Note: Descriptions are shown in the official language in which they were submitted.
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BENZOUREAS HAVING ANTI-DIABETIC ACTIVITY
FIELD OF THE INVENTION
The instant invention is concerned with benzoureas and pharmaceutically
acceptable salts and prodrugs thereof, which are useful as therapeutic
compounds,
particularly in the treatment of Type 2 diabetes mellitus, and of conditions
that are often
associated with this disease, including obesity and lipid disorders.
BACKGROUND OF THE INVENTION
Diabetes is a disease derived from multiple causative factors and
characterized by elevated levels of plasma glucose (hyperglycemia) in the
fasting state or
after administration of glucose during an oral glucose tolerance test. There
are two generally
recognized forms of diabetes. In type 1 diabetes, or insulin-dependent
diabetes mellitus
(IDDM), patients produce little or no insulin, the hormone which regulates
glucose
utilization. In type 2 diabetes, or noninsulin-dependent diabetes mellitus
(NIDDM), insulin
is still produced in the body. Patients having type 2 diabetes often have
hyperinsulinemia
(elevated plasma insulin levels); however, these patients are insulin
resistant, which means
that they have a resistance to the effect of insulin in stimulating glucose
and lipid metabolism
in the main insulin-sensitive tissues, which are muscle, liver and adipose
tissues. Patients
who are insulin resistant but not diabetic compensate for the insulin
resistance by secreting
more insulin, so that serum glucose levels are not elevated enough to meet the
criteria of
Type 2 diabetes. In patients with Type 2 diabetes, even elevated plasma
insulin levels are
insufficient to overcome the pronounced insulin resistance.
Persistent or uncontrolled hyperglycemia that occurs with diabetes is
associated with increased and premature morbidity and mortality. Often
abnormal glucose
homeostasis is associated both directly and indirectly with obesity,
hypertension, and
alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well
as other metabolic
and hemodynamic disease. Patients with type 2 diabetes mellitus have a
significantly
increased risk of macrovascular and microvascular complications, including
atherosclerosis,
coronary heart disease, stroke, peripheral vascular disease, hypertension,
nephropathy,
neuropathy, and retinopathy. Therefore, therapeutic control of glucose
homeostasis, lipid
metabolism, obesity, and hypertension are critically important in the clinical
management
and treatment of diabetes mellitus.
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Many patients who have insulin resistance or Type 2 diabetes often have
several symptoms that together are referred to as syndrome X, or the metabolic
syndrome. A
patient having this syndrome is characterized as having three or more symptoms
selected
from the following group of five symptoms: (1) abdominal obesity; (2)
hypertriglyceridemia;
(3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure;
and (5)
elevated fasting glucose, which may be in the range characteristic of Type 2
diabetes if the
patient is also diabetic. Each of these symptoms is defined in the recently
released Third
Report of the National Cholesterol Education Program Expert Panel on
Detection, Evaluation
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III,
or ATP III),
National Institutes of Health, 2001, NIH Publication No. 01-3670. Patients
with metabolic
syndrome, whether or not they have or develop overt diabetes mellitus, have an
increased risk
of developing the macrovascular and microvascular complications that are
listed above that
occur with type 2 diabetes, such as atherosclerosis and coronary heart
disease.
Insulin resistance is not primarily caused by a diminished number of insulin
receptors but by a post-insulin receptor binding defect that is not yet
completely understood.
This lack of responsiveness to insulin results in insufficient insulin-
mediated activation of
uptake, oxidation and storage of glucose in muscle and inadequate insulin-
mediated
repression of lipolysis in adipose tissue and of glucose production and
secretion in the liver.
There are several available treatments for type 2 diabetes, each of which has
its own limitations and potential risks. Physical exercise and a reduction in
dietary intake of
calories often dramatically improve the diabetic condition and are the best
first line treatment
of type 2 diabetes. Compliance with this treatment is very poor because of
well-entrenched
sedentary lifestyles and excess food consumption, especially of foods
containing high
amounts of fat. A widely used drug treatment involves the administration of
meglitinide or a
sulfonylurea (e.g. tolbutamide or glipizide), which are insulin secretagogues.
These drugs
increase the plasma level of insulin by stimulating the pancreatic 0-cells to
secrete more
insulin. When administration of a sulfonylurea or meglitinide becomes
ineffective, the
amount of insulin in the body can be supplemented by the injection of insulin
so that insulin
concentrations are high enough to stimulate even the very insulin-resistant
tissues. However,
dangerously low levels of plasma glucose can result from administration of
insulin and/or
insulin secretagogues, and an increased level of insulin resistance due to the
even higher
plasma insulin levels can occur.
The biguanides are another class of drugs that are widely used to treat type 2
diabetes. The two best known biguanides, phenformin and metformin, cause some
correction
of hyperglycemia without risk of causing hypoglycemia. The biguanides can be
used either
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with insulin or with an insulin secretagogue without increasing the risk of
hypoglycemia.
However, phenformin and metformin can induce lactic acidosis and
nausea/diarrhea.
Metformin has a lower risk of side effects than phenformin and is widely
prescribed for the
treatment of Type 2 diabetes.
The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a newer class of
compounds that can ameliorate hyperglycemia and other symptoms of type 2
diabetes. These
agents substantially increase insulin sensitivity in muscle, liver and adipose
tissue in several
animal models of type 2 diabetes, resulting in partial or complete correction
of elevated
plasma glucose levels without the occurrence of hypoglycemia. The glitazones
that are
currently marketed (rosiglitazone and pioglitazone) are agonists of the
peroxisome
proliferator activated receptor (PPAR) gamma subtype. PPAR-ganuna agonism is
generally
believed to be responsible for the improved insulin sensititization that is
observed with the
glitazones. New PPAR agonists are being developed for the treatment of Type 2
diabetes
and/or dyslipidemia. Many of the newer PPAR compounds are agonists of one or
more of
the PPAR alpha, gamma and delta subtypes. Compounds that are agonists of both
the PPAR
alpha and PPAR gamma subtypes (PPAR alpha/gamma dual agonists) are promising
because
they reduce hyperglycemia and also improve lipid metabolism.
PPAR agonists, and particularly glitazones, have had shortcomings which
have so far detracted from their attractiveness. Some of the compounds,
especially
troglitazone, have exhibited liver toxicity. Troglitazone was eventually
withdrawn from the
marketplace because of hepatotoxicity. Another weakness in the currently
marketed PPAR
agonists is that monotherapy for type 2 diabetes produces only modest efficacy
- a reduction
in average plasma glucose of = 20% and a decline from z9.0% to z8.0% in
HemoglobinAlC.
The current compounds also do not greatly improve lipid metabolism, and may
actually have
a negative effect on the lipid profile. These shortcomings have provided an
incentive to
develop better insulin sensitizers for Type 2 diabetes which function via
similar
mechanism(s) of action.
Recently, there have been reports of compounds that are PPAR gamma
antagonists or partial agonists. WO01/30343 describes a specific compound that
is a PPAR
partial agonist/antagonist that is useful for the treatment of obesity and
Type 2 diabetes.
W002/08188, W02004/020408, W02004/020409, and W02004/019869 disclose classes
of
PPAR agonists and partial agonists that are indole derivatives and that are
useful in the
treatment of Type 2 diabetes, with reduced side effects relating to body and
heart weight
gain. Benzoureas have not been disclosed as having anti-diabetic activity.
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SUMMARY OF THE INVENTION
The class of compounds described herein is a new class of PPAR-gamma
agonists and partial agonists. The compounds are potent ligands of the PPAR
gamma nuclear
receptor. The class of compounds includes many compounds that are PPARy
partial
agonists, but also may include PPARy full agonists and/or PPARy antagonists..
Some
compounds may also have PPARa activity in addition to PPARy activity. The
compounds
are useful in the treatment and control of hyperglycemia and insulin
resistance. The
compounds are expected to be efficacious in the treatment of non-insulin
dependent diabetes
mellitus (NIDDM) in human and other mammalian patients, particularly in the
treatment of
hyperglycemia, and in the treatment of conditions associated with NIDDM,
including
hyperlipidemia, dyslipidemia, obesity, hypercholesterolemia,
hypertriglyceridemia,
atherosclerosis, vascular restenosis, inflammatory conditions, and other PPAR
mediated
diseases, disorders and conditions.
The compounds may also be useful in the treatment of one or more lipid
disorders, including mixed or diabetic dyslipidemia, isolated
hypercholesterolenzia, which
may be manifested by elevations in LDL-C and/or non-HDL-C,
hyperapoBliproteinemia,
hypertriglyceridemia, an increase in triglyceride-rich-lipoproteins, and low
HDL cholesterol
concentrations. They may also be useful in the treatment or amelioration of
atherosclerosis,
obesity, vascular restenosis, inflammatory conditions, psoriasis, polycystic
ovary syndrome,
and other PPAR mediated diseases, disorders and conditions.
The present invention is directed to compounds having formula I:
R2
N~
(R3)p 0
R
I
and pharmaceutically acceptable salts and prodrugs thereof, wherein
RI is -X-Aryl-Y-Z, and Aryl is optionally substituted with 1-3 groups
independently selected from A;
Aryl is phenyl or naphthyl;
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X and Y are each independently selected from a bond and -CR4R5-;
Zis
~~O
Q-C
R6 I
} C' N\ H
u
0
Q is selected from S and 0;
A is selected from C1-C4 alkyl, C2-C4 alkenyl, -OC1-C4 alkyl, and halogen,
wherein alkyl, alkenyl, and -Oalkyl are each optionally substituted with 1-5
halogens;
R2 is selected from:
(a) Benzisoxazolyl,
(b) Aryl,
(c) -(CH2)Aryl,
(d) -(C=O)Aryl, and
(e) benzothiazolyl,
where R2 is optionally substituted with 1-3 substituent groups which are
independently
selected from halogen, C1-C3 alkyl, and -OC1-C3 alkyl, wherein C1-C3 alkyl and
-OC1-C3
alkyl are optionally substituted with 1-5 halogens;
R3, R4, and R5 are each independently selected from hydrogen, halogen, C1-
C3 alkyl, and -OC1-C3 alkyl, where C1-C3 alkyl and -OC1-C3 alkyl are
optionally
substituted with 1-5 halogens;
R6 is selected from H, C1-C3 alkyl, and halogen, where C1-C3 alkyl is
optionally substituted with 1-3 F; and
p is an integer from 0 to 4.
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In the above definitions and subsequent definitions, alkyl groups may be
either linear or branched, unless otherwise specified.
DETAILED DESCRIPTION OF THE INVENTION
The invention has numerous embodiments, as set forth below. All
embodiments also include pharmaceutically acceptable salts of the compounds
that are
defined.
One embodiment comprises compounds having Formula I, wherein R' is
-X-phenyl-YZ.
In other embodiments of the compounds of Formula I, X and Y each
independently can be a bond or -CH2-.
In other embodiments of the compounds of Formula I, Aryl is optionally
substituted with 1-2 groups A, where each group A can be halogen, -CF3,-OCF3 ,
-CH3 , or
-OCH3.
In other embodiments of the compounds of Formula I, R3 is -CH3, -OCH3,
-OCF3, or -CF3.
In other embodiments, R6 is H, CH3, or CF3.
In other embodiments, p is 0 or 1.
In other embodiments of the compounds of Formula I, R2 is 3-
benzisoxazolyl, which is optionally substituted with 1-2 groups independently
selected from
halogen, -OCH3, -OCF3, CH3, and CF3.
In other embodiments of the compounds of Formula I, R2 is 2-
benzothiazolyl, which is optionally substituted with 1-2 groups independently
selected from
halogen, -OCH3, -OCF3, CH3, and CF3.
In other embodiments of the compounds of Formula I,
R' is -X-phenyl-YZ, where phenyl is optionally substituted with 1-2 groups
independently selected from A;
X and Y are each independently selected from a bond and -CH2-;
A is selected from halogen, -CF3, -OCF3, -CH3, and -OCH3;
R3 is selected from -CF3, -OCF3, -CH3, and -OCH3;
R6 is selected from H, -CH3, and -CF3; and
pis0or1.
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A subset of the compounds of Formula I, or of any of the embodiments
described above, includes compounds in which Q is 0, X is a bond, and Y is -
CH2-.
Another subset of the compounds of Formula I, or of any of the embodiments
described above, includes compounds in which Q is 0, X is -CH2-, and Y is a
bond.
Another subset of the compounds of Formula I, or of any of the embodiments
described above, includes compounds in which Q is 0 and X and Y are each -CH2-
.
Another subset of the compounds of Formula I, or of any of the embodiments
described above, includes compounds in which Q is 0 and X and Y are each a
bond.
Other subsets of the compounds of Formula I, or of any of the embodiments
described above, include compounds in which Q is S.
The invention includes compounds of Formula I, including pharmaceutically
acceptable salts of these compounds, prodrugs of these compounds, and
pharmaceutical
compositions comprising these compounds and a pharmaceutically acceptable
carrier.
Structures of specific compounds are disclosed in the examples and in Table
1. The syntheses of specific compounds are also provided hereinafter in the
Examples.
The compounds of this invention can be used in pharmaceutical
compositions comprising the compound or a pharmaceutically acceptable salt
thereof and a
pharmaceutically acceptable carrier. The compounds of this invention can also
be used in
pharmaceutical compositions in which a compound of Formula I or a
pharmaceutically
acceptable salt thereof is the only active ingredient.
The compounds of the invention and pharmaceutically acceptable salts
thereof can be used in the manufacture of medicaments for the treatment of
type 2 diabetes
mellitus in a human or other mammalian patient, and in the manufacture of
medicaments for
other diseases described herein that are treated by the compounds.
The compounds as defined above may be used in any of the following
methods to treat or control diseases, as well as methods to treat other
diseases not listed
below, in a mammalian patient, especially a human, by administering to the
patient a
therapeutically effective amount of a compound of Formula I:
(1) non-insulin dependent diabetes mellitus (type 2 diabetes);
(2) hyperglycemia;
(3) metabolic syndrome;
(4) obesity;
(5) hypercholesterolemia;
(6) hypertriglyceridemia; and/or
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(7) one or more lipid disorders, including mixed or diabetic
dyslipidemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia,
hypercholesterolemia, and hypertriglyceridemia.
The compounds may also be used in a method for reducing the risks of
adverse sequelae associated with metabolic syndrome in a human or other
mammalian patient
in need of such treatment which comprises administering to the patient a
therapeutically
effective amount of a compound of Formula I.
The compounds may also be used in a method for treating atherosclerosis,
for reducing the risk of developing atherosclerosis, for delaying the onset of
atherosclerosis,
and/or reducing the risk of sequelae of atherosclerosis in a human or other
mammalian
patient in need of such treatment or at risk of developing atherosclerosis or
sequelae of
atherosclerosis, which comprises administering to the patient a
therapeutically effective
amount of a compound of Formula I. Sequelae of atherosclerosis include for
example
angina, claudication, heart attack, stroke, etc.
The compounds are especially useful in the treatment of the following
diseases, by administering a therapeutically effective amount to a patient in
need of
treatment:
(1) type 2 diabetes, and especially hyperglycemia resulting from type 2
diabetes;
(2) metabolic syndrome;
(3) obesity; and
(4) hypercholesterolemia.
Definitions
"Ac" is acetyl, which is CH3C(O)-.
"Alkyl" means saturated carbon chains which may be linear or branched or
combinations thereof, unless the carbon chain is defined otherwise. Other
groups having the
prefix "alk", such as alkoxy and alkanoyl, also may be linear or branched or
combinations
thereof, unless the carbon chain is defined otherwise. Examples of alkyl
groups include
methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,
heptyl, octyl, nonyl,
and the like.
"Alkenyl" means carbon chains which contain at least one carbon-carbon
double bond, and which may be linear or branched or combinations thereof.
Examples of
alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-
propenyl, 2-butenyl,
2-methyl-2-butenyl, and the like.
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"Alkynyl" means carbon chains which contain at least one carbon-carbon
triple bond, and which may be linear or branched or combinations thereof.
Examples of
alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the
like.
"Cycloalkyl" means mono- or bicyclic saturated or partially unsaturated
carbocyclic rings, each having from 3 to. 10 carbon atoms, unless otherwise
stated. The term
also includes a monocyclic ring fused to an aryl group. Examples of cycloalkyl
include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
A cycloalkylidene group is a divalent cycloalkane radical in which both
attachments are at the same carbon. For example, the cyclopropyl group of 1,1-
dimethylcyclopropane is a cyclopropylidene group.
"Aryl" (and "arylene") when used to describe a substituent or group in a
structure means a monocyclic or bicyclic compound in which all the rings are
aromatic and
which contains only carbon ring atoms. The term "aryl" can also refer to an
aryl group that is
fused to a cycloalkyl or heterocycle. "Heterocyclyl," "heterocycle," and
"heterocyclic"
means a fully or partially saturated monocyclic or bicyclic ring system
containing 1-4
heteroatoms independently selected from N, S and 0, each of said rings having
from 3 to 8
atoms. Examples of aryl substitiuents include phenyl and naphthyl. Aryl rings
fused to
cycloalkyls are found in indanyl, indenyl, and tetrahydronaphthyl. Examples of
aryl fused to
heterocyclic groups are found in 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl,
and the
like. Examples of heterocycles include tetrahydrofuran, piperazine, and
morpholine.
Preferred aryl groups are phenyl and naphthyl. Phenyl is generally the most
preferred.
"Heteroaryl" (and heteroarylene) means a mono- or bicyclic aromatic ring
system containing 1-4 heteroatoms selected from N, 0 and S, including -S(O)-
and -S(0)2-,
with each ring containing 5 to 6 atoms. Examples of heteroaryl include
pyrrolyl, isoxazolyl,
isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,
thiazolyl, imidazolyl,
triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl,
pyrazinyl,
benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,
benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl,
indolyl,
isoquinolyl, and the like. Preferred heteroaryl groups include pyridyl (2-, 3-
, and 4-pyridyl)
and quinolyl.
"Halogen" includes fluorine, chlorine, bromine and iodine.
"Me" represents methyl.
The term "composition," as in pharmaceutical composition, is intended to
encompass a product comprising the active ingredient(s), and the inert
ingredient(s) that
make up the carrier, as well as any product which results, directly or
indirectly, from
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combination, complexation or aggregation of any two or more of the
ingredients, or from
dissociation of one or more of the ingredients, or from other types of
reactions or interactions
of one or more of the ingredients. Accordingly, the pharmaceutical
compositions of the
present invention encompass any composition made by admixing a compound of the
present
invention and a pharmaceutically acceptable carrier.
The substituent "tetrazole" means a 2H-tetrazol-5-yl substituent group and
tautomers thereof.
Optical Isomers - Diastereomers - Geometric Isomers - Tautomers
Compounds of Formula I may contain one or more asymmetric centers and
can thus occur as racemates, racemic mixtures, single enantiomers,
diastereomeric mixtures
and individual diastereomers. The present invention is meant to comprehend all
such
isomeric forms of the compounds of Formula I.
Some of the compounds described herein may contain olefinic double bonds,
and unless specified otherwise, are meant to include both E and Z geometric
isomers.
Some of the compounds described herein may exist with different points of
attachment of hydrogen, referred to as tautomers. An example is a ketone and
its enol form,
known as keto-enol tautomers. The individual tautomers as well as mixtures
thereof are
encompassed with compounds of Formula I.
Compounds of Formula I having one or more asymmetric centers may be
separated into diastereoisomers, enantiomers, and the like by methods well
known in the art.
Alternatively, enantiomers and other compounds with chiral centers may be
synthesized by stereospecific synthesis using optically pure starting
materials and/or reagents
of known configuration.
Salts
The term "pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including inorganic or
organic bases
and inorganic or organic acids. Salts derived from inorganic bases include
aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic
salts,
manganous, potassium, sodium, zinc, and the like. Particularly preferred are
the ammonium,
calcium, magnesium, potassium, and sodium salts. Salts in the solid form may
exist in more
than one crystal structure, and may also be in the form of hydrates. Salts
derived from
pharmaceutically acceptable organic non-toxic bases include salts of primary,
secondary, and
tertiary amines, substituted amines including naturally occurring substituted
amines, cyclic
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amines, and basic ion exchange resins, such as arginine, betaine, caffeine,
choline, N,NI -
dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-
dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,
glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine,
piperazine, piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine,
trimethylamine, tripropylanune, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared
from pharmaceutically acceptable non-toxic acids, including inorganic and
organic acids.
Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic,
mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,
succinic, sulfuric,
tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic,
hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, as used herein, references to the compounds of
Formula I are meant to also include the pharmaceutically acceptable salts.
Utilities
Compounds of the present invention are potent ligands having agonist,
partial agonist or antagonist activity on one or more of the various
peroxisome proliferator
activated receptor subtypes, particularly PPARy. The compounds may also be
ligands or
agonists, partial agonists or antagonists of the PPARa subtype as well as the
PPARy subtype,
resulting in mixed PPARa/y agonism. Some compounds (generally less preferred)
may also
be PPARS ligands and have PPARS activity in addition to their other PPAR
activity. The
compounds of this invention are useful in treating or controlling diseases,
disorders or
conditions which are mediated by one or more ligands of the individual PPAR
subtypes (eg.
y or a) or a combination of PPAR subtypes (e.g. (Vy). One aspect of the
present invention
provides a method for the treatment and control of diseases that can be
mediated by
administration of a PPAR agonist or partial agonist, particularly a PPAR y
agonist or partial
agonist, such as type 2 diabetes. One aspect of the present invention provides
a method for
the treatment and control of such diseases, disorders, or conditions in a
mammal which
comprises administering to such mammal a therapeutically effective amount of a
compound
of Formula I. Compounds of the present invention may be useful in treating or
controlling
many PPAR mediated diseases and conditions, including, but not limited to, (1)
diabetes
mellitus, and especially non-insulin dependent diabetes mellitus (NIDDM), (2)
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hyperglycemia, (3) low glucose tolerance, (4) insulin resistance, (5) obesity,
(6) lipid
disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia,
(10)
hypercholesterolemia, (11) low HDL levels, (12) high LDL levels, (13)
atherosclerosis
and its sequelae, (14) vascular restenosis, (15) irritable bowel syndrome,
(16) inflanunatory
bowel disease, including Crohn's disease and ulcerative colitis, (17) other
inflammatory
conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative
disease, (21)
retinopathy, (22) psoriasis, (23) metabolic syndrome, (24) ovarian
hyperandrogenism
(polycystic ovarian syndrome), and other disorders where insulin resistance is
a component.
They may also have utility in treating high blood pressure, neoplastic
conditions, adipose
cell tumors, adipose cell carcinomas, such as liposarcoma, prostate cancer and
other cancers,
including gastric, breast, bladder and colon cancers, angiogenesis, and
Alzheimer's disease.
The present compounds can be used to lower glucose, lipids, and insulin in
non-diabetic patients that have impaired glucose tolerance and/or are in a pre-
diabetic
condition.
The present compounds can be used to treat obesity in a patient in need of
such treatment by administering to the patient a therapeutically effective
amount of a
compound of Formula 1.
The present compounds can be used to treat or reduce the risk of developing
atherosclerosis in a patient in need of such treatment by administering to the
patient a
therapeutically effective amount of a compound of Formula 1.
The present compounds can be used to treat or reduce hyperglycemia in a
diabetic patient in need of such treatment by administering to the patient a
therapeutically
effective amount of a compound of Formula 1.
The compounds may have utility in treating osteoporosis. The compounds of
this invention may treat osteoporosis or reduce the risk of developing
osteoporosis by
slowing or stopping the loss of bone density in a patient who has osteoporosis
or is at risk of
developing osteoporosis. The compounds of this invention may also reverse the
loss of bone
mass in patients who have already begun to lose bone mass.
One aspect of the invention provides a method for the treatment and control
of mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low
HDL levels,
high LDL levels, hyperlipidemia, and/or hypertriglyceridemia, which comprises
administering to a patient in need of such treatment a therapeutically
effective amount of a
compound having formula I. The compound may be used alone or advantageously
may be
administered with a cholesterol biosynthesis inhibitor, particularly an HMG-
CoA reductase
inhibitor such as lovastatin, simvastatin, rosuvastatin, pravastatin,
fluvastatin, atorvastatin,
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rivastatin, itavastatin, or ZD-4522. The compound may also be used
advantageously in
combination with other lipid lowering drugs such as cholesterol absorption
inhibitors (for
example stanol esters, sterol glycosides such as tiqueside, and azetidinones
such as
ezetimibe), ACAT inhibitors (such as avasimibe), CETP inhibitors, niacin,
niacin receptor
agonists, bile acid sequestrants, microsomal triglyceride transport
inhibitors, and bile acid
reuptake inhibitors. These combination treatments may also be effective for
the treatment or
control of one or more related conditions selected from the group consisting
of
hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia,
dyslipidemia,
high LDL, and low HDL.
Another aspect of the invention provides a method of treating inflammatory
conditions, including inflammatory bowel disease, Crohn's disease, and
ulcerative colitis by
administering an effective amount of a compound of this invention to a patient
in need of
treatment. Additional inflanunatory diseases that may be treated with the
instant invention
include gout, rheumatoid arthritis, osteoarthritis, multiple sclerosis,
asthma, ARDS, psoriasis,
vasculitis, ischemia/reperfusion injury, frostbite, and related diseases.
Administration and Dose Ranges
Any suitable route of administration may be employed for providing a
mammal, especially a human, with an effective dose of a compound of the
present invention.
For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and
the like may be
employed. Dosage forms include tablets, troches, dispersions, suspensions,
solutions,
capsules, creams, ointments, aerosols, and the like. Preferably compounds of
Formula I are
administered orally.
The effective dosage of active ingredient employed may vary depending on
the particular compound employed, the mode of adniinistration, the condition
being treated
and the severity of the condition being treated. Such dosage may be
ascertained readily by a
person skilled in the art.
When treating or controlling diabetes mellitus and/or hyperglycemia or
hypertriglyceridemia or other diseases for which compounds of Formula I are
indicated,
generally satisfactory results are obtained when the compounds of the present
invention are
adnunistered at a daily dosage of from about 0.01 milligram to about 100
milligrams per
kilogram of animal body weight, preferably given as a single daily dose or in
divided doses
two to six times a day, or in sustained release form. For most large mammals,
including
humans (e.g. a 70 kg adult), the total daily dosage is from about 0.1
milligrams to about 1000
milligrams, is likely to be from about 0.5 milligrams to about 350 milligrams,
and is often
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from about 1 milligram to about 50 niilligrams. For a particularly potent
compound, the
dosage for an adult human may be as low as 0.1 mg. Examples of daily dosages
for a 70 kg
adult human are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg,
150 mg,
200 mg, 250 mg, 350 mg, and 500 mg per day. The daily dosage regimen may be
adjusted
within the above ranges or even outside of these ranges to provide the optimal
therapeutic
response.
Oral administration will usually be carried out using tablets. Examples of
doses in tablets which may be administered once a day or more than once a day
(e.g. 2x, 3x,
or (rarely) 4 or more times per day, are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10
mg, 25 mg, 50
mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg. Other oral forms (e.g.
capsules
or suspensions) can also be administered in doses having similar sizes.
Pharmaceutical Compositions
Another aspect of the present invention provides pharmaceutical
compositions which comprise a compound of Formula I and a pharmaceutically
acceptable
carrier. The pharmaceutical compositions of the present invention comprise a
compound of
Formula I or a pharmaceutically acceptable salt as an active ingredient, as
well as a
pharmaceutically acceptable carrier and optionally other therapeutic
ingredients. The term
"pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable
non-toxic bases or acids including inorganic bases or acids and organic bases
or acids. A
pharmaceutical composition may also comprise a prodrug, or a pharmaceutically
acceptable
salt thereof, if a prodrug is administered.
The compositions include compositions suitable for oral, rectal, topical,
parenteral (including subcutaneous, intramuscular, and intravenous), ocular
(ophthalmic),
pulmonary (nasal or buccal inhalation), or nasal administration, although the
most suitable
route in any given case will depend on the nature and severity of the
conditions being treated
and on the nature of the active ingredient. They may be conveniently presented
in unit
dosage form and prepared by any of the methods well-known in the art of
pharmacy. In
general, compositions suitable for oral administration are preferred.
In practical use, the compounds of Formula I can be combined as the active
ingredient in intimate admixture with a pharmaceutical carrier according to
conventional
pharmaceutical compounding techniques. The carrier may take a wide variety of
forms
depending on the form of preparation desired for administration, e.g., oral or
parenteral
(including intravenous). In preparing the compositions for oral dosage form,
any of the usual
pharmaceutical media may be employed, such as, for example, water, glycols,
oils, alcohols,
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flavoring agents, preservatives, coloring agents and the like in the case of
oral liquid
preparations, such as, for example, suspensions, elixirs and solutions; or
carriers such as
starches, sugars, microcrystalline cellulose, diluents, granulating agents,
lubricants, binders,
disintegrating agents and the like in the case of oral solid preparations such
as, for example,
powders, hard and soft capsules.and tablets, with the solid oral preparations
being preferred
over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are
employed. If desired, tablets may be coated by standard aqueous or nonaqueous
techniques.
Such compositions and preparations should contain at least 0.1 percent of
active compound.
The percentage of active compound in these compositions may, of course, be
varied and may
conveniently be between about 2 percent to about 60 percent of the weight of
the unit. The
amount of active compound in such therapeutically useful compositions is such
that an
effective dosage will be obtained. The active compounds can also be
administered
intranasally as, for example, liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as
gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium
phosphate; a
disintegrating agent such as corn starch, potato starch, alginic acid; a
lubricant such as
magnesium stearate; and a sweetening agent such as sucrose, lactose or
saccharin. When a
dosage unit form is a capsule, it may contain, in addition to materials of the
above type, a
liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical
form of the dosage unit. For instance, tablets may be coated with shellac,
sugar or both. A
syrup or elixir may contain, in addition to the active ingredient, sucrose as
a sweetening
agent, methyl and propylparabens as preservatives, a dye and a flavoring such
as cherry or
orange flavor.
Compounds of formula I may also be administered parenterally. Solutions or
suspensions of these active compounds can be prepared in water suitably mixed
with a
surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in
glycerol,
liquid polyethylene glycols and mixtures thereof in oils. Under ordinary
conditions of
storage and use, these preparations contain a preservative to prevent the
growth of
microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous
preparation of sterile
injectable solutions or dispersions. In all cases, the form must be sterile
and must be fluid to
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the extent that easy syringability exists. It must be stable under the
conditions of
manufacture and storage and must be preserved against the contaminating action
of
microorganisms such as bacteria and fungi. The carrier can be a solvent or
dispersion
medium containing, for example, water, ethanol, polyol (e.g. glycerol,
propylene glycol and
liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Combination Therapy
Compounds of Formula I may be used in combination with other drugs that
may also be useful in the treatment or amelioration of the diseases or
conditions for which
compounds of Formula I are useful. Such other drugs may be administered, by a
route and in
an amount commonly used therefor, contemporaneously or sequentially with a
compound of
Formula I. When a compound of Formula I is used contemporaneously with one or
more
other drugs, a pharmaceutical composition in unit dosage form containing such
other drugs
and the compound of Formula I is preferred. However, the combination therapy
also
includes therapies in which the compound of Formula I and one or more other
drugs are
administered on different overlapping schedules. It is also contemplated that
when used in
combination with one or more other active ingredients, the compound of the
present
invention and the other active ingredients may be used in lower doses than
when each is used
singly. Accordingly, the pharmaceutical compositions of the present invention
include those
that contain one or more other active ingredients, in addition to a compound
of Formula I.
Examples of other active ingredients that may be administered in
combination with a compound of Formula I, and either administered separately
or in the same
pharmaceutical composition, include, but are not limited to:
(a) other PPAR gamma agonists and partial agonists, such as the glitazones
(e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone,
balaglitazone,
netoglitazone, and the like), and PPAR gamma agonists and partial agonists
that do not have
a glitazone structure;
(b) biguanides such as metformin and phenformin;
(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors,
(d) dipeptidyl peptidase IV (DP-IV) inhibitors, such as MK-0431, LAF-237,
BMS-477118, PSN-9301, and GSK-823093;
(e) insulin or insulin mimetics;
(f) sulfonylureas such as tolbutamide and glipizide, or related materials;
(g) a-glucosidase inhibitors (such as acarbose);
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(h) agents which improve a patient's lipid profile, such as (i) HMG-CoA
reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin,
fluvastatin,
atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins), (ii) bile
acid sequestrants
(cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-
linked dextran), (iii)
nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) niacin receptor
agonists, (v) PPARa
agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate,
fenofibrate and
bezafibrate), (vi) cholesterol absorption inhibitors, such as for example
ezetimibe, (vii) acyl
CoA:cholesterol acyltransferase (ACAT) inhibitors, such as avasimibe, (viii)
CETP
inhibitors, and (ix) phenolic anti-oxidants, such as probucol;
(i) PPARaJy dual agonists, such as KRP-297, muraglitazar, tesaglitazar,
LY-818 and the like;
(j) PPARS agonists such as those disclosed in W097/28149;
(k) antiobesity compounds such as fenfluramine, dexfenfluramine,
phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, Mc4r
agonists, cannabinoid
receptor 1(CB-1) antagonists/inverse agonists, and (33 adrenergic receptor
agonists;
(1) ileal bile acid transporter inhibitors;
(m) agents intended for use in inflammatory conditions such as aspirin, non-
steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo-
oxygenase 2
selective inhibitors;
(n) glucagon receptor antagonists;
(o) GLP-1,
(p) GIP-1, and
(q) GLP-1 analogs, such as exendins.
The above combinations include combinations of a compound of the present
invention not only with one other active compound, but also with two or more
other active
compounds. Non-limiting examples include combinations of compounds having
Formula I
with two or more active compounds selected from biguanides, sulfonylureas, HMG-
CoA
reductase inhibitors, other PPAR agonists, PTP-1B inhibitors, DP-IV
inhibitors, and anti-
obesity compounds.
Compounds of the present invention (i.e. compounds having Formula I) can
be used to treat one or more diseases or conditions selected from
hypercholesterolemia,
atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,
hypertriglyceridemia, and
dyslipidemia by administering a therapeutically effective amount of a compound
of Claim 1
in combination with an HMG-CoA reductase inhibitor to a patient in need of
such treatment.
Statins are the preferred HMG-CoA reductase inhibitors for use in this
combination therapy.
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Preferred statins include lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin,
itavastatin, ZD-4522, rivastatin, and rosuvastatin. This combination treatment
may be
particularly desirable for treating or reducing the risk of developing
atherosclerosis.
BIOLOGICAL ASSAYS
A) PPAR Binding Assays
For preparation of recombinant human PPARy, PPAR8, and PPARa: Human
PPARy2, human PPAR8 and human PPARa were expressed as gst-fusion proteins in
E. coli.
The full length human cDNA for PPARy2 was subcloned into the pGEX-2T
expression
vector (Pharmacia). The full length human cDNAs for PPARS and PPARa were
subcloned
into the pGEX-KT expression vector (Pharmacia). E. coli containing the
respective plasmids
were propagated, induced, and harvested by centrifugation. The resuspended
pellet was
broken in a French press and debris was removed by centrifugation at 12,000 X
g.
Recombinant human PPAR receptors were purified by affinity chromatography on
glutathione sepharose. After application to the column, and one wash, receptor
was eluted
with glutathione. Glycerol (10%) was added to stabilize the receptor and
aliquots were stored
at -80 C.
For binding to PPARy, an aliquot of receptor was incubated in TEGM (10
mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 L/100 mL B-mercaptoethanol, 10 mM
Na
molybdate, 1 mM dithiothreitol, 5 g/mL aprotinin, 2 g/mL leupeptin, 2 g/mL
benzamidine and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 10 nM [3H21
AD5075, (21 Ci/mmol.e), test compound as described in Berger et al (Novel
peroxisome
proliferator-activated receptor (PPARy) and PPAR8ligands produce distinct
biological
effects. J. Biol. Chem. (1999), 274: 6718-6725. Assays were incubated for -16
hr at 4 C in
a final volume of 150 L. Unbound ligand was removed by incubation with 100 L
dextran/gelatin-coated charcoal, on ice, for -10 min. After centrifugation at
3000 rpm for 10
min at 4 C, 50 L of the supernatant fraction was counted in a Topcount.
For binding to PPAR8, an aliquot of receptor was incubated in TEGM (10
mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 L/100 mL B-mercaptoethanol, 10 mM
Na
molybdate, 1 mM dithiothreitol, 5 g/mL aprotinin, 2 g/mL leupeptin, 2 g/mL
benzamide
and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 2.5 nM [3H2]L-783483,
(17
Ci/mmole), test compound as described in Berger et al (Novel peroxisome
proliferator-
activated receptory (PPARy) and PPAR8 ligands produce distinct biological
effects. 1999
J
Biol Chem 274: 6718-6725). (L-783483 is 3-chloro-4-(3-(7-propyl-3-
trifluoromethyl-6-benz-
[4,5]-isoxazoloxy)propylthio)phenylacetic acid, Ex. 20 in WO 97/28137). Assays
were
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incubated for -16 hr at 4 C in a final volume of 150 L. Unbound ligand was
removed by
incubation with 100 L dextran/gelatin-coated charcoal, on ice, for -10 min.
After
centrifugation at 3000 rpm for 10 min at 4 C, 50 L of the supernatant
fraction was counted
in a Topcount.
For binding to PPARa, an aliquot of receptor was incubated in TEGM (10
mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 L/100 mL 6-mercaptoethanol, 10 mM
Na
molybdate, 1 mM dithiothreitol, 5 g/mL aprotinin, 2 g/mL leupeptin, 2 g/mL
benzamide
and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 5.0 nM [3H2]L-797773,
(34
Ci/mmole), test compound. (L-797733 is (3-(4-(3-phenyl-7-propyl-6-benz-[4,5]-
isoxazoloxy)butyloxy))phenylacetic acid, Ex.62 in WO 97/28137). Assays were
incubated
for -16 hr at 4 C in a final volume of 150 L. Unbound ligand was removed by
incubation
with 100 L dextran/gelatin-coated charcoal, on ice, for -10 min. After
centrifugation at
3000 rpm for 10 min at 4 C, 50 L of the supematant fraction was counted in a
Topcount.
B) Gal-4 hPPAR Transactivation Assays
The chimeric receptor expression constructs, pcDNA3-hPPARy/GAL4,
pcDNA3-hPPAR8/GAL4, pcDNA3-hPPARoc/GAL4 were prepared by inserting the yeast
GAL4 transcription factor DBD adjacent to the ligand binding domains (LBDs) of
hPPARy,
hPPARS, hPPARa, respectively. The reporter construct, pUAS(5X)-tk-luc was
generated by
inserting 5 copies of the GAL4 response element upstream of the herpes virus
minimal
thymidine kinase promoter and the luciferase reporter gene. pCMV-lacZ contains
the
galactosidase Z gene under the regulation of the cytomegalovirus promoter. COS-
1 cells
were seeded at 12 X 103 cells/well in 96 well cell culture plates in high
glucose Dulbecco's
modified Eagle medium (DMEM) containing 10% charcoal stripped fetal calf serum
(Gemini
Bio-Products, Calabasas, CA), nonessential amino acids, 100 units/ml
Penicillin G and 100
mg/mi Streptomycin sulfate at 37 C in a humidified atmosphere of 10% C02.
After 24 h,
transfections were performed with Lipofectamine (GIBCO BRL, Gaithersburg, MD)
according to the instructions of the manufacturer. Briefly, transfection mixes
for each well
contained 0.48 l of Lipofectamine, 0.00075 g of pcDNA3-PPAR/GAL4 expression
vector,
0.045 g of pUAS(5X)-tk-luc reporter vector and 0.0002 g of pCMV-lacZ as an
internal
control for transactivation efficiency. Cells were incubated in the
transfection mixture for 5
h at 37 C in an atmosphere of 10% CO2, The cells were then incubated for -48
h in fresh
high glucose DMEM containing 5% charcoal stripped fetal calf serum,
nonessential amino
acids, 100 units/ml Penicillin G and 100 mg/ml Streptomycin sulfate
increasing
concentrations of test compound. Since the compounds were solubilized in DMSO,
control
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cells were incubated with equivalent concentrations of DMSO; final DMSO
concentrations
were < 0.1%, a concentration which was shown not to effect transactivation
activity. Cell
lysates were produced using Reporter Lysis Buffer (Promega, Madison, WI)
according to the
manufacturer's instructions. Luciferase activity in cell extracts was
determined using
Luciferase Assay Buffer (Promega, Madison, WI) in an ML3000 luniinometer
(Dynatech
Laboratories, Chantilly, VA). P-galactosidase activity was determined using (3-
D-
galactopyranoside (Calbiochem, San Diego, CA).
Agonism is determined by comparison of maximal transactivation activity
with a full PPAR agonist, such as rosiglitazone. Generally, if the maximal
stimulation of
transactivation is less than 50% of the effect observed with a full agonist,
then the compound
is designated as a partial agonist. If the maximal stimulation of
transactivation is greater than
50% of the effect observed with a full agonist, then the compound is
designated as a full
agonist. The compounds of this invention generally have EC50 values in the
range of 1nM to
3000 nM.
C) In Vivo Studies
Male db/db mice (10-11 week old C57BUKFJ, Jackson Labs, Bar Harbor,
ME) are housed 5/cage and allowed ad lib. access to ground Purina rodent chow
and water.
The animals, and their food, are weighed every 2 days and are dosed daily by
gavage with
vehicle (0.5% carboxymethylcellulose) test compound at the indicated dose.
Drug
suspensions are prepared daily. Plasma glucose, and triglyceride
concentrations are
determined from blood obtained by tail bleeds at 3-5 day intervals during the
study period.
Glucose and triglyceride, determinations are performed on a Boehringer
Mannheim Hitachi
911 automatic analyzer (Boehringer Mannheim, Indianapolis, IN) using
heparinized plasma
diluted 1:6 (v/v) with normal saline. Lean animals are age-matched
heterozygous mice
maintained in the same manner.
EXAMPLES
The following Schemes and Examples are provided to illustrate the invention
and are not to be construed as limiting the invention in any manner. The scope
of the
invention is defined by the appended claims.
The structures in Table 1 further illustrate compounds of this invention that
were made or can be made using the methods disclosed herein.
Compounds in Table 1 that were synthesized were analyzed using tandem
high pressure liquid chromatography - mass spectrometry (LC-MS) and/or proton
NMR. LC-
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MS samples were analyzed using an Agilent 1100 Series high pressure liquid
chromatograph
coupled to a Waters Micromass ZQ mass spectrometer. The column used was a
Waters
XTerra and compounds were eluted using a gradient elution program (10% B to
100% B in
4.5 nun) with a flow rate of 2.5 mL/min; Solvent A: water containing 0.06%
trifluoroacetic
acid; Solvent B: acetonitrile containing 0.05% trifluoroacetic acid. Retention
times are given
in minutes.
Method A: XTerra MS-C18, 4.5 x 50 mm, 10 - 100% B in 4.5 min, flow rate 2.5
ml/min.
Method B: XTerra C18, 3 x 50 mm, 10 - 98% in 3.75 min, then 98% for 1 min,
flow rate 1
mUmin.
General and specific procedures for making the compounds of this invention
and synthetic intermediates are summarized below. Other compounds claimed
herein can
readily be made by a practitioner of medicinal and/or synthetic organic
chemistry by adapting
the procedures disclosed herein to the specific compound.
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SCHEME 1
F3CO O(Ac)z F3CO \ H.NO3 F3CO N02
IaNH2 AcOH I / AcOH NHAc NHAC
NaOH F3CO I\ N02 Hz/Pd/C FsC \ NHz
/ NHz I
H2N' 'NHz
~'01(
H
F3CO N ~
\
I/ N>= O Oztzt( O F3CO N N
O + F3C0)\ N O ~)::) O
~O
/ N >= (tBuOCO)20 H
H
CI
Cs2CO3 /N
CI / 0
0 H H
I / N>=O I F3C N
NaOMe F3CO N
N I \ N\ I \
O / CI O OMe
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Experimental Procedure:
FsCO N02
F3CO ~ O(Ac)2
I -~ I
/ AcOH
N H 2 NHAc
2-Nitro-4-trifluoromethoxyacetylaniline:
To a solution of 4-trifluoromethoxyaniline (35 g, 200 mmol) in acetic acid (35
mL) at 0 to
C, was added acetic anhydride (75 mL). The reaction mixture was stirred at 10
to 30 C for
30 min. While cooling in ice bath, HZSO4 (96%, 1.5 mL, 26 mmol) was added
followed by
10 HNO3 (90%, 9.4 mL, 200 mmol). The mixture was stirred at room temperature
for one hour
and diluted with water (300 ml). The resulting slurry was stirred in ice bath
for 30 minutes
and filtered. The solid was washed with water and air dried to obtain a yellow
solid. LC-MS
'H NMR (CDC13, 500 MHz)
F3CO ~ NaOH F3CO NO2
I -r I
/ MeOH
NH2 N H 2
2-Nitro-4-trifluoromethoxyaniline:
To a solution of 2-nitro-4-trifluoromethoxyacetylaniline (45 g, 170 mmol) in
methanol (200
mL) at 0 to 10 C, was added sodium hydroxide solution (NaOH, 8.5g, 220 mmol,
in 45 mL
water). The reaction mixture was stirred at room temperature for one hour and
diluted with
300 niL of water. The slurry was stirred in an ice bath for two hours and
filtered. The
yellow solid was washed with 50 mL methanol: water (1:2) and dried under
vacuum to obtain
a yellow solid.
F3CO NO2 pd/C/H2 F3CO NH2
MeOH
NHZ NH2
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1,2-Diamino-4-trifluoromethoxybenzene:
To a solution of 2-Nitro-4-trifluoromethoxyaniline (40g, 180 mmol) in methanol
(250 ml),
was added 10% palladium on carbon (Pd/C, 10% wt/wt, 500 mg). The suspension
was
shaken in a Parr bottle under 45 psi of hydrogen for 4 hours, and then
filtered through celite.
The filtrate was concentrated to dryness to obtain a light gray solid.
O H
F3CO ~ NH2 + H2N ~ NH2 THF ~ F3CO N ~ O
I -- I
/
NH2 H
5-Trifluoromethoxybenzimidazole-2-one:
To a solution of 1, 2-diamino-4-trifluoromethoxybenzene (35g, 180 mmol) in
tetrahydrofuran
(350 ml) was added urea (32 g, 180 mmol). The solution was refluxed at 70 C
overnight,
concentrated under vacuum to a volume of about 100 mL and diluted with water
(500 mL).
The suspension was stirred at room temperature overnight and filtered. The
solid was washed
with water and dried under vacuum to obtain a white crystalline solid. LC-MS:
m/e (M+1) _
219.'H NMR (DMSO, 500 MHz) S 10.85 (d, J=8Hz, 2H), 6.97 (d, J=8.5Hz, 1H), 6.90
(d,
J=1lHz, 2H).
F3CO N ~
\ ~ ~O
F3CO )::~: ~O (tBuOCO)20_ I/ N O O
H ~O + F3C0 N
O N >==O
H
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1-Boc-5-trifluoromethoxybenzimidazole-2-one and 1-Boc-6-
trifluoromethoxybenzimidazole-
2-one:
To a solution of 5-trifluoromethoxybenzimidazole-2-one (35 g, 160 mmol) in DMF
(150 mL)
was added NaH (95%, 4.9 g, 190 mmol). The reaction niixture was stirred at
room
temperature for 2 hours followed by addition of di-tert-butyl dicarbonate (35
g, 160 mmol).
The mixture was stirred at room temperature overnight, diluted with water (400
ml), and
extracted with ethyl acetate (2 x 150 ml). The organic extract was washed with
water (2 x
100m1) and brine (100 ml), dried over anhydrous MgSO4, and concentrated under
vacuum.
The residue was chromatographed on silica gel with hexane/ethyl acetate (3:1)
as the solvent
system to obtain 1-Boc-5-trifluoromethoxybenzimidazole-2-one as an earlier
eluted product.
Fractions containing the later eluted product were combined and concentrated
to dryness to
obtain 1-Boc-5-trifluoromethoxybenzimidazole-2-one. LC-MS (M+1) = 319. 1H NMR
(DMSO, 500 MHz) 8 11.21 (brs, 1H), 7.56 (s, IH), 7.12 (d, J=7Hz, 1H), 7.03 (d,
J=7Hz,
1H),) 1.57 (s, 9H).
cl
F3CO ~ N LXN F3CO N ~ N
N
~O CI ):)IN ~O + I ~O
~ Cs2CO3 F3CO O
I\
O N' I\ N'
j~ O / CI O /
/ CI
1-f (6-chloro)-benzisoxazol-3-yll-5-trifluoromethoxylbenzimidazole-2-one and 1-
f (6-chloro)-
benzisoxazol-3-yll-6-trifluoromethoxylbenzimidazole-2-one:
To a solution of 1-Boc-5-trifluoromethoxybenzimidazole-2-one (5 g, 15.7 mmol)
in DMF (20
ml) was added 3,6-dichlorobenzoisoxazole (3.0 g, 15.7 mmol) and Cs2CO3 (11 g,
31.4
mmol). The suspension was heated to 150 C in an oil bath and stirred
overnight. The mixture
was then cooled to room temperature, diluted with water (30 ml) and extracted
with ethyl
acetate (2x20 ml). The organic extracts were combined, dried over anhydrous
MgzSO4, and
concentrated to dryness. The residue was purified by silica gel column
chromatography
using hexane/ethyl acetate (4:1) as solvent system. Fractions containing
earlier eluted
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product were combined and concentrated to obtain 1-[3-(6-chloro)-
benzisoxazoyl]-5-
trifluoromethoxylbenzimidazole-2-one as a white solid. 'H NMR (DMSO, 500 MHz)
8 8.28
(d, J=9.OHz, 1H), 8.12 (s, 1H), 7.74 (d, J=9.OHz, 1H), 7.54 (d, J=8.5, 1H),
7.14 (d, J=8.5,
1H), 7.13 (s, 1H). Fractions containing later eluted product were combined and
concentrated
to obtain 1-[3-(6-chloro)-benzisoxazoyl]-6-trifluoromethoxylbenzimidazole-2-
one as a white
solid. 'H NMR (DMSO, 500 MHz) S 8.28 (d, J=9.OHz, 1H), 8.12 (s, 1H), 7.74 (d,
J=9.OHz,
IH), 7.66 (brs, IH), 7.54 (d, J=8.5, 1H), 7.13 (brs, IH).
H
i
N ~ n
j:: O NaOCH3 ~O
F3C0 N DW F3C0 00 N
N\ N\ I ~
O O
CI / OCH3
1-[ (6-methoxy)-benzisoxazol-3-yll -6-trifluoromethoxylbenzimidazole-2-one:
To a solution of 1-[3-(6-chloro)-benzisoxazoyl]-6-
trifluoromethoxylbenzimidazole-2-one (1.2
g, 3.25 mmol) in DMF (5 ml) was added NaOMe solution in methanol (30% wt/wt,
20 ml).
The mixture was heated to 80 C under vacuum to remove residual methanol and
then stirred
at 110 C under nitrogen overnight. The mixture was then cooled to room
temperature,
diluted with water (50 ml), adjusted to pH 6 with 10% aqueous HCI. The
resulting
suspension was stirred in an ice bath for 2 hours and filtered. The solid was
washed with
water and dried in an oven (90 C) for 2 hours and then under high vacuum at
room
temperature for 3 hours to obtain a slightly yellow solid. LC-MS m/e: (M+1) =
366.
cl
H
N CII/ N GhN>NaOMe N
-~ --
H CszCO3 N \ N
\/ \
cl OCH3
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1d6-chlorobenzisoxazol-3-yl)benzimidazole-2-one and 1-(6-methoxybenzisoxazol-3-
yl)lbenzimidazole-2-one:
To a solution of benzimidazole-2-one (Aldrich, 1.1 g, 7.5 mmol) in DMF (20 ml)
was added
3,6-dichlorobenzoisoxazole (1.5 g, 7.5 mmol) and Cs2CO3 (4.8 g, 15 mmol). The
suspension
was heated to 150 C in an oil bath and stirred ovemight. The mixture was then
cooled to
room temperature, diluted with water (30 ml) and stirred in a ice bath for 2
hours. The
mixture was then filtered. The solid was washed with water and dried under
high vacuum to
obtain 2.0 g (93%) of a yellow solid as 1-(6-chlorobenzisoxazol-3-
yl)benzimidazole-2-one.
To a solution of the above product (1.0 g, 3.5 mmol) in DMF (15 ml) was added
NaOMe
solution in methanol (30% wt/wt, 10 ml). The mixture was heated to 80 C under
vacuum to
remove residual methanol and then stirred at 110 C under nitrogen overnight.
The mixture
was. then cooled to room temperature, diluted with water (50 ml), adjusted to
pH 6 with 10%
aqueous HCI. The resulting suspension was stirred in an ice bath for 2 hours
and filtered.
The solid was washed with water and dried in an oven (90 C) for 2 hours and
then under high
vacuum at room temperature for 3 hours to obtain a slightly yellow solid. LC-
MS m/e: (M+1)
= 282
~ ci
N gr I/ /Cs2CO3/DMF cl
I / >==O
F3C N
/~-- O 2. TFA C N>=O
F3C N
H
1-(4-chlorobenzyl)-5-trifluoromethylbenzimidazole-2-one:
To the solution of 1-Boc-5-trifluoromethylbenzimidazole-2-one (100 mg, 0.33
mmol) in
DMF (2m1) was added 4-chlorobenzyl bromide (81 mg, 0.39 mmol) and Cs2CO3 (300
mg,
0.92 mmol). The mixture was stirred at room temperature for 2 hours, diluted
with water (4
n-d ), and extracted with ethyl acetate (2x3m1). The organic extracts were
combined, and
concentrated to obtain a solid. The solid was dissolved in TFA (1.5 ml),
stirred at room
temperature for 2 hours, and concentrated to dryness. The residue was purified
by silica gel
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chromatography with hexane/ethyl acetate (4:1) as solvent system to obtain a
white solid. 'H
NMR (DMSO, 500 MHz) S 9.35 (brs, 1H), 7.38 (s, 1H), 7.34 (d, 2H), 7.28 (d,
2H), 7.27 (d,
1H), 6.93 (d, 1H), 5.10 (s. 2H).
~ cl
i. ~
O / O ~ / CI
N ~
I ~~ CI ~
F3C N /-- 2. TFA xIIi \ ~O
O O FC / N
3 H
1-(4-chlorobenzoyl)-5 -trifluoromethylbenzimidazole-2-one:
To the solution of 1-Boc-5-trifluoromethylbenzimidazole-2-one (200 mg, 0.66
mmol) in
anhydrous pyridine (4 ml) was added 4-chlorobenzoyl chloride (115 mg, 0.66
mmol). The
mixture was stirred at room temperature overnight and concentrated to dryness.
The residue
was dissolved in TFA (2 ml), and stirred at room temperature for 2 hours. The
mixture was
concentrated to dryness and purified by silica gel column chromatography to
obtain a solid.
'H NMR (DMSO, 500 MHz) S 7.92 (d, 1H), 7.81 (d, 2H), 7.56 (d, 2H), 7.66 (brs,
1H), 7.48
(d, IH), 7.32 (brs, IH).
~ OCF3 OCF3
N 1 HO~ I /Cu(OAc)2/Et3N
/
I >=O B
F3C N OH
O O I 2. TFA ~ N
~ F3C / N
H
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1-(4-trifluoromethoxyphenyl)-5-trifluoromethylbenzimidazole-2-one:
To the solution of 1-Boc-5-trifluoromethylbenzimidazole-2-one (870 mg, 2.88
mmol) in
methylene chloride (100 ml) was added Cu(OAc)2 (521 mg, 2.88 mmol),
triethylamine (0.94
ml, 14 mmol), and molecular sieves (200 mg). The mixture was stirred at room
temperature
under open air overnight, and filtered. The filtrate was concentrated to
dryness. The residue
was dissolved in TFA (5 ml), stirred at room temperature for 3 hours and
concentrated to
dryness. The residue was dissolved in ethyl acetate (5 ml) and passed through
a silica gel
pad and washed with hexane/ethyl acetate (3:1) (100 ml). The filtrate was
concentrated to
obtain a solid. LC-MS m/e (M+1) = 363.
cl
s cl
1
F)OCN >== S i N
~ Cs2C03/DMF/150 C
o 0 \ N
~ , ~o
F3C H
1-f (6-chloro)benzothiazol-2-yll-5-trifluoromethylbenzimidazole-2-one:
To the solution of 1-Boc-5-trifluoromethylbenzimidazole-2-one (500 mg, 1.65
mmol) in
DMF (5 ml) was added 2,6-dichlorobenzothiazole (336 mg, 1.65 mmol) and CszCO3
(1.2 g,
3.68 mmol). The mixture was heated in an oil bath to 150 C, and stirred
overnight. The
reaction mixture was then cooled to room temperature, diluted with water (50
ml) and
extracted with ethyl acetate (2x20 ml). The organic extracts were combined,
concentrated to
dryness, and purified by silica gel column chromatography with hexane/ethyl
acetate (3:1) as
solvent system to obtain a white powder. LC-MS m/e (M+1) = 372.
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SCHEME 2
\ Wittig AD-mix (3 I \
I OH
/
O OH
\ \
10% Pt/C I/ = OH CH2N2 I/ = OH
O OH O OCH3
Urea/NaOMe I \ _ TrCI/Et3N I \ -_
--> O -~ / - O
>=o N~o
O H O Tr
F3CO N H
NBS/AIBN >==o
-- Br I/ = o N
ccl4 ~o +
O Nr N ~ I \
_ O / OCH3
(QO)
1, Cs
CO3/DMF F CO O
=~ 3
I\ N o H N
2, TFA ~O
/ N
N; "N"
O
OCH3
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Experimental Procedures:
lqzz~ Ph3P+CH3 Br
nBuLi
0
2-(3-Methylphenyl)propene:
To a suspension of methyltriphenylphosphonium bromide (33.2 g, 92.9 mmol) in
diethyl
ether (200 mL) at room temperature was added slowly nBuLi (2.5 M in hexanes,
37 mL). The
resulting yellow solution was stirred for 30 min before 3-methylacetophenone
(12 mL, 90
mmol) was introduced. The reaction was stirred at room temperature overnight.
The
precipitate was removed by filtration. The solvent was removed in vacuum.
Purification by
flash chromatography gave the 2-(3-methylphenyl)propene product.
AD-mix (3 ~
t-BuOH-H20 OH
OH
2(R)-( 3-Methylphenyl)-1,2-propane-diol:
To a suspension of AD-mix-(3 (7 g) in H20/tBuOH (25 mL/25 mL) at 0 C was added
2-(3-
Methylphenyl)propene (0.66 g, 5 mmol). The reaction mixture was stirred at 0 C
overnight.
Na2SO3 (7.5 g) was added. After 1 h at room temperature, the mixture was
extracted with
EtOAc (3X). The combined organic layers were washed with brine, dried over
Na2SO4,
filtered, and concentrated in vacuum. Purification by flash chromatography
gave
2(R)-(3-methylphenyl)- 1,2-propane-diol:
'H NMR (500 MHz, CDC13) S 7.30 (overlapping signals, 2H), 7.12 (d, J = 7.1 Hz,
IH), 3.82
(d, J= 11.2 Hz), 3.66 (d, J = 11.2 Hz, 1H), 2.59 (s, 1H), 2.40 (s, 3H), 1.55
(s, 3H).
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I/ = 0H 10 Io Pt/C - OH
OH O OH
2(R)-(3-Methylphenyl)lactic acid:
To a solution of 2(R)-(3-Methylphenyl)-1,2-propane-diol (0.7 g) in water (50
mL) were
added NaHCO3 (0.4 g) and 10% Pt/C (0.7 g). Air was bubbled through the
reaction mixture
via a gas dispenser at 70 C overnight. The reaction was cooled to room
temperature, then
filtered through Celite. The filtrate was acidified with aqueous H2SO4 (1.0 N)
to pH 2, then
extracted with EtOAc (3X). The combined organic layers were washed with brine,
dried over
Na2SO4, filtered, and concentrated in vacuum to give the acid. 'HNMR (600 MHz,
DMSO)
8(ppm): 7.32 (s, 1H), 7.28 (d, 1H), 7.19 (t, 1H), 7.02 (d, 1H), 2.25 (s, 3H),
1.59 (s, 3H).
I \ = I \ =
OH CH2N2 OH
-
O OH O OCHs
Methyl 2(R)-(3-methylphenyl)lactate:
To a solution of 2(R)-(3-methylphenyl)lactic acid (3.64 g, 20.2 mmol) in
anhydrous diethyl
ether (100 ml) was added diazomethane ether solution (freshly produced
following
procedures in Aldrich Technical Bulletin AL-180) until a bright yellow color
is produced or
no more bubbles were evolved. The solution was then concentrated to dryness to
a white
solid.'HNMR (600 MHz, CDC13) S(ppm): 7.39 (s, 1H), 7.35 (d, 1H), 7.25 (t, 1H),
7.13 (d,
1H), 3.79 (s, 3H), 2.40 (s, 3H), 1.80 (s, 3H).
I / = OH Urea/NaOEt I _
O
O OCH3 O N
H
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(R)-5-Methyl-5-(3-methyphenyl)oxazolidinedione:
To a solution of methyl 2(R)-(3-methylphenyl)lactate (3.9 g, 20.1 mmol) in
anhydrous
ethanol (50 n-fl), was added NaOEt in ethanol (21% wt/wt, 9.8 ml, 30 mmol),
and urea (1.5 g,
24.2 mmol). The mixture was heated to 95 C and refluxed overnight. The
solution was then
cooled to room temperature, acidified with 1N HCI, concentrated to small
volume, and
diluted with water (100 ml). The aqueous mixture was extracted with ethyl
acetate (3x50m1).
The organic extracts were combined, washed with brine, dried over anhydrous
MgzSO4, and
concentrated to dryness to obtain an oil which was used in the next step
without further
purification. 'H NMR (500 MHz, CDC13) S 8.70 (s, broad, IH), 7.4 - 7.2
(overlapping
signals, 4H), 2.40 (s, 3H), 1.96 (s, 3H).
I \ _ TrCUEt3N
O
O
~o >==o
O H O Tr
(R)-5-Methyl-5-(3-methyphenyl)-N-trityloxazolidinedione:
To a solution of (R)-5-methyl-5-(3-methyphenyl)oxazolindione (4.3 g, 20.9
mmol) in
anhydrous methylene chloride (50 ml) was added triethyl amine (2.1 g, 23 mmol)
and trityl
chloride (6.4 g, 23 mmol). The mixture was stirred under nitrogen at room
temperature for 1
hour, washed with water (20 ml), brine (20 ml), dried over anhydrous Mg2SO4,
and
concentrated to dryness to obtain a solid. 'H NMR (500 MHz, CDC13) S 7.40-7.20
(multiple
overlapping peaks, 19H), 2.40 (s, 3H), 1.76 (s, 3H).
NBS/AIBN I _
: O --> Br O
O N>--O CC14 N~O
Tr O Tr
(R)-5-Bromomethyl-5-(3-methyphenyl)-N-trityloxazolidinedione:
To a solution of (R)-5-methyl-5-(3-methyphenyl)-N-trityloxazolidinedione (3.0
g, 6.7 mmol)
in carbon tetrachloride (100 ml) was added N-bromosuccinamide (1.1 g, 6.7
mmol), and
AIBN (catalytic). The mixture was heated to 80 C and refluxed overnight. The
solution was
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then cooled to room temperature, washed with saturated NaHCO3 solution (20 n-
d), water (20
nil), and brine (20 nil), and concentrated to dryness. The residue was
purified by silica gel
column chromatography with hexane/ethyl acetate (9:10) as a solvent to obtain
a white solid.
'H NMR (500 MHz, CDC13) S 7.5-7.2 (multiple overlapping peaks, 19H), 4.56 (s,
2HH),
1.76 (s, 3H).
ci
cl FsCO N I / O
I\ _ I >_
_O F3C0 N N
O N I O H
Br / = ~O + 1 Cs2_~ N ~O
N ~ ~ 2, TFA
Tr I
0 N O / OCH3 N\
O OCH3
(5R)-5-(4-chloro-3-{ [3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-oxo-6-
(trifluoromethoxy)-2,3-
dihxdro-lH-benzimidazol-1-yllmethyl )phenyl)-5-methyl-1,3-oxazolidine-2,4-
dione:
To a solution of 1-[3-(6-methoxy)-benzisoxazoyl]-5-
trifluoromethoxylbenzimidazole-2-one
(700 mg, 1.92 mmol) in DMF (20m1) were added (R)-5-methyl-5-(3-bromomethy-4-
chlorophenyl)-N-trityloxazolidinedione (1.1 g, 1.93 mmol), and Cs2CO3 (1.25 g,
3.8 mmol).
The mixture was stirred at room temperature overnight, diluted with water (30
ml) and
extracted with ethyl acetate (2x30 ml). The organic extracts were combined,
dried over
anhydrous Mg2SO4, and concentrated to obtain 1.5 g (92%) of a solid. The solid
was
dissolved in neat trifluoromethane sulfonic acid (5 ml) and stirred at room
temperature for 6
hours. The mixture was then concentrated to dryness under vacuum, and purified
by silica
gel column chromatography with hexane/ethyl acetate/TFA (3/1/0.01) as solvent
system to
obtain a white solid. 'H NMR (500 MHz, CDC13) 8 8.59 (brs, 1H), 8.14 (d, 1H),
7.95 (d,
1H), 7.62 (s, 1H), 7.56 (s, 2H), 7.03 (m, 3H), 6.91(s, 1H), 5.34 (s, 2H), 3.98
(s, 3H), 1.84 (s,
3H).
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I
H O
N ~
~p N O
O
Br p O
N H
~+ 1' CsZCO3/D-F
)R0
/ \ 2, TFA
N I / I\
O / pCH3 N O /
OCHg
(5R)-5-(3-{ [3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-oxo-2,3-dihydro-lH-
benzimidazol-l-
yl methyl)phenyl)-5-methyl-1,3-oxazolidine-2,4-dione:
To a solution of 1-[3-(6-methoxy)-benzisoxazoyl]benzimidazole-2-one (266 mg,
0.95 mmol)
in DMF (3 n-d) were added (R)-5-methyl-5-(3-bromomethylphenyl)-N-
trityloxazolidinedione
(500 mg, 0.95 mmol), and CszCO3 (620 mg, 1.9 mmol). The mixture was stirred at
room
temperature overnight, diluted with water (10 ml) and extracted with ethyl
acetate (2x10 ml).
The organic extracts were combined, dried over anhydrous MgZSO4, and
concentrated to
obtain a solid. The solid was dissolved in neat trifluoromethane sulfonic acid
(5 n-fl) and
stirred at room temperature for 6 hours. The mixture was then concentrated to
dryness under
vacuum, and purified by silica gel column chromatography with hexane/ethyl
acetate/TFA
(3/1/0.01) as solvent system to obtain a white solid. 'H NMR (500 MHz, CDC13)
S 8.18 (d,
1H), 7.92 (d, 1H), 7.71 (s, 1H), 7.56 (brs, 1H), 7.43 (brs, 2H), 7.23 (m, 2H),
7.08 (s, 1H),
7.02 (m, 2H), 5.28 (dd, 2H), 3.98 (s, 3H), 1.99 (s, 3H).
H
F3C N >==/ O
I I p F3C )4-' N pO 1' CSZC03/D-F ~p
N H
p + / 2, TFA
OCF3
OCF3
5-(3-( [2-oxo-3-f4-(trifluoromethoxx)phenyll-6-(trifluoromethyl)-2,3-dihydro-
lH-
benzimidazol-1-yl1 methyl ) benzyl)-1,3-oxazolidine-2,4-dione:
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To the solution of 1-(4-trifluoromethoxyphenyl)-5-trifluoromethylbenzimidazole-
2-one (362
mg, 1 mmol) in DMF (4 ml) was added 5-(3-bromomethylbenzyl)-N-
trityloxazolidinedione
(525 mg, 1.0 mmol), and Cs2CO3 (620 mg, 1.9 mmol). The mixture was stirred at
room
temperature overnight, diluted with water (10 ml) and extracted with ethyl
acetate (2x 10 ml).
The organic extracts were combined, dried over anhydrous MgZSO4, and
concentrated to
obtain a solid. The solid was dissolved in neat trifluoromethane sulfonic acid
(2 ml) and
stirred at room temperature for 4 hours. The mixture was then concentrated to
dryness under
vacuum, and purified by silica gel column chromatography with hexane/ethyl
acetate/TFA(3/1/0.01) as solvent system to obtain a white solid. LC-MS m/e:
(M+1) = 565
EXAMPLES
Example 1
_
O
O
N O N~
~O H
N
N~ I ~ CI
~
0
(5R)-5-(3-{ f 3-(5-chloro-1,2-benzisoxazol-3-yl)-2-oxo-2,3-dihydro-lH-
benzimidazol-l-
yl methyl}phenyl)-5-methyl-1,3-oxazolidine-2,4-dione:
'H NMR (500 MHz, CDC13) 8 8.39 (s, 1H), 8.33 (brs, IH), 7.92 (d, IH), 7.71 (s,
1H), 7.61
(s, 2H), 7.58 (d, 1H), 7.42 (m, 2H), 7.21 (d, 2H), 7.02(d, 1H), 5.23 (dd, 2H),
1.99 (s, 3H).
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Example 2
ci
I ~ - O
0
F3C N O N
~O
N
N'
O a
OCH3
(5R)-5-(4-chloro-3-{f3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-oxo-6-
(trifluorometh l
dihydro-lH-benzimidazol-1- lly methyl}phenyl)-5-methyl-1,3-oxazolidine-2,4-
dione:
'H NMR (500 MHz, CDC13) S 8.14 (d, 1H), 8.02 (d, 1H), 7.67 (s, 1H), 7.57 (s,
1H), 7.52 (d,
1H), 7.26 (m, 2H), 7.09 (s, IH), 7.06 (d, IH), 5.38 (s, 2H), 3.98 (s, 3H),
1.83 (s, 3H).
Example 3.
cl
I / O
O
N O
O H
N~
O OCH3
(5S)-5-(4-chloro-3-{ f 3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-oxo-2,3-dihydro-
lH-
benzimidazol-1- lly methyl lphenyl)-5-methyl-1,3-oxazolidine-2,4-dione:
'H NMR (500 MHz, CDC13) S 9.30 (brs, IH), 8.09 (d, IH), 7.88 (d, IH), 7.61 (s,
1H), 7.42
(s, 2H), 7.21 (m, 2H), 7.01 (m, 3H), 5.32 (s, 2H), 3.98 (s, 3H), 1.76 (s, 3H).
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Example 4.
o
04
= NH
o
F3C0 rjj
>==o
N
I~
N'
O ~ OCH3
(5R)-5-(4-{ f 3-(6-methoxY-1,2-benzisoxazol-3-yl)-2-oxo-6-(trifluoromethoxy)-
2,3-dihydro-
1 H-benzimi dazol-1-yll methyl 1 phenyl )-5 -methyl-1, 3-oxazolidine-2,4-
dione:
'H NMR (5001VIHz, CDC13) S 8.19 (d, IH), 7.98 (d, 1H), 7.65 (d, 2H), 7.52 (d,
2H), 7.13 (d,
1H), 7.11 (s, 1H), 7.02 (d, 1H), 6.83 (s, 1H), 5.20 (s, 2H), 3.98 (s, 3H),
1.99 (s, 3H).
Example 5.
o~
a
~ N
H
C >==o
N
OCH3
(5S)-5-(4-( f 3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-oxo-2,3-dihydro-lH-
benzimidazol-l-
yl methyl }benzyl)-5-methyl-l,3-oxazolidine-2,4-dione:
'H NMR (500 MHz, CDC13) S 8.19 (d, 1H), 7.90 (d, 1H), 7.40 (d, 2H), 7.23 (d,
2H), 7.21
(m, 2H), 7.05 (s, 1H), 7.00 (d, IH), 6.98 (d, 1H), 5.19 (dd, 2H), 3.98 (s,
3H), 3.18 (dd, 2H),
1.64 (s, 3H).
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Example 6.
_
= O
~O
N
~p p H
N
NO a OCH3
(5R)-5-(3-{f3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-oxo-2,3-dihydro-lH-
benzimidazol-l-
1 methXllnhenyl)-5-methyl-1,3-oxazolidine-2,4-dione:
1H NMR (500 MHz, CDC13) S 8.18 (d, 1H), 7.92 (d, 1H), 7.71 (s, IH), 7.56 (brs,
1H), 7.43
(brs, 2H), 7.23 (m, 2H), 7.08 (s, 1H), 7.02 (m, 2H), 5.28 (dd, 2H), 3.98 (s,
3H), 1.99 (s, 3H).
Examples of other compounds of this invention are shown in Table 1. These
compounds
were made or can be made using the procedures disclosed herein.
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TABLE 1
Structure LC-MS LC-MS
(M+1) (M+1)
557 ~\ a 557
o
~-p
0
F3 I\ N>= 0 H F3C
N 0 N
p N ~ p H
/ N I
N' I ~ N I \
O / CI O /
1\ _ 0 553 _ p 557
~
F3C I\ N~p p H F3C Np p H
\%'N N
N N :10 CI
O / pCH O ,\- 537 ~ j- p 537
~o ~o
F3 ( ~p p H F3C N~p p H
N N
N\ I N; I ~
O /
lj p 537 lp 557
~o ~o ,, r N F3C )::1)0: N~ p O H F3 IN~p p H
N N
N\ N\ CI
O
_ 587 \ ~ 587
o
~
F3C N~pp H F3C N~p
I p H
N 'N
N\ \ N\ \
O / pCH O / OCH
-40-
CA 02565803 2006-11-10
WO 2006/022954 PCT/US2005/018721
587 \ = 569
c ~
0 0
o / p
p H
F3 N p p N I\ ~O
/ N F3C0 / N
N' I \ N/
O/ \
OCH O/
OCH3
i I\ = cl
607 607
>==o >==o
c N~p 0 H I\ ~p H
F3CO N F3CO/ N
N; I \ N I \
O / O /
i I \ = l
603 603
p o
~o >==o
~I\ N>==O 0 H I\ N>==p p H
F CO" N F3Cp / N
3
N; I \ N; I \
o / OCH3 O / OCH
CI I1:1 587 ci 1(\= 587
p / . p
F3CO I~ N~p p N F3CO I~ N~p p H
N; I \ N; I \
O O /
I
I \ _ 603 _ 607
o~p s o
F3CO N 0 N F3CO N~ p N
H H
C ~O O
N N
N I \ N?
I \
O / O /
OC CI
-41-
CA 02565803 2006-11-10
WO 2006/022954 PCT/US2005/018721
polH 607 I\ ~ 603
/ F3C0 N N FgCO I\ N~ O N
~O O H
\% ~N / N
N; I \ N I \
O /
CI O /
OCH
\ CI
603 N o 587
~ ~ \ ~o ~o
I / o 0
F3CO \ N 0 N FaCO / N H
I ~o H N/ \
/ N O ~ / a
N/
OaOCH
xc:cLri:o 583 583
FsCO O H H N O H
N? I \ N; I \
O / ~H O / OCH
\ 583 -~ 587
F~N~O ~O NH
/ N H
/ \
NO I/ F3CO I\ N~ I/
OCH3 O
/ N
N/ ~ \
O /
~\ 0 559 ~ j- 0 555
/
\ N ~O J \ N ~O
~ ~o o H ~ ~o o H
F3C0" v N F3CO/ N
N; I \ N; I \
O / O OCH
I
_ 523 = 519
>==o o~o
NO O H \ ~O O H
N N
N\o / I \ N\ I \
/
CI o
OCH
- 42 -
CA 02565803 2006-11-10
WO 2006/022954 PCT/US2005/018721
cl 519 489
o>==0 _
O
01N>=~ O O
N' I \ N
O / N~/ I \
OCHg
O /
\ 1ON>
I O~O NO H F3c N N
o ~ \
/
566
g F3c I~ N~O O~O
yiN
/ IO ~ C N O H
N~O OJ'NH
I ~ N
F3C O
OCF3
- 43 -
