Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
COMBINATION THERAPY FOR REDUCING THE RISKS
ASSOCIATED WITH CARDIO- AND CEREBROVASCULAR, DISEASE
FIELD OF THE INVENTION
The instant invention involves a drug combination
comprising a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitor (or HMG-CoA RI) in combination with an inhibitor
of cyclooxygenase-2.
BACKGROUND OF THE INVENTION
Inhibitors of cyclooxygenase-2 are a sub-class of the class of
drugs known as non-steroidal antiinflammatory drugs (NSAIDs). The
NSAIDs are active in reducing the prostaglandin-induced pain and
swelling associated with the inflammation process but are also active in
affecting other prostaglandin-regulated processes not associated with
the inflammation process. Thus, use of high doses of most common
NSAIDs can produce severe side effects, including life threatenting
ulcers, that limit their therapeutic potential. An alternative to NSAIDs
is the use of corticosteroids, which have even more drastic side effects,
especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production
of prostaglandin by inhibiting enzymes in the human arachidonic
acid/prostaglandin pathway including the enzyme cyclooxygenase
(COX). The recent discovery that there are two isoforms of the COX
enzyme, the first, COX-1, being involved with physiological functions
and the second, COX-2, being induced in inflamed tissue, has given rise
to a new approach. While conventional NSAIDs block both forms of the
enzyme, the identification of the inducible COX-2 enzyme associated
with inflammation has provided a viable target of inhibition which more
effectively reduces inflammation and produces fewer and less drastic
side effects. Many compounds which have activity as COX-2 inhibitors
have been identified, and much research continues in this area.
Recently, a study published in N. Eng. J. Med. (April 3,
1997) found that after several years of low-level inflammation, men are
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three times as likely to suffer heart attacks and twice as likely to have
strokes. The study evaluated 1,086 men with levels of the C-reactive
protein considered to be within normal range. Researchers found that
those whose levels were in the upper 25% of the group were three times
more likely to have suffered a heart attack more than six years later, and
twice as likely to have a stroke than those whose levels were in the lowest
25%. Aspirin's benefits were particularly pronounced in the group with
highest levels of the protein, suggesting that its anti-inflammatory
effects were responsible for reduction in heart attacks and strokes.
It has been clear for several decades that elevated blood
cholesterol is a major risk factor for coronary heart disease, and many
studies have shown that the risk of coronary heart disease (CHD) events
can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-
lowering armamentarium was limited essentially to a low saturated fat
and cholesterol diet, the bile acid sequestrants (cholestyramine and
colestipol), nicotinic acid (niacin), the fibrates and probucol.
Unfortunately, all of these treatments have limited efficacy or
tolerability, or both. Substantial reductions in LDL (low density
lipoprotein) cholesterol accompanied by increases in HDL (high density
lipoprotein) cholesterol could be achieved by the combination of a lipid-
lowering diet and a bile acid sequestrant, with or without the addition of
nicotinic acid. However, this therapy is not easy to administer or
tolerate and was therefore often unsuccessful except in specialist lipid
clinics. The fibrates produce a moderate reduction in LDL cholesterol
accompanied by increased HDL cholesterol and a substantial reduction
in triglycerides, and because they are well tolerated these drugs have
been more widely used. Probucol produces only a small reduction in
LDL cholesterol and also reduces HDL cholesterol, which, because of the
strong inverse relationship between HDL cholesterol level and CHD risk,
is generally considered undesirable. With the introduction of Iovastatin,
the first inhibitor of HMG-CoA reductase to become available for
prescription in 1987, for the first time physicians were able to obtain
large reductions in plasma cholesterol with very few adverse effects.
Recent studies have unequivocally demonstrated that
lovastatin, simvastatin and pravastatin, all members of the HMG-CoA
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reductase inhibitor class, slow the progression of atherosclerotic lesions
in the coronary and carotid arteries. Simvastatin and pravastatin have
also been shown to reduce the risk of coronary heart disease events, and
in the case of simvastatin a highly significant reduction in the risk of
coronary death and total mortality has been shown by the Scandinavian
Simvastatin Survival Study. This study also provided some evidence for
a reduction in cerebrovascular events.
Despite the substantial reduction in the risk of coronary
morbidity and mortality achieved by simvastatin, the risk is still
substantial in the treated patients. For example, in the Scandinavian
Simvastatin Survival Study, the 42% reduction in the risk of coronary
death still left 5% of the treated patients to die of their disease over the
course of this 5 year study. Further reduction of risk is clearly needed.
Improved therapies far treating, preventing and reducing
the risk of developing atherosclerosis, and cardiovascular and
cerebrovascular events and related disorders are currently being sought
for the large number of individuals who are at risk for these disorders.
The instant invention addresses this problem by providing a combination
therapy comprised of an HMG-CoA RI with a COX-2 inhibitor. When
administered as part of a combination therapy, the COX-2 inhibitor
together with the HMG-CoA RI provide enhanced treatment options as
compared to administration of either the HMG-CoA RI or the COX-2
inhibitor alone.
SUMMARY OF THE INVENTION
The instant invention provides a novel drug combination
comprised of an HMG-CoA reductase inhibitor in combination with a
COX-2 inhibitor, which is useful for treating, preventing, and/or
reducing the risk of developing atherosclerosis and atherosclerotic
disease events.
One object of the instant invention is to administer the
above-described combination therapy to people who do not yet show
clinical signs of atherosclerosis, but who are at risk of developing
atherosclerosis and associated diseases. Clinical manifestations of
atherosclerosis include atherosclerotic cardiovascular disease such as
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coronary heart disease (also known as ischemic heart disease),
cerebrovascular disease, and peripheral vessel disease. Toward this
end, the instant invention provides methods for preventing or reducing
the risk of developing atherosclerotic cardiovascular disease, coronary
heart disease, cerebrovascular disease and peripheral vessel disease,
and preventing or reducing the risk of a first or subsequent occurrence
of a coronary heart disease event, a cerebrovascular event, and/or
intermittent claudication, by administering the above-described
combination therapy to said at-risk persons.
A second object of the instant invention is to provide the
above-described combination therapy to people who have clinical signs of
atherosclerosis. Toward this end, the instant invention provides
methods for halting or slowing the progression of atherosclerotic
cardiovascular disease, coronary heart disease, ischemic heart disease,
cerebrovascular disease and peripheral vessel disease, and preventing
or reducing the risk of a first or subsequent occurrence of a coronary
heart disease event, a cerebrovascular event, and/or intermittent
claudication, by administering the above-described combination therapy
to said persons who have clinically manifest atherosclerotic disease.
A third object of the instant invention involves the above-
described methods further comprising the administration of one or more
additional active agents either in separate or combined dosage
formulations. A fourth object is to provide pharmaceutical compositions
which can be used in the above-described methods. Additional objects
will be evident from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention provides methods for preventing or
reducing the risk of developing atherosclerosis, as well as for halting or
slowing the progression of atherosclerotic disease once it has become
clinically evident, comprising the administration of a therapeutically
effective amount of an HMG-CoA RI in combination with a COX-2
inhibitor to a mammal who is at risk of developing atherosclerosis or
who already has atherosclerotic disease.
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Atherosclerosis encompasses vascular diseases and
conditions that are recognized and understood by physicians practicing
in the relevant fields of medicine. Atherosclerotic cardiovascular
disease, coronary heart disease (also known as coronary artery disease
or ischemic heart disease), cerebrovascular disease and peripheral
vessel disease are all clinical manifestations of atherosclerosis and are
therefore encompassed by the terms "atherosclerosis" and
"atherosclerotic disease."
The combination comprised of an HMG-CoA RI and a COX-
2 inhibitor may be administered to prevent or reduce the risk of
occurrence, or recurrence where the potential exists, of a coronary heart
disease event, a cerebrovascular event, andlor intermittent claudication.
Coronary heart disease events are intended to include CHD death,
myocardial infarction (i.e., a heart attack), and coronary
revascularization procedures. Cerebrovascular events are intended to
include ischemic or hemorrhagic stroke (also known as cerebrovascular
accidents} and transient ischemic attacks. Intermittent claudication is
a clinical manifestation of peripheral vessel disease. The term
"atherosclerotic disease event" as used herein is intended to encompass
coronary heart disease events, cerebrovascular events, and intermittent
claudication. It is intended that persons who have previously
experienced one or more non-fatal atherosclerotic disease events are
those for whom the potential for recurrence of such an event exists.
Accordingly, the instant invention also provides a method
for preventing or reducing the risk of a first or subsequent occurrence of
an atherosclerotic disease event comprising the administration of a
prophylactically effective amount of an HMG-CoA reductase inhibitor in
combination with a COX-2 inhibitor to a patient at risk for such an event.
The patient may already have atherosclerotic disease at the time of
administration, or may be at risk for developing it.
The instant invention also provides a method for treating,
preventing, and/or reducing the risk of developing atherosclerosis and
atherosclerotic disease events and reducing total cholesterol levels alone,
or in conjunction with the treatment for a COX-2 mediated disease or
disorder comprising the administration of a therapeutically effective
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amount of an HMG-CoA reductase inhibitor in combination with a COX-
2 inhibitor to a patient in need of such treatment. COX-2 mediated
diseases and disorders includes inflammatory diseases susceptible to
treatment with a non-steroidal anti-inflammatory agent, arthritis
including rheumatoid arthritis, and degenerative joint diseases
(osteoarthritis).
Persons to be treated with the instant combination therapy
include those at risk of developing atherosclerotic disease and of having
an atherosclerotic disease event. Standard atherosclerotic disease risk
factors are known to the average physician practicing in the relevant
fields of medicine. Such known risk factors include but are not limited
to hypertension, smoking, diabetes, low levels of high density lipoprotein
(HDL) cholesterol, and a family history of atherosclerotic cardiovascular
disease. Published guidelines for determining those who are at risk of
developing atherosclerotic disease can be found in: National Cholesterol
Education Program, Second report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel II), National Institute of Health, National Heart Lung
and Blood Institute, NIH Publication No. 93-3095, September 1993;
abbreviated version: Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults, Summary of the second
report of the national cholesterol education program (NCEP) Expert
Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults (Adult Treatment Panel II), JAMA, 1993, 269, pp. 3015-23.
People who are identified as having one or more of the above-noted risk
factors are intended to be included in the group of people considered at
risk for developing atherosclerotic disease. People identified as having
one or more of the above-noted risk factors, as well as people who already
have atherosclerosis, are intended to be included within the group of
people considered to be at risk for having an atherosclerotic disease
event.
A compound which inhibits HMG-CoA reductase is used in
combination with a COX-2 inhibitor to practice the instant invention.
Compounds which have inhibitory activity for HMG-CoA reductase can
be readily identified by using assays well-known in the art. For
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example, see the assays described or cited in U.S. Patent 4,231,938 at col.
6, and WO 84/02131 at pp. 30-33.
Examples of HMG-CoA reductase inhibitors that may be
used include but are not limited to lovastatin (MEVACOR~; see US
Patent No. 4,231,938), simvastati.n (ZOCOR~; see US Patent No.
4,444,784), pravastatin (PRAVACHOL~; see US Patent No. 4,346,227),
fluvastatin (LESCOL~; see US Patent No. 5,354,772), atorvastatin
(LIPITOR~; see US Patent No. 5,273,995) and cerivastatin (also known
as rivastatin; see US Patent No. 5,177,080). The structural formulas of
these and additional HMG-CoA reductase inhibitors that may be used in
the instant methods are described at page 87 of M. Yalpani, "Cholesterol
Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996).
The term HMG-CoA reductase inhibitor is intended to include all
pharmaceutically acceptable salt, ester and lactone forms of compounds
which have HMG-CoA reductase inhibitory activity, and therefor the use
of such salts, esters and lactone forms is included within the scope of
this invention. Preferably, the HMG-CoA RI is selected from lovastatin
and simvastatin, and most preferably simvastatin.
Herein, the term "pharmaceutically acceptable salts" shall
mean non-toxic salts of the compounds employed in this invention which
are generally prepared by reacting the free acid with a suitable organic
or inorganic base. Examples of salt forms of HMG-CoA reductase
inhibitors may include, but are not limited to, acetate, benzenesulfonate,
benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium,
calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide,
isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,
mesylate, methylbromide, methylnitrate, methylsulfate, mutate,
napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate,
phosphate/diphosphate, polygalacturonate, potassium, salicylate,
sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate,
tosylate, triethiodide, and valerate.
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Ester derivatives of the described compounds may act as
prodrugs which, when absorbed into the bloodstream of a warm-blooded
animal, may cleave in such a manner as to release the drug form and
permit the drug to afford improved therapeutic efficacy.
The terms "inhibitor of cyclooxygenase-2", "cyclooxygenase-
2 inhibitor" and "COX-2 inhibitor" as used herein embrace compounds
which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
Employing the human whole blood COX-1 assay and the human whole
blood COX-2 assay described in C. Brideau et al, Inflamm. Res. 45: 68-74
(1996), herein incorporated by reference, preferably, the compounds have
a cyclooxygenase-2 IC50 of less than about 2 ~M in the human whole
blood COX-2 assay, yet have a cyclooxygenase-1 IC50 of greater than
about 5 ~tM in the human whole blood COX-1 assay. Also preferably, the
compounds have a selectivity ratio of cyclooxygenase-2 inhibition over
cyclooxygenase-1 inhibition of at least 10, and more preferably of at least
40. The resulting selectivity may indicate an ability to reduce the
incidence of common NSAID-induced side effects.
As explained in J. Talley, Exp. Opin. Ther. Patents ( 1997),
7(1), pp. 55-62, three distinct structural classes of selective COX-2
inhibitor compounds have been identified. One class is the methane
sulfonanilide class of inhibitors, of which NS-398, flosulide, nimesulide
and L-745,337 are example members.
NHSO~CH3 NHS02CH3 NHSO~CH~
\ O~ ( \ O \
F
N02 N02
O
NS-398 Nimesuiide L-745,337, X = S
Flosulide, X = O
A second class is the tricyclic inhibitor class, which can be
further divided into the sub-classes of tricyclic inhibitors with a central
carbocyclic ring (examples include SC-57666, 1, and 2); those with a
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central monocyclic heterocyclic ring (examples include DuP 697, SC-
58125, SC-58635, and 3, 4 and 5); and those with a central bicyclic
heterocyclic ring (examples include 6, 7, 8, 9 and 10). Compounds 3, 4
and 6 are described in U.S. Patent No. 5,474,995 .
CH3S0 ' " izSO; ~' ' DSO
z
F
SC-57666
CH3S0; CHs,SO;
Br CF3
DuP 697 5
NH2SOz CHs,SOz
CF3
H3C SC-58635
3
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CH9S0 CH3SO2
F
4
5
CH3S0; CH3SO2
O
N S
N ~ N N
_ ~J
6
CH3SO2 NH2S02
N~N
CF3
r / S
CH30 1
F 9
NH2S02
N
N, ~ CFs
r,
C H30
The third identified class can be referred to as those which
are structurally modified NSAIDS, and includes L-761,066 and structure
5 11 as example members.
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CH.. CQ~"'~ H
CH. CI
L-761,066 U 1 i
In addition to the structural classes, sub-classes, specific
COX-2 inhibitor compound examples, and reference journal and patent
publications described in the Talley publication which are all herein
incorporated by reference, examples of compounds which selectively
inhibit cyclooxygenase-2 have also been described in the following patent
publications, all of which are herein incorporated by reference: U.S.
Patent No.'s 5,344,991, 5,380,738, 5,393,790, 5,409,944, 5,434,178,
5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, 5,550,142, 5,552,422,
5,604,253 , 5,604,260, 5,639,780; and International Patent Specification
Nos. 94/13635, 94/15932, 94/20480, 94/26731, 94/27980, 95/00501, 95/15316,
96/03387, 96/03388, 96/06840; and International Publication No.'s WO
94/20480, WO 96/21667, WO 96J31509, WO 96/36623, WO 97/14691, WO
97/16435.
Additional COX-2 inhibitor compounds which are included
in the scope of this invention include:
O, / O~ ,
n
O
CI
O
12 13
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0. / ~, /
O
F
O
14 F 15
i
Q. / O. /
..
0
_ F O ~N
16 17 '(S~~
O.~ /
/ S, S,.
O O
O
O~
O
18 O 19
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,~ /
O
Na+
7
ci o
20 21
O, / O. /
1
/'~S O
i
off ~ off
22 23
F
C
24 25
Some of the compounds above can also be identified by the
following chemical names:
3: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;
4: 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-{5H)-furanone;
5: 5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(3-fluorophenyl)-5H-furan-
2-one;
SO
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12: 5,5-dimethyl-4-(4-(methylsulfonyl)phenyl}-3-(2-propoxy)-5H-furan-2-
one ;
13: 5-chloro-3-(4-(methylsulfonyl)phenyl~2-(2-methyl-5-
pyridinyl)pyridine;
14: 2-( 3, 5-difluorophenyl )-3-(4-(methyl sulfonyl )phenyl )-2-cyclopenten-1-
one;
15: 5(S)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-
furan-2-one;
16: 5-a thyl-5-methyl-4-(4-(methylsulfonyl)phenyl )-3-(3,4-difluorophenyl )-
5H-furan-2-one;
17: 3-((2-thiazolyl)methoxy}-4-(4-(methylsulfonyl)phenyl)-5,5-dimethyl-
5H-furan-2-one ;
18: 3-propyloxy-4-(4-(methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-
one;
19: 3-( 1-cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-
furan-2-one;
20: sodium 2-(4-chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-4-oxo-2-
pentenoate ;
21: 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-
furan-2-one;
22: 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-2,5-
dihydrofuran-2-ol;
23: 3-isopropoxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-2,5-
dihydrofuran-2-ol;
24:5,5-dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-
(methylsulfonyl)phenyl)-2,5-dihydrofuran;
25: 5-Chloro-3-(4-(methylsulfonyl)phenyl)-2-(3-pyridinyl)pyridine.
The following publications describe and/or provide methods
for making the compounds as indicated: compounds 12, 15, 17, 18, 19 and
21, WO 97/14691; compounds 22, 23 and 24, WO 97/16435; compound 20,
WO 96/36623; compound 14, U.S. Patent No. 5,536,752; compound 16, U.S.
Patent No. 5,474,995. See Examples herein for compounds 13 and 25 .
Also incorporated herein by reference are those compounds
described in WO 96/41645 as having structural Formula I, shown below,
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and the definition and preferred definitions and species described
therein:
R2 ~O R~
A~R3
O
Particularly preferred compounds of formula (I) include:
5-(4-fluorophenyl )-1-[4-(methylsulfonyl )phenyl]-3-
(trifluoromethyl)pyrazole;
4-(4-fluorophenyl )-5-[4-(methylsulfonyl )phenyl]-1-phenyl-3-
(trifluoromethyl)pyrazole;
4-(5-{4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazal-1-
yl)benzenesulfonamide;
4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl )-3-(4-nitrophenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(5-phenyl)-3-(trifluoromethyl)-1H-pyrazal-1-yl)benzenesulfonamide;
4-(5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazal-1-
yl)benzenesulfonamide;
4-(5-{4-methoxyphenyl)-3-(trifluoromethyl)-IH-pyrazol-1-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
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4-( 5-(4-methylphenyl )-3-(trifluoromethyl )-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-( 3-(difluoromethyl )-5-phenyl-1H-pyrazol-1-yl )benzenesulfonamide;
4-(3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(3-(difluoromethyl)-5-{3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(4-chloro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-( 5-(4-chlorophenyl )-3-(hydroxyphenyl )-1H-pyrazol-1
yl)benzenesulfonamide;
4-(5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yI)benzenesulfonamide;
5-(4-fluorophenyl)-6-(4-(methylsulfonyl)phenyl)spiro(2.4]hept-5-ene;
4-(6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl)benzenesulfonamide;
6-(4-fluorophenyl)-7-(4-(methylsulfonyl)phenyl)spiro(3.4]oct-6-ene;
5-(3-chloro-4-methoxyphenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.4]hept-
5-ene;
4-(6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-
yl)benzenesulfonamide;
5-(3,5-dichloro-4-methoxyphenyl)-6-(4-
(methylsulfonyl)phenyl)spiro[2.4]hept-5-ene;
5-(3-chlaro-4-fluorophenyl )-6-(4-(methylsulfonyl)phenyl)spiro(2.4]hept-5-
ene;
4-(6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl)benzenesulfonamide;
2-( 3-chloro-4-fluorophenyl )-4-(4-fluorophenyl )-5-(4-
methylsulfonylphenyl)thiazole;
2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;
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WO 99/20110 PCT/US98/21901
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole;
4-(4-fluorophenyl )-5-(4-methylsulfonylphenyl )-2-( 1-propylamino )thiazole;
2-((3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-(4-
(methylsulfonyl)phenyl)thiazole;
5-( 4-fluorophenyl )-4-(4-methyl sulfonylphenyl )-2-trifluoromethylthi azole;
1-methylsulfonyl-4-( 1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-
yl)benzene;
4-(4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-
yl)benzenesulfonamide;
5-(4-fluorophenyl)-fi-(4-(methylsulfonyl)phenyl)spiro[2.4]hepta-4,6-diene;
4-(6-(4-fluorophenyl)spiro[2.4]hepta-4,6-lien-5-yl)benzenesulfonamide;
6-(4-fluorophenyl)-2-methoxy-5-(4-(methylsulfonyl)phenyl)-pyridine-3-
carbonitrile;
2-bromo-6-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-pyridine-3-
carbonitrile;
6-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-phenyl-pyridine-3-
carbonitrile;
4-(2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
4-( 2-(5-methylpyridin-3-yl )-4-(trifluoromethyl )-1H-imidazol-1-
yl)benzenesulfonamide;
4-( 2-(2-methylpyridin-3-yl )-4-( trifluoromethyl )-1H-imidazol-1-
yl)benzenesulfonamide;
3-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-2-
yl)benzenesulfonamide;
2-( 1-(4-(methyl sulfonyl )phenyl )-4-(trifluoromethyl )-1H-imidazal-2-
yl)pyridine;
2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-
imidazol-2-yl)pyridine;
2-methyl-6-( 1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-
imidazol-2-yI)pyridine;
4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
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WO 99/20110 PCT/US98/21901
2-(3,4-difluorophenyl)-I-(4-(methylsulfonyl )phenyl )-4-(trifluoromethyl )-
1H-imidazole;
4-(2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-methyl-1H-imidazole;
2-(4-chlorophenyl)-1-(4-(methylsulfonyl}phenyl)-4-phenyl-1H-imidazole;
2-(4-chlorophenyl )-4-(4-fluorophenyl )-1-(4-(methylsulfonyl )phenyl )-1H-
imidazole;
2-(3-fluoro-4-methoxyphenyl )-1-{4-(methylsulfonyl )phenyl )-4-
(trifluoromethyl)-IH-imidazole;
1-(4-(methylsulfonyl)phenyl)-2-phenyl-4-trifluoromethyl-1H-imidazole;
2-(4-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-trifluoromethyl-1H-
imidazole;
4-(2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
2-(3-fluoro-5-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-
(trifluoromethyl)-1H-imidazole;
4-( 2-(3-fluoro-5-methylphenyl )-4-(trifluoromethyl )-1H-imidazol-1-
yl)benzenesulfonamide;
2-(3-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-{trifluoromethyl)-1H-
imidazole;
4-(2-(3-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
1-(4-(me thylsulfonyl)phenyl)-2-(3-chlorophenyl )-4-(trifl uoromethyl )-1H-
imidazole;
4-(2-{3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
4-(2-phenyl-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;
4-(2-(4-methoxy-3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
1-allyl-4-(4-fluorophenyl~3-(4-(methylsulfonyl)phenyl)-5-
(trifluoromethyl)-1H-pyrazole;
4-( 1-ethyl-4-(4-fluorophenyl )-5-(trifluoromethyl )-1H-pyrazol-3-
yl)benzenesulfonamide;
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WO 99J20110 PCT/US98J21901
N-phenyl-(4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-
(trifluoromethyl)-1H-pyrazol-1-yl)acetamide;
ethyl (4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-
1H-pyrazol-1-yl)acetate;
4-(4-fluorophenyl )-3-(4-(methyl sulfonyl)phenyl)-1-( 2-phenylethyl )-1H-
pyrazole;
4-(4-fluorophenyl)-3-(4-(methylsulfonyl~henyl)-1-(2-phenylethyl)-5-
(trifluoromethyl~yrazole;
1-ethyl-4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-
(trifluoromethyl)-1H-pyrazole;
5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)-1H-
imidazole;
4-(4-(methylsulfonyl)phenyl)-5-{2-thiophenyl)-2-(trifluoromethyl)-1H-
imidazole;
5-(4-fluorophenyl)-2-methoxy-4-(4-(methyisulfonyl)phenyl)-6-
(trifluoromethyl)pyridine;
2-ethoxy-5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-6-
(trifluoromethyl)pyridine;
5-(4-fluorophenyl)-4-{4-(methylsulfonyl)phenyl)-2-(2-propynyloxy)-6-
(trifluoromethyl)pyridine;
2-bromo-5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-6-
(trifluoromethyl)pyridine;
4-(2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl)benzenesulfonamide;
1-(4-fluorophenyl)-2-{4-(methylsulfonyl)phenyl)benzene;
5-difluoromethyl-4-(4-(methylsulfonyl)phenyl)-3-phenylisoxazole;
4-(3-ethyl-5-phenylisoxazol-4-yl)benzenesulfonamide;
4-( 5-difluoromethyl-3-phenyli soxazol-4-yl)benzene sulfonamide;
4-(5-hydroxymethyl-3-phenylisoxazol-4-yl)benzenesulfonamide;
4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide;
1-(2-(4-fluorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-(2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl)-4-
(methylsulfonyl)benzene;
1-(2-(4-chlorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-(2-(2,4-dichlorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
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WO 99/20110 PCTNS98I21901
I-(2-(4-trifluoromethylphenyl)cyclopenten-1-yl)-4-
(methylsulfonyl)benzene; .
1-(2-(4-methylthiophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-{2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl)-4-
(methylsulfonyl)benzene;
4-( 2-(4-fluorophenyl )-4,4-dimethylcyclopenten-1-yl)benzenesulfonamide;
1-{2-(4-chlorophenyl )-4,4-dimethylcyclopenten-1-yl )-4-
(methylsulfonyl)benzene;
4-(2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl)benzenesulfonamide;
IO 4-(2-(4-fluorophenyl)cyclopenten-1-yl)benzenesulfonamide;
4-(2-(4-chlorophenyl)cyclopenten-1-yl)benzenesulfonamide;
1-(2-(4-methoxyphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-(2-(2,3-difluorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
4-{2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl)benzenesulfonamide;
1-(2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl)-4-
(methylsulfonyl)benzene;
4-(2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl)benzenesulfonamide;
4-(2-(2-methylpyridin-5-yl)cyclopenten-1-yl)benzenesulfonamide;
ethyl 2-(4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl)-2-
benzyl-acetate;
2-(4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl)acetic acid;
2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazole;
4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-phenyloxazole;
4-{4-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)oxazole; and
4-(5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-
oxazolyl)benzenesulfonamide;
or a pharmaceutically acceptable salt thereof.
The compounds of use in this invention may have one or
more chiral centers and the present compounds may occur as
racemates, racemic mixtures and as individual diasteriomers or
enantiomers with all such isomeric forms and mixtures thereof being
included within the scope of this invention. Furthermore, some of the
crystalline forms for compounds of the present invention may exist as
polymorphs and as such are intended to be included in the present
invention. In addition, some of the compounds of the instant invention
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WO 99120110 PCT/US98/21901
may form solvates with water or common organic solvents. Such
solvates and hydrates, as well as anhydrous compositions, are
encompassed within the scope of this invention. 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.
The COX-2 inhibitors that may be used with this invention
encompass all pharmaceutically acceptable salt forms of the
compounds. Examples of such salt forms of COX-2 inhibitors include
but are not limited to salts derived from inorganic bases including
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 derived from
pharmaceutically acceptable organic non-toxic bases include salts of
primary, secondary, and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines, and basic ion
exchange resins, such as arginine, betaine, caffeine, choline, N,N-
dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-
dimethylaminoethanol, ethanolamine, ethylenediamine, N-
ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,
hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,
piperazine, piperidine, polyamine resins, procaine, purines,
theobromine, triethylamine, trimethylamine, tripropylamine,
tromethamine, and the like.
The instant pharmaceutical combination comprising an
HMG-CoA reductase inhibitor in combination with a COX-2 inhibitor
includes administration of a single pharmaceutical dosage formulation
which contains both the HMG-CoA reductase inhibitor and the COX-2
inhibitor, as well as administration of each active agent in its own
separate pharmaceutical dosage formulation. Where separate dosage
formulations are used, the HMG-CoA reductase inhibitor and the COX-2
inhibitor can be administered at essentially the same time, i.e.,
concurrently, or at separately staggered times, i.e, sequentially. The
instant pharmaceutical combination is understood to include all these
regimens. Administration in these various ways are suitable for the
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present invention as long as the beneficial pharmaceutical effect of the
HMG-CoA reductase inhibitor and the COX-2 inhibitor are realized by
the patient at substantially the same time. Such beneficial effect is
preferably achieved when the target blood level concentrations of each
active drug are maintained at substantially the same time. It is
preferred that the HMG-CoA reductase inhibitor and the COX-2
inhibitor be co-administered concurrently on a once-a-day dosing
schedule; however, varying dosing schedules, such as the HMG-CoA RI
once per day and the COX-2 inhibitor once, twice or more times per day,
is also encompassed herein. A single oral dosage formulation
comprised of both an HMG-CoA reductase inhibitor and the COX-2
inhibitor is preferred. A single dosage formulation will provide
convenience for the patient, which is an important consideration
especially for patients who already have coronary heart disease and may
be in need of multiple medications.
The term "therapeutically effective amount" is intended to
mean that amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, a system, animal or human
that is being sought by a researcher, veterinarian, medical doctor or
other clinician. The term "prophylactically effective amount" is
intended to mean that amount of a pharmaceutical drug that will
prevent or reduce the risk of occurrence of the biological or medical event
that is sought to be prevented in a tissue, a system, animal or human by
a researcher, veterinarian, medical doctor or other clinician. The
dosage regimen utilizing an HMG-CoA RI in combination with COX-2
inhibitor is selected in accordance with a variety of factors including
type, species, age, weight, sex and medical condition of the patient; the
severity of the condition to be treated; the route of administration; the
renal and hepatic function of the patient; and the particular compound
or salt or ester thereof employed. Since two different active agents are
being used together in a combination therapy, the potency of each of the
agents and the interactive effects achieved by combining them together
must also be taken into account. A consideration of these factors is well
within the purview of the ordinarily skilled clinician for the purpose of
determining the therapeutically effective or prophylactically effective
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dosage amounts needed to prevent, counter, or arrest the progress of the
condition.
The term "patient" includes mammals, especially humans,
who take an HMG-CoA reductase inhibitor in combination with a COX-2
inhibitor for any of the uses described herein. Administering of the drug
combination to the patient includes both self administration and
administration to the patient by another person.
In particular, the daily dosage amounts of the HMG-CoA
reductase inhibitor are intended to be the same or similar to those
amounts which are employed for anti-hypercholesterolemic treatment
and which are described in the Physicians' Desk Reference (PDR). For
example, see the 50th Ed. of the PDR, 1996 (Medical Economics Co); in
particular, see at page 216 the heading "Hypolipidemics," sub-heading
"HMG-CoA Reductase Inhibitors," and the reference pages cited
therein. Preferably, the oral dosage amount of HMG=CoA RI is from
about 1 to 200 mg/day, and more preferably from about 5 to 1fi0 mg/day.
However, dosage amounts will vary depending on the potency of the
specific HMG-CoA reductase inhibitor used as well as other factors as
noted above. An HMG-CoA RI which has sufficiently greater potency
may be given in sub-milligram daily dosages. The HMG-CoA reductase
inhibitor may be administered from 1 to 4 times per day, and preferably
once per day.
As examples, the daily dosage amount for simvastatin may
be selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg; for
lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20
mg, 40 mg and 80 mg; for pravastatin sodium, 10 mg, 20 mg, and 40 mg;
and for atorvastatin calcium, 10 mg, 20 mg, and 40 mg.
The inhibitor of cyclooxygenase-2 may be administered at a
dosage level up to conventional dosage levels for NSAIDs. Suitable
dosage levels will depend upon the antiinflammatory effect of the chosen
inhibitor of cyclooxygenase-2, but typically suitable levels will be about
0.001 to 50 mg/kg per day, preferably 0.005 to 30mg/kg per day, and
especially 0.05 to lOmg/kg per day. The compound may be administered
on a regYmen of up to 6 times per day, preferably 1 to 4 times per day, and
especially once per day.
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Additional active agents may be used in combination with
the HMG-CoA RI and COX-2 inhibitor in a single dosage formulation, or
may be administered to the patient in a separate dosage formulation,
which allows for concurrent or sequential administration. One or more
additional active agents may be administered with the HMG-CoA RI and
COX-2 inhibitor. The additional active agent or agents can be cholesterol
lowering compounds. Examples of additional active agents which may
be employed include HMG-CoA synthase inhibitors; squalene epoxidase
inhibitors; squalene synthetase inhibitors (also known as squalene
synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase
(ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate,
fenofibrate, and gemfibrizol; cholesterol absorption inhibitors; bile acid
sequestrants; LDL (low density lipoprotein) receptor inducers; platelet
aggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogen
receptor antagonists and aspirin; vitamin B6 (also known as pyridoxine)
and the pharmaceutically acceptable salts thereof such as the HCl salt;
vitamin B12 (also known as cyanocobalamin); beta-blockers; folic acid or
a pharmaceutically acceptable salt or ester thereof such as the sodium
salt and the methylglucamine salt; and anti-oxidant vitamins such as
vitamin C and E and beta carotene.
Examples of HMG-CoA synthase inhibitors include: the
beta-lactone derivatives disclosed in U.S. Patent No. 4,806,564, 4,816,477,
4,847,271, and 4,751,237; the beta lactam derivatives disclosed in U.S.
4,983,597 and the substituted oxacyclopropane analogues disclosed in
European Patent Publication EP O 411 703. The squalene synthetase
inhibitors suitable for use herein include, but are not limited to, those
disclosed by Biller et al., J. Med. Chem., 1988 Vol. 31, No. 10, pp. 1869-
1871, including isoprenoid (phosphinylmethyl)-phosphonates such as
those of the formula
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WO 99/20110 PCT/US98/21901
0
R -IP-CH2-i -O- R~-P-CF -P-O-
O- O- ~_ 2~_
wherein R1 is:
a / /
b / / /
c / /
d / /
including the triacids thereof, triesters thereof and tripotassium and
trisodium salts thereof as well as other squalene synthetase inhibitors
disclosed in pending U.S. Patent No. 4,$71,721 and 4,924,024 and in Biller
et al., J. Med.Chem., 1988, Vol. 31, No. 10, pp. 1869 to 1871.
In addition, other squalene synthetase inhibitors suitable
for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz
de Montellano et al., J. Med. Chem., 1977, 20, 243-249, the farnesyl
diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs
as disclosed by Corey and Volante, J. Am. Chem. Soc. 1976, 98, 1291-
1293, phosphinylphosphonate reported by McClard, R. W. et al.,
J.A.C.S., 1987, 109, X544 and cyclopropanes reported by Capson, T.L.,
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WO 99/20110 PCTNS98/21901
PhD dissertation, June, 1987, Dept. Med. Chem. U. of Utah, Abstract,
Table of Contents, pp. 16, 17, 40-43, 48-51, Summary.
Further, the benzodiazepine squalene synthase inhibitors
described in EP O 567 026 to Takeda Chemical Industries, and the
quinuclidinyl squalene synthase inhibitors described in PCT
publications WO 94/03451, WO 93/09115, WO 93/21183, WO 93/21184, WO
93/24486, and U.S. 5,135,935, may be co-administered with the HMG-CoA
RI plus COX-2 inhibitor combination of the present invention. In
addition, the zaragozic acid type squalene synthase inhibitors as
described in U.S. Patents 5,284,758; 5,283,256; 5,262,435; 5,260,332;
5,264,593; 5,260,215; 5,258,401; 5,254,727; 5,256,689; 5,132,320; 5,278,067,
and PCT Publications WO 92/12156; WO 92/12157; WO 92/12158; WO
92/12159; WO 92112160; WO 93/18040; WO 93/18039; WO 93/07151; and
European Patent Publications EP O 512 865, EP O 568 946; EP O 524,677
and EP O 450 812, as well as the acyclic tricarboxylic acid compounds of
U.S. patent 5,254,727, may be employed.
Illustrative examples of squalene epoxidase inhibitors are
disclosed in European Patent Publication EP O 318 860 and in Japanese
Patent Publication J02 169-571A. LDL-receptor gene inducer molecules
are disclosed in U.S. Patent No. 5,182,298.
Examples of bile acid sequestrants which may be employed
in the present method include cholestyramine, colestipol, and
poly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide] and
those disclosed in W095/34585 to Geltex Pharmaceuticals, Inc. and EP 0
622 078 assigned to Hisamitsu Pharmaceutical Co., Inc.
Examples of cholesterol absorption inhibitors which may be
employed in the present method include those described in WO 95/18143
and WO 95/18144 both assigned to Pfizer Inc., and WO 94//7038, WO
95/08532 and WO 93/02048 each assigned to Schering Corp.
The additional active agents described above which may be
employed along with the HMG-CoA RI and COX-2 inhibitor combination
therapy can be used, for example, in amounts as indicated in the PDR or
in amounts as indicated in the reference disclosures, as appropriate.
The active agents employed in the instant combination
therapy can be administered in such oral forms as tablets, capsules
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(each of which includes sustained release or timed release
formulations), pills, powders, granules, elixirs, tinctures, suspensions,
syrups, and emulsions. The instant invention includes the use of both
oral rapid-release and time-controlled release pharmaceutical
formulations. A particular example of an oral time-controlled release
pharmaceutical formulation is described in U.S Patent No. 5,366,738.
Oral formulations are preferred. Such pharmaceutical compositions
are known to those of ordinary skill in the pharmaceutical arts; for
example, see Remington's Pharmaceutical Sciences, Mack Publishing
Co., Easton, PA.
In the methods of the present invention, the active agents
are typically administered in admixture with suitable pharmaceutical
diluents, excipients or carriers (collectively referred to herein as
"carrier" materials) suitably selected with respect to the intended form
of administration, that is, oral tableta, capsules, elixirs, syrups and the
like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet
or capsule, the active drug component can be combined with a non-toxic,
pharmaceutically acceptable, inert carrier such as lactose, starch,
sucrose, glucose, modified sugars, modified starches, methyl cellulose
and its derivatives, dicalcium phosphate, calcium sulfate, mannitol,
sorbitol and other reducing and non-reducing sugars, magnesium
stearate, steric acid, sodium stearyl fumarate, glyceryl behenate,
calcium stearate and the like. For oral administration in liquid form,
the drug components can be combined with non-toxic, pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the like.
Moreover, when desired or necessary, suitable binders, lubricants,
disintegrating agents and coloring and flavoring agents can also be
incorporated inta the mixture. Stabilizing agents such as antioxidants
(BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be
added to stabilize the dosage forms. Other suitable components include
gelatin, sweeteners, natural and synthetic gums such as acacia,
tragacanth or alginates, carboxymethylcellulose, polyethylene glycol,
waxes and the like.
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The active drugs can also be administered in the farm of
liposome delivery systems, such as small unilamellar vesicles, large
unilamellar vesicles and multilamellar vesicles. Liposomes can be
formed from a variety of phospholipids, such as cholesterol,
stearylamine or phosphatidylcholines.
Active drug may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules are
coupled. Active drug may also be coupled with soluble polymers as
targetable drug carriers. Such polymers can include polyvinyl-
pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-
phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-
polylysine substituted with palmitoyl residues. Furthermore, active
drug may be coupled to a class of biodegradable polymers useful in
achieving controlled release of a drug, for example, polylactic acid,
polyglycolic acid, copolymers of polylactic and polyglycolic acid,
polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or
amphipathic block copolymers of hydrogels.
Although the active agents of the present method may be
administered in divided doses, for example two or three times daily, a
single daily dose of each of the HMG-CoA RI and the COX-2 inhibitor is
preferred, with a single daily dose of both agents in a single
pharmaceutical composition being most preferred.
The instant invention also encompasses a process for
preparing a pharmaceutical composition comprising combining the
HMG-CoA RI and the COX-2 inhibitor with a pharmaceutically
acceptable carrier, as well as the pharmaceutical composition which is
made by combining the HMG-CoA RI and the COX-2 inhibitor with a
pharmaceutically acceptable carrier.
A therapeutically effective amount of an HMG-CoA RI and
a COX-2 inhibitor can be used together for the preparation of a
medicament useful for preventing or reducing the risk of developing
atherosclerotic disease, halting or slowing the progression of
atherosclerotic disease once it has become clinically manifest, and
preventing or reducing the risk of a first or subsequent occurrence of an
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atherosclerotic disease event. For example, the medicament may be
comprised of a COX-2 inhibitor in combination with about 1 mg to 200 mg
of an HMG-CoA RI, or more particularly about 5 mg to 160 mg of the
HMG-CoA RI. More specific amounts of HMG-CoA RI which may be
used in the medicament preparation include 1 mg, 5 mg, 10 mg, 20 mg,
40 mg, 80 mg, and 160 mg, as well as sub-milligram amounts of HMG-
CoA RI's which have sufficient potency at such levels. As a further
example, the medicament may be comprised of an HMG-CoA RI in
combination with about 0.1 to 20 mg of a COX-2 inhibitor.
The instant invention also encompasses the use of an HMG-
CoA reductase inhibitor for the preparation of a medicament for the
combined use with a cyclooxygenase-2 inhibitor for preventing or
reducing the risk of developing atherosclerotic disease, for halting or
slowing the progression of atherosclerotic disease, or far preventing or
reducing the risk of occurrence or recurrence of an atherosclerotic
disease event; and the use of a cyclooxygenase-2 inhibitor for the
preparation of a medicament for the combined use with an HMG-CoA
reductase inhibitor for preventing or reducing the risk of developing
atherosclerotic disease, for halting or slowing the progression of
atherosclerotic disease, or for preventing or reducing the risk of
occurrence or recurrence of an atherosclerotic disease event. The
medicament or pharmaceutical combination comprised of the HMG-Co
RI and the COX-2 inhibitor may also be prepared with one or more
additional active agents, such as those described supra.
Examples of dosage formulations suitable for use in
practicing the instant invention follow.
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EXAMPLE 1
Ingredient Amountser tablet
Simvastatin 5.0 mg
BHA 0.02mg
Ascorbic acid 2.50 mg
Citric acid 1.25 mg
Microcrystalline cellulose5.0 mg
Pregel starch 10.0 mg
Magnesium stearate 0.5 mg
Lactose 74.73 mg
All the ingredients except magnesium stearate are blended
together in a suitable mixer. The powder mixture is then granulated
with adequate quantities of granulating solvent(s). The wet granulated
mass is dried in a suitable dryer. The dried granulation is sized
through a suitable screen. The sized granulation is mixed with
magnesium stearate before tableting. The tablets may be coated if
deemed necessary. Additional ingredients that may be added to the
IO above include suitable color and mixtures of colors.
EXAMPLE 2
Ingredient
Simvastatin 5.0 mg
BHA 0.04 mg
Citric acid 2.5 mg
Microcrystalline cellulose10.0 mg
Pregel starch 20.0 mg
Magnesium stearate 1.0 mg
Lactose 148.4fi mg
Hydrolized gelatin 8.0 mg
The process of manufacture
is essentially the
same as in
Example 1, above.
I5
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EXAMPLE 3
In edient oun~,Ber tablet
Simvastatin 80.0 mg
BHA 0.16 mg
Ascorbic acid 20.0 mg
Citric acid 10.0 mg
Microcrystalline cellulose40.0 mg
Pregel starch 80.0 mg
Lactose 550.0
mg
Colorant 5.0 mg
Magnesium stearate 4.8 mg
The process of manufacture is essentially the same as in
Example 1, above.
EXAMPLE 4
Wet granulated tablet composition
Amount per tabletIngredient
25 mg COX-2 Inhibitor
79.7 mg Microcrystalline cellulose
79.7 mg Lactose monohydrate
6 mg Hydroxypropyl cellulose
8 mg Croscarmellose sodium
0.6 mg Iron oxide
1 mg Magnesium stearate
Tablet dose strengths of between 5 and 125 mg can be
accomodated by varying total tablet weight, and the ratio of the first three
ingredients. Generally it is preferable to maintain a 1:1 ratio for
microcrystalline cellulose : lactose monohydrate.
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EXAMPLE 4A
Amount ner tabletIngredient
12.5 mg COX-2 Inhibitor
86 mg Microcrystalline cellulose
86 mg Lactose monohydrate
6 mg Hydroxypropyl cellulose
8 mg Croscarmellose sodium
0.6 mg Iron oxide
I mg Magnesium stearate
EXAMPLE 4B
Yet eranulated tablet conc,~osition
Amount per tabletIngredient
mg COX-2 Inhibitor
87.2 mg Microcrystalline cellulose
87.2 mg Lactose monohydrate
6 mg Hydroxypropyl cellulose
8 mg Croscarmellose sodium
0.6 mg Iron oxide
1 mg Magnesium stearate
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EXAMPLE 4C
Wet granulated tablet comDOSition
Amount er tabletIngredient
mg COX-2 Inhibitor
89.7 mg Microcrystalline cellulose
89.7 mg Lactose monohydrate
6 mg Hydroxypropyl cellulose
8 mg Croscarmellose sodium
0.6 mg Iron oxide
1 mg Magnesium stearate
5 EXAMPLE 5
~irectl~nressed tablet corr.~osition
Amount ner tabletIngredient
25 mg COX-2 Inhibitor
106.9 mg Microcrystalline cellulose
106.9 mg Lactose anhydrate
7.5 mg Crosmellose sodium
3.7 mg Magnesium stearate
Tablet dose strengths of between 5 and 125 mg can be
accomodated by varying total tablet weight, and the ratio of the first three
ingredients. Generally it is preferable to maintain a 1:1 ratio for
microcrystalline cellulose : lactose monohydrate.
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EXAMPLE 5A
Directly com~~ressed tablet s,~~~~g
Amount per tablet Ingredient
12.5 mg COX-2 Inhibitor
113.2 mg Microcrystalline cellulose
113.2 mg Lactose anhydrate
7.5 mg Croscarmellose sodium
3.7 mg Magnesium stearate
EXAMPLE 5B
Amount ver tabletIneredient
mg COX-2 Inhibitor
42.5 mg Microcrystalline cellulose
42.5 mg Lactose anhydrate
4 mg Croscarmellose sodium
1 mg Magnesium stearate
EXAMPLE 5C
10 Directl~~ressed ~,ablet composition
Amount per tablet Ingredient
5 mg COX-2 Inhibitor
45 mg Microcrystalline cellulose
45 mg Lactose anhydrate
4 mg Croscarmellose sodium
1 mg Magnesium stearate
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EXAMPLE 6
Bard eelatin caps l~ com»osition
Amount eoa r cap,,~yleIneredient
25 mg COX-2 Inhibitor
37 mg Microcrystalline cellulose
37 mg Lactose anhydrate
1 mg Magnesium stearate
1 capsule Hard gelatin capsule
Capsule dose strengths of between 1 and 50 mg can be
accomodated by varying total fill weight, and the ratio of the first three
ingredients. Generally it is preferable to maintain a I:1 ratio for
microcrystalline cellulose : lactose monohydrate.
EXAMPLE 7
fount pga~ 5 mL dose Ingredient
50 mg COX-2 Inhibitor
to 5 mL with Polyethylene oxide 400
Solution dose strengths of between 1 and 50 mg/5mL can be
accomodated by varying the ratio of the two ingredients.
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EXAMPLE 8
Oral suspension
Amount »er 5 mL dose Ineredient
101 mg COX-2 Inhibitor
150 mg Polyvinylpyrrolidone
2.5 mg Poly oxyethylene sorbitan monolaurate
mg Benzoic acid
to 5 mL with sorbitol solution (70%)
5 Suspension dose strengths of between 1 and 50 mg/5m1 can
be accomodated by varying the ratio of the first two ingredients.
EXAMPLE 9
Intravenous infusion
Amount per ,~ dose Ingrgdient
QOmL
,
1 mg COX-2 inhibitor
0.2 mg Polyethylene oxide 400
1.8 mg Sodium chloride
to 200mL Purified water
EXAMPLE 10
5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine
(Compund 13)
Ste~l: Trifluoromethanesulfonic acid 2-methvlnvridin-5-vl ester
To a mixture of 5-hydroxy-2-methylpyridine (2 g) and
pyridine (1.9 mL) in dichloromethane (100 mL) at 0°C was added
trifluoromethanesulfonic acid anhydride (3.4 mL). The mixture was
stirred at this temperature for I5 min and then at r.t. fox 45 min.
Ammonium acetate (25%) was added and the organics were removed
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and washed with 1N HCl, dried and concentrated. The title compound
was obtained as a beige liquid (4 g) that was used as such.
! ten 2: 2-Methvl-5-trimeth3~lgtannvlnvri ine
A mixture of trifluoromethanesulfonic acid 2-methyl-
pyridin-5-yl ester (2.1 g), hexamethylditin (2.85 g), lithium chloride (1.1
g) and palladium tetrakis(triphenylphosphine) (190 mg) was heated at
reflux for 180 min and then cooled to r.t.. The mixture was filtered
through a bed of celite, washing with ethyl acetate. The filtrate was
washed twice with 5% potassium fluoride, dried and concentrated.
Flash chromatography (eluting with hexane/ethyl acetate, 6:1 v/v) of the
residue provided the title compound as a pale yellow oil (1.3 g).
5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-
wridvl)wridine
A mixture of 2,5-dichloro-3-(4-methylsulfonyl)phenyl-
pyridine from Example 20, Step 5 (750 mg), 2-methyl-5-trimethyl-
stannylpyridine (1.3 g) and palladium tetrakis(triphenylphosphine) (290
mg) in NMP (10 mL) was heated at 100 °C for 15 h. The mixture was
cooled to r.t., diluted with ethyl acetate and filtered through a bed of
celite. The filtrate was washed with water, twice with 5% potassium
fluoride and then extracted with 1 N HCl. The aqueous phase was
neutralized with 10 N sodium hydroxide and then extracted with ethyl
acetate. The organics were concentrated and the residue subjected to
flash chromatography (eluting with ethyl acetate) to provide the title
compound as a white solid, m.p. 127-128°C.
EXAMPLE 11
5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-pyridinyl)pyridine
Ste~l: 3-Bromo-5-chloro-2-hvdroxyRvridine
A mixture of 5-chloro-2-hydroxypyridine (100 g) and
bromine (40.1 mL) in acetic acid (400 mL) was stirred at r.t. for 1 h. The
mixture was poured into 3 L of water and stirred for 30 min then filtered.
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The residual solid was washed with 2 L of cold water, air dried and then
coevaporated with toluene three times and with benzene two times. The
white solid (81 g) so obtained was used in the subsequent reaction.
Ste~2: 2-Benzylox3~-3-bromo-5-chlorop3 'rridine
A mixture of 3-bromo-5-chloro-2-hydroxypyridine (81 g),
benzyl bromide (52 mL) and silver carbonate (97 g) in benzene (1 L) was
heated at 70 °C for 1 h. The mixture was cooled to r.t. and then
filtered
through a bed of celite. The filtrate was concentrated and the residual
ofd white solid was recrystallized from hexane to provide the title
compound as a white solid (102 g).
t~gg~: 2-Benzvloxv-5-chloro-3-(4-m~ .gt~y~ lfnnvi nhen3~lgvridine
Following the procedures described in Example 1, Steps 2
and 3, but substituting 2-benzyloxy-3-bromo-5-chloropyridine (81 g) from
Step 2 for 2-amino-3-bromo-5-trifluoromethylpyridine, the title compound
was obtained as a white solid (72 g).
Stew 4: 5-Chloro-2-hvdroxv-3-(4-met~vl_sLfon~~phenvlg 'dine
A solution of 2-benzyloxy-5-chloro-3-(4-methylsulfonyl)-
phenylpyridine (72 g) in trifluoroacetic acid (250 mL) was stirred at
40°C
for 15 min and then poured into ice/water (~1 L). After stirring for 10
min, the white solid was filtered, washed twice with a further 1 L of
water and then air dried to provide the title compound.
Steg5_: 2.5-Dichloro-3-(4-methvlsulfon3~1_)~ heny~g ' 'ne
The crude 5-chloro-2-hydroxy-3-(4-methylsulfonyl)-
phenylpyridine from Step 4 was heated in a sealed bomb at 150°C with
POC13 (400 mL) for 15 h. After cooling to r.t. the excess POC13 was
removed by distillation under vacuum. The residue was diluted with
ethyl acetate and water and then neutralized with sodium hydroxide ( 10
N) to ~pH 7. The organics were removed, washed with brine and
concentrated. The residual solid was recrystallized from ether to
provide the title compound as white solid (61 g).
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Ste~6,: ~~ithium Tri-n- ,fro oxv-2-gvridvlbornonate
Following the procedures described in Example 15, Step 1
but substituting 2-bromopyridine (1.9 mL) for 3-bromopyridine, the title
compound was prepared as an ofd white solid (4.1 g).
Step 7: 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-pyridinyl)-uvrig,
A mixture of 2,5-dichloro-3-(4-methylsulfonyl)phenyi-
pyridine ( 1 g), lithium tri-n-propoxy-2-pyridylboronate ( 1.22 g), sodium
carbonate (5 mL, 2M) and bis(triphenylphosphine)palladium dibromide
(520 mg) in toluene (100 mL), isopropanol (10 mL) and water (25 mL) was
heated at reffux for 7 h. The mixture was cooled to r.t., diluted with
ethyl acetate and filtered through a bed of celite. The filtrated was
extracted with 6 N HCl and the aqueous was washed with ethyl acetate.
The aqueous phase was basified to ~pH 10 with 10 N sodium hydroxide
and then extracted with ethyl acetate. The organics were washed with
brine, dried and concentrated. Flash chromatography (eluting with
hexane/ethyl acetate, 1:1 v/v) of the residue provided the title compound
as a white solid, m.p. 134-135°C (350 mg).
EXAMPLE 12
Lithium Tri-n-fro oxv-3-gvridinvlboronate
To a solution of 3-bromopyridine (39.5 g) in ether (800 mL) at
-90°C (internal temperature) was added n-BuLi (100 mL, 2.5 M) at a rate
so that the internal temperature did not exceed -78°C. The resulting
mixture was stirred for 1 h at -78°C and then triisopropoxy-borate (59
mL) was added and the resulting mixture was warmed to 0°C.
Methanol was added and the mixture was evaporated three times from
methanol and then two times from n-propanol. The residue was
pumped under high vacuum For 3 days and the resulting foam (76 g of a
1:1 mixture of the title compound:n-propanol) was used as such in the
subsequent reaction.
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EXAMPLE 13
5-Chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)pyridine
(Compound 25)
Following the procedures described in Example 11, Step 7,
but substituting lithium tri-n-propoxy-3-pyridinylboronate from Example
12 for lithium tri-n-propoxy-2-pyridinylboronate, the title compound was
obtained as a white solid, m.p. 168-169°C.
While the invention has been described and illustrated with
reference to certain particular embodiments thereof, those skilled in the
art will appreciate that various changes, modifications and substitutions
can be made therein without departing from the spirit and scope of the
invention. For example, effective dosages other than the particular
dosages as set forth herein above may be applicable as a consequence of
variations in the responsiveness of the mammal being treated fox any of
the indications for the active agents used in the instant invention as
indicated above. Likewise, the specific pharmacological responses
observed may vary according to and depending upon the particular
active compound selected or whether there are present pharmaceutical
carriers, as well as the type of formulation and mode of administration
employed, and such expected variations or dif~'erences in the results are
contemplated in accordance with the objects and practices of the present
invention. It is intended, therefore, that the invention be defined by the
scope of the claims which follow and that such claims be interpreted as
broadly as is reasonable.
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