
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-methyl-4-piperidinyl)-1H-imidaz-
ole-4-carboxamide
[0239] 47
[0240] To a solution of
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperid-
inyl)-1H-imidazole-4-carboxamide (Example 37) (80 mg, 0.2 mmol) in
CH.sub.2Cl.sub.2 (6 mL) was added CH.sub.3I (28.4 mg, 0.2 mmol) and
Et.sub.3N (0.031 mL, 0.22 mmol). The reaction mixture was heated at
reflux for 5 h, cooled to rt, and washed with brine. The organic
layer was dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by flash chromatography (2M NH.sub.3 in
methanol : EtOAc=1:10) to afford the product
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(
1-methyl4-piperidinyl)-1H-imidazole-4-carboxamide (24 mg, 28%
yield): LC-MS m/z 429.1 (MH.sup.+), retention time 2.27 min (method
1); Rf=0.31 (EtOAc: 2M NH.sub.3 in MeOH=9:1).
Example 40
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[trans-2-(2-hydroxyethoxy)cyclohex-
yl]-1H-imidazole-4-carboxamide
[0241] 48
[0242] To a solution of
2-{[trans-2-({[2-(2-chlorophenyl)-1-(4-chloropheny-
l)-1H-imidazol-4-yl]carbonyl}amino)cyclohexyl]oxy}-ethyl acetate
(Table entry 286) (31 mg, 0.06 mmol) in THF (7 mL) and water (0.7
mL) was added NaBH.sub.4 (5 mg, 0.13 mmol) portionwise over 1 h
with the temperature kept below 20.degree. C. The mixture was
stirred at rt overnight, cooled to 5.degree. C., treated with
acetone (1 mL), and then concentrated. The residue was dissolved in
CH.sub.2Cl.sub.2 and washed with brine. The organic layer was dried
over MgSO.sub.4, filtered, and concentrated. The residue was
purified by flash chromatography (2.5% methanol in EtOAc) to give
the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[(1R,
2S)-2-(2-hydroxyethoxy)cyclohexyl]-1H-imidazole-4-carboxamide (7.5
mg, 26% yield): LC-MS m/z (474.8 MH.sup.+), retention time 2.91 min
(method 1); Rf=0.17 (EtOAc).
Example 41
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[trans-2-methoxycyclohexyl]-1H-imi-
dazole-4-carboxamide
[0243] 49
[0244] A flask was charged with
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[t-
rans-2-hydroxycyclohexyl]-1H-imidazole-4-carboxamide (Table entry
336) (35 mg, 0.1 mmol), benzene (3 mL), 50% aqueous NaOH (2.5 mL),
and Bu.sub.4NHSO.sub.4 (17 mg). While the mixture was stirred
vigorously at 10.degree. C., CH.sub.3I (19 .mu.L, 0.3 mmol) was
added dropwise rapidly. The mixture was stirred for another 30
minutes, and diluted with water (5 mL) and hexane (10 mL). The
organic layer was dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography (75%
EtOAc in hexane) to give the product
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[(1R,2S)-2-methoxycyclohexyl]-1H--
imidazole-4-carboxamide (23 mg, 63% yield): LC-MS m/z 444.2
(MH.sup.+), retention time 3.24 min (method 1).
Example 42
4-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}thiomo-
rpholine 1-oxide
[0245] 50
[0246] To a solution of
4-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imida-
zol-4-yl]carbonyl}thiomorpholine (Table entry 176) (30 mg, 0.072
mmol) in acetone (2 mL), was added 30% aqueous H.sub.2O.sub.2 (0.09
mmol). The resulting solution was stirred at rt for 36 h, diluted
with water, neutralized with NaHCO.sub.3, and extracted with
CH.sub.2Cl.sub.2. The organic layer was dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by flash
chromatography (20% MeOH in EtOAc) to give the product
4-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]ca-
rbonyl}thiomorpholine 1-oxide (17 mg, 54% yield): LC-MS m/z 434.5
(MH.sup.+), retention time 2.55 min (method 1); Rf=0.47 (17% EtOAc
in hexane).
Example 43
N-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-bromo-2-(2-chlorophenyl)-1-(4-chloro-
phenyl)-1H-imidazole-4-carboxamide
[0247] 51
[0248] A solution of
N-[(1S,2S)-2-(benzyloxy)cyclohexyl]-2-(2-chlorophenyl-
)-1-(4-chlorophenyl)-1H-imidazole-4-carboxamide (Table entry 276)
(198 mg, 0.380 mmol) and N-bromosuccinimide (88 mg, 0.49 mmol) in
dimethylformamide (5 mL) was stirred at 75.degree. C. for 3 days.
The solution was purified by preparative HPLC to give
N-[(1S,2S)-2-(benzyloxy-
)cyclohexyl]-5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4--
carboxamide as a white solid (196 mg, 86%). LC-MS m/z 598.1
(MH.sup.+), retention time 3.72 min (method 2).
Example 44
5-Bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[(1S,2S)-2-hydroxycyclohex-
yl]-1H-imidazole-4-carboxamide
[0249] 52
[0250] As described previously for Example 35,
N-[(1S,2S)-2-(benzyloxy)cyc-
lohexyl]-5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carb-
oxamide (Example 43) was de-benzylated by treatment with
iodotrimethylsilane to give
5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-
-N-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxamide. LC-MS
m/z 508.1 (MH.sup.+), retention time 2.96 min (method 2). .sup.1H
NMR (CD.sub.2Cl.sub.2, 400 MHz) .delta. 7.43 (d, 1H, Ph), 7.27 (m,
5H, Ph), 7.06 (m, 2H, Ph), 3.70 (m, 1H, CHOH), 3.44 (m, 1H, CHN),
1.95 (m, 2H, cyclohexane), 1.64 (m, 2H, cyclohexane), 1.24 (m, 4H,
cyclohexane).
Example 45
1-(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(1-piperidinyl)-1H-imidazo-
le-4-carboxamide
[0251] 53
[0252] A sample of
2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-N-(1-pipe-
ridinyl)-1H-imidazole-4-carboxamide (Table entry 41) (111 mg, 0.25
mmol) was added as a suspension in ethanol (5 mL) to Degussa-type
palladium on carbon (10% by weight, 12 mg). The mixture was
hydrogenated at atmospheric pressure and rt for 2 h. Filtration of
the mixture through Celite and concentration of the filtrate gave
1-(4-aminophenyl)-2-(2-chlo-
rophenyl)-5-methyl-N-(1-piperidinyl)-1H-imidazole-4-carboxamide as
a yellow foam (104 mg, 100%). This material was used without
purification for the preparation of compounds of the invention,
such as Example 46.
Example 46
2-(2-chlorophenyl)-1-(4-{[(ethylamino)carbonyl]amino}phenyl)-5-methyl-N-(1-
-piperidinyl)-1H-imidazole-4-carboxamide trifluoroacetate
[0253] 54
[0254]
1-(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(1-piperidinyl)-1H--
imidazole-4-carboxamide (Example 45) (52 mg, 0.13 mmol) was
dissolved in dry dichloromethane (2 mL) and added to ethyl
isocyanate (20 .mu.L, 0.25 mmol). The solution was stirred at rt
for 6 h before more ethyl isocyanate (30 .mu.L, 0.38 mmol) was
added. After stirring overnight, the mixture was heated at reflux
for 1 h. The solvent was evaporated to give a yellow solid which
was chromatographed over silica gel (3% MeOH in EtOAc) to afford
semi-pure product (21 mg). This material was further purified by
HPLC (YMC-packed Pro C18 15.times.200 mm column, 30-90% CH.sub.3CN
in H.sub.2O/TFA, 20 mL/min.) to give 2-(2-chlorophenyl)-1-(4-{-
[(ethylamino)carbonyl]amino}phenyl)-5-methyl-N-(1-piperidinyl)-1H-imidazol-
e-4-carboxamide trifluoroacetate as a white solid (12 mg, 13%
yield): LC-MS m/z 481.4 (MH.sup.+), retention time 2.35 min (method
1).
Example 47
1-[4-(acetylamino)phenyl]-2-(2-chlorophenyl)-5-methyl-N-(1-piperidinyl)-1H-
-imidazole-4-carboxamide
[0255] 55
[0256]
1-(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(1-piperidinyl)-1H--
imidazole-4-carboxamide (Example 45) (51 mg, 0.12 mmol) was
dissolved in dry dichloromethane (2 mL) and treated with acetic
anhydride (14 .mu.L, 0.15 mmol) dropwise. The solution was stirred
at rt for 4 h, and then the solvent was evaporated to give an amber
oil. It was purified by HPLC (YMC-packed Pro C18 15.times.200 mm
column, 30-90% CH.sub.3CN in H.sub.2O/TFA, 20 mL/min.) to afford an
off-white solid (13 mg, 15%): LC-MS m/z 452.3 (MH.sup.+), retention
time 2.31 min (method 1).
Example 48
2-(2-Chlorophenyl)-5-methyl-1-{4-[(methylsulfonyl)amino]phenyl}-N-(1-piper-
idinyl)-1H-imidazole-4-carboxamide trifluoroacetate
[0257] 56
[0258]
1-(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(1-piperidinyl)-1H--
imidazole-4-carboxamide (Example 45) (52 mg, 0.13 mmol) was
dissolved in dry dichloromethane (2 mL), cooled by an ice water
bath, and the mixture was then treated with methanesulfonyl
chloride (12 .mu.L, 0.16 mmol) and triethylamine (21 .mu.L, 0.15
mmoL). The solution was stirred at rt overnight, and then the
solvent was evaporated. The residue was purified by HPLC
(YMC-packed Pro C18 15.times.200 mm column, 30-90% CH.sub.3CN in
H.sub.2O/TFA, 20 mL/min.) to afford a light tan solid (21 mg, 27%):
LC-MS m/z 488.4 (MH.sup.+), retention time 2.29 min (method 1).
Example 49
1-{[1-(4-Chlorophenyl)-2-(2-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-phe-
nyl-1,2,3,6-tetrahydropyridine
[0259] 57
[0260] A 30-mg sample of
1-{[2-(2-methylphenyl)-1-(4-chlorophenyl)-1H-imid-
azol-4-yl]carbonyl}-4-phenyl-4-piperidinol (Table entry 414), was
dissolved in 20 mL dichloromethane, and then 5 mL 2M HCl in ether
was added to the solution. Evaporation of the solvent at high
temperature (ca. 70.degree. C., 16 hr) in a multiple sample
evaporator (GeneVac) gave
1-{[1-(4-chlorophenyl)-2-(2-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-ph-
enyl-1,2,3,6-tetrahydropyridine (yellow solid). .sup.1H NMR (400
MHz, CD.sub.3COCD.sub.3) .delta. 8.31 (s, 1H), 7.05-7.35 (m, 13 H),
6.05 (s, 1 H), 4.2 (m, 2 H), 3.85 (m, 2H), 2.5 (m, 2H), 2.0 (s,
3H); LC-MS m/z 454 (MH.sup.+) retention time 2.92 min (method
2).
[0261] Preparation of Intermediates
[0262] Experimental procedures for the preparation of chemical
reagents that are not commercially available are described
below.
Intermediate A
Ethyl 3-bromo-2-oxobutanoate
[0263] 58
[0264] This bromo pyruvate was prepared by oxidative bromination of
the corresponding hydroxyesters, by the procedure described by
Plouvier et al., (Heterocycles 32:693-701, 1991). In a similar
manner, ethyl 3-bromo-2-oxopentanoate and ethyl
3-bromo-2-oxohexanoate were prepared.
Intermediate B
Ethyl 3-bromo-3-cyclopropyl-2-oxopropanoate
[0265] 59
[0266] The procedure was similar to that reported in the literature
(see, e.g., J. Org. Chem. 37, 505-506, 1972).
[0267] Step 1. To a solution of BF.sub.3.Et.sub.2O (57.5 mL, 0.454
mmol) in CHCl.sub.3 (180 mL) heated at reflux was added dropwise,
over a 1-h period, a solution of 1,3-propanedithiol (22.7 mL, 0.227
mmol), followed by ethyl diethoxyacetate (40 g, 0.227 mmol) in
CHCl.sub.3 (40 mL). The resulting mixture was heated for 30
minutes, and then cooled to rt. The cooled solution was washed 2
times with water, once with saturated aqueous NaHCO.sub.3, and then
re-washed with water. The combined organic phases were dried over
MgSO.sub.4, then evaporated to give 41 g (94%) of ethyl
1,3-dithiane-2-carboxylate as a yellow oil, which was used in the
next step without purification. .sup.1H NMR (CDCl.sub.3): .delta.
4.24 (2H, q, J=7.2 Hz), 4.17 (1H, s), 3.46-3.39 (2H, m), 2.64-2.58
(2H, m), 2.18-2.01 (2H, m), 1.30 (3H, t, J=7.2 Hz).
[0268] Step 2. To a suspension of NaH (95%, 2.8 g, 111 mmol) in dry
toluene (120 mL) stirring at 0.degree. C. was dropwise added, over
10 minutes, a solution of bromomethylcyclopropane (15 g, 111 mmol),
and ethyl 1,3-dithiane-2-carboxylate (17.77 g, 92.58 mmol) in dry
DMF (40 mL). The ice bath was removed and the solution was stirred
overnight at rt. Water was added to the solution and the phases
were separated. The organic phase was dried over MgSO.sub.4, then
evaporated to give 19.6 g (50%) of ethyl
2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate, which was used in
the next step without purification. .sup.1H NMR (CDCl.sub.3):
.delta. 4.26 (2H, q, J=7.2 Hz), 3.30-3.23 (2H, m), 2.69-2.64 (2H,
m), 2.16-2.11 (1H, m), 1.96 (2H, d, J=6.8 Hz), 1.91-1.81 (1H, m),
1.34 (3H, t, J=7.2 Hz), 0.93-0.86 (1H, m), 0.52-0.47 (2H, m),
0.20-0.16 (2H, m).
[0269] Step 3. A solution of ethyl
2-(cyclopropylmethyl)-1,3-dithiane-2-ca- rboxylate (19.6 g, 79.67
mmol) in CH.sub.3CN (20 mL) was slowly added, over 30 minutes, to a
well-stirred suspension of NBS (N-bromosuccinimide) in CH.sub.3CN
(210 mL) and water (55 mL). After the mixture was stirred for 1 h,
the resulting red solution was poured into an ice-cold
CH.sub.2Cl.sub.2-Hexane solution (1:1 500 mL). The resulting
mixture was washed with saturated aqueous NaHSO.sub.3 and water.
The colorless organic phase was carefully washed with saturated
aqueous K.sub.2CO.sub.3 and water. The organic phase was dried over
MgSO.sub.4, then evaporated to give 6.88 g (55%) of ethyl
3-cyclopropyl-2-oxopropanoate as a yellow oil. .sup.1H NMR
(CDCl.sub.3): .delta. 4.29 (2H, q, J=8 Hz), 2.71 (2H, d, J=9 Hz),
1.35 (3H, t, J=8 Hz), 1.05-0.98 (1H, m), 0.59-0.54 (2H, m),
0.17-0.14 (2H, m).
[0270] Step 4. To a solution of ethyl 3-cyclopropyl-2-oxopropanoate
(4.75 g, 30.44 mmol) in CCl.sub.4 (60 mL) at rt was added NBS (5.96
g 33.49 mmol). The resulting mixture was heated at reflux
overnight, then cooled, filtered, and evaporated to provide ethyl
3-bromo-3-cyclopropyl-2-oxoprop- anoate; .sup.1H NMR (CDCl.sub.3):
.delta. 4.46-4.32 (3H, m), 1.41 (3H, t, J=8 Hz), 0.96-0.86 (1H, m),
0.55-0.50 (2H, m), 0.07-0.03 (2H, m). This compound was used
without purification for the preparation of compounds of the
invention such as 1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piper-
idinyl)-5-cyclopropyl-1H-imidazole-4-carboxamide hydrochloride
(Table entry 22). In a similar manner, ethyl
3-bromo-3-cyclobutyl-2-oxopropanoat- e and ethyl
3-bromo-3-isobutyl-2-oxopropanoate were prepared.
Intermediate C
Ethyl 3-bromo-2-oxoheptanoate
[0271] 60
[0272] Step 1. To a suspension of LiI (23.61 g, 176.44 mmol) in THF
(200 mL) at rt was slowly added Cu.sub.2Br.sub.2 (25.30 g, 88.22
mmol). A vigorous exothermic reaction occurred, and the mixture was
then cooled to -78.degree. C. Pentylmagnesium bromide (2M, 36.76
mL, 88.22 mmol) was slowly added at -78.degree. C., and followed
soon after by ethyl chloro(oxo)acetate (10 g, 73.52 mmol). The
resulting solution was stirred 10 minutes at -78.degree. C., then
quenched by dropwise addition of water. The mixture was allowed to
warm to rt, and then the organic phase was separated, dried
(MgSO4), and evaporated. Purification by flash chromatography using
9:1 hexane/EtOAc as eluant gave ethyl 2-oxoheptanoate as a
colorless oil (3.0 g, 23%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.33-4.21 (m, 2 H), 2.82 (m, 2 H), 1.63-1.59 (m, 2 H),
1.63-11.19 (m, p H), 0.9-0.83 (m, 3 H), LC-MS m/z 279.21
(MH.sup.+), retention time 2.42 min (method 2).
[0273] Step 2. To a cold solution of ethyl 2-oxoheptanoate (2 g,
11.62 mmol) in AcOH (20 mL), was added Br.sub.2 (596 .mu.L, 11.62
mmol). The mixture was stirred 20 minutes at 0.degree. C., then the
mixture was allowed to warm to rt. After the mixture was stirred
for 3 h, water and CH.sub.2Cl.sub.2 were added. The organic phase
was separated, dried (MgSO.sub.4), and evaporated to give crude
ethyl 3-bromo-2-oxoheptanoate as a dark oil; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.05-5.01 (m, 1 H), 4.45-4.20 (m, 2 H),
2.18-1.94 (m, 2 H), 1.74-1.57 (m, 2 H), 1.48-1.17 (m, 5 H),
0.95-0.82 (m, 3 H). This compound was used without purification for
the preparation of compounds of the invention such as
1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidinyl)-5-butyl-1H-imidaz-
ole-4-carboxamide hydrochloride (Table entry 20).
Intermediate D
4-Piperidinone trifluoroacetate
[0274] 61
[0275] A suspension of t-butyl 4-oxo-1-piperidine carboxylate (10
g, 0.05 mol) in trifluoroacetic acid (10 mL) was stirred rt
overnight and concentrated to give a pale yellow solid (11.26 g,
crude). MS (Electron spray) 100 (MH.sup.+), free amine; .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 3.27-3.12 (m, 4H), 2.01-1.86 (m,
4H).
Intermediate E
trans-1-Amino-2-hydroxyindan
[0276] 62
[0277] This compound was prepared as described by Thompson et al.,
(J. Med. Chem. 35:1685-1701, 1992). To 1 liter of 12 N NH.sub.4OH
cooled to 0.degree. C. was added 50 g (0.235 mol) of 2-1-indanol.
After stirring for 30 minutes, the mixture was allowed to warm, and
then stirred for 24 hours. The mixture was concentrated under
reduced pressure to remove excess ammonia and then allowed to stand
open at rt overnight. The mixture was made basic (pH>10) by
addition of 20% KOH, cooled in an ice bath, and filtered. After the
residue was dried in a vacuum oven at 60.degree. C. overnight, the
desired product was obtained as a tan solid (24 g, 69%).
Intermediate F
cis-1-Hydroxy-2-aminoindan
[0278] 63
[0279] Following the procedure described in Tetrahedron: Asymmetry
7:1559-1562, 1996, trans-2-bromo-1-indanol (500 mg, 2.35 mmol) was
dissolved in DMF (5 mL) and sodium azide (305 mg, 4.69 mmol) was
added dropwise. The mixture was stirred at rt for 1 h, and then
heated to 70.degree. C. and stirred for an additional 18 h. The
mixture was cooled, water was added, and extracted with ether. The
ether was removed and the crude (412 mg) was dissolved in THF (15
mL). This solution was added to Pd/C (41 mg) and stirred under
hydrogen at rt for 3 days. The reaction mixture was filtered and
the filtrate was concentrated down to provide the desired product,
which was used without purification.
Intermediate G
trans-1-Amino-2-hydroxy-1,2,3,4-tetrahydronaphthalene
[0280] 64
[0281] This compound was prepared from dihydronaphthalene according
to the procedures described by Bellucci et al., (Tetrahedron:
Asymmetry 8:895-902, 1997).
Intermediate H
trans-(2R,3R)-3-[(2,4-Dimethoxybenzyl)amino]-1,2,3,4-tetrahydro-2-naphthal-
enol
[0282] 65
[0283] This compound was prepared by following the procedure
described by Efange et al., (J. Med. Chem. 40:3905-3914, 1997).
Intermediate I
(1S,2R,3S,4R)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol
[0284] 66
[0285] This compound, and its enantiomer, were obtained by
LiAlH.sub.4 reduction of the respective camphorquinone 3-oximes, by
the procedure described by Gawley and Zhang, (J. Org. Chem.
61:8103-8112, 1996).
Intermediate J
Ethyl [(trans-2-aminocyclohexyl)oxy]acetate
[0286] 67
[0287] To a solution of trans-2-amino-cyclohexanol hydrochloride
(455 mg, 3.0 mmol) in THF (7 mL) was added sodium hydride (78 mg,
3.25 mmol) under argon. The mixture was stirred at rt for 12 h
before ethyl bromoacetate (500 mg, 3.0 mmol) was added, and the
solution was stirred at rt for another 12 h. After filtration, the
solution was concentrated and the residue taken up in
CH.sub.2Cl.sub.2 and washed with brine. The organic layer was
separated and concentrated. The residue was purified by flash
chromatography over silica gel (ethyl acetate) to afford the
desired product (51 mg, 8.5% yield): LC-MS m/z 202.2 (MH.sup.+),
retention time 0.73 min (method 1); Rf=0.23 (ethyl acetate).
Intermediate K
[(2S)-1-Amino-2-piperidinyl]methanol
[0288] 68
[0289] [(2S)-1-Amino-2-piperidinyl]methanol was prepared according
to the method described by Rosling et al., (Heterocycles 95-106,
1997). In a similar manner were prepared
[(2R)-1-amino-2-piperidinyl]-methanol,
[(2S)-1-amino-2-pyrrolidinyl]methanol, and
[(2R)-1-amino-2-pyrrolidinyl]m- ethanol.
Intermediate L
3-Methylisonicotinonitrile
[0290] 69
[0291] This nitrile was synthesized the procedure described by van
den Haak et al., ( J. Heterocycl. Chem. 18:1349-1352, 1981.
Summary of Examples
[0292] Using appropriate starting materials and the experimental
procedures described above for Examples 1-49 and Intermediates A-L,
the following compounds in Tables 1-18 were prepared. It will be
understood by those skilled in the art that some minor
modifications to the referenced procedures may have been made, but
such modifications do not significantly affect the results of the
preparation.
[0293] LC-MS characterization of compounds, as listed in the
tables, was carried out by using the instrumentation and methods
set forth above.
1TABLE 1 70 Syn- thesis MS HPLC Method Entry m/z TLC Rf RT HPLC of
No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 IUPAC name [MH+] (solvent)
(min) method Ex. No. 1 2,3-Cl.sub.2-Ph 4-Cl-Ph H 1-piperidinyl
1-(4-chlorophenyl)-2-(2,3- 449.1 3.05 1 8 dichlorophenyl)-N-
(1-piperidinyl)-1H- imidazole-4-carboxamide 2 2,4-Cl.sub.2-Ph
4-Cl-Ph H 1-piperidinyl 1-(4-chlorophenyl)-2-(2,4- 449.3 0.47
(EtOAc) 3.14 1 13, 14 dichlorophenyl)-N- (1-piperidinyl)-1H-
imidazole-4-carboxamide hydrochloride 3 2,4-Cl.sub.2-Ph 4-F-Ph H
1-piperidinyl 1-(4-fluorophenyl)-2-(2,4- 433.3 0.20 (33% 2.89 1 15
dichlorophenyl)-N- EtOAc in (1-piperidinyl)-1H- Hexane)
imidazole-4-carboxamide hydrochloride 4 2,4-Cl.sub.2-Ph 4-I-Ph H
1-piperidinyl 1-(4-iodophenyl)-2-(2,4- 541.0 3.24 1 13, 14
dichlorophenyl)-N- (1-piperidinyl)-1H- imidazole-4-carboxamide 5
2,4-Cl.sub.2-Ph 4-Meo-Ph H 1-piperidinyl
1-(4-methoxyphenyl)-2-(2,4- 445.3 0.53 (EtOAc) 2.92 1 10
dichlorophenyl)-N- (1-piperidinyl)-1H- imidazole-4-carboxamide
hydrochloride 6 2,4-Cl.sub.2-Ph 4-Me-Ph H 1-piperidinyl
1-(4-methylphenyl)-2-(2,4- 429.3 0.25 (75% 2.96 1 15
dichlorophenyl)-N- (1-piperidinyl)-1H- EtOAc in
imidazole-4-carboxamide Hexane) hydrochloride 7 2,4-F.sub.2-Ph
4-Cl-Ph H 1-piperidinyl 1-(4-chlorophenyl)-2-(2,4- 417.2 0.35
(EtOAc) 2.80 1 8 difluorophenyl)-N- (1-piperidinyl)-1H-
imidazole-4-carboxamide 8 2,4-Me.sub.2-Ph 4-Cl-Ph H 1-piperidinyl
1-(4-chlorophenyl)-2-(2,4- 409.3 0.62 (EtOAc) 2.77 1 10
dimethylphenyl)-N- (1-piperidinyl)-1H- imidazole-4-carboxamide
hydrochloride 9 2,4-Me.sub.2-Ph 4-Cl-Ph Me 1-piperidinyl
1-(4-chlorophenyl)-2(2,4 423.2 2.89 1 8 dimethylphenyl)-
5-methyl-N-(1- piperidinyl)-1H-imidazole-4- carboxamide
hydrochloride 10 2,5-Cl.sub.2-Ph 4-Cl-Ph H 1-piperidinyl
1-(4-chlorophenyl)-2-(2,5- 449.1 0.34 (75% 3.11 1 8
dichlorophenyl)-N- EtOAc in (1-piperidinyl)-1H- Hexane)
imidazole-4-carboxamide 11 2-CF.sub.3-Ph 4-Cl-Ph H 1-piperidinyl
1-(4-chlorophenyl)-N- 449.3 0.25 (90% 2.95 1 13, 14
(1-piperidinyl)-2 EtOAc in [2-(trifluoromethyl)phenyl]-1H- Hexane)
imidazole-4-carboxamide hydrochloride 12 2-Cl-4-F-Ph 4-F-Ph H
1-piperidinyl 1-(4-fluorophenyl)-2- 417.3 0.33 (EtOAc) 2.69 1 10
(2-chloro-4- fluorophenyl)-N- (1-piperidinyl)-1H-
imidazole-4-carboxamide hydrochloride 13 2-Cl-Ph 2,4-F.sub.2-Ph H
1-piperidinyl 1-(2,4-difluorophenyl)-2-(2- 417.2 0.18 (1:1 2.64 1
13, 14 chlorophenyl)-N- EtOAc/ (1-piperidinyl)-1H- Hexane)
imidazole-4-carboxamide 14 2-Cl-Ph 2-Cl-4-F-Ph H 1-piperidinyl
1-(2-chloro-4- 433.2 0.20 (1:1 2.74 1 13, 14 fluorophenyl)-2-(2-
EtOAc in chlorophenyl)-N- Hexane) (1-piperidinyl)-1H-
imidazole-4-carboxamide 15 2-Cl-Ph 3-Cl-Ph H 1-piperidinyl
1-(3-chlorophenyl)- 415.8 0.15 (50% 2.90 1 13, 14
2-(2-chlorophenyl)-N- EtOAc in (1-piperidinyl)-1H- Hexane)
imidazole-4-carboxamide 16 2-Cl-Ph 3-Cl-Ph Pr 1-piperidinyl
1-(3-chlorophenyl)-2- 457.2 0.37 (1:1 2.98 1 13, 14
(2-chlorophenyl)-N- EtOAc/ (1-piperidinyl)-5- Hexane)
propyl-1H-imidazole- 4-carboxamide 17 2-Cl-Ph 4-Br-Ph Et
1-piperidinyl 1-(4-bromophenyl)-2- 487.2 0.48 (EtOAc) 3.05 1 13, 14
(2-chlorophenyl)-N- (1-piperidinyl)-5- ethyl-1H-imidazole-
4-carboxamide 18 2-Cl-Ph 4-Br-Ph Pr 1-piperidinyl
1-(4-bromophenyl)-2-(2- 503.1 0.28 (1:1 3.06 1 13, 14
chlorophenyl)-N- EtOAc/ (1-piperidinyl)-5- Hexane)
propyl-1H-imidazole- 4-carboxamide 19 2-Cl-Ph 4-Cl-Ph Br
1-piperidinyl 1-(4-chlorophenyl)-2- 493.0 2.64 2 13, 14
(2-chlorophenyl-N- (1-piperidinyl)-5- bromo-1H-imidazole-
4-carboxamide hydrochloride 20 2-Cl-Ph 4-Cl-Ph Bu 1-piperidinyl
1-(4-chlorophenyl)-2-(2- 471.3 2.88 2 13, 14 chlorophenyl)-N-
(1-piperidinyl)-5- butyl-1H-imidazole- 4-carboxamide hydrochloride
21 2-Cl-Ph 4-Cl-Ph Cl 1-piperidinyl 1-(4-chlorophenyl)-2-(2- 451.2
0.16 (50% 3.07 1 10 chlorophenyl)-N- EtOAc in (1-piperidinyl)-5-
Hexane) chloro-1H-imidazole- 4-carboxamide 22 2-Cl-Ph 4-Cl-Ph cy-
1-piperidinyl 1-(4-chlorophenyl)-2- 455.2 2.94 2 13, 14 clo-
(2-chlorophenyl)-N- pro- (1-piperidinyl)-5- pyl
cyclopropyl-1H-imidazole-4- carboxamide hydrochloride 23 2-Cl-Ph
4-Cl-Ph Et 1-piperidinyl 1-(4-chlorophenyl)-2-(2- 443.6 0.21 (60%
2.91 1 8 chlorophenyl)-N- EtOAc in (1-piperidinyl)-5- Hexane)
ethyl-1H-imidazole- 4-carboxamide 24 2-Cl-Ph 4-Cl-Ph H
1-piperidinyl 1-(4-chlorophenyl)-2-(2- 415.1 0.25 (75% 2.88 1 13,
14 chlorophenyl)-N- EtOAc in (1-piperidinyl)-1H- Hexane)
imidazole-4-carboxamide hydrochloride 25 2-Cl-Ph 4-Cl-Ph H 2,6-di-
2-(2-chlorophenyl)-1-(4- 443.3 0.20 (50% 2.94 1 13, 14 methyl
chlorophenyl)-N- EtOAc in 1-piperidinyl (2,6-dimethyl-1- Hexane)
piperidinyl)-1H- imidazole-4- carboxamide 26 2-Cl-Ph 4-Cl-Ph H
(2S)-2- 2-(2-chlorophenyl)-1-(4- 445.1 0.37 (EtOAc) 2.93 1 8
hydroxy- chlorophenyl)-N-[(2S)-2- methyl)- (hydroxymethyl)-1-
1-piperidinyl piperidinyl]-1H- imidazole-4-carboxamide 27 2-Cl-Ph
4-Cl-Ph H (2R)-2- 2-(2-chlorophenyl)-1-(4- 445.6 0.40 (0.2% 2.94 1
13, 14 (hyrdroxy- chlorophenyl)-N-[(2R)-2- MeOH in methyl)-
(hydroxymethyl)-1- EtOAc) 1-piperidinyl piperidinyl]-1H-
imidazole-4-carboxamide 28 2-Cl-Ph 4-Cl-Ph iPr 1-piperidinyl
1-(4-chlorophenyl)-2-(2- 457.2 3.23 2 13, 14 chlorophenyl)-N-
(1-piperidinyl)-5- isopropyl-1H-imidazole-4- carboxamide
hydrochloride 29 2-Cl-Ph 4-Cl-Ph Me 1-piperidinyl
1-(4-chlorophenyl)-2-(2- 429.2 0.33 (EtOAc) 2.97 1 6
chlorophenyl)-N- (1-piperidinyl)-5- methyl-1H-imidazole-
4-carboxamide 30 2-Cl-Ph 4-Cl-Ph Pr 1-piperidinyl
1-(4-chlorophenyl)-2-(2- 457.7 0.2 (40% 3.04 1 8 chlorophenyl)-N-
EtOAc in (1-piperidinyl)-5- Hexane) propyl-1H-imidazole-4-
carboxamide 31 2-Cl-Ph 4-EtNHCO Me 1-piperidinyl
2-(2-chlorophenyl)-1-(4- 481.4 2.35 1 46 NH-Ph
{[(ethylamino)carbonyl ]amino}phenyl) 5-methyl-N-(1-
piperidinyl)-1H- imidazole-4-carboxamide trifluoroacetate 32
2-Cl-Ph 4-F-Ph H 1-piperidinyl 1-(4-fluorophenyl)- 399.3 0.15 (50%
2.61 1 13, 14 2-(2-chlorophenyl)- EtOAc in N-(1-piperidinyl)-
Hexane) 1H-imidzaole-4- carboxamide 33 2-Cl-Ph 4-F-Ph Pr
1-piperidinyl 1-(4-fluorophenyl)-2- 441.2 0.23 (1:1 2.84 1 13, 14
(2-chlorophenyl)- EtOAc/ N-(1-piperidinyl)- Hexane) 5-propyl-1H-
imidazole-4-carboxamide 34 2-Cl-Ph 4-iPr-Ph Et 1-piperidinyl
1-(4-isopropylphenyl)-2-(2- 451.2 0.4 (2:1 3.06 1 13, 14
chlorophenyl)-N- EtOAc/ (1-piperidinyl)-5- Hexane)
ethyl-1H-imidazole- 4-carboxamide 35 2-Cl-Ph 4- Me 1-piperidinyl
1-[4-acetylamino)phenyl]-2-(2- 452.3 2.31 1 47 MeCONH- chloro-
phenyl)- Ph 5-methyl-N-(1- piperidinyl)-1H-imidazole-4- carboxamide
trifluoroacetate 36 2-Cl-Ph 4-MeO-Ph H 1-piperidinyl
1-(4-methoxyphenyl)-2-(2- 411.3 0.29 (EtOAc) 2.62 1 13, 14
chlorophenyl)-N- (1-piperidinyl)-1H- imidazole-4-carboxamide
hydrochloride 37 2-Cl-Ph 4-MeO-Ph Pr 1-piperidinyl
1-(4-methocyphenyl)-2-(2- 453.1 0.19 (1:1 2.84 1 13, 14
chlorophenyl)-N- EtOAc/ (1-piperidinyl)-5- Hexane)
propyl-1H-imidazole- 4-carboxamide 38 2-Cl-Ph 4-Me-Ph H
1-piperidinyl 1-(4-methylphenyl)-2-(2- 395.3 0.43 (EtOAc) 2.77 1 10
chlorophenyl)-N- (1-piperidinyl)-1H- imidazole-4-carboxamide 39
2-Cl-Ph 4-MeSO.sub.2 Me 1-piperidinyl 2-(2-chlorophenyl)-5- 488.4
2.29 1 48 NH-Ph methyl-1-{4- [(methylsulfonyl) amino]phenyl}-N-(1-
piperidinyl)-1H-imidazole-4- carboxamide trifluoroacetate 40
2-Cl-Ph 4-MeSO.sub.2Ph Me 1-piperidinyl 2-(2-chlorophenyl)-5- 473.6
0.25 (EtOAc) 2.45 1 13, 14 methyl-1-[4- (methylsulfonyl)
phenyl]-N-(1- piperidinyl)-1H-imidazole-4- carboxamide 41 2-Cl-Ph
4-NO.sub.2-Ph Me 1-piperidinyl 2-(2-chlorophenyl)-5- 440.3 0.47
(EtOAc) 2.68 1 8 methyl-1-(4- nitrophenyl)-N- (1-piperidinyl)-1H-
imidazole-4-carboxamide 42 2-Cl-Ph Ph H 1-piperidinyl
2-(2-chlorophenyl)- 381.4 0.19 (75% 2.64 1 13, 14 1-phenyl-N-(1-
EtOAc in piperidinyl)-1H-imidazole-4- Hexane) carboxamide 43
2-Et-Ph 4-Cl-Ph H 1-piperidinyl 1-(4-chlorophenyl)- 409.2 0.2 (50%
2.95 1 8 2-(2-ethylpheynyl)- EtOAc in N-(1-piperidinyl)- Hexane)
1H-imidazole-4- carboxamide 44 2-MeO-Ph 4-Cl-Ph H 1-piperidinyl
1-(4-chlorophenyl)-2-(2- 411.3 0.38 (75% 2.73 1 8 methoxyphenyl)-N-
EtOAc in (1-piperidinyl)-1H- Hexane) imidazole-4-carboxamide 45
2-Me-Ph 2-Me-Ph H 1-piperidinyl 1-(2-methylphenyl)-2-(2-
methlphenyl)-N- 375.4 0.28 (75% 2.68 1 13, 14 (1-piperidinyl)-1H-
EtOAc in imidazole-4-carboxamide Hexane) hydrochloride 46 2-Me-Ph
4-Cl-Ph H 1-piperidinyl 1-(4-chlorophenyl)-2-(2- 395.3 0.56 (EtOAc)
2.83 1 8 methylphenyl)-N-(1- piperidinyl)-1H-
imidazole-4-carboxamide hydrochloride 47 2-Me-Ph 4-Me-Ph H
1-piperidinyl 1-(4-methylphenyl)-2-(2- 375.4 0.17 (50% 2.66 1 13,
14 methylphenyl)-N-(1- EtOAc in piperidinyl)-1H- Hexane)
imidazole-4-carboxamide 48 2-NO.sub.2-Ph 4-Cl-Ph H 1-piperidinyl
1-(4-chlorophenyl)- 426.4 0.20 (80% 2.60 1 13, 14
2-(2-nitrophenyl)- EtOAc in N-(1-piperidinyl)- Hexane)
1H-imidazole-4- carboxamide 49 4-Br-Ph 2,4-Cl.sub.2-Ph H
1-piperidinyl 2-(4-bromophenyl)-1-(2,4- 495.0 3.23 1 13, 14
dichlorophenyl)-N- (1-piperidinyl)-1H- imidazole-4-carboxamide 50
4-Cl-Ph 2,4-Cl.sub.2Ph H 1-piperidinyl 2-(4-chlorophenyl)-1-(2,4-
451.1 3.19 1 13, 14 dichlorophenyl)-N- (1-piperidinyl)-1H-
imidazole-4-carboxamide hydrochloride 51 4-I-Ph 2,4-Cl.sub.2-Ph H
1-piperidinyl 2-(4-iodophenyl)-1-(2,4- 541.0 3.30 1 13, 14
dichlorophenyl)-N- (1-piperidinyl)-1H- imidazole-4-carboxamide 52
Ph 4-Cl-Ph H 1-piperidinyl 1-(4-chlorophenyl)- 381.3 2.65 1 8
2-phenyl-N-(1- piperidinyl)-1H- imidazole-4- carboxamide 53 Ph Ph H
1-piperidinyl 1,2-diphenyl-N- 347.2 3.50 1 13, 14
(1-piperidinyl)-1H- imidazole-4-carboxamide
[0294]
2TABLE 2 71 HPLC Synthesis Entry MS m/z TLC Rf RT HPLC Method of
No. R.sup.1 R.sup.2 n R.sup.12 IUPAC name [MH +] (solvent) (min)
method Ex. No. 54 2-MeO-Ph 4-Cl-Ph 1 H
1-(4-chlorophenyl)-2-(2-methox- yphenyl) 397.3 0.2 (75% 2.46 1 13,
14 N-(1-pyrrolidinyl)-1H-im- idazole-4- EtOAc in hexane) 55 2-Cl-Ph
4-Cl-Ph 1 H 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N- 401.2 0.4 (5%
2.55 1 8 (1-pyrrolidinyl)-1H-imidazole-4- MeOH in carboxamide
trifluoroacetate EtOAc) 56 2-Cl-Ph 4-Cl-Ph 1 (R)-
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N- 445.2 0.4 (35% 2.84 1 8
CH.sub.2OMe [(2R)-2-(methoxymethyl)-1-pyrrolidinyl]- EtOAc in
1H-imidazole-4-carboxamide hexane) trifluoroacetate 57 2-Cl-Ph
4-Cl-Ph 1 (S)- 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N- 445.2 0.4
(5% 2.89 1 8 CH.sub.2OMe [(2S)-2-(methoxymethyl)-1-pyrroli- dinyl]-
MeOH in 1H-imidazole-4-carboxamide EtOAC) trifluoroacetate 58
2-Meo-Ph 4-Cl-Ph 1 (R)- 1-(4-chlorophenyl)-N-[(2R)-2- 441.3 0.25
2.72 1 13, 14 CH.sub.2OMe (methoxymethyl)-1-pyrrolidinyl]-2-(2-
(EtOAc) methoxyphenyl)-1H-imidazole-4- carboxamide 59 2-MeO-Ph
4-Cl-Ph 1 (S)- 1-(4-chlorophenyl)-N-[(2S)-2- 441.3 0.25 2.73 1 13,
14 CH.sub.2OMe (methoxymethyl)-1-pyrrolidinyl]2-(2- (EtOAc)
methoxyphenyl)-1H-imidazole-4- carboxamide 60 2-MeO-Ph 4-Cl-Ph 3 H
N-(1-azepanyl)-1-(4-chlorophenyl)-2-(2- 425.3 0.5 (50% 2.72 1 13,
14 methoxyphenyl)-1H-imidazole-4- EtOAc in carboxamide hexane) 61
2,4-Cl.sub.2-Ph 4-Cl-Ph 1 H
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)- 453.1 0.36 2.78 1 13, 14
N-(1-pyrrolidinyl)-1H-imidazole-4- (EtOAc) carboxamide
trifluoroacetate 62 2,4-Cl.sub.2-Ph 4-Cl-Ph 1 (R)-
1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)- 479.2 0.36 3.13 1 13, 14
Ch.sub.2OMe N-[(2R)-2-(methoxymethyl)-1-pyrrolidinyl]- (EtOAc)
1H-imidazole-4-carboxamide trifluoroacetate 63 2-Me-Ph 4-Cl-Ph 1 H
1-(4-chlorophenyl)-2-(2-methylphenyl)-N- 381.3 0.2 2.48 1 13, 14
(1-pyrrolidinyl)-1H-imidazole-4- (EtOAc) carboxamide 64 2-Me-Ph
4-Cl-Ph 1 (R)- 1-(4-chlorophenyl)-N-[(2R)-2- 425.3 0.33 2.78 1 13,
14 CH.sub.2OMe (methoxymethyl)-1-pyrrolidinyl]-2-(2- (EtOAc)
methylphenyl)-1H-imidazole-4- carboxamide 65 2-Me-Ph 4-Cl-Ph 1 (S)-
1-(4-chlorophenyl)-N-[(2S)-2- 425.3 0.33 2.79 1 13, 14 Ch.sub.2OMe
(methoxymethyl)-1-pyrrolidinyl]-2-(2- (EtOAc)
methylphenyl)-1H-imidazole-4- carboxamide 66 2-Me-Ph 4-Cl-Ph 3 H
N-(1-azepanyl)-1-(4-chlorophenyl)-2-(2- 409.3 0.57 2.82 1 13, 14
methylphenyl)-1H-imidazole-4- (EtOAc) carboxamide 67
2,4-Me.sub.2-Ph 4-Cl-Ph 1 H
1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)- 395.3 0.25 2.61 1 13, 14
N-(1-pyrrolidinyl)-1H-imidazole-4- (EtOAc) carboxamide 68
2,4-Me.sub.2-Ph 4-Cl-Ph 1 (R)- 1-(4-chlorophenyl)-2-(2,4-dimeth-
ylphenyl)- 493.3 0.32 2.90 1 13, 14 CH.sub.2OMe
N-[(2R)-2-(methoxymethyl)-1-pyrroiidinyl] (EtOAc)
1H-imidazole-4-carboxamide 69 2,4-Me.sub.2-Ph 4-Cl-Ph 1 (S)-
1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)- 493.3 0.32 2.91 1 13, 14
CH.sub.2OMe N-[(2S)-2-(methoxymethyl)-1-pyrrolidinyl] (EtOAc)
1H-imidazole-4-carboxamide 70 2,4-Me.sub.2-Ph 4-Cl-Ph 3 H
N-(1-azepanyl)-1-(4-chlorophenyl)-2-(2,4- 423.3 0.6 2.93 1 13, 14
dimethylphenyl)-1H-imidazole-4- (EtOAc) carboxamide 71
2,4-Cl.sub.2-Ph 4-Me-Ph 3 H
N-(1-azepanyl)-2-(2,4-dichlorophenyl)-1- 443.3 0.4 (75% 3.03 1 15
(4-methylphenyl)-1H-imidazole-4- EtOAc in carboxamide
trifluoroacetate hexane) 72 2,4-Cl.sub.2-Ph 4-F-Ph 3 H
N-(1-azepanyl)-2-(2,4-dichlorophenyl)-1- 447.3 0.4 (75% 2.96 1 15
(4-fluorophenyl)-1H-imidazole-4- EtOAc in carboxamide
trifluoroacetate hexane) 73 2-Cl-Ph 4-Cl-Ph 1 (S)-
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N- 431.1 0.24 1 8 CH.sub.2OMe
[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]-1H- (EtOAc)
imidazole-4-carboxamide 74 2-Cl-Ph 4-Cl-Ph 1 (R)-
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N- 431.2 0.35 2.71 1 13, 14
CH.sub.2OMe [(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]-1H- (EtOAc)
imidazole-4-carboxamide
[0295]
3TABLE 3 72 HPLC Synthesis Entry MS m/z RT HPLC Method of No.
R.sup.1 R.sup.2 Z IUPAC name [MH+] TLC Rf (solvent) (min.) method
Ex. No. 75 2-Cl-Ph 4-Cl-Ph O 2-(2-chlorophenyl)-1-(4- 417.0 0.45
(7& MeOH in 3.32 1 8 chlorophenyl)-N-(4-morpholinyl) CH2Cl2)
1H-imidazole-4-carboxamide 76 2-MeO-Ph 4-Cl-Ph O
1-(4-chlorophenyl)-2-(2- 413.2 0.22 (75% EtOAc in 2.55 1 13, 14
methoxyphenyl)-N- hexane) (4-morpholinyl)-
1H-imidazole-4-carboxammde 77 2,4-Cl.sub.2-Ph 4-Cl-Ph O
1-(4-chlorophenyl)-2-(2,4- 453.2 0.57 (50% EtOAc in 3.03 1 13, 14
dichlorophenyl)-N-(4-morpholinyl) hexane)
1H-imidazole-4-carboxamide 78 2,4-F-Ph 4-Cl-Ph O
1-(4-chlorophenyl)-2-(2,4- 419.2 0.28 (5% MeOH in 2.73 1 8
difluorophenyl)-N-(4-morpholinyl) EtOAc) 1H-imidazole-4-carboxamide
79 2-Me-Ph 4-Cl-Ph O 1-(4-chlorophenyl)-2-(2- 397.3 0.18 (EtOAc)
2.63 1 13, 14 methylphenyl)-N-(4-morpholinyl)-
1H-imidazole-4-carboxamide 80 2,4-Me-Ph 4-Cl-Ph O
1-(4-chlorophenyl)-2-(2,4- 411.3 0.19 (EtOAc) 2.77 1 13, 14
dimethylphenyl)-N- (4-morpholinyl)- 1H-imidazole-4-carboxamide 81
2,4-Me-Ph 4-Cl-Ph NMe 1-(4-chlorophenyl)-2-(2,4- 421.2 0.6 (20% 2M
2.82 1 13, 14 dimethylphenyl)-N-(4-methyl-1- NH3/MeOH in
piperazinyl)-1H-imidazole-4- EtOAc) carboxamide
bis(trifluoroacetate) 82 2,4-Cl.sub.2Ph 4-Me-Ph NMe
2-(2,4-dichlorophenyl)-1-(4- 444.3 2.29 1 15
methylphenyl)-N-(4-methyl-1- piperazinyl)-1H-imidazole-4-
carboxamide bis(trifluoroacetate) 83 2,4-Cl.sub.2-Ph 4-F-Ph NMe
2-(2,4-dichlorophenyl)-1-(4- 448.2 2.21 1 15
fluorophenyl)-N-(4-methyl-1- piperazinyl)-1H-imidazole-4-
carboxamide bis(trifluoroacetate) 84 2-Et-Ph 4-Cl-Ph NMe
1-(4-chlorophenyl)-2-(2- 424.3 0.62 (25% 2M) 2.28 1 13, 14
ethylphenyl)-N-(4-methyl-1- NH3/MeOH in
piperazinyl)-1H-imidazole-4- EtOAC) carboxamide
[0296]
4TABLE 4 73 HPLC Synthesis Entry MS m/z Retention HPLC Method of
No. R.sup.1 R.sup.2 R.sup.6 R.sup.7 IUPAC name [MH+] time (min.)
method Ex. No. 85 2,4-Cl.sub.2-Ph 4-Cl-Ph Me Me
2-(4-chlorophenyl)-1-(2,4- 409.0 2.9 1 8
dichlorophenyl)-N',N'-dimethyl-1H- imidazole-4-carbohydrazide 86
2,4-Cl.sub.2-Ph 4-MeO-Ph 74 2-(2,4-dichlorophenyl)-N-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl-1-
(4-methoxyphenyl)-1H-imidazole-4- carboxamide hydrochloride 471
2.98 2 10, 11, 12 87 2-Me-Ph 4-Cl-Ph 75 1-(4-chlorophenyl)-N-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl-2-
(2-methylphenyl)-1H-imidazote-4- carboxamide hydrochloride 421 2.82
2 10, 11, 12 88 2,4-Cl.sub.2-Ph 4-F-Ph 76
2-(2,4-dichlorophenyl)-1-(4- fluorophenyl)-N-
hexahydrocyclopenta[c]pyrrol-2(1H)-yl- 1H-imidazole-4-carboxamide
hydrochloride 459 3.38 2 10, 11, 12 89 2,4-Cl.sub.2-Ph 4-Cl-Ph 77
1-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-N-
hexahydrocyclopenta[c]pyrro- l-2(1H)-yl- 1H-imidazole-4-carboxamide
hydrochloride 475 3.16 2 10, 11, 12 90 2-Cl-Ph 4-Cl-Ph 78
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N
hexahydrocyclopenta[c]pyrrol-2(1H)-yl- 1H-imidazole-4-carboxamide
hydrochloride 441 3.23 2 10, 11, 12
[0297]
5TABLE 5 79 HPLC Synthesis Entry MS m/z TLC RT HPLC Method of No.
R.sup.1 R.sup.2 R.sup.3 R.sup.6 R.sup.7 IUPAC name [MH+] (solvent)
(min) method Ex. No. 91 2,4-Cl.sub.2-Ph 4-Cl-Ph H 2-CF.sub.3-Ph H
1-(4-chlorophenyl)- 525 0.4 (20% 4.25 2 10, 11, 12 2-(2,4- EtOAc/
(trifluoromethyl)phenyl]- Hexane) 1H-imidazole-4- carbohydrazide 92
2,4-Cl.sub.2-Ph 4-Cl-Ph H Ph Me 2-(2,4-dichlorophenyl)- 473 0.6
(50% 3.70 1 8 1-(4-chlorophenyl)-N'- EtOAc in methyl-N'- Hexane)
phenyl-1H-imidazole-4- carbohydrazide 93 2,4-Cl.sub.2-Ph 4-Cl-Ph H
3-Cl-4-F- H N'-(3-chloro-4- Ph fluorophenyl)-
2-(2,4-dichlorophenyl)-1- (4-chlorophenyl)-1H- imidazole-4-
carbohydrazide hydrochloride 94 2,4-Cl.sub.2-Ph 4-F-Ph H 2-Cl-Ph H
N'-(2-chlorophenyl)-2-(2,4- 475 3.40 2 10, 11, 12
dichlorophenyl)-1-(4- fluorophenyl)-1H- imidazole-4- carbohydrazide
hydrochloride 95 2,4-Cl.sub.2-Ph 4-F-Ph H 3-Cl-4-F- H
N'-(3-chloro-4- 493 3.39 2 10, 11, 12 fluorophenyl)-2- Ph
(2,4-dichlorophenyl)-1-(4- fluorophenyl)-1H- imidazole-4-
carbohydrazide hydrochloride 96 2,4-Cl.sub.2-Ph 4-F-Ph H 2-Cl-4- H
N'-[2-chloro-4- 543 3.66 2 10, 11, 12 CF.sub.3-Ph (trifluoromethyl)
phenyl]-2-(2,4- dichlorophenyl)-1-(4- fluorophenyl)-
1H-imidazole-4- carbohydrazide hydrochloride 97 2,4-Cl.sub.2-Ph
4-MeO-Ph H 3-Cl-4-F- H N'-(3-chloro-4- 505 3.36 2 10, 11, 12 Ph
fluorophenyl)-2- (2,4-dichlorophenyl)-1 -(4- methoxyphenyl)-
1H-imidazole- 4-carbohydrazide hydrochloride 98 2,4-F.sub.2-Ph
4-Cl-Ph H Ph Me 1-(4-chlorophenyl)-2-(2,4- 439 0.27 (50% 3.39 1 8
difluorophenyl)-N'- EtOAc in methyl-N'- Hexane)
phenyl-1H-imidazole-4- carbohydrazide 99 2,4-Me.sub.2-Ph 4-Cl-Ph H
Ph Me 1-(4-chlorophenyl)-2-(2,4- 431 0.64 (50% 3.48 1 8
dimethylphenyl)-N'- EtOAc in methyl-N'- Hexane)
phenyl-1H-imidazole-4- carbohydrazide 100 2,5-Cl.sub.2-Ph 4-Cl-Ph H
2-CF.sub.3-Ph H 1-(4-chlorophenyl)-2-(2,5- 525 0.41 (25% 3.76 1 8
dichlorophenyl)-N'-[2- EtOAc in (trifluoromethyl) Hexane)
phenyl]-1H- imidazole-4-carbohydrazide 101 2,5-Cl.sub.2-Ph 4-Cl-Ph
H 3-CF.sub.3-Ph H 1-(4-chlorophenyl)-2-(2,5- 526 0.2 (33% 3.69 1 8
dichlorophenyl)-N'-[3- EtOAc in (trifluoromethyl) Hexane)
phenyl]-1H- imidazole-4-carbohydrazide 102 2,5-Cl.sub.2-Ph 4-Cl-Ph
H 4-CF.sub.3-Ph H 1-(4-chlorophenyl)-2-(2,5- 526 0.2 (33% 3.70 1 8
dichlorophenyl)-N'-[4- EtOAc in (trifluoromethyl) Hexane)
phenyl]-1H- imidazole-4-carbohydrazide 103 2-CF.sub.3-Ph 4-Cl-Ph H
4-CF.sub.3-Ph H 1-(4-chlorophenyl)-2-[2- 525 3.38 2 10, 11, 12
(trifluoromethyl) phenyl]-N'-[4- (trifluoromethyl) phenyl]-1H-
imidazole-4-carbohydrazide trifluoroacetate 104 2-CF.sub.3-Ph
4-Cl-Ph H 2-CF.sub.3-Ph H 1-(4-chlorophenyl)- 525 3.97 2 10, 11, 12
N',2-bis[2- (trifluoromethyl) phenyl]-1H-
imidazole-4-carbohydrazide hydrochloride 105 2-Cl-Ph 4-Br-Ph Et
2-CF.sub.3-Ph H 1-(4-bromophenyl)-2-(2- 563 0.24 (20% 3.88 1 8
chlorophenyl)-5- EtOAc in ethyl-N'-[2- Hexane) (trifluoromethyl)
phenyl]-1H- imidazole-4-carbohydrazide 106 2-Cl-Ph 4-Br-Ph Et
4-CF.sub.3-Ph H 1-(4-bromophenyl)-2-(2- 563 0.27 (33% 3.82 1 8
chlorophenyl)-5- EtOAc in ethyl-N'-[4- Hexane) (trifluoromethyl)
phenyl]-1H- imidazole-4-carbohydrazide 107 2-Cl-4-Ph 4-Br-Ph Et
2-Cl-4- H 1-(4-bromophenyl)-2-(2- 597 0.18 (20% 3.98 1 6
CF.sub.3-Ph chlorophenyl)-N'- EtOAc in [2-chloro-4- Hexane)
(trifluoromethyl) phenyl]-5-ethyl- 1H-imidazole-4- carbohydrazide
108 2-Cl-Ph 4-Cl-Ph Cyclopropyl 2-CF.sub.3-Ph H
2-(2-chlorophenyl)-1-(4- 531 3.61 2 13, 14 chlorophenyl)-5-
cyclopropyl-N'- [2-(trifluoromethylphenyl]
imidazole-4-carbohydrazide hydrochloride 109 2-Cl-Ph 4-Cl-Ph
Cyclopropyl 4-CF.sub.3-Ph H 2-(2-chlorophenyl)-1-(4- 531 3.62 2 13,
14 chlorophenyl)-5- cyclopropyl-N'- [4-(trifluoromethyl)
phenyl]-1H- imidazole-4-carbohydrazide hydrochloride 110 2-Cl-Ph
4-Cl-Ph Et 2,4-Cl.sub.2-Ph H 2-(2-chlorophenyl)-1-(4- 5.19 0.6 (33%
4.02 1 6 chlorophenyl)-N'-(2,4- EtOAc in dichlorophenyl)-5- Hexane)
ethyl-1H- imidazole-4-carbohydrazide 111 2-Cl-Ph 4-Cl-Ph Et
2,4-(CF.sub.3).sub.2- H N'-[2,4- 587 0.47 (30% 3.75 1 8
bis(trifluoromethyl) EtOAc in phenyl]-2-(2 Hexane)
chlorophenyl)-1-(4- chlorophenyl)-5-ethyl-1H-
imidazole-4-carbohydrazide 112 2-Cl-Ph 4-Cl-Ph H 2-CF.sub.3-Ph H
2-(2-chlorophenyl)-1-(4- 491 4.02 2 10, 11, 12 chlorophenyl)-N'-[2-
(trifluoromethyl) phenyl]-1H- imidazole-4-carbohydrazide
hydrochloride 113 2-Cl-Ph 4-Cl-Ph H 3-CF.sub.3-Ph H
2-(2-chlorophenyl)-1-(4- 491 3.99 2 10, 11, 12 chlorophenyl
)-N'-[3- (trifluoromethyl) phenyl]-1H- imidazole-4-carbohydrazide
hydrochloride 114 2-Cl-Ph 4-Cl-Ph H 4-CF.sub.3-Ph H
2-(2-chlorophenyl)-1-(4- 491 3.99 2 10, 11, 12 chlorophenyl)-N'-[4-
(trifluoromethyl) phenyl]-1H- imidazole-4-carbohydrazide
hydrochloride 115 2-Cl-Ph 4-Cl-Ph H 2-CF.sub.3-4- H
2-(2-chlorophenyl)-1-(4- 525 3.55 2 10, 11, 12 Cl-Ph
chlorophenyl)-N'- [4-chloro-2- (trifluoromethyl) phenyl]-1H-
hydrochloride 116 2-Cl-Ph 4-Cl-Ph H Ph Me 2-(2-chlorophenyl)-1-(4-
437 0.5 (60% 3.85 1 8 chlorophenyl)- EtOAc in N'-methyl-N'- Hexane)
phenyl-1H-imidazole-4- carbohydrazide 117 2-Cl-Ph 4-Cl-Ph H Ph H
2-(2-chlorophenyl)-1-(4- 423 3.07 2 10, 11, 12 chlorophenyl)-
N'-phenyl-1H- imidazole-4-carbohydrazide hydrochloride 118 2-Cl-Ph
4-Cl-Ph H 2,4-Cl.sub.2-Ph H N'-(2,4-dichlorophenyl)- 492 3.55 2 10,
11, 12 2-(2-chloro- phenyl)-1-(4- chlorophenyl)-1H- imidazole-4-
carbohydrazide hydrochloride 119 2-Cl-Ph 4-Cl-Ph H 2,4-F.sub.2-Ph H
N'-(2,4-difluorophenyl)- 460 3.07 2 10, 11, 12 2-(2-chloro-
phenyl)-1-(4- chlorophenyl)- 1H-imidazole-4- carbohydrazide
hydrochloride 102 2-Cl-Ph 4-Cl-Ph H 2-Cl-4-CN- H N'-(2-chloro-4-
482 3.03 2 10, 11, 12 Ph cyanophenyl)-2 (2-chlorophenyl)-1-(4-
chlorophenyl)-1H- imidazole-4- carbohydrazide hydrochloride 121
2-Cl-Ph 4-Cl-Ph H 2-Cl-Ph H N'-(2-chlorophenyl)-2-(2- 457 3.18 2
10, 11, 12 chlorophenyl)-1-(4- chlorophenyl)- 1H-imidazole-4-
carbohydrazide hydrochloride 122 2-Cl-Ph 4-Cl-Ph H 3-Cl-4-F- H
N'-(3-chloro-4- 475 3.28 2 10, 11, 12 Ph fluorophenyl)-2-
(2-chlorophenyl)-1-(4- chlorophenyl)-1H- imidazole-4-
carbohydrazide hydrochloride 123 2-Cl-Ph 4-Cl-Ph H 2-Me-4-Cl- H
N'-(4-chloro-2- 471 3.36 2 10, 11, 12 Ph methylphenyl)-
2(2-chlorophenyl)-1-(4- chlorophenyl)- 1H-imidazole-4-
carbohydrazide hydrochloride 124 2-Cl-Ph 4-Cl-Ph H 2,4- H N'-[2,4-
559 3.62 2 10, 11, 12 (CF.sub.3).sub.2-Ph bis(trifluoromethyl)
phenyl]-2-(2 chlorophenyl)-1-(4- chlorophenyl)- 1H-imidazole-4-
carbohydrazide hydrochloride 125 2-Cl-Ph 4-Cl-Ph H 2-Cl-4- H
N'-[2-chloro-4- 525 3.55 2 10, 11, 12 CF.sub.3-Ph (trifluoromethyl)
phenyl]-2-(2- chlorophenyl)-1-(4- chlorophenyl)- 1H-imidazole-4-
carbohydrazide hydrochloride 126 2-Cl-Ph 4-Cl-Ph Me 2,4-Cl.sub.2-Ph
H 2-(2-chlorophenyl)-1-(4- 505 0.71 (50% 3.88 1 6
chlorophenyl)-N'-(2,4- EtOAc in dichlorophenyl)-5- Hexane)
methyl-1H imidazole-4- carbohydrazide 127 2-Cl-Ph 4-Cl-Ph Pr
2,4-Cl.sub.2-Ph H 2-(2-chlorophenyl)-1-(4- 533 3.87 2 10, 11, 12
chlorophenyl)-N'-(2,4- dichlorophenyl)- 5-propyl-1H-
imidazole-4-carbohydrazide 128 2-Cl-Ph 4-Cl-Ph Pr 2,4-Cl.sub.2-Ph H
2-(2-chlorophenyl)-1-(4- 533 3.87 2 10, 11, 12
chlorophenyl)-N'-(2,4- dichlorophenyl)- 5-propyl-1H-
imidazole-4-carbohydrazide hydrochloride 129 2-Cl-Ph 4-Cl-Ph Pr
2,4- H N'-[2,4- 601 4.00 2 10, 11, 12 (CF.sub.3).sub.2-Ph
bis(trifluoromethyl) phenyl]-2(2 chlorophenyl)-1-(4-
chlorophenyl)-5-propyl-1H- imidazole-4-carbohydrazide hydrochloride
130 2-Cl-Ph 4-Cl-Ph H 2-CF.sub.3-Ph H 2-(2-chlorophenyl)-1-(4- 475
3.68 2 10, 11, 12 fluorophenyl)-N'-[2- (trifluoromethyl)
phenyl]-1H- imidazole-4-carbohydrazide hydrochloride 131 2-Cl-Ph
4-Cl-Ph H 4-CF.sub.3-Ph H 2-(2-chlorophenyl)-1-(4- 475 3.27 2 10,
11, 12 fluorophenyl)-N'-[4- (trifluoromethyl) phenyl]-1H-
imidazole-4-carbohydrazide hydrochloride 132 2-Cl-Ph 4-Me-Ph H
2-CF.sub.3-Ph H 2-(2-chlorophenyl)-1-(4- 471 4.02 2 10, 11, 12
methylphenyl)-N'-[2- (trifluoromethyl) phenyl]-1H-
imidazole-4-carbohydrazide trifluoroacetate 133 2-Cl-Ph 4-Me-Ph H
3-CF.sub.3-Ph H 2-(2-chlorophenyl)-1-(4- 471 3.88 2 10, 11, 12
methylphenyl)-N'-[3- (trifluoromethyl) phenyl]-1H-
imidazole-4-carbohydrazide trifluoroacetate 134 2-Cl-Ph 4-Me-Ph H
4-CF.sub.3-Ph H 2-(2-chlorophenyl)-1-(4- 471 3.28 2 10, 11, 12
methylphenyl)-N'-[4- (trifluoromethyl) phenyl]-1H-471
imidazole-4-carbohydrazide hydrochloride 135 2-Cl-Ph 4-NO.sub.2-Ph
Me 2-CF.sub.3-Ph H 2-(2-chlorophenyl)- 516 0.4 (33% 3.56 1 8
5-methyl-1- EtOAc in (4-nitrophenyl)-N'-]2- Hexane)
(trifluoromethyl) phenyl]-1H- imidazole-4-carbohydrazide 136
2-Et-Ph 4-Cl-Ph H Ph Me 1-(4-chlorophenyl)-2-(2- 431 0.68 (50% 3.52
1 8 ethylphenyl)-N'-methyl-N"- EtOAc in phenyl-1H-imidazole-4-
Hexane) carbohydrazide 137 2-MeO-Ph 4-Cl-Ph H Ph Me
2-(2-methoxyphenyl)-1-(4- 433 0.45 (50% 3.26 1 8
chloropheny-N'-methyl-N'- EtOAc in phenyl-1H-imidazole-4- Hexane)
carbohydrazide 138 2-Me-Ph 4-Cl-Ph H 2-CF.sub.3-PH H
1-(4-chlorophenyl)-2-(2- 471 0.4 (20% 3.89 2 10, 11, 12
methylphenyl)-N'-[2- EtOAc/ (trifluoromethyl) Hexane) phenyl]-1H-
imidazole-4-carbohydrazide 139 2-Me-Ph 4-Cl-Ph H Ph Me
1-(4-chlorophenyl)-2-(2- 417 0.54 (50% 3.34 1 8 methylphenyl)-
EtOAc in N'-methyl-N'- Hexane) phenyl-1H-imidazole-4-
carbohydrazide 140 2-Me-Ph 4-Cl-Ph H 3-Cl-4-F- H N'-(3-chloro-4-
455 3.78 2 10, 11, 12 Ph fluorophenyl)-2- (2-methylphenyl)-1-(4-
chlorophenyl)- 1H-imidazole-4- carbohydrazide hydrochloride
[0298]
6TABLE 6 80 Synthesis Entry MS m/z HPLC RT HPLC Method of No.
R.sup.1 R.sup.2 R.sup.3 R.sup.4 IUPAC name [MH.sup.+] TLC Rf
(solvent) (min) method Ex. No. 141 4-Br-Ph 2,4-Cl.sub.2-Ph H H
2-(4-bromophenyl)-N-cyclohexy-1-(2,4- 494.0 3.96 1 8
dichlorophenyl)-1H-imidazole-4- carboxamide 142 4-Cl-Ph
2,4-Cl.sub.2-Ph H H 2-(4-chlorophenyl)-N-cyclohexyl-1-(2,4- 13, 14
dichlorophenyl)-1H-immdazole-4- carboxamide 143 Ph Ph H H
N-cyclohexyl-1,2-diphenyl-1H-imidazole- 346.2 3.22 1 8
4-carboxamide 144 4-I-Ph 2,4-Cl.sub.2-Ph H H
N-cyclohexyl-1-(2,4-dichlorophenyl)-2-(4- 540.0 4.03 1 8
iodophenyl)-1H-imidazole-4- carboxamide 145 2,4-Cl.sub.2-Ph 4-Cl-Ph
H H 1-(4-chlorophenyl)-N-cyclohexyl-2-(2,4- 448.2 0.57 (50% EtOAc
in 3.84 1 13, 14 dichlorophenyl)-1H-imidazole-4- hexane)
carboxamide 146 2-Cl-Ph 4-Cl-Ph H H
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N- 414.2 0.21 (35% EtOAc in
3.48 1 8 cyclohexyl-1H-imidazole-4-carboxa- mide hexane) 147
2-MeO-Ph 4-Cl-Ph H H 1-(4-chlorophenyi)-N-cyclohe- xyl-2-(2- 410 2
0.5 (50% EtOAc in 3.25 1 13, 14 methoxyphenyl)-1H-imidazole-4-
hexane) carboxamide 148 2-Me-Ph 4-Cl-Ph H H
1-(4-chlorophenyl)-N-cyclohexyl-2-(2- 394.2 0.64 (50% EtOAc in 3.44
1 13, 14 methylphenyl)-1H-imidazole-4- hexane) carboxamide 149
2,4-Me.sub.2- 4-Cl-Ph H H 1-(4-chlorophenyl)-N-cyclohexyl-2-(2,4-
408.3 0.68 (50% EtOAc in 3.56 1 13, 14 Ph
dimethylphenyl)-1H-imidazole-4- hexane) carboxamide 150
2,4-Cl.sub.2-Ph 4-MeO-Ph H H
N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(4- 444.2 3.55 1 8
methoxyphenyl)-1H-imidazole-4- carboxamide 151 2-F-Ph 2-NO.sub.2-Ph
Me H N-cyclohexyl-2-(2-fluorophenyl)-5-methyl 423.2 0.11 (33% EtOAc
in 3.22 1 8 1-(2-nitrophenyl)-1H-imidazole-4- hexane) carboxamide
152 2,4-Cl.sub.2-Ph 4-Me-Ph H H
N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(4- 428.2 0.6 (30% EtOAc in
3.76 1 15 methylphenyl)-1H-imidazole-4- hexane) carboxamide 153
2,4-Cl.sub.2-Ph 4-F-Ph H H N-cyclohexyl-2-(2,4-dic-
hlorophenyl)-1-(4- 432.2 0.17 (30% EtOAc in 3.62 1 15
fluorophenyl)-1H-imidazole-4- hexane) carboxamide 154
2,4-F.sub.2-Ph 4-Cl-Ph H H 1-(4-chlorophenyl)-N-cyclohexyl-2-(2,4-
416.3 0.22 (30% EtOAc in 1 15 difluorophenyl)-1H-imidazole-4-
hexane) carboxamide 155 2-Cl-Ph 4-NO.sub.2-Me H H
2-(2-chlorophenyl)-N-cyclohexyl-5- 439.2 3.41 1 8
methyl-1-(4-nitrophenyl)-1H-imidazole-4- carboxamide 156 2-Et-Ph
4-Cl-Ph H H 1-(4-chlorophenyl)-N-cyclohexyl-2-(2- 408.3 0.72 (50%
EtOAc in 3.62 1 ethylphenyl)-1H-imidazole-4- hexane) carboxamide
157 2-Cl-Ph 4-Cl-Ph H Me 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-
428.2 0.19 (50% EtOAc in 3.47 1 8
cyclohexyl-N-methyl-1H-imidazole-4- hexane) carboxamide 158 2-Cl-Ph
4-F-Ph H H 2-(2-chlorophenyl)-N-cyclohexyl- -1 -(4- 398.3 0.52 (50%
EtOAc in 3.22 1 10, 11, 12 fluorophenyl)-1H-imidazole-4- hexane)
carboxamide 159 2-Cl-Ph 4-MeO-Ph H H
2-(2-chlorophenyl)-N-cyclohexyi-1 -(4- 410.3 0.47 (50% EtOAc in
3.16 1 10, 11, 12 methoxyphenyl)-1H-imidazole-4- - hexane)
carboxamide 160 2-Cl-Ph 4-Me-Ph H H
2-(2-chlorophenyl)-N-cyclohexyl-1 -(4- 394.3 0.6 (50% EtOAc in 3.31
1 10, 11, 12 methylphenyl)-1H-imidazole-4- hexane) carboxamide 161
Ph 4-Cl-Ph H H 1-(4-chlorophenyl)-N-cyclohexyl-2-p- henyl 380.3
3.35 1 8 1H-imidazole-4-carboxamide 162 2,5-Cl.sub.2-Ph 4-Cl-Ph H H
1-(4-chlorophenyl)-N-cyclohexyl-2-(2,5- 448.6 0.15 (25% EtOAc in
3.83 1 8 dichlorophenyl)-1H-imidazole-4- hexane) carboxamide
[0299]
7TABLE 7 81 MS HPLC Synthesis Entry m/z TLC Rf RT HPLC Method No.
R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 IUPAC name [MH+] (solvent)
(min) method of Ex. No. 163 4-Cl-Ph 2,4-Cl.sub.2-Ph H
--(CH.sub.2).sub.5-- 1-{[2-(4-chlorophenyl)- 436.1 3.59 1 13, 14
1-(2,4-dichlorophenyl)- 1H-imidazol-4-yl] carbonyl}piperidine 164
4-Cl-Ph 2,4-Cl.sub.2-Ph H Me Me 2-(4-chlorophenyl)-1-(2, 13, 14
4-dichlorophenyl)-N,N- dimethyl-1H-imidazole- 4-carboxamide 165
2,4-Cl.sub.2-Ph 4-Me-Ph H --(CH.sub.2).sub.5-- 1-{[2-(2,4- 414.3
0.2 (50% 3.34 1 9 dichlorophenyl)-1-(4- EtOAc in methylphenyl)-1H-
hexane) imidazol-4-yl] carbonyl}piperidine 166 2,4-Cl.sub.2-Ph
4-MeO-Ph H --CH.sub.2CH.dbd.CH(Ph)CH.sub.2CH.sub.2-- 1-{[2-(2,4-
522 3.53 2 10, 11, 12 dichlorophenyl)-1-(4- methoxyphenyl)-1H-
imidazol-4-yl] carbonyl}-4-phenyl-1,2, 3,6-tetrahydropyridine 167
2,4-Cl.sub.2-Ph 4-Cl-Ph H --CH.sub.2CH.dbd.CH(Ph)CH.sub.2CH.sub.2--
1-{[1-(4-chlorophenyl)- 526 3.33 2 10, 11, 12
2-(2,4-dichlorophenyl)- 1H-imidazol-4-yl] carbonyl}-4-phenyl-1,2,
3,6-tetrahydropyridine 168 2-Me-Ph 4-Cl-Ph H
--CH.sub.2CH.dbd.CH(Ph)CH.sub.2CH.sub.2-- 1-{[1-(4-chlorophenyl)-
472 2.9 2 10, 11, 12 2-(2-methylphenyl)- 1H-imidazol-4-yl]
carbonyl}-4-phenyl-1,2, 3,6-tetrahydropyridine 169 2,4-Cl.sub.2-Ph
4-F-Ph H --CH.sub.2CH.dbd.CH(Ph)CH.sub.2CH.sub.2-- 1-{[2-(2,4- 510
3.05 2 10, 11, 12 dichlorophenyl)-1-(4- fluorophenyl)-1H-
imidazol-4-yl]carbonyl}- 4-phenyl-1,2,3,6- tetrahydropyridine 170
2-Cl-Ph 4-Cl-Ph H --CH.sub.2CH.dbd.CH(Ph)CH- .sub.2CH.sub.2--
1-{[2-(2-chlorophenyl)- 492 3.47 2 10, 11, 12
1-(4-chlorophenyl)-1H- imidazol-4-yl] carbonyl}-4-phenyl-1,2,
3,6-tetrahydropyridine 171 2-Cl-Ph 4-Cl-Ph H
--(CH.sub.2).sub.3CH(CH.sub.2OH)CH.sub.2-- (1-{[2-(2-chlorophenyl)-
430 2.52 2 10, 11, 12 1-(4-chlorophenyl)-1H- imidazol-4-yl]
carbonyl}-3- piperidinyl)methanol 172 2-Cl-Ph 4-Cl-Ph H Me 82
2-(2-chlorophenyl)-1-(4-chlorophenyl)-- N-methyl- N-(1-methyl-3-
pyrrolidinyl)-1H- imidazole-4-carboxamide hydrochloride 429 2.15 2
10, 11, 12 173 2-Cl-Ph 4-Cl-Ph H
--(CH.sub.2).sub.2CH[N(Et).sub.2]CH.sub.2-- N-(1-{[2-(2- 457 2.08 2
10, 11, 12 chlorophenyl)-1-(4- chlorophenyl)-1H-
imidazol-4-yl]carbonyl}- 3-pyrrolidinyl)-N,N- diethylamine
hydrochloride 174 2,4-Cl.sub.2-Ph 4-Cl-Ph H Me 83
1-(4-chlorophenyl)-2-(2, 4-dichlorophenyl)-N- methyl-N[(1R,2R)-2-
(methylamino)cyclo hexyl]-1H-imidazole-4- carboxamide hydrochloride
491.2 2.41 2 10, 11, 12 175 2,4-Cl.sub.2-Ph 4-Cl-Ph H Me 84
1-(4-chlorophenyl)-2-(2, 4-dichlorophenyl)-N- methyl-N-
(methylamino)cyclo hexyl]-1H-imidazole-4- carboxamide hydrochloride
491.2 2.34 2 10, 11, 12 176 2-Cl-Ph 4-Cl-Ph H
--(CH.sub.2).sub.2S(CH.sub.2).sub.2-- 4-{[2-(2-chlorophenyl)- 418.6
0.3 (50% 3.15 1 13, 14 1-(4-chlorophenyl)-1H- EtOAc in
imidazol-4-yl]carbonyl} hexane) thiomorpholine 177 2-Cl-Ph 4-Cl-Ph
H --(CH.sub.2).sub.2C(.dbd.O)(CH.sub.2).sub.2--
1-{[2-(2-chlorophenyl)- 414.1 0.29 (50% 2.75 1 13, 14
1-(4-chlorophenyl)-1H- EtOAc in imidazol-4-yl]carbonyl}- hexane)
4-piperidinone 178 2-Cl-Ph 4-Cl-Ph H 85 4-{[2-(2-chlorophenyl)-
1-(4-chlorophenyl)-1H- imidazol-4-yl]carbonyl}- thiomorpholine
1-oxide 434.5 0.47 (1:5 EtOAc/ Hexane 2.55 1 13, 14 179 2-Cl-Ph
4-Cl-Ph Et --(CH.sub.2).sub.2C(.dbd.O)(CH.sub.2).sub.- 2--
1-{[2-(2-chlorophenyl)- 442.1 0.06 (1:1 2.99 1 13, 14
1-(4-chlorophenyl)-5- EtOAc/ ethyl-1H-imidazol-4-yl] Hexanes)
carbonyl}-4-piperidinone 180 2-Cl-Ph 4-Cl-Ph n-Pr
--(CH.sub.2).sub.2C(.dbd.O)(CH.sub.2).sub.2--
1-{[2-(2-chlorophenyl)- 456.1 0.06 (1:1 3.13 1 13, 14
1-4-chlorophenyl)-5- EtOAc/ propyl-1H-imidazol-1H- Hexanes)
yl]carbonyl}-4- piperidinone 181 2-Cl-Ph 4-Cl-Ph H Me OMe
2-(2-chlorophenyl)-1-(4- 376.1 0.22 2.77 1 13, 14 chlorophenyl)-N-
(EtOAc) methoxy-N-methyl-1H- imidazole-4-carboxamide 182 2-Cl-Ph
2,4-F.sub.2-Ph H --(CH.sub.2).sub.5-- 1-{[2-(2-chlorophenyl)- 402.2
0.36 (2:1 02.97 1 13, 14 1-(2,4-difluorophenyl)- EtOAc/
1H-imidazol-4-yl] Hexanes) carbonyl}piperidine 183 2-Cl-Ph 4-iPr-Ph
Et --(CH.sub.2).sub.5-- 1-{[2-(2-chlorophenyl)- 436.1 0.06 (1:1
3.36 1 13, 14 5-ethyl-1-(4- EtOAc/ isopropylphenyl)-1H- Hexanes)
imidazol-4-yl]carbonyl} piperidine
[0300]
8TABLE 8 86 Synthesis Entry MS m/z HPLC RT HPLC Method of No.
R.sup.1 R.sup.2 R.sup.4 IUPAC name [MH+] TLC Rf (solvent) (min)
method Ex. No. 184 2-MeO-Ph 4-Cl-Ph Ph 1-(4-chlorophenyl)-2-(2-
404.1 0.83 (50% EtOAc in 3.42 1 13, 14 methoxyphenyl)-N-phenyl-
-1H- hexane) imidazole-4-carboxamide 185 2,4-Cl.sub.2-Ph 4-Cl-Ph Ph
1-(4-chlorophenyl)-2-(2,4- 444.1 0.89 (50% EtOAc in 3.87 1 13, 14
dichlorophenyl)-N-phenyl-1H-imidazole hexane) 4-carboxamide 186
2-Cl-Ph 4-Cl-Ph 4H-1,2,4 2-(2-chlorophenyl)-1-(4-chlorophenyl)-
399.1 <0.1 (15% MeOH in 2.71 1 8 triazol-4-yl
N-(4H-1,2,4-triazol-4-yl)-1H-imidazole- EtOAc) 4-carboxamide 187
2-Cl-Ph 4-Cl-Ph Ph 2-(2-chlorophenyl)-1-(4-chlorophenyl)- 408.1 0.4
(35% EtOAc in 3.54 1 8 N-phenyl-1H-imidazole-4-carboxamide hexane)
188 2,4-F.sub.2-Ph 4-Cl-Ph Ph 1-(4-chlorophenyl)-2-(2,4- 410.1 0.5
(35% EtOAc in 3.52 1 8 difluorophenyl)-N-phenyl-1H-imidazole-
hexane) 4-carboxamide 189 2-Me-Ph 4-Cl-Ph Ph
1-(4-chlorophenyl)-2-(2-methylphenyl)- 388.1 0.86 (50% EtOAc in
3.52 1 13, 14 N-phenyl-1H-imidazole-4-carboxamide hexane) 190
2,4-Me.sub.2- 4-Cl-Ph Ph 1-(4-chlorophenyl)-2-(2,4- 402.2 0.92 (50%
EtOAc in 3.67 1 13, 14 Ph dimethylphenyl)-N-phenyl-1H-imidazole
hexane) 4-carboxamide 191 2,4-Me.sub.2- 4-Cl-Ph 4H-1,2,4-
1-(4-chlorophenyl)-2-(2,4- 393.1 0.19 (20% 2M 2.87 1 13, 14 Ph
triazol-4-yl dimethylphenyl)-N-(4H-1,2,4-triazol-4- NH3/MeOH in
yl)-1H-imidazole-4-carboxamide EtOAc) 192 2,4-Me.sub.2- 4-Cl-Ph
3,5- 1-(4-chlorophenyl)-2-(2,4- 424.2 0.26 (20% 2M 2.37 1 13, 14 Ph
dimethyl- dimethylphenyl)-N-(3,5-dimethyl-4H- NH3/MeOH in 4H-1,2,4-
1,2,4-triazol-4-yl)-1H-imidazole-4 EtOAc) triazol-4-yl carboxamide
193 2,4-Cl.sub.2-Ph 4-F-Ph Ph 2-(2,4-dichlorophenyl)-1-(4- 426.1
0.46 (30% EtOAc in 3.61 1 15 fluorophenyl)-N-phenyl-1H-imidazole-4-
hexane) carboxamide 194 2-Cl-Ph 4-Cl-Ph 3-pyridinyl
2-(2-chlorophenyl)-1-(4-chlorophenyl)- 409.3 0.25 (5% MeOH in 2.44
1 15 N-(3-pyridinyl)-1H-imidazole-4- EtOAc) carboxamide 195 2-Cl-Ph
4-Cl-Ph 2-pyridinyl 2-(2-chlorophenyl)-1-(4-chlorophenyl- )- 409.1
0.25 (5% MeOH in 2.99 1 15 N-(2-pyridinyl)-1H-imidazol- e-4-
CH2Cl2) carboxamide 196 2-Cl-Ph 4-Cl-Ph 4-Cl-Ph
2-(2-chlorophenyl)-N,1-bis(4- 442.1 0.65 (30% EtOAc in 3.79 1 15
chlorophenyl)-1H-imidazole-4- hexane) carboxamide 197 2-Et-Ph
4-Cl-Ph Ph 1-(4-chlorophenyl)-2-(2-ethylphenyl)-N- 402.1 0.4 (50%
EtOAc in 3.71 1 13, 14 phenyl-1H-imidazole-4-carboxamide hexane)
198 2-Cl-Ph 4-Cl-Ph 4-pyridinyl 2-(2-chlorophenyl)-1-(4-ch-
lorophenyl)- 409.5 0.37 (EtOAc) 2.45 1 10, 11, 12
N-(4-pyridinyl)-1H-imidazole-4- carboxamide 199 2-Cl-Ph 4-Cl-Ph
4-CF.sub.3-3- 2-(2-chlorophenyl)-1-(4-chlorophenyl)- 477.3 0.44
(50% EtOAc in 3.39 1 13, 14 pyridinyl N-[4-(trifluoromethyl)-3--
pyridinyl]-1H- hexane) imidazole-4-carboxamide 200 2-Cl-Ph 4-Cl-Ph
4-Me-3- 2-(2-chlorophenyl)-1-(4-chlorophenyl)- 423.3 0.31 (EtOAc)
2.41 1 8 pyridinyl N-(4-methyl-3-pyridinyl)-1H-imidazol- e-4-
carboxamide 201 2-Cl-Ph 4-Cl-Ph 4-
2-(2-chlorophenyl)-1-(4-chlorophenyl)- 410.4 0.27 (50% EtOAc in
3.04 1 13, 14 pyrimidinyl N-(4-pyrimidinyl)-1H-imidazole-4- hexane)
carboxamide hydrochloride 202 2-Cl-Ph 4-Cl-Ph 2-
2-(2-chiorophenyl)-1 -(4-chlorophenyl)- 410.6 0.32 (50% EtOAc in
2.85 1 6 pyrimidinyl N-(2-pyrimidinyl)-1H-imidazole-4- hexane)
carboxamide 203 2-Cl-Ph 4-Cl-Ph 2-pyrazinyl
2-(2-chlorophenyl)-1-(4-chlorophenyl)- 410.6 0.47 (75% EtOAc in
3.18 1 6 N-(2-pyrazinyl)-1H-imidazole-4- hexane) carboxamide 204
2-Cl-Ph 4-Cl-Ph 5-CF3-2- 2-(2-chlorophenyl)-1-(4-c- hlorophenyl)-
477.2 0.4 (25% EtOAc in 3.77 1 6 pyridinyl
N-[5-(trifluoromethyl)-2-pyridinyl]-1H- hexane)
imidazole-4-carboxamide
[0301]
9TABLE 9 87 Synthesis Entry MS m/z TLC Rf HPLC RT HPLC method of
No. R.sup.1 R.sup.2 R.sup.4 IUPAC name [MH.sup.+] (solvent) (min)
method Ex. No. 205 4-Cl-Ph 2,4-Cl.sub.2- 2-(1-piperidinyl)ethyl
2-(4-chlorophenyl)-1-(2,4- 477 13, 14 Ph dichlorophenyl)-N-[2-(1-
piperidinyl)ethyl]-1H-imidazole-4- carboxamide 206 4-Cl-Ph
2,4-Cl.sub.2- 2-(Et.sub.2N)ethyl 2-(4-chlorophenyl)-1-(2,4- 465
2.54 1 13, 14 Ph dichlorophenyl)-N-[-
(diethylamino)ethyl]-1H-imidazole-4- carboxamide 207 4-Cl-Ph
2,4-Cl.sub.2- 2-(Me.sub.2N)ethyl 2-(4-chlorophenyl)-1-(2,4- 437
2.46 1 8 Ph dichlorophenyl)-N-[2-
(dimethylamino)ethyl]-1H-imidazole-4- carboxamide 208 4-Cl-Ph
2,4-Cl.sub.2- 3-(Me.sub.2N)-1-propyl 2-(4-chlorophenyl)-1-(2,4- 451
2.48 1 13, 14 Ph dichlorophenyl)-N-[3-
(dimethylamino)propyl]-1H-imidaz- ole- 4-carboxamide 209 2-Cl-Ph
4-Cl-Ph endo-2-norbornyl N-endo-bicyclo[2.2.1]hept-2-yl-2-(2- 426
0.21 3.50 1 15 chlorophenyl)-1-(4-chlorophenyl)-1H- (40%
imidazole-4-carboxamide EtOAc in hexane) 210 2-Cl-Ph 4-Cl-Ph
exo-2-norbornyl N-exo-bicyclo[2.2.1]hept-2-yl-2-(2- 426 0.19 3.49 1
15 chlorophenyl)-1-(4-chlorophenyl)-1H- (30%
imidazole-4-carboxamide EtOAc in hexane) 211 2-Cl-Ph 4-Cl-Ph
1-propyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)- 374 0.5 (30% 3.10 1
15 N-propyl-1H-imidazole-4-carboxamide EtOAc in hexane) 212 2-Cl-Ph
4-Cl-Ph 3-pentyl 2-(2-chlorophenyl)-1-(4-chlo- rophenyl)- 402 0.21
3.33 1 13, 14 N-(1-ethylpropyl)-1H-imidazol- e-4- (30% carboxamide
EtOAc in hexane) 213 2-Cl-Ph 4-Cl-Ph 1,7,7-
2-(2-chlorophenyl)-1-(4-chlorophenyl)- 468 0.29 3.97 1 8
trimethylbicyclo[2.2.1] N-(1,7,7-trimethylbicyclo- [2.2.1]hept-2-
(30% hept-2-yl yl)-1H-imidazole-4-carboxamide EtOAc in hexane) 214
2-Cl-Ph 4-Cl-Ph trans-2-(HOCH.sub.2)-
trans-2-(2-chlorophenyl)-1-(4- 444 30% 3.51 2 10, 11, 12 cyclohexyl
chlorophenyl)-N-[2- EtOAc/ (hydroxymethyl)cyclohexyl]-1H Hexane
imidazole-4-carboxamide 215 2-Cl-Ph 4-Cl-Ph 2,3-dihydro-1,4-
2-(2-chlorophenyl)-1-(4-chlorop- henyl)- 480 3.88 2 10, 11, 12
benzodioxin-2-yl-CH.sub.2 N-(2,3-dihydro-1,4-benzodioxin-2-
ylmethyl)-1H-imidazole-4-car- boxamide 216 2-Cl-Ph 4-Cl-Ph
2,4-Cl.sub.2-benzyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)- 490 4.21
2 10, 11, 12 N-(2,4-dichlorobenzyl)-1H-imidazole-4- carboxamide 217
2-Cl-Ph 4-Cl-Ph 3-(1-pyrrolidinyl)-1-
2-(2-chlorophenyl)-1-(4-chloropheny- l)- 443 2.48 2 10, 11, 12
propyl N-[3-(1-pyrrolidinyl)propyl]-1- H- imidazole-carboxamide
hydrochloride 218 2,4-Cl.sub.2- 4-Cl-Ph 3-(1-pyrrolidinyl)-1-
1-(4-chlorophenyl)-2-(2,4- 477 0.67 2.45 1 13, 14 Ph
dichlorophenyl)-N-[3-(1- (40% 2M propylpyrrolidinyl)propyl]-1H-
NH3/Me imidazole-4-carboxamide OH in EtOAc) 219 2-CF.sub.3- 4-Cl-Ph
3-(1-pyrrolidinyl)-1- 1-(4-chlorophenyl)-N-[3-(1- 477 2.55 2 10,
11, 12 Ph propyl pyrrolidinyl)propyl]-2-[2-
(trifluoromethyl)phenyl]-1H-imidazole- 4-carboxamide 220 2-Cl-Ph
4-Cl-Ph 1-benzyl-4-piperidinyl N-(1-benzyl-4-piperidinyl)-2-(- 2-
505 2.66 2 10, 11, 12 chlorophenyl)-1-(4-chlorophenyl)-1H-
imidazole-4-carboxamide 221 2-Cl-Ph 4-Cl-Ph
1-CO.sub.2Et-4-piperidinyl ethyl 4-({[2-(2-chlorophenyl)-1-(4- 487
0.25 3.01 1 13, 14 chlorophenyl)-1H-imidazol-4- (83%
yl]carbonyl}amino)-1- EtOAc in piperidinecarboxylate hexane) 222
2,4-Cl.sub.2- 4-MeO- trans-2-(HOCH.sub.2)-
trans-2-(2,4-dichlorophenyl)-N-[2- 474 3.58 2 10, 11, 12 Ph Ph
cyclohexyl (hydroxymethyl)cyclohexyl]-1-(4-
methoxyphenyl)-1H-imidazole-4- carboxamide 223 2,4-Cl.sub.2- 4-MeO-
1-benzyl-4-piperidinyl N-(1-benzyl-4-piperidinyl)-2-- 2,4- 535 2.74
2 10, 11, 12 Ph Ph dichlorophenyl)-1-(4-methoxyphe- nyl)-
1H-imidazole-4-carboxamide 224 2-Cl-Ph 4-Cl-Ph 4-piperidinyl
2-(2-chlorophenyl)-1-(4-chlorophenyl)- 415 0.25 2.22 1 37
N-(4-piperidinyl)-1H-imidazole-4- (50% 2M carboxamide NH3/Me OH in
EtOAc) 225 2,4-Cl.sub.2- 4-MeO- CiS-2-(HOCH.sub.2)-
cis-2-(2,4-dichlorophenyl)-N-[2- 474 3.69 2 10, 11, 12 Ph Ph
cyclohexyl (hydroxymethyl)cyclohexyl- ]-1-(4-
methoxyphenyl)-1H-imidazole-4- carboxamide 226 2,4-Cl.sub.2- 4-MeO-
cis-2-OH-cycloheptyl- cis-2-(2,4-dichlorophenyl)-N-{2- 488 3.66 2
10, 11, 12 Ph Ph CH.sub.2 hydroxycycloheptyl]methyl}-1-(4-
methoxyphenyl)-1H-imidazole-4- carboxamide 227 2,4-Cl.sub.2- 4-MeO-
trans-2-OH- trans-2-(2,4-dichlorophenyl)-N-{[2- 474 3.47 2 10, 11,
12 Ph Ph cyclohexyl-CH.sub.2 hydroxycyclohexyl]methyl}-1-(4-
methoxyphenyl)-1H-imidazole-4- carboxamide 228 2,4-Cl.sub.2- 4-MeO-
3-exo-HOCH.sub.2-2-exo- exo,exo-2-(2,4-dichlorophenyl)-N-[3- 486
3.44 2 10, 11, 12 Ph Ph norbornyl
(hydroxymethyl)bicyclo[2.2.1]hept-2-
yl]-1-(4-methoxyphenyl)-1H-imidazole- 4-carboxamide 229 2-Cl-Ph
4-Cl-Ph 1-Me-4-piperidinyl 2-(2-chlorophenyl)-1-(4-chlor- ophenyl)-
429 0.31 (90% 2.27 1 13, 14 N-(1-methyl-4-piperidinyl- )-1H- MeOH
in imidazole-4-carboxammde 2 M NH3 in MeOH 230 2-Cl-Ph 4-Cl-Ph
1-(2-pyridinyl)-4- 2-(2-chlorophenyl)-1-(4-chlorophenyl)- 492 0.33
2.47 1 13, 14 piperidinyl N-`-(2-pyridinyl)-4-piperidinyll-1 H-
(33% imidazole-4-carboxamide EtOAc in hexane) 231 2-Cl-Ph 4-Cl-Ph
trans-2-(acetyloxy)- trans-2-({[2-(2-chlorophenyl)-1 -(4- 472 0.33
3.25 1 13, 14 cyclohexyl chlorophenyl)-1H-imidazol-4- (50%
yl]carbonyl}amino)cyclohexyl acetate EtOAc in hexane) 232 2-Cl-Ph
4-Cl-Ph 1-benzyl-3- N-(1-benzyl-3-pyrrolidin- yl)-2-(2- 491 2.34 2
10, 11, 12 pyrrolidinyl chlorophenyl-1-4-chlorophenyl-1H-
imidazole-4-carboxamide hydrochloride 233 2-Cl-Ph 4-Cl-Ph
1-Et-2-pyrrolidinyl- 2-(2-chlorophenyl)-1-(4-chlorophenyl)- 443
2.26 2 10, 11, 12 CH.sub.2 N-[(1-ethyl-2-pyrrolidinyl)methyl]-1H-
imidazole-4-carboxamide hydrochloride 234 2,4-Cl.sub.2- 4-Cl-Ph
(R,R)-2-amino- N-[(1R,2R)-2-aminocyclohexyl]-1-(4- 463 2.37 2 10,
11, 12 Ph cyclohexyl chlorophenyl)-2-(2,4-dichlorophenyl)-
1H-imidazole-4-carboxamide hydrochloride 235 2,4-Cl.sub.2- 4-Cl-Ph
(S,S)-2-amino- N-[(1S,2S)-2-aminocyclohexyl]-1-(4- 463 2.34 2 10,
11, 12 Ph cyclohexyl chlorophenyl)-2-(2,4-dichlo- rophenyl)-
1H-imidazole-4-carboxamide hydrochloride
[0302]
10TABLE 10 88 MS HPLC Synthesis Entry m/z TLC Rf RT HPLC Method of
No. R.sup.1 R.sup.2 R.sup.3 n R.sup.13 IUPAC name [MH+] (solvent)
(min) method Ex. No. 236 2,4-Cl.sub.2- 4-Cl-Ph H 1 2,3-Me.sub.2-Ph
1-{[1-(4-chlorophenyl)-2-(2,4- 539 0.55 (50% 4.17 1 13, 14 Ph
dichlorophenyl)-1H-imidazol-4- EtOAc in yl]carbonyl}-4-(2,3-
hexane) dimethylphenyl)piperazine 237 2,4-Cl.sub.2- 4-Cl-Ph H 1
2,4-F.sub.2-Ph 1-{[1-(4-chlorophenyl)-2-(- 2,4- 549 0.27 (60% 3.71
1 13, 14 Ph dichlorophenyl)-1H-imidazo- l-4- EtOAc in
yl]carbonyl}-4-(2,4- hexane) difluorophenyl)piperazine 238
2,4-Cl.sub.2- 4-Cl-Ph H 1 2-CN-Ph 2-(4-{[1-(4-chlorophenyl)-2-(2,4-
536 0.73 3.69 1 13, 14 Ph dichlorophenyl)-1H-imidazol-4- (EtOAc)
yl]carbonyl}-1- piperazinyl)benzonitrile 239 2,4-Cl.sub.2- 4-Cl-Ph
H 1 2-phenyl- 1-{[1-(4-chlorophenyl)-2-(2,4- 539 0.30 (2% 2.79 1
13, 14 Ph ethyl dichlorophenyl)-1H-imidazol-4- MeOH in
yl]carbonyl}-4-(2- EtOAc) phenylethyl)piperazine 240 2,4-Cl.sub.2-
4-Cl-Ph H 1 2-pyridinyl 1 -{[1-(4-chlorophenyl)-2-(2,4- 512 0.6
2.48 1 10, 11, 12 Ph dichlorophenyl)-1H-imidazol-4- (EtOAC)
yl]carbonyl}-4-(2- pyridinyl)piperazine 241 2,4-Cl.sub.2- 4-Cl-Ph H
1 3-CF.sub.3-Ph 1-{[1-(4-chlorophenyl)-2-(2,4- 579 0.44 (50% 4.11 1
13, 14 Ph dichlorophenyl)-1H-imidazol-4- EtOAc yl]carbonyl}-4-[3-
hexane) (trifluoromethyl)phenyl]piperazine 242 2,4-Cl.sub.2-
4-Cl-Ph H 1 3-MeO-Ph 1-{[1-(4-chlorophenyl)-2-(2,4- 541 0.31 (60%
3.62 1 13, 14 Ph dichlorophenyl)-1H-imidazol-4- EtOAc in
yl]carbonyl}-4-(3- hexane) methoxyphenyl)piperazine 243
2,4-Cl.sub.2- 4-Cl-Ph H 1 4-Cl-Ph 1-(4-chlorophenyl)-4-{[1-(4- 545
0.72 4.13 1 13, 14 Ph chlorophenyl)-2-(2,4- (EtOAc)
dichlorophenyl)-1H-imidazol-4- -yl] carbonyl}piperazine 244
2,4-Cl.sub.2- 4-Cl-Ph H 1 4-CN-Ph 4-(4-{[1-(4-chlorophenyl)-2-(2,4-
536 0.3 (66% 3.61 1 13, 14 Ph dichlorophenyl)-1H-imidazol-4- EtOAc
in yl]carbonyl}-1- hexane) piperazinyl)benzonitrale 245
2,4-Cl.sub.2- 4-Cl-Ph H 1 benzyl 1-benzyl-4-{[1-(4-chlorophenyl)-2-
525 0.30 2.62 1 13, 14 Ph (2,4-dichlorophenyl)-1H-imidazol-4-
(EtOAc) yl]carbonyl}piperazine 246 2,4-Cl.sub.2- 4-Cl-Ph H 1
cyclohexyl 1-{[1-(4-chlorophenyl)-2-(2,4- 519 0.07 2.61 1 13, 14 Ph
dichlorophenyl)-1H-imidazol-4- (EtOAc) yl]carbonyl}-4-
cyclohexylpiperazine hydrochloride 247 2,4-Cl.sub.2- 4-F-Ph H 1
4-CF.sub.3L -Ph 1-{[2-(2,4-dichlorophenyl)-1- -(4- 563 3.73 2 10,
11, 12 Ph fluorophenyl)-1H-imidazol-4- yl]carbonyl}-4-[4-
(trifluoromethyl)phenyl]piperaz- ine trifluoroacetate 248
4-Cl.sub.2- 4-MeO- H 1 2-HO-Ph 2-(4-{[2-(2,4-dichlorophenyl)-1-(4-
523 2.81 2 10, 11, 12 Ph Ph methoxyphenyl)-1H-imidazol-4-
yl]carbonyl}-1-piperazinyl)phenol hydrochloride 249 2,4-Cl.sub.2-
4-MeO- H 1 2-pyrazinyl 2-(4-{[2-(2,4-dichlorophenyl)-1-(4- 509 2.59
2 10, 11, 12 Ph Ph methoxyphenyl)-1H-imidazol-4-
yl]carbonyl}-1-piperazinyl)pyrazine bis(trifluoroacetate) 250
2,4-Cl.sub.2- 4-MeO- H 1 3-CF.sub.3-Ph
1-{[2-(2,4-dichlorophenyl)-1-(4- 575 4.24 2 10, 11, 12 Ph Ph
methoxyphenyl)-1H-imidazol-4- yl]carbonyl}-4-[3-
(trifluoromethyl)phenyl]piperazine hydrochloride 251 2,4-Cl.sub.2-
4-MeO- H 1 6-Me-2- 1-{[2-(2,4-dichlorophenyl)-1-(4- 522 2.19 2 10,
11, 12 Ph Ph pyridinyl methoxyphenyl)-1H-imidazol-4-
yl]carbonyl}-4-(6-methyl-2- pyridinyl)piperazine hydrochloride 252
2,4-Cl.sub.2- 4-MeO- H 1 4-CF.sub.3-Ph
1-{[2-(2,4-dichlorophenyl)-1-(4- 574 4.34 2 10, 11, 12 Ph Ph
methoxyphenyl)-1H-imidazol-4- yl]carbonyl}-4-[4-
(trifluoromethyl)phenyl]piperazine 253 2,4-Cl.sub.2- 4-MeO- H 1
4-CF.sub.3-Ph 1-{[2-(2,4-dichlorophenyl)-1-(- 4- 574 4.34 2 10, 11,
12 Ph Ph methoxyphenyl)-1H-imidazol-4- yl]carbonyl}-4-[4-
(trifluoromethyl)phenyl]pipera- zine hydrochloride 254
2,4-Cl.sub.2- 4-MeO- H 1 4-HO-Ph
4-(4-{[2-(2,4-dichlorophenyl)-1-(4- 523 2.52 2 10, 11, 12 Ph Ph
methoxyphenyl)-1H-imidazol-4- yl]carbonyl}-1-piperazinyl)phenol
hydrochloride 255 2,4-Cl.sub.2- 4-MeO- H 1 4-pyridinyl
1-{[2-(2,4-dichlorophenyl)-1-(4- 508 2.56 2 10, 11, 12 Ph Ph
methoxyphenyl)-1H-imidazol-4- yl]carbonyl}-4-(4-
pyridinyl)piperazine hydrochloride 256 2,4-Cl.sub.2- 4-MeO- H 1
4-pyridinyl- 1-{[2-(2,4-dichlorophenyl)- -1-(4- 522 2.04 2 10, 11,
12 Ph Ph methyl methoxyphenyl)-1H-imidazol-4- yl]carbonyl}-4-(4-
pyridinylmethyl)piperazine dihydrochloride 257 2,5-Cl.sub.2-
4-Cl-Ph H 1 4-CN-Ph 4-(4-{[1-(4-chlorophenyl)-2-(2,5- 536 3.69 1 8
Ph dichlorophenyl)-1H-imidazol-4- yl]carbonyl}-1-
piperazinyl)benzonitrile 258 2-CF.sub.3- 4-Cl-Ph H 1 3-CF.sub.3-Ph
1-({1-(4-chlorophenyl)-2-[2- 579 4.25 2 10, 11, 12 Ph
(trifluoromethyl)phenyl]-1H- imidazol-4-yl}carbonyl)-4-[3-
(trifluoromethyl)phenyl]piper- azine hydrochloride 259 2-Cl-Ph
4-Cl-Ph H 1 2,4-F.sub.2-Ph 1-{[2-(2-chlorophenyl)-1-(4- 513 3.4 2
10, 11, 12 chlorophenyl)-1H-imidazol-4- yl]carbonyl}4-(2,4-difluor-
ophenyl) piperazine hydrochloride 260 2-Cl-Ph 4-Cl-Ph H 1 2-CN-Ph
2-(4-{[2-(2-chlorophenyl)-1-(4- 502 3.25 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-1- perazinyl)benzonitrile
hydrochloride 261 2-Cl-Ph 4-Cl-Ph H 1 2-HO-Ph
2-(4-{[2-(2-chlorophenyl)-1-(4- 493 2.78 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-1- piperazinyl)phenol
hydrochloride 262 2-Cl-Ph 4-Cl-Ph H 1 2-
2-(4-{[2-(2-chlorophenyl)-1-(4- 445 2.42 2 10, 11, 12 hydroxyethyl
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-1- piperazinyl)ethanol
hydrochloride 263 2-Cl-Ph 4-Cl-Ph H 1 2-pyridinyl
1-{[2-(2-chlorophenyl)-1-(4- 478 2.63 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-4-(2-
pyridinyl)piperazine dihydrochloride 264 2-Cl-Ph 4-Cl-Ph H 1
3-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4- 545 4.24 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-4-[3-
(trifluoromethyl)phenyl]piperazine hydrochloride 265 2-Cl-Ph
4-Cl-Ph H 1 3-Cl-Ph 1-(3-chlorophenyl)-4-{[2-(2- 511 4.13 2 10, 11,
12 chlorophenyl)-1-(4-chlorophenyl)- 1H-imidazol-4-yl]carbonyl}
piperazine hydrochloride 266 2-Cl-Ph 4-Cl-Ph cyclo- 1 4-CF.sub.3-Ph
1-{[2-(2-chlorophenyl)-1-(4- Pr chlorophenyl)-5-cyclopropyl-1H- 585
3.7 2 13, 14 imidazol-4-yl]carbonyl}-4-[4-
(trifluoromethyl)phenyl]pipe- razine hydrochloride 267 2-Cl-Ph
4-Cl-Ph H 1 4-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4- 545 4.21 2
10, 11, 12 chlorophenyl)-1H-imidazol-4- yl]carbonyl}-4-[4-
(trifluoromethyl)phenyllpiperazine hydrochloride 268 2-Cl-Ph
4-Cl-Ph cyclo- 1 4-CN-Ph 4-(4-{[2-(2-chlorophenyl)-1-(4- 542 3.29 2
13, 14 Pr chlorophenyl)-5-cyclopropyl-1H-
imidazol-4-yl]carbonyl}-1- piperazinyl)benzonitrile hydrochloride
269 2-Cl-Ph 4-Cl-Ph H 1 4-CN-Ph 4-(4-{[2-(2-chlorophenyl)-1-(4- 502
3.18 2 10, 11, 12 chlorophenyl)-1H-imidazol-4- yl]carbonyl}-1-
piperazinyl)benzonitrile 270 2-Cl-Ph 4-Cl-Ph H 2 4-F-benzyl
1-{[2-(2-chlorophenyl)-1-(4- 523 2.68 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-4-(4-fluorobenzyl)- -
1,4-diazepane hydrochloride 271 2-Cl-Ph 4-Cl-Ph H 1 4-F-benzyl
1-{[2-(2-chlorophenyl)-1-(4- 509 2.67 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-4-(4-fluorobenzy- l)
piperazine hydrochloride 272 2-Cl-Ph 4-Cl-Ph H 1 4-HO-Ph
4-(4-{[2-(2-chlorophenyl)-1-(4- 493 2.44 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-1- piperazinyl)phenol
hydrochloride 273 2-Cl-Ph 4-Cl-Ph H 1 cyclohexyl
1-{[2-(2-chlorophenyl)-1-(4- 483 2.63 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-4- cyclohexylpiperazine
hydrochloride 274 2-Cl-Ph 4-Me- H 1 2-
2-(4-{[2-(2-chlorophenyl)-1-(4- 425 2.34 2 10, 11, 12 Ph
hydroxyethyl methylphenyl)-1H-imidazol-4- yl]carbonyl}-
1-piperazinyl)ethanol hydrochloride 275 2-Cl-Ph 4-NO.sub.2- Me 1
3-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-5-methyl-1- 570 0.35 (67% 3.64
1 8 Ph (4-nitrophenyl)-1H-imidazol- EtOAc in 4-yl]carbonyl}-4-
hexane) [-(trifluoromethyl)phenyl]piperazine
[0303]
11TABLE 11 89 HPLC MS ret. Synthesis Entry m/z TLC time HPLC Method
of No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 IUPAC name [MH+] (solvent)
(min) method Ex. No. 276 2-Cl- 4-Cl-Ph H (1S,2S)-2- N-[(1S,2S)-2-
520.3 0.35 (60% 3.69 1 13, 14 Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-2-(2- EtOAc in cyclohexyl
chlorophenyl)-1-(4-chlorophenyl)- Hexane)
1H-imidazole-4-carboxamide 277 2-Cl- 4-Cl-Ph H (1R,2R)-2-
N-[(1R,2R)-2- 506.3 0.56 (50% 3.51 1 13, 14 Ph (benzyloxy)-
(benzyloxycyclopentyl]2(2- EtOAc in cyclopentyl
chlorophenyl)-1-(4-chlorophenyl)- Hexane)
1H-imidazole-4-carboxamide 278 2,4-Cl.sub.2- 4-Cl-Ph H (1R,2R)-2-
N-[(1R,2R)-2- 554.4 0.46 (50% 3.99 1 13, 14 Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-1-(4- EtOAc in cyclohexyl
chlorophenyl)-2-(2,4- Hexane) dichlorophenyl)-1H-
imidazole-4-carboxamide 279 2,4-Cl.sub.2- 4-Cl-Ph H (1S,2S)-2-
N-[(1S,2S)-2- 554.4 0.46 (50% 4.00 1 13, 14 Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-1-(4- EtOAc in cyclohexyl
chlorophenyl)-2-(2,4- Hexane) dichlorophenyl)-1H-
imidazole-4-carboxamide 280 2-Cl- 4-Cl-Ph H (1R,2R)-2- N-[1R,2R)-2-
520.3 0.33 (66% 3.67 1 13, 14 Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-1- EtOAc in cyclohexyl
(4-chlorophenyl-2-2-chlorophenyl)- Hexane)
1H-imidazole-4-carboxamide 281 2,4-Cl.sub.2- 4-Cl-Ph H (1R,2R)-2-
N-[(1R,2R)-2- 540.0 0.41 (40% 4.07 1 13, 14 Ph (benzyloxy)-
(benzyloxy)cyclopentyl]-2-(2-4- EtOAc in cycopentyl
dichlorophenyl)-1-(4-chlorophenyl)- Hexane)
1H-imidazole-4-carboxamide 282 2,4-Cl.sub.2- 4-Cl-Ph H (1S,2S)-2-
N-[(1S,2S)-2- 540.0 0.41 (40% 4.07 1 13, 14 Ph (benzyloxy)-
(benzyloxycyclopentyl]-2-(2,4- EtOAc in cyclopentyl
dichlorophenyl)-1-(4-chlorophenyl)- Hexane)
1H-imidazole-4-carboxamide 283 2-Cl- 4-Cl-Ph H (1S,2S)-2-
N-[(1S,2S)-2- 506.1 0.32 (40% 3.78 1 13, 14 Ph (benzyloxy)-
(benzyloxy)cyclopentyl]-2-(2- EtOAc in cyclopentyl
chlorophenyl)-1-(4-chlorophenyl)- Hexane)
1H-imidazole-4-carboxamide 284 2-Cl- 4-Cl-Ph Et (1S,2S)-2-
N-[(1S,2S)-2- 548.6 0.33 (33% 3.81 1 13, 14 Ph (benzyloxy)-
benzyloxycyclohexyl]-2-(2- EtOAc in cyclohexyl
chlorophenyl)-1-(4-chlorophenyl)-5- Hexane)
ethyl-1H-imidazole-4-carboxamide 285 2-Cl- 4-Cl-Ph Pr (1S,2S)-2-
N-[(1S,2S)-2- 562.2 0.20 (25% 4.18 1 13, 14 Ph (benzyloxy)-
(benzyloxycyclohexyl]-2-(2- EtOAc in cyclohexyl
chlorophenyl)-1-(4-chlorophenyl)-5- Hexane)
propyl-1H-imidazole-4-carboxamide 286 2-Cl- 4-Cl-Ph H trans-2-
ethyl {[trans-2-({[2-(2- 516.2 0.37 (67% 3.37 1 13, 14 Ph
(ethoxycarbonyl chlorophenyl)-1-(4-chlorophenyl)- EtOAc in
methoxy)- 1H-imidazol-4-yl]carbonyl}amino) Hexane) cyclohexyl
cyclohexyl]oxy}acetate 287 2-Cl- 4-Cl-Ph H trans-2-
2-(2-chlorophenyl)-1-(4- 474.8 0.17 2.91 1 13, 14 Ph
(2'-hydroxyethoxy)- chlorophenyl)-N-[trans-2-(2- (EtOAc) cyclohexyl
hydroxyethoxy)cyclohexyl]-1H- imidazole-4-carboxamide 288 2-Cl-
4-Br- Et (1S,2S)-2- N-[(1S,2S)-2- 592.9 0.29 (33% 4.31 1 13, 14 Ph
Ph (benzyloxy)- (benzyloxycyclohexyl]-1-(4- EtOAc in cyclohexyl
bromophenyl)-2-(2-chlorophenyl)-5- Hexane)
ethyl-1H-imidazole-4-carboxamide 289 2-Cl- 4-iPr- Et (1S,2S)-2-
N-[(1S,2S)-2- 556.3 0.79 (2:1 4.09 1 13, 14 Ph Ph (benzyloxy)-
(benzyloxycyclohexyl]-1-(4- EtOAc/ cyclohexyl
isopropylphenyl)-2-(2-chlorophenyl)- Hexane)
5-ethyl-1H-imidazole-4-carboxamide 290 2-Cl- 4-Cl-Ph Br (1S,2S)-2-
N-[(1S,2S)-2- 598 3.80 2 13, 14 Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-5-bromo-2- cyclohexyl
(2-chlorophenyl)-1-(4-chlorophenyl)- 1H-imidazole-4-carboxami- de
291 2-Cl- 4-MeO- Pr (1S,2S)-2- N-[(1S,2S)-2- 558.3 0.60 (1:1 3.86 1
13, 14 Ph Ph (benzyloxy)- (benzyloxy)cyclohexyl]-2- EtOAc/
cyclohexyl (2-chlorophenyl)-1-(4- Hexane)
methoxyphenyl)-5-propyl-1H- imidazole-4-carboxamide 292 2-Cl-
4-F-Ph Pr (1S,2S)-2- N-[(1S,2S)-2- 546.3 0.19 (1:1 3.90 1 13, 14 Ph
(benzyloxy)- (benzyloxy)cyclohexyl]-2-(2- EtOAc/ cyclohexyl
chlorophenyl)-1-(4-fluorophenyl)-5- Hexane)
propyl-1H-imidazole-4-carboxamide 293 2-Cl- 3-Cl-Ph Pr (1S,2S)-2-
N-[(1S,2S)-2- 562.3 0.73 (1:1 4.07 1 13, 14 Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-2-(2- EtOAc/ cyclohexyl
chlorophenyl)-1-(3-chlorophenyl)-5- Hexane)
propyl-1H-imidazole-4-carboxamide 294 2-Cl- 2-Cl-4- H (1S,2S)-2-
N-[(1S,2S)-2- 538.2 0.44 (1:1 3.64 1 13, 14 Ph F-Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-2-(2- EtOAc/ cyclohexyl
chlorophenyl)-1-(2-chloro-4- Hexane) fluorophenyl)-1H-imidaz- ole-
4-carboxamide 295 2-Cl- 2,4-F.sub.2- H (1S,2S)-2- N-[(1S,2S)-2-
522.2 0.29 (1:1 3.56 1 13, 14 Ph Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-2-(2- EtOAc/ cyclohexyl
chlorophenyl)-1-(2,4-difluorophenyl)- Hexane)
1H-imidazole-4-carboxamide 296 2-Cl- 4-CF.sub.3O Pr (1S,2S)-2-
N-[(1S,2S)-2- 612.3 0.41 (1:1 4.17 1 13, 14 Ph Ph (benzyloxy)-
(benzyloxy)cyclohexyl]-2-(2- cyclohexyl chlorophenyl)-1-(4- EtOAc/
trifluoromethoxyphenyl)-5-propy-1H- Hexane) imidazole-4-carboxamide
297 2-Cl- 4-Cl-Ph i-Pr (1S,2S)-2- N-[(1S,2S)-2- 562 3.98 2 13, 14
Ph (benzyloxy)- (benzyloxy)cyclohexyl]-2-(2- cyclohexyl
chlorophenyl)-1-(4-chlorophenyl)-5- isopropyl-1H-imidazole-
4-carboxamide 298 2-Cl- 4-Cl-Ph cyclo- (1S,2S)-2- N-[(1S,2S)-2-
560.3 3.72 2 13, 14 Ph Pr (benzyloxy)- (benzyloxy)cyclohexyl]-2-(2-
cyclohexyl chlorophenyl)-1-(4-chlorophenyl)-5-
cyclopropyl-1H-imidazole- 4-carboxamide
[0304]
12TABLE 12 90 Entry No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5
IUPAC name 299 2-Cl-Ph 4-i-Pr- Ph Et H 91
2-(2-chlorophenyl)-5-ethyl-N- [(1S,2S)-2-hydroxycyclohexyl]-1-(4-
isopropylphenyl)-1H-imidazole-4-Hexan- e) carboxamide 300 2-Cl-Ph
4-MeO- Ph n-Pr H 92 2-(2-chlorophenyl)-5-propyl-N-
[(1S,2S)-2-hydroxycyclohexyl]-1-(4- methoxyphenyl)-1H-imidazole-4-
carboxamide 301 2-Cl-Ph 4-F-Ph n-Pr H 93
2-(2-chlorophenyl)-5-propyl-N- [(1S,2S)-2-hydroxycyclohe-
xyl]-1-(4- fluorophenyl)-1H-imidazole-4- carboxamide 302 2-Cl-Ph
3-Cl-Ph n-Pr H 94 2-(2-chlorophenyl)-5-propyl-N-
[(1S,2S)-2-hydroxycyclohexyl]-1-(3- chlorophenyl)-1H-imidazole-4-
carboxamide 303 2-Cl-Ph 2-Cl-4-F- Ph H H 95
1-(2-chloro-4-fluorophenyl)-2-(2- chlorophenyl)-N-[(1S,2S)-2-
hydroxycyclohexyl]-1H-imidazole-4- carboxamide 304 2-Cl-Ph
2,4-F.sub.2- Ph H H 96 2-(2-chlorophenyl)-1-(2,4-
difluorophenyl)-N-[(1S,2S)-2- hydroxycyclohexyl]-1H-imidazole-4-
carboxamide 305 2-Cl-Ph 4-Cl-Ph H H 97 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[cis-1-hydroxy-2,3-
dihydro-1H-inden-2-yl]-1H-imidazole- 4-carboxamide 306 2-Cl-Ph
4-Cl-Ph H H 98 2-(2-chlorophenyl)-1-(4- chlorophenyl)-N-[trans-1--
hydroxy- 2,3-dihydro-1H-inden-2-yl]-1H- imidazole-4-carboxamide 307
2-Cl-Ph 4-Cl-Ph H 2,4- (MeO).sub.2- Ph-CH.sub.2-
2-(2-chlorophenyl)-1-(4- chlorophenyl)-N-(2,4-
dimethoxybenzyl)-N-[trans-- 3- hydroxy-1,2,3,4-tetrahydro-2-
naphthalenyl]-1H-imidazole-4- carboxamide 308 2-Cl-Ph 4-Cl-Ph Br H
5-bromo-2-(2-chlorophenyl)1-(4- chlorophenyl)-N-[(1S,2S)-2-
hydroxycyclohexyl]-1H-imidazole-4- carboxamide 309 2-Cl-Ph 4-Cl-Ph
i-Pr H 2-(2-chlorophenyl)-1-(4- chlorophenyl)-N-[(1S,2S)-2-
hydroxycyclohexyl]-5-isopropyl-1H- imidazole-4-carboxamide 310
2-Cl-Ph 4-Cl-Ph H H 99 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[trans-2-hydroxy- 2,3-dihydro-1H-inden-1-yl]1H-
imidazole-4-carboxamide 311 2-Cl-Ph 4-Cl-Ph H 100
((3S)-2-{[2-(2-chlorophenyl)-1-(4- chlorophenyl)-1H-imidazo- l-4-
yl]carbonyl}-1,2,3,4-tetrahydro-3- isoquinolinyl)methanol 312
2-Cl-Ph 4-Cl-Ph H 101 1-{[2-(2-chlorophenyl)-1-(4-
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-3-piperidinol 313 2-Cl-Ph
4-Cl-Ph H 102 ((2S)-1 -{[2-(2-chlorophenyl)-1-(4-
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-2-pyrrolidinyl)methanol
314 2,4-Cl.sub.2- Ph 4-MeO- Ph H H 103
2-(2,4-dichlorophenyl)-N-[cis-2- hydroxycyclohexyl]-1-(4-
methoxyphenyl)-1H-imidazole-4- carboxamide 315 2,4-Cl.sub.2- Ph
4-MeO- Ph H H 104 2-(2,4-dichlorophenyl)-N-[trans-2-
hydroxycyclohexyl]-1-(4- methoxyphenyl)-1H-imidazole-4- carboxamide
316 2-Me- Ph 4-Cl-Ph H H 105 1-(4-chlorophenyl)-N-[trans-2-
hydroxycyclohexyl]-2-(2- methylphenyl)-1H-imidazole-4- carboxamide
317 2,4-Cl.sub.2- Ph 4-F-Ph H H 106 1-(4-fluorophenyl)-N-[trans--
2- hydroxycyclohexyl]-2-(2,4- dichlorophenyl)-1H-imidazole-
carboxamide 318 2,4-CL.sub.2- Ph 4-Cl-Ph H H 107
1-(4-chlorophenyl)-2-(2- ,4- dichlorophenyl)-N-[(1S,2R)-2-
hydroxy-2,3-dihydro-1H-inden-1-yl]- 1H-imidazole-4-carboxamide 319
2,4-Cl.sub.2- Ph 4-Cl-Ph H H 108 1-(4-chlorophenyl)-2-(2,4-
dichlorophenyl)-N-[(1R,2S)-2- hydroxy-2,3-dihydro-1H-inden-1-yl]-
1H-imidazole-4-carboxamide 320 2-Cl-Ph 4-Cl-Ph H H 109
1-(4-chlorophenyl)-2-(2- chlorophenyl)-N-[(1s,2R)-2-hydroxy
2,3-dihydro-1H-inden-1-yl]-1H- imidazole-4-carboxamide 321 2-Cl-Ph
4-Cl-Ph H H 110 1-(4-chlorophenyl)-2-(2-
chlorophenyl)-N-[(1R,2S)-2-hydroxy- 2,3-dihydro-1H-inden-1-yl]-1H-
imidazole-4-carboxamide 322 2,4-Cl.sub.2- Ph 4-MeO- Ph H H 111
2-(2,4-dichlorophenyl)-N-[(1R)-2- hydroxy-1-phenylethyl]-1-(4-
methoxyphenyl)-1H-immdazole-4- carboxamide 323 2,4-Cl.sub.2- Ph
4-MeO- Ph H H 112 2-(2,4-dichlorophenyl)-N-[(1S)-2-
hydroxy-1-phenylethyl]-1-(4- methoxyphenyl)-1H-imidazole-4-
carboxamide 324 2-Cl-Ph 4-Cl-Ph H H 113
2-(2-chlorophenyl)-N-[(1R)-2- hydroxy-1-phenylethyl]-1-(4- -
chlorophenyl)-1H-imidazole-4- carboxamide 325 2-Cl-Ph 4-Cl-Ph H H
114 2-(2-chlorophenyl)-N-[(1S)-2- hydroxy-1-phenylethyl]-1-(4- -
chlorophenyl)-1H-imidazole-4- carboxamide 326 2-Cl-Ph 4-Cl-Ph H H
115 2-(2-chlorophenyl)-1-(4- chlorophenyl)-N-[1-
(hydroxymethyl)cyclopentyl]-1H- imidazole-4-carboxamide 327 2-Cl-Ph
4-Cl-Ph H H 116 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[trans-2-hydroxy-
1,2,3,4-tetrahydro-1-naphthalenyl]- 1H-imidazole-4-carboxamide 328
2,4-Cl.sub.2- Ph 4-Cl-Ph H H 117 1-(4-chlorophenyl)-2-(2,4-
dichlorophenyl)-N-[trans- hydroxycyclohexyl]-1H-imidazole-4-
carboxamide 329 2-Cl-Ph 4-Cl-Ph H H 118 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[(1S,2S)- -2- hydroxycyclopentyl]-1H-imidazole-4-
carboxamide 330 2,4-Cl.sub.2- Ph 4-Cl-Ph H H 119
1-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-N-[(1R,2R)-2-
hydroxycyclopentyl]-1H-imidazole-4- carboxamide 331 2,4-Cl.sub.2-
Ph 4-Cl-Ph H H 120 1-(4-chlorophenyl)-2-(2,4-
dichlorophenyl)-N-[(1S,2S)-2- hydroxycyclopentyl]-1H-imidazole-4-
carboxamide 332 2,4-Cl.sub.2- Ph 4-Cl-Ph H H 121
1-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-N-[(1R,2R)-2-
hydroxycyclohexyl]-1H-imidazole-4- carboxamide 333 2-Cl-Ph 4-Cl-Ph
H H 122 2-(2-chlorophenyl)-1-(4- chlorophenyl)-N-[(1R,2R)-2-
hydroxycyclopentyl]-1H-imidazole-4- carboxamide 334 2,4-Cl.sub.2-
Ph 4-Cl-Ph H H 123 1-(4-chlorophenyl)-2-(2,4-
dichlorophenyl)-N-[(1S,2S)-2- hydroxycyclohexyl]-1H-imidzole-4-
carboxamide 335 2-Cl-Ph 4-Cl-Ph H H 124 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[(1S,2R,3S,4R)-3- hydroxy-4,7,7-
trimethylbicyclo[2.2.1]hept-2-yl]-1H- imidazole-4-carboxamide 336
2-Cl-Ph 4-Cl-Ph H H 125 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[trans-2- hydroxycyclohexyl]-1H-imidazole-4-
carboxamide 337 2-Cl-Ph 4-Cl-Ph H H 126 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[cis-2- hydroxycyclohexyl]-1H-imidazole-4-
carboxamide 338 2-Cl-Ph 4-Cl-Ph H H 127 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[(1S,2S)-2- hydroxycyclohexyl]-1H-imidazole-4-
carboxamide 339 2-Cl-Ph 4-Cl-Ph H H 128 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-N-[(1R,2R)-2- hdroxcclohexyl]-1H-imidazole-4-
carboxamide 340 2-Cl-Ph 4-Cl-Ph Et H 129 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-5-ethyl-N-[(1S,2S- )-2-
hydroxycyclohexyl]-1H-imidazole-4- carboxamide 341 2-Cl-Ph 4-Cl-Ph
n-Pr H 130 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-5-propyl-N-[(1S,2S)-2-
hydroxycyclohexyl]-1H-imidazole-4- carboxamide 344 2-Cl-Ph 4-Cl-Ph
Et H 131 2-(2-chlorophenyt)-1 -(4-
bromophenyl)-5-ethyl-N-[(1S,2S)-2-
hydroxycyclohexyl]-1H-imidazole-4- carboxamide 343 2-Cl-Ph 4-Cl-Ph
Me H 132 2-(2-chlorophenyl)-1-(4- chlorophenyl)-5-methyl--
N-[(1S,2S)-2- hydroxycyclohexyl]-1H-imidazole-4- carboxamide 344
2-Cl-Ph 4-Cl-Ph Et H 133 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-5-ethyl-N-[(1S,2S)-2-
hydroxycyclopentyl]-1H-imidazole-4- carboxamide 345 2-Cl-Ph 4-Br-Ph
Et H 134 2-(2-chlorophenyl)-1-(4- bromophenyl)-N-[(1S,2R,3S,4R)-3-
hydroxy-4,7,7- trimethylbicyclo[2.2.1]hept-2-yl]-5-
ethyl-1H-imidazole-4-carboxamide 346 2-Cl-Ph 4-Br-Ph Et H 135
2-(2-chlorophenyl)-1-(4- bromophenyl)-N-[(1R,2S,3R,4S)-3-
hydroxy-4,7,7- trimethylbicyclo[2.2.1]he- pt-2-yl]-5-
ethyl-1H-imidazole-4-carboxamide 347 2-Cl-Ph 4-Br-Ph Et H 136
1-(4-bromophenyl)-2-(2- chlorophenyl)-5-ethy-N-[1R,2R)-2-
-hydroxycyclohexyl]-1H-imidazole-4- carboxamide 348 2-Cl-Ph 4-Br-Ph
Et H 137 1-(4-bromophenyl)-2-(2- chlorophenyl)-5-ethyl-N-- [cis-2-
hydroxycyclohexyl]-1H-imidazole-4- carboxamide MS HPLC Synthesis
Entry m/z TLC ret. time HPLC Method of No. [MH+] (solvent) (min)
method Ex. No. 299 466 0.49 (2:1 3.38 1 13, 14 EtOAc/ Hexane) 300
468 0.66 3.09 1 13, 14 (EtOAc) 301 456 0.35 (2:1 3.16 1 13, 14
EtOAc/ Hexane) 302 472 0.45 (2:1 3.29 1 13, 14 EtOAc/ Hexane) 303
448 0.5 2.90 1 13, 14 (EtOAc) 304 432 0.5 2.82 1 13, 14 (EtOAc) 305
464 3.16 1 13, 14 306 464 3.15 1 13, 14 307 529 0.15 (1:1 3.72 1
13, 14 EtOAc/ Hexane) 308 508 2.99 2 13, 14 309 472 3.22 2 13, 14
310 464 3.05 2 10, 11, 12 311 478 3.00 2 10, 11, 12 312 416 2.56 2
10, 11, 12 313 416 2.59 2 10, 11, 12 314 460 3.69 2 10, 11, 12 315
460 3.40 2 10, 11, 12 316 411 2.74 2 10, 11, 12 317 449 2.85 2 10,
11, 12 318 498 3.29 2 10, 11, 12 319 498 3.29 2 10, 11, 12 320 464
3.11 2 10, 11, 12 321 464 3.11 2 10, 11, 12 322 483 2.99 2 10, 11,
12 323 483 2.96 2 10, 11, 12 324 452 2.88 2 10, 11, 12 325 453 2.89
2 10, 11, 12 326 431 2.89 2 10, 11, 12 327 477 2.92 2 10, 11, 12
328 464 0.14 (50% 3.20 1 13, 14 EtOAc in Hexane) 329 416 0.43 (50%
2.96 1 36 EtOAc in Hexane) 330 450 0.45 (50% 3.24 1 36 EtOAC in
Hexane) 331 450 0.45 (50% 3.24 1 36 EtOAc in Hexane) 332 464 0.67
3.22 1 35 (EtOAc) 333 416 0.4 2.83 1 36 (EtOAc) 334 466 0.67 3.32 1
35 (EtOAc) 335 484 0.22 (50% 3.55 1 8 EtOAc in Hexane) 336 430 0.45
(5% 2.95 1 13, 14 MeOH in CH.sub.2Cl.sub.2) 337 430 0.31 (66% EtOAc
in 2.94 1 13, 14 Hexane) 338 430 0.30 (66% 3.02 1 35 EtOAc in
Hexane) 339 430 0.30 (66% 2.96 1 35 EtOAc in Hexane) 340 458 0.37
(75% 3.24 1 35 EtOAc in Hexane) 341 472 0.41 (75% 3.38 1 35 EtOAc
in Hexane) 342 502 0.45 3.19 1 35 (EtOAc) 343 444 0.29 (80% 3.06 1
35 EtOAc in Hexane) 344 444 0.30 (67% 3.15 1 36 EtOAc in Hexane)
345 556 0.40 (50% 3.97 1 8 EtOAc in Hexane) 346 556 0.40 (50% 4.00
1 8 EtOAc in Hexane) 347 502 0.45 3.31 1 35 (EtOAc) 348 502 0.26
(50% 502.3 1 23 EtOAc in hexane)
[0305]
13TABLE 13 138 HPLC Synthesis Entry MS m/z TLC Rf RT HPLC Method of
No. R.sup.1 R.sup.2 R.sup.3 R.sup.14 IUPAC name (MH+ 1) (solvent)
(min) method Ex. No. 349 2-Cl-Ph 4-Cl-Ph H 1,1-dioxido-1-
1-{[2-(2-chlorophenyl)-1-(4- 580 0.29 3.10 1 18 benzothien-2-yl
chlorophenyl)-1H-imidazol-4- (EtOAc) yl]carbonyl}-4-(1,1-dioxido-1-
benzothien-2-yl)-4-piperidinol 350 2-Cl-Ph 4-Cl-Ph H
1,3-thiazol-2-yl 1-{[2-(2-chlorophenyl)-1-(4- - 499 0.10 (1:2 2.83
1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(1,3-thiazol-2-yl)4- EtOAc) piperidinol 351 2-Cl-Ph
4-Cl-Ph H 1-benzofuran-2-yl 4-(1-benzofuran-2-yl)-1-{[2-(2- 532
0.45 344 1 18 chlorophenyl)-1-(4-chlorophenyl)-1H- (EtOAc)
imidazol-4-yl]carbonyl}-4-piperidinol 352 2-Cl-Ph 4-Cl-Ph Et
1-benzofuran-2-yl 4-(1-benzofuran-2-yl)-1-{[2-(2- 560 0.39 3.43 1
18 chlorophenyl)-1-(4-chlorophenyl)-5- (EtOAc)
ethyl-1H-imidazol-4-yl]carbonyl}-4- piperidinol 353 2-Cl-Ph 4-Cl-Ph
nPr 1-benzofuran-2-yl 4-(1-benzofuran-2-yl)-1-{[2-(2- 574 0.40 3.55
1 18 chlorophenyl)-1-(4-chlorophenyl)-5- (EtOAc)
propyl-1H-imidazol-4-yl]carbonyl}-4- piperidinol 354 2-Cl-Ph
4-Cl-Ph H 1-benzothien-2-yl 4-(1-benzothien-2-yl)-1-{[2-(- 2- 548
0.50 3.45 1 18 chlorophenyl)-1-(4-chlorophenyl)-1H- (EtOAc)
imidazol-4-yl]carbonyl}-4-pipermdinol 355 2-Cl-Ph 4-Cl-Ph nPr
1-benzothien-2-yl 4-(1-benzothien-2-yl)-1-{[2-(2- 590 0.45 3.66 1
18 chlorophenyl)-1-(4-chlorophenyl)-5- (EtOAc)
propyl-1H-imidazol-4-yl]carbonyl}-4- piperidinol 356 2-Cl-Ph
4-Cl-Ph Et 1-benzothien-2-yl 4-(1-benzothien-2-yl)-1-{[2-- (2- 576
0.44 3.54 1 18 chlorophenyl)-1-(4-chloropheny-5- (EtOAc)
ethyl-1H-imidazol-4-yl]carbonyl}-4- piperidinol 357 2-Cl-Ph 4-Cl-Ph
H 2,3-dihydro-1,4- 1-{[2-(2-chlorophenyl)-1-(4- 550 0.20 (1:2 3.02
1 18 benzodioxin-6-yl chlorophenyl)-1 H-imidazol-4 Hexane/
yllcarbonyl}-4-(2,3-dihydrol-4- EtOAc)
benzodioxin-6-yl)-4-piperidinol 358 2-Cl-Ph 4-Cl-Ph H
2,6-dimethyl-3- 1-{[2-(2-chlorophenyl)-1-(4- 521 0.04 2.24 1 18
pyridinyl chlorophenyl)-1 H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(2,6-dimethyl-3- pyridinyl)-4-piperidinol 359
2-Cl-Ph 4-Cl-Ph H 2,4-(MeO).sub.2-Ph 1-{[2-(2-chlorophenyl)-1-(4-
552 0.16 (1:2 3.20 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(2,4-dimethoxyphenyl) EtOAC) 4-piperidinol 360
2-Cl-Ph 4-Cl-Ph H 2,5-F.sub.2-Ph 1-{[2-(2-chlorophenyl)-1-(4- 528
0.24 (1:2 3.28 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(2,5-dlf- luorophenyl)-4- EtOAc) piperidinol 361
2-Cl-Ph 4-Cl-Ph H 2,5-(MeO).sub.2-Ph 1-{[2-(2-chlorophenyl)-1 -(4-
552 0.23 (1:2 3.15 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(2,5-dimethoxyphenyl) EtOAc) 4-piperidinol 362
2-Cl-Ph 4-Cl-Ph H 2-CF.sub.3O-Ph 1-{[2-(2-chlorophenyl)-1-(4- 576
0.22 (1:2 3.45 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-[2- EtOAc) (trifluoromethoxy)phenyl]-- 4-piperidinol
363 2-Cl-Ph 4-Cl-Ph H 2-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4-
560 0.24 (1:2 3.41 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-[2- EtOAc) (trifluoromethyl)phenyl]-4-piperidinol
364 2-Cl-Ph 4-Cl-Ph H 2-Cl-Ph 1-{[2-(2-chlorophenyl)-1-(4- 526 0.13
(1:2 3.34 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(2-chlorophenyl)-4- EtOAc) piperidinol 365 2-Cl-Ph
4-Cl-Ph H 2-F-Ph 1-{[2-(2-chlorophenyl)-1-(4- 510 0.13 (1:2 3.24 1
18 chlorophenyl)-1H-imidazol-4- Hexane/
yl[carbonyl}-4-(2-fluorophenyl)-4- EtOAc) piperidinol 366 2-Cl-Ph
4-Cl-Ph H 2-furyl 1-{[2-(2-chlorophenyl)-1-(4- 482 0.22 (1:2 2.98 1
18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(2-furyl)-4-piperidinol EtOAc) 367 2-Cl-Ph 4-Cl-Ph
Et 2-furyl 1-{[2-(2-chlorophenyl)-1-(4- 510 0.29 (1:2 3.04 1 18
chlorophenyl)-5-ethyl-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(2-furyl)-4-piperidinol EtOAc) 368 2-Cl-Ph 4-Cl-Ph H
2-MeO-Ph 1-{[2-(2-chlorophenyl)-1 -(4- 522 0.22 (1:2 3.23 1 18
chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(2-methoxymphenyl)-4- EtOAc) piperidinol 369 2-Cl-Ph
4-Cl-Ph H 2-pyridinyl 1 -{[2-(2-chlorophenyl)-1 -(4- 493 0.05 (1:2
2.26 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(2-pyridinyl)-4- EtOAc) piperidinol 370 2-Cl-Ph
4-Cl-Ph H 2-thienyl 1-{[2-(2-chlorophenyl)-1-(4- 498 0.22 (1:2
3.141 1 18 chlorophenyl)-1H-imidazol-4-
yl]carbonyl}-4-(2-thienyl-4-piperidinol 371 2-Cl-Ph 4-Cl-Ph nPr
2-thienyl 1-{(2-2-chlorophenyl)-1-(4- 540 0.41 3.33 1 18
chlorophenyl)-5-propyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(2-thienyl)-4-piperidinol 372 2-Cl-Ph 4-Cl-Ph Et
2-thienyl 1-{(2-2-chlorophenyl)-1-(4- 5.26 0.42 3.20 1 18
chlorophenyl)-5-ethyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(2-thienyl)-4-piperidinol 373 2-Cl-Ph 4-Cl-Ph Et
3-CF.sub.3-4-Cl-Ph 1-{[2-(2-chlorophenyl)-1-(4- 622 0.47 3.73 1 18
chlorophenyl)-5-ethyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-[4-chloro-3- (trifluoromethyl)phenyl]-4-piperi-
dinol 374 2-Cl-Ph 4-Cl-Ph nPr 3-CF.sub.3-4-Cl-Ph
1-{[2-(2-chlorophenyl)-1-(4- 636 0.42 382 1 18
chlorophenyl)-5-propyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-[4-chloro-3- (trifluoromethyl)phenyl]-4-piperi-
dinol 375 2-Cl-Ph 4-Cl-Ph H 3-CF.sub.3O-Ph
1-{[2-(2-chlorophenyl)-1- -(4- 576 0.38 (1:2 3.37 1 18
chlorophenyl)-1H-imidazol-4- Hexane/ yl]carbonyl}-4-[3- EtOAc)
(trifluoromethoxy)phenyl]-4-piperidinol 376 2-Cl-Ph 4-Cl-Ph Et
3-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4- 588 0.46 3.55 1 18
chlorophenyl)-5-ethyl-1H-imidazol-4- (EtOAc) yl]carbonyl}-4-[3-
(trifluoromethyl)phenyl]-4-piperidinol 377 2-Cl-Ph 4-Cl-Ph nPr
3-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4- 602 0.43 3.65 1 18
chlorophenyl)-5-propyl-1H-imidazol-4- (EtOAc) yl]carbonyl}-4-[3-
(trifluoromethyl)phenyl]-4-pip- eridinol 378 2-Cl-Ph 4-Cl-Ph H
3-Cl-Ph 1-{[2-(2-chlorophenyl)-1-(4- 526 0.18 (1:2 3.39 1 18
chlorophenyl)-1 H-imidazol-4- Hexane/
yl]carbonyl}-4-(3-chlorophenyl)-4- (EtOAc) piperidinol 379 2-Cl-Ph
4-Cl-Ph Et 3-Cl-Ph 1-{[2-(2-chlorophenyl)-1-(4- 554 0.42 3.44 1 18
chlorophenyl)-5-ethyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(3-chlorophenyl)-4- piperidinol 380 2-Cl-Ph 4-Cl-Ph
nPr 3-Cl-Ph 1-{[2-(2-chlorophenyl)-1-(4-
chlorophenyl)-5-propyl-1H-imidazol-4- 568 0.41 3.58 1 18
yl]carbonyl}-4-(3-chlorophenyl)-4- (EtOAc) piperidinol 381 2-Cl-Ph
4-Cl-Ph H 3-F-4-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4- 578 0.22
(1:2 3.53 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-[3-fluoro-4- EtOAc)
(trifluoromethyl)phenyl]-4-piperidinol 382 2-Cl-Ph 4-Cl-Ph H
3-F-4-Cl-Ph 1-{[2-(2-chlorophenyl)-1-(4- 544 0.25 (1.2 3.36 1 18
chlorophenyl)-1H-imidazol-4- Hexane/ yl]carbonyl}-4-(3-fluoro-4-
EtOAc) chlorophenyl)-4-piperidin- ol 383 2-Cl-Ph 4-Cl-Ph H 3-F-Ph
1-{[2-(2-chlorophenyl)-1-(4- 510 0.24 (1:2 3.19 1 18
chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(3-fluorophenyl)-4- EtOAc) piperidinol 384 2-Cl-Ph
4-Cl-Ph Et 3-F-Ph 1-{[2-(2-chlorophenyl)-1- -(4- 538 0.43 3.30 1 18
chlorophenyl)-5-ethyl-1 H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(3-fluorophenyl)-4- piperidinol 385 2-Cl-Ph 4-Cl-Ph
nPr 3-F-Ph 1-{[2-(2-chlorophenyl)-- 1-(4- 552 0.43 3.41 1 18
chlorophenyl)-5-propyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(3-fluorophenyl)-4- piperidinol 386 2-Cl-Ph 4-Cl-Ph
H 6-methyl-2- 1-{[2-(2-chlorophenyl)-1-(4- 507 0.32 2.29 1 18
pyridinyl chlorophenyl)-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(6-methy- l-2-pyridinyl)- 4-piperidinol 387 2-Cl-Ph
4-Cl-Ph Et 6-methyl-2- 1-{[2-(2-chlorophenyl)-1-(4- 535 0.27 (1:2
2.75 1 18 pyridinyl chlorophenyl)-5-ethyl-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(6-methyl-2-pyridinyl)- EtOAc) 4-piperidinol 388
2-Cl-Ph 4-Cl-Ph H 3-Me-4-MeO-Ph 1-{[2-(2-chlorophenyl)-1-(4- 537
0.20 (1:2 3.25 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(4-methoxy-3 EtOAc) methylphenyl)-4-piperidinol 389
2-Cl-Ph 4-Cl-Ph H 3-MeO-Ph 1-{[2-(2-chlorophenyl)-1-(4- 522 0.24
(1:2 3.12 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(3-metho- xyphenyl)-4- EtOAc) piperidinol 390
2-Cl-Ph 4-Cl-Ph H 3-thienyl 1-{[2-(2-chlorophenyl)-1-(4- 498 0.22
(1:2 3.10 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(3-thienyl)-4-piperidinol EtOAc) 391 2-Cl-Ph 4-Cl-Ph
H 4,6-dimethyl-2- 1-{[2-(2-chlorophenyl)-1-(4- 522 0.09 2.55 1 18
pyridinyl chlorophenyl)-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(6-methyl-2- pyrimidinyl)-4-piperidinol 392 2-Cl-Ph
4-Cl-Ph H 4-CF.sub.3O-Ph 1-{[2-(2-chlorophenyl)-1-(4- 576 0.18 (1:2
3.48 1 18 chlorophenyl)-1H-imidazol-4- Hexane/ yl[carbonyl}-4-(4-
EtOAc) trifluoromethoxyphenyl)-4-- piperidinol 393 2-Cl-Ph 4-Cl-Ph
Et 4-CF.sub.3O-Ph 1-{[2-(2-chlorophenyl)-1-(4- 604 0.39 3.58 1 18
chlorophenyl)-5-ethyl-1H-imidazol-4- (EtOAc) yl]carbonyl}-4-(4-
trifluoromethoxyphenyl)-4-piperidinol 394 2-Cl-Ph 4-Cl-Ph nPr
4-CF.sub.3O-Ph 1-{[2-(2-chlorophenyl)-1-(4- 618 0.40 3.70 1 18
chlorophenyl)-5-propyl-1H-imidazol-4- (EtOAc) yl]carbonyl}-4-(4-
trifluoromethoxyphenyl)-4-pip- eridinol 395 2-Cl-Ph 4-Cl-Ph Et
4-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4- 588 0.42 3.55 1 18
chlorophenyl)-5-ethyl-1H-imidazol-4- (EtOAc) yl]carbonyl}-4-(4-
trifluoromethylphenyl)-4-piperidinol 396 2-Cl-Ph 4-Cl-Ph nPr
4-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4- 602 0.40 3.66 1 18
chlorophenyl)-5-propyl-1H-imidazol-4- (EtOAc) yl]carbonyl}-4-(4-
trifluoromethylphenyl)-4-piper- idinol 397 2-Cl-Ph 4-Cl-Ph Et
4-Cl-Ph 1-{[2-(2-chlorophenyl)-1-(4- 554 0.42 3.48 1 17
chlorophenyl)-5-ethyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(4-chlorophenyl)-4- piperidinol 398 2-Cl-Ph 4-Cl-Ph
nPr 4-Cl-Ph 1-{[2-(2-chlorophenyl)-1-(4- 568 0.38 3.57 1 17
chlorophenyl)-5-propyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(4-chlorophenyl)-4- piperidinol 399 2-Cl-Ph 4-Cl-Ph
H 4-F-Ph 1-{[2-(2-chlorophenyl)-1-(4- 510 0.25 (1:2 3.18 1 17
chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(4-fluorophenyl)-4- EtOAc) piperidinol 400 2-Cl-Ph
4-Cl-Ph Et 4-F-Ph 1-{[2-(2-chlorophenyl)-1-(4- 538 0.36 3.29 1 17
chlorophenyl)-5-ethyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(4-fluorophenyl)-4- piperidinol 401 2-Cl-Ph 4-Cl-Ph
nPr 4-F-Ph 1-{[2-(2-chlorophenyl)-1-(4- 552 0.36 341 1 17
chlorophenyl)-5-propyl-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(4-fluorophenyl)-4- piperidinol 402 2-Cl-Ph 4-Cl-Ph
H 5-methyl-2- 1-{[2-(2-chlorophenyl)-1-(4- 507 0.15 (1:2 2.31 1 18
pyridinyl chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(5-methyl-2-pyridinyl)- EtOAc) 4-piperidinol 403
2-Cl-Ph 4-Cl-Ph H 4-MeO-Ph 1-{[2-(2-chlorophenyl)-1-(4- 522 0.21
(1:2 3.10 1 17 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-(4-metho- xyphenyl)-4- EtOAc) piperidinol 404
2-Cl-Ph 4-Cl-Ph H 4-MeS-Ph 1-{[2-(2-chlorophenyl)-1-(4- 538 0.18
(1:2 3.29 1 18 chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-[4- EtOAc) (methylsulfanyl)phenyl]-4-piperidinol 405
2-Cl-Ph 4-Cl-Ph H 4-methyl-2- 1-{[2-(2-chlorophenyl)-1-(4- 521 0.18
2.24 1 18 pyridinyl chlorophenyl)-1H-imidazol-4- (EtOAc)
yl]carbonyl}-4-(4-methyl-2-pyridinyl)- 4-piperidinol 406 2-Cl-Ph
4-Cl-Ph H Et 1-{[2-(2-chlorophenyl)-1-(4- 444 0.15 (1:2 2.86 1 17
chlorophenyl)-1H-imidazol-4- Hexane/
yl]carbonyl}-4-ethyl-4-piperidinol EtOAc) 407 2-Cl-Ph 4-Cl-Ph H
iso-butyl 1-{[2-(2-chlorophenyl)-1-(4 472 0.10 (1:2 3.24 1 17
chlorophenyl)-1 H-imidazol-4- Hexane/
yl]carbonyl}-4-isobutyl-4-piperidinol EtOAc) 408 2-Cl-Ph 4-Cl-Ph H
Me 1-{[2-(2-chlorophenyl)-1-(4- 431 0.08 (1:2 2.69 1 17
chlorophenyl)-1H-imidazol-4- Hexane/ yl]carbonyl}-4-methyl-4-
-piperidinol EtOAc) 409 2-Cl-Ph 4-Cl-Ph H n-butyl
1-{[2-(2-chlorophenyl)-1-(4- 472 0.11 (1:2 3.84 1 18
chlorophenyl)-1H-imidazol-4- Hexane/ yl]carbonyl}-4-butyl-4-p-
ipermdinol EtOAc) 410 2-Cl-Ph 4-Cl-Ph H n-pentyl
1-{[2-(2-chlorophenyl)-1-(4- 486 0.30 3.45 1 17 chlorophenyl)-1
H-imidazol-4- (EtOAc) yl]carbonyl}-4-pentyl-4-piperidinol 411
2-Cl-Ph 4-Cl-Ph H Ph 1-{[2-(2-chlorophenyl)-1-(4- 474 3.03 2 10,
11, 12 chlorophenyl)-1H-imidazol-4-
yl]carbonyl}-4-phenyl-4-piperidi- nol 412 2,4-Cl.sub.2- 4-MeO- H Ph
1-{[2-(2-chlorophenyl)-1-(4- 522 3.55 2 10, 11, 12 Ph Ph
methoxyphenyl)-1H-imidazol-4- yl]carbonyl}-4-phenyl-4-piperidinol
413 2,4-Cl.sub.2- 4-Cl-Ph H Ph 1-{[2-(2,4-dichlorophenyl)-1-(4- 526
3.33 2 10, 11, 12 Ph chlorophenyl)-1H-immdazol-4-
yl]carbonyl}-4-phenyl-4-pipermdi- nol 414 2-Me- 4-Cl-Ph H Ph
1-{[2-(2-methylphenyl)-1-(4- 472 2.90 2 10, 11, 12 Ph
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-4-phenyl-4-piperidinol
415 2,4-Cl.sub.2- 4-F-Ph H Ph 1-{[2-(2,4-dichlorophenyl)-1 -(4- 509
3.03 2 10, 11, 12 fluorophenyl)-1H-imidazol-4-
yl]carbonyl}-4-phenyl-4-piperidi- nol 416 2-Cl-Ph 4-Cl-Ph H 4-Br-Ph
1 -{[2-(2-chlorophenyl)-1-(4- 570 3.14 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl}-4-(4-bromophenyl)-4-
piperidinol 417 2-Cl-Ph 4-Cl-Ph H benzyl
1-{[2-(2-chlorophenyl-1-(4- 506 2.98 2 10, 11, 12
chlorophenyl)-1H-imidazol-4- yl]carbonyl{-4-benzyl-4-piperidinol
418 2-Cl-Ph 4-Cl-Ph H 3-CF.sub.3-4-Cl-Ph 1-55
[2-(2-Chlorophenyl)-1-(4- 594 3.38 2 1, 11, 12
chlorophenyl)-4-}4-chloro-3- (trifluoromethyl)phenyl]-4-piperidinol
419 2-Cl-Ph 4-Cl-Ph H 4-Cl-Ph 1-{[2-(2-chlorophenyl-1-(4- 526 3.11
2 10, 11, 12 chlorophenyl)-1H-imidazol-4-
yl]carbonyl}-4-(4-chlorophenyl)-- 4- piperidinol 420 2-Cl-Ph
4-Cl-Ph H 3-CF.sub.3-Ph 1-{[2-(2-chlorophenyl)-1-(4- 560 3.17 2 10,
11, 12 chlorophenyl)-1H-imidazol-4- yl]carbonyl)-4(3-
(trifluoromethyl)phenyl-4-piperidinol
[0306]
14TABLE 14 139 MS Synthesis Entry m/z TLC Rf HPLC RT HPLC Method of
No. R.sup.1 R.sup.2 R.sup.4 IUPAC name [MH+] (solvent) (min.)
method Ex. No. 421 2-Cl--Ph 3-pyridinyl cyclohexyl
2-(2-chlorophenyl)-N-cyclohexyl-1- 381.2 0.23 (4% 2.71 1 8
(3-pyridinyl)-1H-imidazole-4- MeOH in carboxamide CH.sub.2Cl.sub.2)
422 2-Cl-3- 4-F--Ph 1-piperidinyl 2-(2-chloro-3-pyridinyl)-1-(4-
400.3 0.19 2.32 1 10,11,12 pyridinyl
fluorophenyl)-N-(1-piperidinyl)-1H- (EtOAc) imidazole-4-carboxamide
423 4-CF.sub.3-3- 4-Cl--Ph 1-piperidinyl
1-(4-chlorophenyl)-N-(1-piperidinyl)- 450.3 0.45 (10% 2.58 1 8
pyridinyl 2-[4-(trifluoromethyl)-3-pyridinyl]- MeOH in
1H-imidazole-4-carboxamide EtOAc) 424 3-Me-2- 4-Cl--Ph
1-piperidinyl 1-(4-chlorophenyl)-2-(3-methyl-2- 396.2 0.25 2.27 1 8
pyridinyl pyridinyl)-N-(1-piperidinyl)-1H- (EtOAc)
imidazole-4-carboxamide 425 3-Me-4- 4-Cl--Ph 1-piperidinyl
1-(4-chlorophenyl)-2-(3-methyl-4- 396.3 0.30 (2% 2.10 1 13,14
pyridinyl pyridinyl)-N-(1-piperidinyl)-1H- MeOH in
imidazole-4-carboxamide EtOAc) 426 4-CF.sub.3-3- 4-Cl--Ph
2-CF.sub.3-anilino 1-(4-chlorophenyl)-N'-[2- 525 3.65 1 10,11,12
pyridinyl (trifluoromethyl)phenyl]-2[4-
(trifluoromethyl)-3-pyridinyl]1H- imidazole-4-carbohydrazide
hydrochloride 427 3-Me-2- 4-Cl--Ph 1-piperidinyl
1-(4-chlorophenyl)-2-(3-methyl-2- 401.2 0.22 (67% 2.8 1 6 thienyl
thienyl)-N-(1-piperidinyl-1H- EtOAc in imidazole-4-carboxamide
hexane) 428 2-furyl 4-Cl--Ph 1-piperidinyl
1-(4-chlorophenyl)-2-(2-furyl)-N-(1- 371.2 0.27 (80% 2.57 1 6
piperidinyl)-1H-imidazole-4- EtOAc in carboxamide hexane) 429
2-Cl--Ph 5-t-Bu-3- 1-piperidinyl
1-(5-tert-butyl-3-isoxazolyl)-2-(2- 428.2 0.12 (1:1 3.06 1 13,14
isoxazolyl chlorophenyl)-N-(1-piperidinyl)-1H- EtOAc/
imidazole-4-carboxamide hexane) 430 2-Cl--Ph 5-t-Bu-3- cyclohexyl
1-(5-tert-butyl-3-isoxazolyl)-2-(2- 427.2 0.39 (1:1 3.68 1 13,14
isoxazolyl chlorophenyl)-N-cyclohexyl-1H- EtOAc/
imidazole-4-carboxamide hexane) 431 2-Cl--Ph 5-t-Bu-3- 2-(S)-
N-[(1S,2S)-2- 533.1 0.34 (1:1 3.89 1 13,14 isoxazolyl benzyloxy-1-
(benzyloxy)cyclohexyl]-1-(5-tert- EtOAC/ (S)-cyclohexyl
butyl-3-isoxazolyl)-2-(2- hexane) chlorophenyl)-1H-imidazole-4-
carboxamide 432 2-Cl--Ph 3-quinolinyl 1-piperidinyl
2-(2-chlorophenyl)-N-(1-piperidinyl)- 432.2 0.11 2.61 1 13,14
1-(3-quinolinyl)-1H-imidazole-4- (EtOAc) carboxamide 433 2-Cl--Ph
3-quinolinyl cyclohexyl 2-(2-chlorophenyl)-N-cyclohexyl-1- 431.2
0.44 3.23 1 13,14 (3-quinolinyl)-1H-imidazole-4- (EtOAc)
carboxamide 434 2-Cl--Ph 3-quinolinyl 2-(S)- N-[(1S,2S)-2- 537.1
0.46 3.51 1 13,14 benzyloxy-1- (benzyloxycyclohexyl]-2-(2- (EtOAc)
(S)-cyclohexyl chlorophenyl)-1-(3-quinolinyl)-1H-
imidazole-4-carboxamide 435 2-Cl--Ph 5-t-Bu-3- 2-(S)-hydroxy-
1-(5-tert-butyl-3-isoxazolyl)-2-(2- 443.2 0.43 3.07 1 35 isoxazolyl
1-(S)- chlorophenyl)-N-[(1S,2S)-2- (EtOAc) cyclohexyl
hydroxycyclohexyl]-1H-imidazole-4- carboxamide 436 2-Cl--Ph
3-quinolinyl 2-(S)-hydroxy- 2-(2-chlorophenyl)-N-[(1S,2S)-- 2-
447.2 0.19 2.65 1 35 1-(S)- hydroxycyclohexyl]-1-(3-quinoliny- l)
(EtOAc) cyclohexyl 1H-imidazole-4-carboxamide 437 2-Me-4- 4-Cl--Ph
1-piperidinyl 1-(4-chlorophenyl)-2-(2-methyl-1,3- 402.2 0.21 2.41 1
6 thiazolyl thiazol-4-yl)-N-(1-piperidinyl)-1H- (EtOAc)
imidazole-4-carboxamide 438 1-naphthyl 4-Cl--Ph 1-piperidinyl
1-(4-chlorophenyl)-2(1-naphthyl)- 431.2 0.42 3.06 1 6
N-(1-piperidinyl)-1H-imidazole-4- (EtOAc) carboxamide 439 2-Cl--Ph
1,3-thiazol-2-yl 1-piperidinyl 2-(2-chlorophenyl)-N-(1-p-
iperidinyl)- 388.1 0.27 2.46 1 13,14 1-(1,3-thiazol-2-yl)-1H-im-
idazole-4- (EtOAc) carboxamide 440 2-Cl--Ph 1,3-thiazol-2-yl
cyclohexyl 2-(2-chlorophenyl)-N-cyclohexyl-1- 387.1 0.52 3.15 1
13,14 (1,3-thiazol-2-yl)-1H-imidazole-4- (EtOAc) carboxamide
[0307]
15TABLE 15 140 Synthesis Entry MS m/z TLC Rf HPLC RT HPLC Method of
No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 IUPAC name [MH.sup.+] (solvent)
(min.) method Ex. No. 441 2-Cl--Ph 4-Cl-benzyl Me cyclohexyl
1-(4-chlorobenzyl)-2-(2- 442.2 2.65 1 8
chlorophenyl)-N-cyclohexyl-5- methyl-1H-imidazole-4- carboxamide
442 2-Cl--Ph 1-piperidinyl H 1-piperidinyl
2-(2-chlorophenyl)-N,1-di(1- 388.3 0.10 (1:1 2.76 1 10,11,12
piperidinyl)-1H-imidazole-4- EtOAc/ carboxamide hexane) 443
2-Cl--Ph 1-piperidinyl H cyclohexyl 2-(2-chlorophenyl)-N- 387.3
0.38 (1:1 3.44 1 10,11,12 cyclohexylcyclohexyl-1-(1-piperidin- yl)-
EtOAc/ 1H-imidazole-4-carboxamide hexane) 444 2-Cl--Ph
4-morpholinyl H 1-piperidinyl 2-(2-chlorophenyl)-1-(4- 390.4 0.13
2.21 1 10,11,12 morpholinyl)-N-(1-piperidinyl) (EtOAc)
1H-imidazole-4-carboxamide 445 2-Cl--Ph 4-morpholinyl H cyclohexyl
2-(2-chlorophenyl)-N- 389.3 0.13 (1:1 2.87 1 10,11,12
cyclohexylcyclohexyl-1-(4-morpholinyl)- EtOAc/
1H-imidazole-4-carboxamide hexane) 446 2-Cl--Ph cyclohexyl H
1-piperidinyl 2-(2-chlorophenyl)-1- 387.4 0.18 2.60 1 10,11,12
cyclohexyl-N-(1-piperidinyl) (EtOAc) 1H-imidazole-4-carboxamide 447
2-Cl--Ph cyclohexyl H cyclohexyl 2-(2-chlorophenyl)-N,1- 386.4 0.30
(1:1 3.23 1 10,11,12 dicyclohexyl-1H-imidazole-4- EtOAc/
carboxamide hexane) 448 2-Cl--Ph 4-Me-cyclohexyl H cyclohexyl
2-(2-chlorophenyl)-N- 400.4 0.38 (1:1 3.43 1 10,11,12
cyclohexyl-1-(4- EtOAc/ methylcyclohexyl)-1H- hexane)
imidazole-4-carboxamide 449 2-Cl--Ph 4-Me-cyclohexyl H
1-piperidinyl 2-(2-chlorophenyl)-1-(4- 401.4 0.32 2.83 1 10,11,12
methylcyclohexyl)-N-(1- (EtOAc) piperidinyl)-1H-imidazole-4-
carboxamide 450 2-Me-1- 4-Cl--Ph H 1-piperidinyl
1-(4-chlorophenyl)-2-isobutyl- 361.2 0.28 2.43 1 6 propyl
N-(1-piperidinyl)-1H- (EtOAc) imidazole-4-carboxamide 451 2-Cl--Ph
4-F-benzyl Et 1-piperidinyl 2-(2-chlorophenyl)-5-ethyl-1- 441.2
0.21 2.75 1 13,14 (4-fluorobenzyl)-N-(1- (EtOAc)
piperidinyl)-1H-imidazole-4- carboxamide 452 2-Cl--Ph 4-MeO--PhCO
Et 1-piperidinyl 2-(2-chlorophenyl)-5-ethyl-1- 467.2 0.24 (1:1 3.01
1 6 (4-methoxybenzoyl)-N-(1- EtOAc/ piperidinyl)-1H-imidazole-4-
hexane) carboxamide 453 benzyl 4-Cl--Ph H 1-piperidinyl
2-benzyl-1-(4-chlorophenyl)- 395.2 0.26 2.75 1 6
N-(1-piperidinyl)-1H- (EtOAc) imidazole-4-carboxamide 454 n-hexyl
4-Cl--Ph H 1-piperidinyl 1-(4-chlorophenyl)-2-hexyl-N- 389.2 0.30 3
1 6 (1-piperidinyl)-1H-imidazole-4- (EtOAc) carboxamide
[0308]
16TABLE 16 141 HPLC Synthesis MS m/z LC-MS RT method Method of Ex.
Entry No. R.sup.10 IUPAC name [MH+] (min) method No. 455 Me
N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)- 410 2.70 2 16
1H-imidazol-4- yl]carbonyl}methanesulfonamide 456 4-CF.sub.3--Ph
N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)- 540 3.55 2 16
1H-imidazol-4-yl]carbonyl}-4- (trifluoromethyl)benzenesul- fonamide
457 Ph N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl) 472 3.14 2 16
1H-imidazol-4- yl]carbonyl}benzenesulfonamide 458 4-MeO--Ph
N-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)- 502 3.22 2 16
1H-imidazol-4-yl]carbonyl}-4- methoxybenzenesulfonamide
[0309]
17TABLE 17 142 HPLC Synthesis Entry MS m/z TLC Rf RT HPLC Method of
No. R.sup.1 R.sup.2 R.sup.8 R.sup.9 IUPAC name [MH.sup.+] (solvnet)
(min) method Ex. No. 459 2-MeO-- 4-Cl--Ph H 4-F-benzyl
N-{[1-(4-chlorophenyl)-2-(2-methoxyphenyl)- 422 0.3 (88% 2.48 1 33
Ph 1H-imidazol-4-yl]methyl}-N-(4- EtOAc in fluorobenzyl)amine
hexane) 460 2,4-Cl.sub.2-- 4-F--Ph Me cyclohexyl
N-cyclohexyl-N-{[2-(2,4-dlchlorophenyl)-1- 432 0.19 2.65 1 34 Ph
(4-fluorophenyl)-1H-imidazol-4-yl]methyl}-N- (10% methylamine MeOH
in hexane) 461 2,4-Cl.sub.2-- 4-Cl--Ph H 4-F--benzyl
N-{[1-(4-chlorophenyl)-2-(2,4- 460 0.33 2.88 1 33 Ph
dichlorophenyl)-1H-imidazol-4-yl]methyl}-N- (10%
(4-fluorobenzyl)amine MeOH in EtOAc) 462 2,4-Cl.sub.2-- 4-Cl--Ph H
4-CF.sub.3- N-{[1-(4-chlorophenyl)-2-(2,4- 510 0.33 (5% 3.03 1 33
Ph benzyl dichlorophenyl)-1H-imidazol-4-yl]m- ethyl}-N- MeOH in
[4-(trifluoromethyl)benzyl]amine EtOAc) 463 2,4-Cl.sub.2-- 4-Cl--Ph
H trans-2-OH- trans-2-({[1-(4-chloropheny- l)-2-(2,4- 451 0.3 (33%
2.69 1 33 Ph cyclohexyl dichlorophenyl)-1H-imidazol-4- MeOH in
yl]methyl}amino)cyclohexanol EtOAc) 464 2,4-Cl.sub.2-- 4-Cl--Ph H
cyclohexyl N-{[1-(4-chlorophenyl)-2-(2,4- 434 0.31 2.83 1 33 Ph
dichlorophenyl)-1H-imidazol-4-yl]methyl}-N- (25% cyclohexyamine
MeOH in EtOAc) 465 2,4-Cl.sub.2-- 4-Cl--Ph H 4-(4-Me-
1-{[1-(4-chlorophenyl)-2-(2,4- 511 2.94 1 34 Ph Ph)-1-
dichlorophenyl)-1H-imidazol-4-yl]methyl}-4- piperazinyl
(4-methylphenyl)piperazine bis(trifluoroacetate) 466 2-Cl--Ph
4-Cl--Ph H cyclohexyl N-{[2-(2-chlorophenyl)-1-(4-chl- orophenyl)-
401 0.35 2.32 1 33 1H-imidazol-4-yl]methyl}-N- (50% cyclohexylamine
EtOAc in MeOH)
[0310]
18TABLE 18 143 HPLC RT Synthesis Entry MS m/z TLC Rf (min) Method
of No. R.sup.1 R.sup.2 R.sup.3 R.sup.11 IUPAC name (MH+) (solvent)
(LS-MS) Ex. No. 467 2-Cl--Ph 4-Cl--Ph Et 2-thienyl
[2-(2-chlorophenyl)-1-(4-chlorophenyl)- 427 0.13 (1:5 3.93 31
5-ethyl-1H-imidazol-4-yl](2- EtOAc/ thienyl)methanone Hexane) 468
2-Cl--Ph 4-Cl--Ph H n-propyl 1-[2-(2-chlorophenyl)-1-(- 4- 359 0.49
(1:1 3.30 29 chlorophenyl)-1H-imidazol-4-yl]-1- EtOAc/ butanone
Hexane) 469 2-Cl--Ph 4-Cl--Ph H 1-methylpropyl
1-[2-(2-chlorophenyl)-1-(4- 373 0.53 (1:1 3.47 29
chlorophenyl)-1H-imidazol-4-yl]-3- EtOAc/ methyl-1-butanone Hexane)
470 2-Cl--Ph 4-Cl--Ph H 1-methylpropyl 1-[2-(2-chlorophenyl)-1-(4-
373 0.56 (1:1 3.47 29 chlorophenyl)-1H-imidazol-4-yl]-2- EtOAc/
methyl-1-butanone Hexane) 471 2-Cl--Ph 4-Cl--Ph H n-pentyl
1-[2-(2-chlorophenyl)-1-(- 4- 387 0.56 (1:1 3.71 29
chlorophenyl)-1H-imidazol-4-yl]-1- EtOAc/ hexanone Hexane) 472
2-Cl--Ph 4-Cl--Ph H cyclopentyl
[2-(2-chlorophenyl)-1-(4-chlorophenyl)- 385 0.54 (1:1 3.54 29
1H-imidazol-4- EtOAc/ yl](cyclopentyl)methanone Hexane) 473
2-Cl--Ph 4-Cl--Ph H cyclohexyl [2-(2-chlorophenyl)-1-(-
4-chlorophenyl)- 399 0.56 (1:1 3.71 29 1H-imidazol-4- EtOAc/
yl](cyclohexyl)methanone Hexane) 474 2-Cl--Ph 4-Cl--Ph H 4-F--Ph
[2-(2-chlorophenyl)-1-(4-chlorophenyl)- 411 0.58 (1:1 3.57 29
1H-imidazol-4-yl](4- EtOAc/ fluorophenyl)methanone Hexane) 475
2-Cl--Ph 4-Cl--Ph H 4-Cl--Ph (4-chlorophenyl)[2-(2-chlorophenyl)-1-
427 0.37 (1:3 3.83 29 (4-chlorophenyl)-1H-imidazol-4- EtOAc/
yl]methanone Hexane) 476 2-Cl--Ph 4-Cl--Ph H 2-MeO--Ph
[2-(2-chlorophenyl)-1-(4-chlorop- henyl)- 423 0.20 (1:3 3.52 29
1H-imidazol-4-yl](3- EtOAc/ methoxyphenyl)methanone Hexane) 477
2-Cl--Ph 4-Cl--Ph H 4-MeO--Ph
[2-(2-chlorophenyl)-1-(4-chlorophenyl)- 423 0.18 (1:3 3.51 29
1H-imidazol-4-yl](4- EtOAc/ methoxyphenyl)methanone Hexane) 478
2-Cl--Ph 4-Cl--Ph H Et 1-[2-(2-chlorophenyl)-1-(4- 345 0.42 (1:1
3.10 29 chlorophenyl)-1H-imidazol-4-yl]-1- EtOAc/ propanone Hexane)
479 2-Cl--Ph 4-Cl--Ph H benzyl 1-[2-(2-chlorophenyl)-1-(4- 407 0.51
(1:1 3.54 29 benzylchlorophenyl)-1H-imidazol-4-yl]-2- EtOAc/
phenylethanone Hexane) 480 2-Cl--Ph 4-Cl--Ph H Ph
[2-(2-chlorophenyl)-1-(4-chlorophenyl)- 393 0.5 (1:1 EtOAc/ 3.48 29
1H-imidazol-4-yl](phenyl)methanone Hexane)
Evaluation of Biological Activity
[0311] Evaluation of Compound's Efficacy on the Reduction of Food
Intake in Lean Overnight Fasted Rats
[0312] Fasted-Refed Acute Feeding Assay
[0313] The purpose of this protocol is to determine the effect of a
single dose of an unknown compound on food consumption of lean
overnight fasted rats. The fasted-refed rat model is frequently
used in the field of obesity to identify compounds with potential
for anorectic effects. This animal model has been successfully used
in the identification and characterization of the efficacy profile
of compounds that are or have been used in the management of body
weight in obese humans (see, e.g., Balvet et al., Gen. Pharmacol.
13:293-297, 1982; Grignaschi et al., Br. J. Pharmacol.
127:1190-1194, 1999; McTavish and Heel, Drug 43:713-733, 1992;
Rowland et al., Life Sci. 36:2295-2300, 1985).
[0314] A typical study includes 60-80 male rats (n=10/treatment
group) with an average body weight of approximately 280 g. Rats are
kept in standard animal rooms under controlled temperature and
humidity and a 12/12 light dark cycle. Rats are single-housed in
suspended cages with a mesh floor. Water and food are continuously
available unless the animals are being fasted for the study.
[0315] The vehicle test: The rats are grouped based upon their
performance on a vehicle test. The vehicle test is performed
between 2 and 7 days before the efficacy test. The rats are fasted
overnight during the dark phase (total of approx. 16-18 hrs). The
animal is dosed with 0.5 mL deionized water. One hour after dosing,
pre-weighed food jars are returned to the animal home cage. The
rats are allowed one hour of feeding time. After 1 hour, the
spillage is returned to the food jar and the amount of food
consumed is determined. The rats are assigned to groups so that the
mean and standard error of the mean of 1-hour food consumption are
similar between groups.
[0316] The efficacy test: The rats are fasted overnight during the
dark phase (total of approx. 16-18 hr). The animal is dosed with an
assigned treatment (2 mg/ml). One hour after dosing, pre-weighed
food jars are returned to the cage. Food intake is recorded 30, 60,
90, 180, and 240 minutes post-food return. At each time point,
spillage is returned to the food jar and then the food jars are
weighed. The amount of food consumed is determined for each time
point. Difference between treatment group is determined using
appropriate statistical analysis.
[0317] Compounds of the present invention were found to be active
in this fasted-refed acute feeding assay. For example, when the
imidazole derivative
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[(1S,2S)-2-hydroxycycl-
ohexyl]-1H-imidazole-4-carboxamide was dosed at 10 mg/kg p.o., food
consumption was reduced (relative to the food consumption observed
for the vehicle control group) by 34% to 62% when measured at time
points from 30 to 240 minutes. Likewise, when the imidazole
derivative
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N'-[4-(trifluoromethyl)phenyl]-1H-i-
midazole4-carbohydrazide hydrochloride was dosed at 10 mg/kg p.o.,
food consumption was reduced (relative to the food consumption
observed for the vehicle control group) by 31% to 53% when measured
at time points from 30 to 240 minutes.
[0318] Evaluation of Compound's Efficacy on the Reduction of Body
Weight and Food and Water Consumption in Obese Zuckerfalfa Rats
[0319] Chronic Feeding Assay
[0320] The purpose of this protocol is to determine the effect of
chronic administration of an unknown compound on body weight and
food and water consumption in obese Zucker fa/fa rats. Obese Zucker
fa/fa rats are frequently used in the determination of compound
efficacy in the reduction of body weight. This animal model has
been successfully used in the identification and characterization
of the efficacy profile of compounds that are or have been used in
the management of body weight in obese humans (see, e.g.,
Al-Barazanji et al., Obes Res. 8:317-323, 2000;
Assimacopoulos-Jeannet et al., Am. J. Physiol. 260(2 Pt
2):R278-283, 1991; Dryden et al., Horm. Metab. Res. 31:363-366,
1999; Edwards and Stevens, Pharmacol. Biochem. Behav. 47:865-872,
1994; Grinker et al., Pharmacol. Biochem. Behav. 12:265-275,
1980).
[0321] A typical study includes 60-80 male Zucker fa/fa
(n=10/treatment group) with an average body weight of approximately
550 g. Rats are kept in standard animal rooms under controlled
temperature and humidity and a 12/12 light dark cycle. Water and
food are continuously available. Rats are single-housed in large
rat shoeboxes containing grid floor. Animals are adapted to the
grid floors and sham-dosed with study vehicle for at least four
days before the recording of two-days baseline measurement of body
weight and 24-hr food and water consumption. Rats are assigned to
one of 6-8 treatment groups based upon their body weight on
baseline. The groups are set up so that the mean and standard error
of the mean of body weight were similar.
[0322] Animals are orally gavaged (2 mL/kg) daily before the dark
phase of the LD/cycle for a pre-determined number of days
(typically 6-14 days) with their assigned dose/compound. At this
time, body weight, food and water consumption are measured. On the
final day, animals are euthanized by CO.sub.2 inhalation, and the
body weight is measured.
[0323] Compounds of this invention were found to be active in this
chronic feeding assay. For example, when the imidazole derivative
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-1H--
imidazole-4-carboxamide was dosed once a day at 10 mg/kg p.o., on
day 6 of treatment the increase in body weight from baseline was
approximately 2.4%, representing approximately 50% reduction in
body weight gain as compared to the vehicle control group, where an
approximately 4.6% increase in body weight from baseline was
observed. Likewise, when the imidazole derivative
2-(2-chlorophenyl)-1-(4-chlorophenyl)-N'-[4-(trifluo-
romethyl)phenyl]-1H-imidazole-4-carbohydrazide hydrochloride was
dosed once a day at 10 mgtkg p.o., on day 6 of treatment the
increase in body weight from baseline was approximately 1.8%,
representing approximately 60% reduction in body weight gain as
compared to the vehicle control group, where an approximately 4.6%
increase in body weight from baseline was observed.
[0324] Measurement of Brain Exposure
[0325] Male obese Zucker fa/fa rats were administered compounds,
typically at 10 mg/kg p.o., and then brains were collected at 2
hours post-dosing for determination of brain concentration. Brains
were weighed and homogenized with 4 mL 10 mM ammonium acetate
buffer (pH 3), and the brain tissue homogenate samples were
extracted via protein precipitation with acetonitrile. Samples were
vortexed, centrifuged, and analyzed by liquid chromatography
utilizing mass spectrometer selective detection (LC/MS/MS) using
the heated nebulizer interface. Samples were quantitated using
weighted (1/x.sup.2) linear internal standard calibration curve.
For example, when
1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidinyl)-5-b-
utyl-1H-imidazole-4-carboxamide was dosed at 10 mg/kg p.o., a brain
homogenate exposure level of approximately 200 nM was determined;
when
2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-N-[(1S,2S)-2-hydroxycyclohe-
xyl]-1H-imidazole-4-carboxamide was dosed at 10 mg/kg p.o., a brain
homogenate exposure level of approximately 200 nM was
determined.
[0326] Demonstration of additional biological activities of the
compounds of the present invention may be accomplished through in
vitro, ex vivo, and in vivo assays that are well known in the art.
For example, to demonstrate the efficacy of a pharmaceutical agent
for the treatment of obesity-related disorders such as diabetes,
Syndrome X, or atherosclerotic disease and related disorders such
as hypertriglyceridemia and hypercholesteremia, the following
assays may be used.
[0327] Method for Measuring Blood Glucose Levels
[0328] db/db mice (obtained from Jackson Laboratories, Bar Harbor,
Me.) are bled (by either eye or tail vein) and grouped according to
equivalent mean blood glucose levels. They are dosed orally (by
gavage in a pharmaceutically acceptable vehicle) with the test
compound once daily for 14 days. At this point, the animals are
bled again by eye or tail vein and blood glucose levels are
determined. In each case, glucose levels are measured with a
Glucometer Elite XL (Bayer Corporation, Elkhart, Ind.).
[0329] Method for Measuring Triglyceride Levels
[0330] hApoA1 mice (obtained from Jackson Laboratories, Bar Harbor,
Me.) are bled (by either eye or tail vein) and grouped according to
equivalent mean serum triglyceride levels. They are dosed orally
(by gavage in a pharmaceutically acceptable vehicle) with the test
compound once daily for 8 days. The animals are then bled again by
eye or tail vein, and serum triglyceride levels are determined. In
each case, triglyceride levels are measured using a Technicon Axon
Autoanalyzer (Bayer Corporation, Tarrytown, N.Y.).
[0331] Method for Measuring HDL-Cholesterol Levels
[0332] To determine plasma HDL-cholesterol levels, hApoA1 mice are
bled and grouped with equivalent mean plasma HDL-cholesterol
levels. The mice are orally dosed once daily with vehicle or test
compound for 7 days, and then bled again on day 8. Plasma is
analyzed for HDL-cholesterol using the Synchron Clinical System
(CX4) (Beckman Coulter, Fullerton, Calif.).
[0333] Method for Measuring Total Cholesterol, HDL-Cholesterol,
Triglycerides, and Glucose Levels
[0334] In another in vivo assay, obese monkeys are bled, then
orally dosed once daily with vehicle or test compound for 4 weeks,
and then bled again. Serum is analyzed for total cholesterol,
HDL-cholesterol, triglycerides, and glucose using the Synchron
Clinical System (CX4) (Beckman Coulter, Fullerton, Calif.).
Lipoprotein subclass analysis is performed by NMR spectroscopy as
described by Oliver et al., (Proc. Natl. Acad. Sci. USA
98:5306-5311, 2001).
[0335] Method for Measuring an Effect on Cardiovascular
Parameters
[0336] Cardiovascular parameters (e.g., heart rate and blood
pressure) are also evaluated. SHR rats are orally dosed once daily
with vehicle or test compound for 2 weeks. Blood pressure and heart
rate are determined using a tail-cuff method as described by
Grinsell et al., (Am. J. Hypertens. 13:370-375, 2000). In monkeys,
blood pressure and heart rate are monitored as described by Shen et
al., (J. Pharmacol. Exp. Therap. 278:1435-1443, 1996).
[0337] In addition, to demonstrate CNS activities of the compounds
of the present invention, the following in vivo assays may be
used.
[0338] Method for Testing Task Learning and Spatial Memory
[0339] The Morris Water Maze is routinely used to assess task
learning and spatial memory (Jaspers et al., Neurosci. Lett.
117:149-153, 1990; Morris, J. Neurosci. Methods 11:47-60, 1984). In
this assay, animals are placed in a water pool which is divided
into quadrants. One platform is hidden in one of the quadrants. The
animal is placed in the water pool and is expected to locate the
hidden platform within a predetermined time. During a number of
training trials, the animal learns the location of the platform and
escape from the pool. The animal receives multiple trials in this
task. Total distance traveled, number of trials to locate platform,
latency to find platform, and the swimming path is recorded for
each animal. The animal's learning ability is measured by the
length of time or number of trials required to find the hidden
platform. Memory deficit or improvement is determined by the number
of trials or the latency to find the platform at predetermined
delay time after acquisition. Leaning and memory may be measured by
the number of times that the animal crosses the quadrant where the
platform was located during the acquisition phase.
[0340] Method for Testing Drug Dependence
[0341] Self-administration in animals is a predictor of a
compound's abuse potential in humans. Modifications to this
procedure may also be used to identify compounds that prevent or
block the reinforcing properties of drugs that have abuse
potential. A compound that extinguishes the self-administration of
a drug may prevent that drug's abuse or its dependence. (Ranaldi et
al., Psychopharmacol. 161:442-448, 2002; Campbell et al., Exp.
Clin. Psychopharmacol. 8:312-25, 2000). In a self-administration
test, animals are placed in the operant chambers containing both an
active and inactive lever. Each response on the active lever
produces an infusion of either the test compound or a drug known to
be self-administered. Presses on the inactive lever have no effect,
but are also recorded. Animals are then trained to self-administer
compound/drug over a set period of time by having drug access
during each daily session. Illumination of the chamber house light
signals the beginning of the session and the availability of the
compound/drug. When the session ends, the house light is turned
off. Initially, a drug infusion occurs with every press of the
active lever. Once lever-pressing behavior has been established,
the number of presses to produce a drug infusion is increased.
After stable compound/drug self-administration is obtained, the
effect of a second compound on the drug-reinforced behavior may be
evaluated. Administration of this second compound prior to the
session can either potentiate, extinguish, or produce no change to
the self-administrating behavior. Tests are conducted every two
days, and the order of the administration of the test compound
doses is controlled.
[0342] Pharmaceutical Compositions
[0343] Based on the above tests, or other well known assays used to
determine the efficacy for treatment of conditions identified above
in mammals, and by comparison of these results with the results of
known medicaments that are used to treat these conditions, the
effective dosage of the compounds of this invention can readily be
determined for treatment of each desired indication. The amount of
the active ingredient to be administered in the treatment of one of
these conditions can vary widely according to such considerations
as the particular compound and dosage unit employed, the mode of
administration, the period of treatment, the age and sex of the
patient treated, and the nature and extent of the condition
treated.
[0344] The total amount of the active ingredient to be administered
may generally range from about 0.001 mg/kg to about 200 mg/kg, and
preferably from about 0.01 mg/kg to about 200 mg/kg body weight per
day. A unit dosage may contain from about 0.05 mg to about 1500 mg
of active ingredient, and may be administered one or more times per
day. The daily dosage for administration by injection, including
intravenous, intramuscular, subcutaneous, and parenteral
injections, and use of infusion techniques may be from about 0.01
to about 200 mg/kg. The daily rectal dosage regimen may be from
0.01 to 200 mg/kg of total body weight. The transdermal
concentration may be that required to maintain a daily dose of from
0.01 to 200 mg/kg.
[0345] Of course, the specific initial and continuing dosage
regimen for each patient will vary according to the nature and
severity of the condition as determined by the attending
diagnostician, the activity of the specific compound employed, the
age of the patient, the diet of the patient, time of
administration, route of administration, rate of excretion of the
drug, drug combinations, and the like. The desired mode of
treatment and number of doses of a compound of the present
invention or a pharmaceutically acceptable salt thereof may be
ascertained by those skilled in the art using conventional
treatment tests.
[0346] The compounds of this invention may be utilized to achieve
the desired pharmacological effect by administration to a patient
in need thereof in an appropriately formulated pharmaceutical
composition. A patient, for the purpose of this invention, is a
mammal, including a human, in need of treatment for a particular
condition or disease. Therefore, the present invention includes
pharmaceutical compositions which are comprised of a
pharmaceutically acceptable carrier and a pharmaceutically
effective amount of a compound identified by the methods described
herein, or a pharmaceutically acceptable salt or ester thereof. A
pharmaceutically acceptable carrier is any carrier which is
relatively non-toxic and innocuous to a patient at concentrations
consistent with effective activity of the active ingredient so that
any side effects ascribable to the carrier do not vitiate the
beneficial effects of the active ingredient. A pharmaceutically
effective amount of a compound is that amount which produces a
result or exerts an influence on the particular condition being
treated. The compounds identified by the methods described herein
may be administered with a pharmaceutically-acceptable carrier
using any effective conventional dosage unit forms, including, for
example, immediate and timed release preparations, orally,
parenterally, topically, or the like.
[0347] For oral administration, the compounds may be formulated
into solid or liquid preparations such as, for example, capsules,
pills, tablets, troches, lozenges, melts, powders, solutions,
suspensions, or emulsions, and may be prepared according to methods
known to the art for the manufacture of pharmaceutical
compositions. The solid unit dosage forms may be a capsule which
can be of the ordinary hard- or soft-shelled gelatin type
containing, for example, surfactants, lubricants, and inert fillers
such as lactose, sucrose, calcium phosphate, and corn starch.
[0348] In another embodiment, the compounds of this invention may
be tableted with conventional tablet bases such as lactose,
sucrose, and cornstarch in combination with binders such as acacia,
cornstarch, or gelatin; disintegrating agents intended to assist
the break-up and dissolution of the tablet following administration
such as potato starch, alginic acid, corn starch, and guar gum;
lubricants intended to improve the flow of tablet granulation and
to prevent the adhesion of tablet material to the surfaces of the
tablet dies and punches, for example, talc, stearic acid, or
magnesium, calcium or zinc stearate; dyes; coloring agents; and
flavoring agents intended to enhance the aesthetic qualities of the
tablets and make them more acceptable to the patient. Suitable
excipients for use in oral liquid dosage forms include diluents
such as water and alcohols, for example, ethanol, benzyl alcohol,
and polyethylene alcohols, either with or without the addition of a
pharmaceutically acceptable surfactant, suspending agent, or
emulsifying agent. Various other materials may be present as
coatings or to otherwise modify the physical form of the dosage
unit. For instance tablets, pills or capsules may be coated with
shellac, sugar or both.
[0349] Dispersible powders and granules are suitable for the
preparation of an aqueous suspension. They provide the active
ingredient in admixture with a dispersing or wetting agent, a
suspending agent, and one or more preservatives. Suitable
dispersing or wetting agents and suspending agents are exemplified
by those already mentioned above. Additional excipients, for
example, those sweetening, flavoring and coloring agents described
above, may also be present.
[0350] The pharmaceutical compositions of this invention may also
be in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil such as liquid paraffin or a mixture of vegetable
oils. Suitable emulsifying agents may be (1) naturally occurring
gums such as gum acacia and gum tragacanth, (2) naturally occurring
phosphatides such as soy bean and lecithin, (3) esters or partial
esters derived from fatty acids and hexitol anhydrides, for
example, sorbitan monooleate, and (4) condensation products of said
partial esters with ethylene oxide, for example, polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0351] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil such as, for example, arachis oil,
olive oil, sesame oil, or coconut oil; or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening
agent such as, for example, beeswax, hard paraffin, or cetyl
alcohol. The suspensions may also contain one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate;
one or more coloring agents; one or more flavoring agents; and one
or more sweetening agents such as sucrose or saccharin.
[0352] Syrups and elixirs may be formulated with sweetening agents
such as, for example, glycerol, propylene glycol, sorbitol, or
sucrose. Such formulations may also contain a demulcent, and
preservative, flavoring and coloring agents.
[0353] The compounds of this invention may also be administered
parenterally, that is, subcutaneously, intravenously,
intramuscularly, or interperitoneally, as injectable dosages of the
compound in a physiologically acceptable diluent with a
pharmaceutical carrier which may be a sterile liquid or mixture of
liquids such as water, saline, aqueous dextrose and related sugar
solutions; an alcohol such as ethanol, isopropanol, or hexadecyl
alcohol; glycols such as propylene glycol or polyethylene glycol;
glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4- -methanol,
ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a
fatty acid ester or glyceride; or an acetylated fatty acid
glyceride with or without the addition of a pharmaceutically
acceptable surfactant such as a soap or a detergent, suspending
agent such as pectin, carbomers, methycellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or
emulsifying agent and other pharmaceutical adjuvants.
[0354] Illustrative of oils which can be used in the parenteral
formulations of this invention are those of petroleum, animal,
vegetable, or synthetic origin, for example, peanut oil, soybean
oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum,
and mineral oil. Suitable fatty acids include oleic acid, stearic
acid, and isostearic acid. Suitable fatty acid esters are, for
example, ethyl oleate and isopropyl myristate. Suitable soaps
include fatty alkali metal, ammonium, and triethanolamine salts and
suitable detergents include cationic detergents, for example,
dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and
alkylamine acetates; anionic detergents, for example, alkyl, aryl,
and olefin sulfonates, alkyl, olefin, ether, and monoglyceride
sulfates, and sulfosuccinates; nonionic detergents, for example,
fatty amine oxides, fatty acid alkanolamides, and
polyoxyethylenepolypropylene copolymers; and amphoteric detergents,
for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline
quarternary ammonium salts, as well as mixtures.
[0355] The parenteral compositions of this invention may typically
contain from about 0.5% to about 25% by weight of the active
ingredient in solution. Preservatives and buffers may also be used
advantageously. In order to minimize or eliminate irritation at the
site of injection, such compositions may contain a non-ionic
surfactant having a hydrophile-lipophile balance (HLB) of from
about 12 to about 17. The quantity of surfactant in such
formulation ranges from about 5% to about 15% by weight. The
surfactant can be a single component having the above HLB or can be
a mixture of two or more components having the desired HLB.
[0356] Illustrative of surfactants used in parenteral formulations
are the class of polyethylene sorbitan fatty acid esters, for
example, sorbitan monooleate and the high molecular weight adducts
of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol.
[0357] The pharmaceutical compositions may be in the form of
sterile injectable aqueous suspensions. Such suspensions may be
formulated according to known methods using suitable dispersing or
wetting agents and suspending agents such as, for example, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents which may be a naturally occurring phosphatide such
as lecithin, a condensation product of an alkylene oxide with a
fatty acid, for example, polyoxyethylene stearate, a condensation
product of ethylene oxide with a long chain aliphatic alcohol, for
example, heptadecaethyleneoxycetanol, a condensation product of
ethylene oxide with a partial ester derived form a fatty acid and a
hexitol such as polyoxyethylene sorbitol monooleate, or a
condensation product of an ethylene oxide with a partial ester
derived from a fatty acid and a hexitol anhydride, for example
polyoxyethylene sorbitan monooleate.
[0358] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent. Diluents and solvents that may be
employed are, for example, water, Ringer's solution, and isotonic
sodium chloride solution. In addition, sterile fixed oils are
conventionally employed as solvents or suspending media. For this
purpose, any bland, fixed oil may be employed including synthetic
mono or diglycerides. In addition, fatty acids such as oleic acid
may be used in the preparation of injectables.
[0359] A composition of the invention may also be administered in
the form of suppositories for rectal administration of the drug.
These compositions may be prepared by mixing the drug with a
suitable non-irritation excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such material
are, for example, cocoa butter and polyethylene glycol.
[0360] Another formulation employed in the methods of the present
invention employs transdermal delivery devices ("patches"). Such
transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art
(see, e.g., U.S. Pat. No. 5,023,252, incorporated herein by
reference). Such patches may be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
[0361] It may be desirable or necessary to introduce the
pharmaceutical composition to the patient via a mechanical delivery
device. The construction and use of mechanical delivery devices for
the delivery of pharmaceutical agents is well known in the art. For
example, direct techniques for administering a drug directly to the
brain usually involve placement of a drug delivery catheter into
the patient's ventricular system to bypass the blood-brain barrier.
One such implantable delivery system, used for the transport of
agents to specific anatomical regions of the body, is described in
U.S. Pat. No. 5,011,472, incorporated herein by reference.
[0362] The compositions of the invention may also contain other
conventional pharmaceutically acceptable compounding ingredients,
generally referred to as carriers or diluents, as necessary or
desired. Any of the compositions of this invention may be preserved
by the addition of an antioxidant such as ascorbic acid or by other
suitable preservatives. Conventional procedures for preparing such
compositions in appropriate dosage forms can be utilized.
[0363] Commonly used pharmaceutical ingredients which may be used
as appropriate to formulate the composition for its intended route
of administration include: acidifying agents, for example, but are
not limited to, acetic acid, citric acid, fumaric acid,
hydrochloric acid, nitric acid; and alkalinizing agents such as,
but are not limited to, ammonia solution, ammonium carbonate,
diethanolamine, monoethanolamine, potassium hydroxide, sodium
borate, sodium carbonate, sodium hydroxide, triethanolamine,
trolamine.
[0364] Other pharmaceutical ingredients include, for example, but
are not limited to, adsorbents (e.g., powdered cellulose and
activated charcoal); aerosol propellants (e.g., carbon dioxide,
CCl.sub.2F.sub.2, F.sub.2ClC--CClF.sub.2 and CClF.sub.3); air
displacement agents (e.g., nitrogen and argon); antifungal
preservatives (e.g., benzoic acid, butylparaben, ethylparaben,
methylparaben, propylparaben, sodium benzoate); antimicrobial
preservatives (e.g., benzalkonium chloride, benzethonium chloride,
benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol,
phenylethyl alcohol, phenylmercuric nitrate and thimerosal);
antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid,
monothioglycerol, propyl gallate, sodium ascorbate, sodium
bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);
binding materials (e.g., block polymers, natural and synthetic
rubber, polyacrylates, polyurethanes, silicones and
styrene-butadiene copolymers); buffering agents (e.g., potassium
metaphosphate, potassium phosphate monobasic, sodium acetate,
sodium citrate anhydrous and sodium citrate dihydrate); carrying
agents (e.g., acacia syrup, aromatic syrup, aromatic elixir, cherry
syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil,
peanut oil, sesame oil, bacteriostatic sodium chloride injection
and bacteriostatic water for injection); chelating agents (e.g.,
edetate disodium and edetic acid); colorants (e.g., FD&C Red
No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue
No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No.
8, caramel and ferric oxide red); clarifying agents (e.g.,
bentonite); emulsifying agents (but are not limited to, acacia,
cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin,
sorbitan monooleate, polyethylene 50 stearate); encapsulating
agents (e.g., gelatin and cellulose acetate phthalate); flavorants
(e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil,
peppermint oil and vanillin); humectants (e.g., glycerin, propylene
glycol and sorbitol); levigating agents (e.g., mineral oil and
glycerin); oils (e.g., arachis oil, mineral oil, olive oil, peanut
oil, sesame oil and vegetable oil); ointment bases (e.g., lanolin,
hydrophilic ointment, polyethylene glycol ointment, petrolatum,
hydrophilic petrolatum, white ointment, yellow ointment, and rose
water ointment); penetration enhancers (transdermal delivery)
(e.g., monohydroxy or polyhydroxy alcohols, saturated or
unsaturated fatty alcohols, saturated or unsaturated fatty esters,
saturated or unsaturated dicarboxylic acids, essential oils,
phosphatidyl derivatives, cephalin, terpenes, amides, ethers,
ketones and ureas); plasticizers (e.g., diethyl phthalate and
glycerin); solvents (e.g., alcohol, corn oil, cottonseed oil,
glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil,
purified water, water for injection, sterile water for injection
and sterile water for irrigation); stiffening agents (e.g., cetyl
alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl
alcohol, white wax and yellow wax); suppository bases (e.g., cocoa
butter and polyethylene glycols (mixtures)); surfactants (e.g.,
benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80,
sodium lauryl sulfate and sorbitan monopalmitate); suspending
agents (e.g., agar, bentonite, carbomers, carboxymethylcellulose
sodium, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth
and veegum); sweetening e.g., aspartame, dextrose, glycerin,
mannitol, propylene glycol, saccharin sodium, sorbitol and
sucrose); tablet anti-adherents (e.g., magnesium stearate and
talc); tablet binders (e.g., acacia, alginic acid,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose,
gelatin, liquid glucose, methylcellulose, povidone and
pregelatinized starch); tablet and capsule diluents (e.g., dibasic
calcium phosphate, kaolin, lactose, mannitol, microcrystalline
cellulose, powdered cellulose, precipitated calcium carbonate,
sodium carbonate, sodium phosphate, sorbitol and starch); tablet
coating agents (e.g., liquid glucose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, ethylcellulose, cellulose acetate phthalate and
shellac); tablet direct compression excipients (e.g., dibasic
calcium phosphate); tablet disintegrants (e.g., alginic acid,
carboxymethylcellulose calcium, microcrystalline cellulose,
polacrillin potassium, sodium alginate, sodium starch glycollate
and starch); tablet glidants (e.g., colloidal silica, corn starch
and talc); tablet lubricants (e.g., calcium stearate, magnesium
stearate, mineral oil, stearic acid and zinc stearate);
tablet/capsule opaquants (e.g., titanium dioxide); tablet polishing
agents (e.g., carnuba wax and white wax); thickening agents (e.g.,
beeswax, cetyl alcohol and paraffin); tonicity agents (e.g.,
dextrose and sodium chloride); viscosity increasing agents (e.g.,
alginic acid, bentonite, carbomers, carboxymethylcellulose sodium,
methylcellulose, povidone, sodium alginate and tragacanth); and
wetting agents (e.g., heptadecaethylene oxycetanol, lecithins,
polyethylene sorbitol monooleate, polyoxyethylene sorbitol
monooleate, and polyoxyethylene stearate).
[0365] The compounds identified by the methods described herein may
be administered as the sole pharmaceutical agent or in combination
with one or more other pharmaceutical agents where the combination
causes no unacceptable adverse effects. For example, the compounds
of this invention can be combined with known anti-obesity, or with
known antidiabetic or other indication agents, and the like, as
well as with admixtures and combinations thereof.
[0366] The compounds identified by the methods described herein may
also be utilized, in free base form or in compositions, in research
and diagnostics, or as analytical reference standards, and the
like. Therefore, the present invention includes compositions which
are comprised of an inert carrier and an effective amount of a
compound identified by the methods described herein, or a salt or
ester thereof. An inert carrier is any material which does not
interact with the compound to be carried and which lends support,
means of conveyance, bulk, traceable material, and the like to the
compound to be carried. An effective amount of compound is that
amount which produces a result or exerts an influence on the
particular procedure being performed.
[0367] Formulations suitable for subcutaneous, intravenous,
intramuscular, and the like; suitable pharmaceutical carriers; and
techniques for formulation and administration may be prepared by
any of the methods well known in the art (see, e.g., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.,
20.sup.th edition, 2000)
[0368] The following examples are presented to illustrate the
invention described herein, but should not be construed as limiting
the scope of the invention in any way.
[0369] Capsule Formulation
19 A capsule formula is prepared from: Compound of this invention
40 mg Starch 109 mg Magnesium stearate 1 mg
[0370] The components are blended, passed through an appropriate
mesh sieve, and filled into hard gelatin capsules.
[0371] Tablet Formulation
[0372] A tablet is prepared from:
20 A tablet is prepared from: Compound of this invention 25 mg
Cellulose, microcrystaline 200 mg Colloidal silicon dioxide 10 mg
Stearic acid 5.0 mg
[0373] The ingredients are mixed and compressed to form tablets.
Appropriate aqueous and non-aqueous coatings may be applied to
increase palatability, improve elegance and stability or delay
absorption.
[0374] Sterile IV Solution
[0375] A 5 mg/ml solution of the desired compound of this invention
is made using sterile, injectable water, and the pH is adjusted if
necessary. The solution is diluted for administration to 1-2 mg/ml
with sterile 5% dextrose and is administered as an IV infusion over
60 minutes.
[0376] Intramuscular Suspension
[0377] The following intramuscular suspension is prepared:
21 The following intramuscular suspension is prepared: Compound of
this invention 50 mg/ml Sodium carboxymethylcellulose 5 mg/ml TWEEN
80 4 mg/ml Sodium chloride 9 mg/ml Benzyl alcohol 9 mg/ml
[0378] The suspension is administered intramuscularly.
[0379] Hard Shell Capsules
[0380] A large number of unit capsules are prepared by filling
standard two-piece hard galantine capsules each with 100 mg of
powdered active ingredient, 150 mg of lactose, 50 mg of cellulose
and 6 mg of magnesium stearate.
[0381] Soft Gelatin Capsules
[0382] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil or olive oil is prepared and injected
by means of a positive displacement pump into molten gelatin to
form soft gelatin capsules containing 100 mg of the active
ingredient. The capsules are washed and dried. The active
ingredient can be dissolved in a mixture of polyethylene glycol,
glycerin and sorbitol to prepare a water miscible medicine mix.
[0383] Immediate Release Tablets/Capsules
[0384] These are solid oral dosage forms made by conventional and
novel processes. These units are taken orally without water for
immediate dissolution and delivery of the medication. The active
ingredient is mixed in a liquid containing ingredient such as
sugar, gelatin, pectin and sweeteners. These liquids are solidified
into solid tablets or caplets by freeze drying and solid state
extraction techniques. The drug compounds may be compressed with
viscoelastic and thermoelastic sugars and polymers or effervescent
components to produce porous matrices intended for immediate
release, without the need of water.
[0385] The structures, materials, compositions, and methods
described herein are intended to be representative examples of the
invention, and it will be understood that the scope of the
invention is not limited by the scope of the examples. Those
skilled in the art will recognize that the invention may be
practiced with variations on the disclosed structures, materials,
compositions and methods, and such variations are regarded as
within the ambit of the invention.
* * * * *