U.S. patent application number 10/295347 was filed with the patent office on 2003-06-12 for novel combination of an adp-receptor blocking antiplatelet drug and a thromboxane a2 receptor antagonist and a method for inhibiting thrombus formation employing such combination.
Invention is credited to Ogletree, Martin L..
Application Number | 20030109543 10/295347 |
Document ID | / |
Family ID | 26804052 |
Filed Date | 2003-06-12 |
United States Patent
Application |
20030109543 |
Kind Code |
A1 |
Ogletree, Martin L. |
June 12, 2003 |
Novel combination of an ADP-receptor blocking antiplatelet drug and
a thromboxane A2 receptor antagonist and a method for inhibiting
thrombus formation employing such combination
Abstract
A method is provided for inhibiting platelet aggregation and
thrombus formation by administering to a patient an ADP-receptor
blocking antiplatelet drug, such as clopidogrel, in combination
with a thromboxane A.sub.2 receptor antagonist, such as ifetroban,
and optionally a cholesterol lowering drug, such as an HMG CoA
reductase inhibitor, for example, pravastatin.
Inventors: |
Ogletree, Martin L.;
(Newtown, PA) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
26804052 |
Appl. No.: |
10/295347 |
Filed: |
November 15, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10295347 |
Nov 15, 2002 |
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09428611 |
Oct 27, 1999 |
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6509348 |
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60106813 |
Nov 3, 1998 |
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Current U.S.
Class: |
514/301 ;
514/374; 514/381; 514/469 |
Current CPC
Class: |
A61K 31/41 20130101;
A61K 31/55 20130101; A61K 31/44 20130101; A61K 31/42 20130101; A61K
31/41 20130101; A61K 31/44 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/42 20130101; A61K 31/55 20130101 |
Class at
Publication: |
514/301 ;
514/381; 514/374; 514/469 |
International
Class: |
A61K 031/557; A61K
031/4743 |
Claims
What is claimed is:
1. A pharmaceutical combination comprising an ADP-receptor blocking
antiplatelet drug and a thromboxane A.sub.2 receptor
antagonist.
2. The combination as defined in claim 1 wherein the antiplatelet
drug is clopidogrel or ticlopidine or
2-acetoxy-5-(.alpha.-cyclopropylcarboxyl-2--
fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
3. The combination as defined in claim 1 wherein the thromboxane
A.sub.2 receptor antagonist is ifetroban or vapiprost.
4. The combination as defined in claim 1 wherein the thromboxane
A.sub.2 receptor antagonist is a 7-oxabicyclo-heptane substituted
amino-prostaglandin analog, a 7-oxabicycloheptane substituted
diamide prostaglandin analog, an interphenylene 7-oxabicycloheptyl
substituted heterocyclic amide prostaglandin analog, a
7-oxabicyclo-heptyl substituted heterocyclic amide prostaglandin
analog, or a 7-oxabicycloheptane imidazole prostaglandin
analog.
5. The combination as defined in claim 4 wherein the thromboxane
A.sub.2 receptor antagonist is [1S-[1.alpha.,
2.alpha.(Z)),3.alpha.((1E, 3S*, 4R*),
4.alpha.]]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]-
hept-2-yl]-5-heptenoic acid; has the name [1S-[1.alpha.,
2.alpha.(Z),3.alpha.,
4.alpha.]]-7-[3-[[[[(1-oxoheptyl)-amino]acetyl]amin-
o]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the
corresponding tetrazole; [1S-[1.alpha., 2.alpha.((Z), 3.alpha.,
4.alpha.]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)-amino]acaetyl]amino]methyl]-
-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; [1S-[1.alpha.,
2.alpha.(Z), 3.alpha.,
4.alpha.]]-7-[3-[[2-(phenyl-amino)carbonyl]hydrazi-
no]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid;
[1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-2-[[3-[4-[[(4-cyclohexylbutyl)amino]carbon-
yl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoic
acid (SQ 33,961), or esters or salts thereof; [1S-(1.alpha.,
2.alpha., 3.alpha.,
4.alpha.)]-2-[[3-[4-[[[4-chlorophenyl)butyl]amino]carbonyl]-2-o-
xazolyl]-7-oxabicyclo [2.2.1]hept-2-yl]methyl]benzenepropanoic acid
or esters, or salts thereof; [1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-3-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-ox-
abicyclo[2.2:1]hept-2-yl]methyl]benzeneacetic acid, or esters or
salts thereof; [1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-[2-[[3-[4-[[(4-cyc-
lohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]meth-
yl]phenoxy]acetic acid or esters or salts thereof; [1S-(1.alpha.,
2.alpha., 3.alpha.,
4.alpha.)]-2-[[3-[4-[[(7,7-dimethyloctyl)amino]carbon-
yl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic
acid, or esters or salts thereof; [1S-[1.alpha., 2.alpha.(Z),
3.alpha.,
4.alpha.]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxa-
bicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts
thereof; [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.]]-6-[3-[[4-(4-cyclohexyl-1-
-hydroxybutyl)-1H-imidazol-l-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-he-
xenoic acid or its methyl ester; [1S-[1.alpha., 2.alpha.(Z),
3.alpha.,
4.alpha.]]-6-[3-[[4-(3-cyclohexyl-propyl)-1H-iomidazol-1-yl]methyl]-7-oxa-
bicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester;
[1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.]]-6-[3-[[4-(4-cyclohexyl-1-
-oxobutyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexeno-
ic acid or its methyl ester; [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.]]-6-[3-(1H-imidazol-1-ylmethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4--
hexenoic acid or its methyl ester; [1S-[1.alpha., 2.alpha.(Z),
3.alpha.,
4.alpha.]]-6-[3-[[4-[[(4-cyclohexylbutyl)amino]-carbonyl]-1H-imidazol-1-y-
l]methyl-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or its
methyl ester;
(E)-5-[[[(pyridinyl)[3-(trifluoromethyl)phenyl]methylene]amino]-ox-
y]pentanoic acid (R 68,070); [1S-[1.alpha.(Z), 2.beta., 3.beta.,
5.alpha.]]-(+)-7-[5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidi-
nyl)cyclopentyl]-4-heptenoic acid (GR 32,191 Vapiprost);
4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]-
hexenoic acid (ICI 192,605); 7-[2.alpha.,
4.alpha.-(dimethylmethano)-6.bet-
a.-(2-cyclopentyl-2.beta.-hydroxyacetamido)-1.alpha.-cyclohexyl]-5(Z)-hept-
enoic acid (ONO 3708); or
3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetr-
ahydro-9H-carbazole-9-propanoic acid (BAY u 3405) ramatroban;
(.+-.)(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo[2.2.1]-hept-2-exo-yl]-
heptenoic acid (domitroban),
(-)6,8-difluoro-9-p-methylsulfonylbenzyl-1,2,-
3,4-tetrahydro-carbazol-1-yl-acetic acid (L670596, Merck) and
(3-[l-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]-2,2-dimethylpropanoi-
c acid (L655240, Merck).
6. The combination as defined in claim 1 wherein the thromboxane
A.sub.2 receptor antagonist is ifetroban and the antiplatelet drug
is clopidogrel.
7. The combination as defined in claim 1 wherein the antiplatelet
drug is employed in a weight ratio to the thromboxane A.sub.2
receptor antagonist within the range of from about 0.001:1 to about
1000:1.
8. The combination as defined in claim 1 further including a
cholesterol lowering agent.
9. The combination as defined in claim 8 wherein the cholesterol
lowering drug is an inhibitor of the enzyme
3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase.
10. The combination as defined in claim 9 wherein said inhibitor of
the enzyme HMG CoA reductase is lovastatin, pravastatin,
simvastatin, atorvastatin, fluvastatin or cerivastatin.
11. The combination as defined in claim 8 wherein the cholesterol
lowering drug is a fibric acid derivative.
12. The combination as defined in claim 8 wherein the cholesterol
lowering drug is gemfibrozil, fenofibrate, clofibrate, bezafibrate,
ciprofibrate, clinofibrate, dextrothyroxine or its sodium salt,
colestipol or its hydrochloride, cholestyramine, nicotinic acid,
neomycin or p-aminosalicylic acid.
13. The combination as defined in claim 8 wherein the cholesterol
lowering agent is an MTP inhibitor.
14. The combinaiton as defined in claim 12 wherein the MTP
inhibitor is BMS 201,038 or BMS 212,122.
15. A method for preventing or inhibiting platelet aggregation
and/or thrombus formation in a mammalian species, which comprises
administering to a patient in need of treatment a therapeutically
effective amount of a pharmaceutical combination as defined in
claim 1.
16. A method of preventing or inhibiting onset of an ischemic event
which is a cardiovascular, cerebrovascular or peripheral vascular
event in a mammalian species, which comprises administering to a
patient in need of treatment a therapeutically effective amount of
a pharmaceutical combination as defined in claim 1.
17. The method as defined in claim 16 wherein the ischemic event is
a primary or secondary ischemic event.
18. The method as defined in claim 16 wherein the ischemic event is
a myocardial infarction, unstable angina, stable angina, acute
reocclusion after percutaneous transluminal coronary angioplasty,
restenosis after percutaneous transluminal coronary angioplasty,
thrombotic stroke, transient ischemic attack, reversible ischemic
neurological deficit, or intermittent claudication.
19. The method as defined in claim 15 wherein the pharmaceutical
combination administered comprises an ADP-receptor blocking
antiplatelet drug, a thromboxane A.sub.2 receptor antagonist and
optionally a cholesterol lowering agent.
20. The method as defined in claim 15 wherein the pharmaceutical
combination administered comprises an ADP-receptor blocking agent
and a thromboxane A.sub.2 receptor antagonist, and optionally
aspirin.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a novel combination of an
ADP-receptor blocking antiplatelet drug, such as clopidogrel, and a
thromboxane A.sub.2 receptor antagonist such as ifetroban, and
optionally a cholesterol lowering drug, such as pravastatin, and to
a method for inhibiting platelet aggregation and thrombus formation
employing such combination.
BACKGROUND OF THE INVENTION
[0002] Clopidogrel is a thieno-[3,2-c]pyridine derivative which has
the chemical name methyl
(4)-(S)-.alpha.-(o-chloro-phenyl)-6,7-dihydrothieno[-
3,2-c]pyridine-5-acetate and the formula 1
[0003] including pharmaceutically acceptable acid addition salts
thereof, preferably the hydrogen sulfate salt, and is disclosed in
U.S. Pat. Nos. 4,529,596 to Aubert et al and 4,847,265 to Badorc et
al as having blood platelet aggregation inhibiting activity and
anti-thrombotic activity and thus useful in inhibiting or
preventing arterial and venous thrombosis.
[0004] U.S. Pat. No. 5,576,328 to Herbert et al discloses that
clopidogrel may be employed in secondary prevention of ischemic
events such as myocardial infarction, unstable or stable angina,
acute reocclusion after percutaneous transluminal coronary
angioplasty (PTCA), restenosis after PTCA, thrombotic stroke,
transient ischemic attack, reversible ischemic neurological
deficit, and intermittent claudication.
[0005] The above patents are incorporated herein by reference.
[0006] WO 97/29753 published Aug. 21, 1997, discloses a
pharmaceutical composition containing clopidogrel and aspirin.
[0007] Ticlopidine hydrochloride is disclosed in U.S. Pat. No.
4,591,592 as a platelet aggregation inhibitor and is marketed in
the U.S. under the name Ticlid.RTM. by Roche Laboratories and has
the chemical name
5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
hydrochloride and the structure 2
[0008] U.S. Pat. No. 5,288,726 (assigned to Sankyo) discloses a
platelet aggregation inhibitor CS-747 which has the structure and
name as follows: 3
[0009]
2-acetoxy-5-(.alpha.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-te-
trahydrothieno[3,2-c]pyridine.
[0010] U.S. Pat. No. 5,100,889 to Misra et al discloses
7-oxabicycloheptyl substituted heterocyclic amide prostacyclin
analogs which are potent thromboxane A.sub.2 receptor antagonists
and thus are useful in inhibiting platelet aggregation and thrombus
formation. The Misra et al compounds have the structure 4
[0011] and including all stereoisomers thereof, wherein
[0012] m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;
[0013] Z is --(CH.sub.2).sub.2--, --CH.dbd.CH-- or 5
[0014] wherein Y is O, a single bond or vinyl (--CH.dbd.CH--), with
the provisos that when n is 0, if Z is 6
[0015] then Y cannot be 0; and when Z is --CH.dbd.CH--, n is 1,2,3,
or 4; and when Y=vinyl, n=0;
[0016] R is CO.sub.2H, CO.sub.2lower alkyl, CO.sub.2alkali metal,
CH.sub.2OH, CONHSO.sub.2R.sup.3, CONHR.sup.3a, or 7
[0017] (--CH.sub.2-5-tetrazolyl);
[0018] X is O, S or NH;
[0019] R.sup.1 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl,
cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or
heteroarylalkyl, or amide 8
[0020] wherein t is 1 to 12 and R.sub.a is lower alkyl, aryl,
cycloalkyl, or cycloalkylalkyl);
[0021] R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or
[0022] R.sup.1 and R.sup.2 together with the nitrogen to which they
are linked may form a 5- to 8-membered ring;
[0023] R.sup.3 is lower alkyl, aryl or aralkyl; and
[0024] R.sup.3a is hydrogen, lower alkyl, aryl or aralkyl.
[0025] Ifetroban which is a particularly potent thromboxane A.sub.2
antagonist is disclosed in the Misra et al patent and has the
structure 9
[0026] and the name [1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-2-[[3-[4-[(pentylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2-
.1]hept-2-yl]methyl]-benzenepropanoic acid or a pharmaceutically
acceptable salt thereof such as its sodium salt.
[0027] U.S. Pat. No. 5,312,818 to Rubin et al discloses use of
thromboxane A.sub.2 receptor antagonists in combination with
anti-inflammatory agents including aspirin to prevent or treat
ulcerative conditions caused by anti-inflammatory agents.
DESCRIPTION OF THE INVENTION
[0028] In accordance with the present invention, a method for
preventing or inhibiting platelet aggregation and thrombus
formation in mammals is provided wherein an ADP-receptor blocking
antiplatelet drug, such as clopidogrel, in combination with a
thromboxane A.sub.2 receptor antagonist, such as ifetroban, and
optionally a cholesterol lowering drug, is administered in
therapeutically effective amounts to inhibit platelet aggregation
and thrombus formation.
[0029] Furthermore, in accordance with the present invention, a
method is provided for preventing or inhibiting onset of ischemic
events including cardiovascular, cerebrovascular and peripheral
vascular events, such as myocardial infarction, unstable and stable
angina, acute reocclusion after percutaneous transluminal coronary
angioplasty (PTCA), restenosis after PTCA, thrombotic stroke,
transient ischemic attack, reversible ischemic neurological
deficit, and intermittent claudication wherein a combination of an
ADP-receptor blocking antiplatelet drug, such as clopidogrel, and a
thromboxane A.sub.2 receptor antagonist, such as ifetroban, and
optionally a cholesterol lowering agent, is administered in
therapeutic effective amounts.
[0030] In addition, in accordance with the present invention, a
novel combination of antithrombotic agents is provided which
includes an ADP receptor blocking antiplatelet drug, such as
clopidogrel, and a thromboxane A.sub.2 receptor antagonist, such as
ifetroban, and optionally a cholesterol lowering drug, such as an
HMG CoA reductase inhibitor such as pravastatin.
[0031] It is believed that the combination of ADP-receptor blocking
antiplatelet drug and thromboxane A.sub.2 receptor antagonist,
which works by a mechanism other than inhibition of ADP-induced
platelet aggregation, is a surprising and unique concept in
treating diseases involved with platelet aggregation, thrombus
formation and ischemic events, in that the combination may provide
additional antiplatelet aggregation, anti-ischemic, anti-thrombus
effects over that which may be obtained using each of the
components of the combination alone. It may be expected that
reduced levels of each of the ADP receptor blocking antiplatelet
drug and thromboxane A.sub.2 receptor antagonist may be employed to
achieve desired results, albeit with reduced side effects.
[0032] In addition, in accordance with the present invention, a
method is provided wherein a combination of an ADP-receptor
blocking antiplatelet drug and a thromboxane A.sub.2 receptor
antagonist, and optionally aspirin, is employed to prevent or
inhibit platelet aggregation and thrombus formation and to prevent
or inhibit any of the disease states set out above, including
thrombotic stroke.
[0033] The ADP-receptor blocking antiplatelet drug suitable for use
herein includes antiplatelet drugs which inhibit ADP-induced
platelet aggregation and include clopidogrel and/or ticlopidine
and/or CS-747 (described herein), and do not include drugs such as
aspirin which inhibit platelet aggregation by other mechanisms.
[0034] The term "clopidogrel" as employed herein includes
clopidogrel in its free acid form, ester thereof, including the
acetate, and/or pharmaceutically acceptable acid addition salts
thereof, including the hydrogen sulfate salt.
[0035] The term "ticlopidine" as employed herein includes all
pharmaceutical acceptable salts thereof including the hydrochloride
salt thereof.
[0036] The term "CS-747" as employed herein includes
2-acetoxy-5-(.alpha.(-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahy-
drothieno[3,2-c]pyridine and pharmaceutically acceptable salts
thereof.
[0037] Thromboxane A.sub.2 receptor antagonists which may be
employed herein include the interphenylene 7-oxabicyclo-heptyl
substituted heterocyclic amide prostaglandin analogs as disclosed
in U.S. Pat. No. 5,100,889, issued Mar. 31, 1992, including
[1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-2-[[3-[4-[[(4-cyclo-hexylbutyl)amino]carbonyl]-2-oxa-
zolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoic acid
(SQ 33,961) which is preferred, or esters or salts thereof;
[0038] [1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-2-[[3-[4-[[[(4-chloro-
phenyl)-butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]met-
hyl]benzenepropanoic acid or esters, or salts thereof;
[0039] [1S-((1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-3-[[3-[4-[[(4-cycloh-
exylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo]2.2.1]hept-2-yl]benzen-
eacetic acid, or esters or salts thereof;
[0040] [1S-((1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-[2-[[3-[4-[[(4-cyclo-
hexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methy-
l]phenoxy]acetic acid, or esters or salts thereof;
[0041] [1S-((1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-2-[[3-[4-[[(7,7-dime-
thyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methy-
l]benzenepropanoic acid, or esters or salts thereof and ifetroban,
with ifetroban being most preferred;
[0042] 7-oxabicycloheptyl substituted heterocyclic amide
prostaglandin analogs as disclosed in U.S. Pat. No. 5,100,889,
issued Mar. 31, 1992, including [1S-[1.alpha., 2.alpha.(Z),
3.alpha., 4.alpha.)]-6-[3-[4-[[(4-c-
yclohexylbutyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]--
4-hexenoic acid, or esters or salts thereof;
[0043] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cycl-
ohexyl-butyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4--
hexenoic acid, or esters or salts thereof;
[0044] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cycl-
ohexyl-butyl)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2--
yl]-4-hexenoic acid, or esters or salts thereof;
[0045] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[(1-pyrro-
lidinyl)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic
acid, or esters or salts thereof;
[0046] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[(cyclohe-
xylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-4-hexenoic
acid or esters or salts thereof;
[0047] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(2-cycl-
ohexyl-ethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-h-
exenoic acid, or esters or salts thereof;
[0048] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[[2-(4-c-
hloro-phenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2--
yl]-4-hexenoic acid, or esters or salts thereof;
[0049] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]-6-[3-[4-[[(4-chlor-
ophenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexen-
oic acid, or esters or salts thereof;
[0050] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[[4-(4-c-
hloro-phenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2--
yl]-4-hexenoic acid, or esters or salts thereof;
[0051] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4.alpha.-[[-
(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2--
yl]-4-hexenoic acid, or esters, or salts thereof;
[0052] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(6-cycl-
ohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-h-
exenoic acid, or esters or salts thereof;
[0053] [1S-[1.alpha., 2.alpha.(Z) , 3.alpha.,
4.alpha.)]]-6-[3-[4-[(propyl-
amino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic
acid, or esters or salts thereof
[0054] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-buty-
lphenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexen-
oic acid, or esters or salts thereof;
[0055] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[(2,3-dih-
ydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo(
2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof;
[0056] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cycl-
ohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-N-(-
phenylsulfonyl)-4-hexenamide;
[0057] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cycl-
ohexyl-butyl)amino]carbonyl]-2-oxazolyl]-N-(methylsulfonyl)-7-oxabicyclo[2-
.2.1]hept-2-yl]-4-hexenamide;
[0058] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-7-[3-[4-[[(4-cycl-
ohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo
(2.2.1]hept-2-yl]-5-heptenoic acid, or esters or salts threof;
[0059] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cycl-
ohexyl-butyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo-[2.2.1]hept-2--
yl]-4-hexenoic acid or esters or salts thereof;
[0060] [1S-[1.alpha., 2.alpha., 3.alpha., 4.alpha.)]-6-[3-[4-[[(7,
7-dimethyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-
]-4-hexenoic acid, or esters or salts thereof;
[0061] [1S-[1.alpha., 2.alpha.(E), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cycl-
ohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-h-
exenoic acid;
[0062] [1S-[1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-3-[4-[[(4-(cyclohexyl-
butyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]heptane-2-hexanoic
acid or esters or salts thereof, with a preferred compound being
[1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cyclohexyl-
butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoi-
c acid, or esters or salts thereof;
[0063] 7-oxabicycloheptane and 7-oxabicycloheptene compounds
disclosed in U.S. Pat. No. 4,537,981 to Snitman et al, especially
[1S-(1.alpha., 2.alpha.(Z), 3.alpha.(1E, 3S*, 4R*),
4.alpha.)]]-7-[3-(3-hydroxy-4-phenyl-
-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ
29,548); the 7-oxabicycloheptane substituted aminoprostaglandin
analogs disclosed in U.S. Pat. No. 4,416,896 to Nakane et al,
especially, [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-7-[3-[[2-(phenylamino)carbonyl]-hydraz-
ino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; the
7-oxabicycloheptane substituted diamide prostaglandin analogs
disclosed in U.S. Pat. No. 4,663,336 to Nakane et al, especially,
[1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-7-[3-[[[[(1-oxoheptyl)amino]-acetyl]am-
ino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid and the
corresponding tetrazole, and [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)-amino]acetyl]amino]methyl]-
-7-oxabicyclo]2.2.1]hept-2-yl]-5-heptenoic acid;
[0064] 7-oxabicycloheptane imidazole prostaglandin analogs as
disclosed in U.S. Pat. No. 4,977,174, issued Dec. 11, 1990,
including [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[[4-(4-cyclohexyl-1-hydroxybutyl)-
-1H-imidazole-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic
acid or its methyl ester;
[0065] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[[4-(3-cyclo-
hexyl-propyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hex-
enoic acid or its methyl ester;
[0066] [1S-[1.alpha., 2.alpha.(X(Z), 3.alpha.,
4.alpha.)]]-6-[3-[[4-(4-cyc-
lohexyl-1-oxobutyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-
-4-hexenoic acid or its methyl ester;
[0067] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.]]-6-[3-(1H-imidazol--
1-ylmethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its
methyl ester; or
[0068] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[[4-[[(4-cyc-
lohexyl-butyl)amino]carbonyl]-1H-imidazol-1-yl]methyl-7-oxabicyclo-[2.2.1]-
hept-2-yl]-4-hexenoic acid, or its methyl ester;
[0069] the phenoxyalkyl carboxylic acids disclosed in U.S. Pat. No.
4,258,058 to Witte et al, especially
4-[2-(benzenesulfamido)ethyl]phenoxy- acetic acid (BM
13,177-Boehringer Mannheim), the sulphonamidophenyl carboxylic
acids disclosed in U.S. Pat. No. 4,443,477 to Witte et al,
especially 4-[2-(4-chlorobenzenesulfonamido)ethyl]-phenylacetic
acid (BM 13,505, Boehringer Mannheim), the arylthioalkylphenyl
carboxylic acids disclosed in U.S. Pat. No. 4,752,616, especially
4-(3-((4-chlorophenyl)-s- ulfonyl)propyl)benzeneacetic acid.
[0070] Other examples of thromboxane A.sub.2 receptor antagonists
suitable for use herein include, but are not limited to vapiprost
(which is a preferred example),
(E)-5-[[[(pyridinyl)]3-(trifluoromethyl)phenyl]methyl-
ene]amino]-oxy]pentanoic acid also referred to as R68,070-Janssen
Research Laboratories,
3-[1-(4-chlorophenylmethyl)-5-fluoro-3-methylindol-2-yl]-2,-
2-dimethylpropanoic acid [(L-655240 Merck-Frosst) Eur. J.
Pharmacol. 135(2):193, Mar. 17, 87],
5(Z)-7-([2,4,5-cis]-4-(2-hydroxyphenyl)-2-trifl-
uoromethyl-1,3-dioxan-5-yl)heptenoic acid (ICI 185282, Brit. J.
Pharmacol. 90 (Proc. Suppl):228 P-Abs, March 87),
5(Z)-7-[2,2-dimethyl-4-phenyl-1,3-- dioxan-cis-5-yl]heptenoic acid
(ICI 159995, Brit. J. Pharmacol. 86 (Proc. Suppl):808 P-Abs.,
December 85), N,N'-bis[7-(3-chlorobenzeneamino-sulfony-
l)-1,2,3,4-tetrahydro-isoquinolyl]disulfonylimide (SKF 88046,
Pharmacologist 25(3):116 Abs., 117 Abs, August 83),
(1.alpha.(Z)-2.beta.,
5.alpha.]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]-methoxy]-2-(4-morpholinyl)-3-o-
xocyclopentyl]-4-heptenoic acid (AH 23848 -Glaxo, Circulation
72(6):1208, December 85, levallorphan allyl bromide (CM 32,191
Sanofi, Life Sci. 31 (20-21):2261, Nov. 15, 82),
(Z,2-endo-3-oxo)-7-(3-acetyl-2-bicyclo
[2.2.1]heptyl-5-hepta-3Z-enoic acid, 4-phenyl-thiosemicarbazone
(EP092-Univ. Edinburgh, Brit. J. Pharmacol. 84(3):595, March 85);
GR 32,191 (Vapiprost)-[1R-[1.alpha.(Z), 2.beta., 3.beta.,
5.alpha.]]-(+)-7-[5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidi-
nyl)cyclopentyl]-4-heptenoic acid; ICI
192,605-4(Z)-6-[(2,4,5-cis)2-(2-chl-
orophenyl)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl]hexenoic acid; BAY u
3405
(ramatroban)-3-[[(4-fluorophenyl)-sulfonyl]amino]-1,2,3,4-tetrahydro-9H-c-
arbazole-9-propanoic acid; or ONO 3708-7-[2.alpha.,
4.alpha.-(di-methylmethano)-6.beta.-(2-cyclopentyl-2.beta.-hydroxyacetami-
do)-1.alpha.-cyclohexyl]-5(Z)-heptenoic acid;
(.+-.)(5Z)-7-[3-endo-((pheny-
lsulfonyl)amino]-bicyclo[2.2.1]hept-2-exo-yl]-heptenoic acid
(S-1452, Shionogi domitroban, Anboxan.RTM.);
(-)6,8-difluoro-9-p-methylsulfonylben-
zyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (L670596, Merck)
and
(3-[l-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]-2,2-dimethylpropanoi-
c acid (L655240, Merck).
[0071] The disclosure of the above-mentioned U.S. patents are
incorporated herein by reference.
[0072] The optional cholesterol lowering drug employed herein
includes, but is not limited to, HMG CoA reductase inhibitors, MTP
inhibitors, squalene synthetase inhibitors, fibrates, resins and
the like.
[0073] The term "MTP" as employed herein refers to a polypeptide or
protein complex that (1) if obtained from an organism (e. g., cows,
humans, etc.), can be isolated from the microsomal fraction of
homogenized tissue; and (2) stimulates the transport of
triglycerides, cholesterol esters, or phospholipids from synthetic
phospholipid vesicles, membranes or lipoproteins to synthetic
vesicles, membranes, or lipoproteins and which is distinct from the
cholesterol ester transfer protein [Drayna et al., Nature 327,
632-634 (1987)] which may have similar catalytic properties.
[0074] The combination of the invention will include the
ADP-receptor blocking antiplatelet drug and thromboxane A.sub.2
receptor antagonist in a weight ratio to each other within the
range from about 1000:1 to about 0.001:1, preferably from about
0.05:1 to about 100:1.
[0075] When employed, the cholesterol lowering drug will be
employed in a weight ratio to the ADP-receptor blocking
antiplatelet drug of within the range of from about 1000:1 to about
0.001:1 and preferably from about 0.05:1 to about 100:1.
[0076] When present, the cholesterol lowering drug to be used in
combination with the ADP-receptor blocking antiplatelet drug and
thromboxane A.sub.2 receptor antagonist in accordance with the
present invention is preferably an HMG CoA reductase inhibitor.
[0077] The HMG CoA reductase inhibitors suitable for use herein
include, but are not limited to, mevastatin and related compounds
as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and
related compounds as disclosed in U.S. Pat. No. 4,231,938,
pravastatin and related compounds such as disclosed in U.S. Pat.
No. 4,346,227, simvastatin and related compounds as disclosed in
U.S. Pat. Nos. 4,448,784 and 4,450,171, with pravastatin,
lovastatin or simvastatin being preferred. Other HMG CoA reductase
inhibitors which may be employed herein include, but are not
limited to, fluvastatin, cerivastatin, atorvastatin, pyrazole
analogs of mevalonolactone derivatives as disclosed in U.S. Pat.
No. 4,613,610, indene analogs of mevalonolactone derivatives as
disclosed in PCT application WO 86/03488,
6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones and derivatives
thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355
(a 3-substituted pentanedioic acid derivative) dichloroacetate,
imidazole analogs of mevalonolactone as disclosed in PCT
application WO 86/07054,, 3-carboxy-2-hydroxy-propane-phosphonic
acid derivatives as disclosed in French Patent No. 2,596,393,
2,3-di-substituted pyrrole, furan and thiophene derivatives as
disclosed in European Patent Application No. 0221025, naphthyl
analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237,
octahydro-naphthalenes such as disclosed in U.S. Pat. No.
4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in
European Patent Application No. 0,142,146 A2, as well as other
known HMG CoA reductase inhibitors.
[0078] In addition, phosphinic acid compounds useful in inhibiting
HMG CoA reductase suitable for use herein are disclosed in GB
2205837.
[0079] MTP inhibitors to be employed in the methods of the
invention include MTP inhibitors disclosed in Canadian Patent
Application No. 2,091,102 (corresponding to U.S. application Ser.
No. 117,362), U.S. application Ser. No. 472,067, filed Jun. 6, 1995
(file DC21e), U.S. application Ser. No. 548,811 (file DC21h), U.S.
application Ser. No. 08/767,923, filed Dec. 17, 1996 (file HX79c),
U.S. provisional application No. 60/017,253, (file HX82*) and U.S.
provisional application No. 60/017,254, (file HX84*).
[0080] All of the above U.S. applications are incorporated herein
by reference.
[0081] The MTP inhibitors disclosed in U.S. application Ser. No.
472,067, filed Jun. 6, 1995 (file DC21e) are piperidine compounds
of the structure 10
[0082] where
[0083] Q is 11
[0084] X is: CHR.sup.8, 12
[0085] R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
[0086] Y is --(CH.sub.2).sub.m-- or 13
[0087] wherein
[0088] m is 2 or 3;
[0089] R.sup.1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
arylalkyl wherein alkyl has at least 2 carbons, diarylalkyl,
arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl,
diarylalkylaryl, heteroarylalkyl wherein alkyl has at least 2
carbons, cycloalkyl, or cycloalkylalkyl wherein alkyl has at least
2 carbons, all optionally substituted through available carbon
atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl,
alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl,
heteroarylalkyl, hydroxy or oxo;
[0090] or R.sup.1 is a fluorenyl-type group of the structure 14
[0091] R.sup.1 is an indenyl-type group of the structure 15
[0092] Z.sup.1 and Z.sup.2 are the same or different and are
independently a bond, O, S, 16
[0093] with the proviso that with respect to B, at least one of
Z.sup.1 and Z.sup.2 will be other than a bond; R.sup.11 is a bond,
alkylene, alkenylene or alkynylene of up to 10 carbon atoms;
arylene or mixed arylenealkylene; R.sup.12 is hydrogen, alkyl,
alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl,
heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl,
aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos
that
[0094] (1) when R.sup.12 is H, aryloxy, alkoxy or arylalkoxy, then
Z.sup.2 is 17
[0095] or a bond and
[0096] (2) when Z.sup.2 is a bond, R.sup.12 cannot be heteroaryl or
heteroarylalkyl;
[0097] Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene
from 1 to 5 carbon atoms; R.sup.13, R.sup.14, R.sup.15, and
R.sup.16 are independently hydrogen, alkyl, halo, haloalkyl, aryl,
cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy,
nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio,
arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino,
alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or
aryloxy;
[0098] R.sup.15a and R.sup.16a are independently hydrogen, alkyl,
halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl,
alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio,
aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino,
alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or
aryloxy;
[0099] or R.sup.1 is a group of the structure 18
[0100] wherein
[0101] p is 1 to 8 and R.sup.17 and R.sup.18 are each independently
H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl or cycloalkylalkyl at least one of R.sup.17 and R.sup.18
being other than H;
[0102] or R.sup.1 is a group of the structure 19
[0103] wherein
[0104] R.sup.19 is aryl or heteroaryl;
[0105] R.sup.20 is aryl or heteroaryl;
[0106] R.sup.21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,
cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
[0107] R.sup.2, R.sup.3, R.sup.4 are independently hydrogen, halo,
alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
heteroarylalkyl, hydroxy or haloalkyl;
[0108] R.sup.5 is independently alkyl, alkenyl, alkynyl, aryl,
alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl,
heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl,
polycycloalkylalkyl, cycloalkenyl,, cycloheteroalkyl,
heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl,
polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino,
arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all
optionally substituted through available carbon atoms with 1, 2, 3
or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
cycloheteroalkyl, cyclohetero-alkylalkyl, aryl, heteroaryl,
arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy,
aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl,
heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino,
substituted amino, thiol, alkylthio, arylthio, heteroarylthio,
arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl,
alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl,
alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,
arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl,
heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;
[0109] R.sup.6 is hydrogen or C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkenyl; all optionally substituted with 1, 2, 3 or
4 groups which may independently be any of the substituents listed
in the definition of R.sup.5 set out above;
[0110] R.sup.7 is alkyl, aryl or arylalkyl wherein alkyl by itself
or as part of arylalkyl is optionally substituted with oxo 20
[0111] are the same or different and are independently selected
from heteroaryl containing 5- or 6-ring members; and
[0112] N-oxides 21
[0113] thereof; and
[0114] pharmaceutically acceptable salts thereof.
[0115] The MTP inhibitors disclosed in U.S. application Ser. No.
548,811 filed Jan. 11, 1996 (file DC21h), have the structure 22
[0116] including the piperidine N-oxide thereof or a
pharmaceutically acceptable salt thereof, wherein Z is a bond, O or
S;
[0117] X.sup.1 and X.sup.2 are independently selected from H or
halo;
[0118] x is an integer from 2 to 6;
[0119] R.sup.5 is heteroaryl, aryl, heterocycloalkyl or cycloalkyl,
each R.sup.5 group being optionally substituted with 1, 2, 3 or 4
substituents which may be the same or different.
[0120] The MTP inhibitors disclosed in U.S. application Ser. No.
08/767,923, filed Dec. 17, 1996 (file HX79c) have the structure
23
[0121] including pharmaceutically acceptable salts thereof,
[0122] wherein
[0123] q is 0, 1 or 2;
[0124] A is
[0125] (1) a bond;
[0126] (2) --O--; or
[0127] (3) 24
[0128] where R.sup.5 is H or lower alkyl or R.sup.5 together with
R.sup.2 forms a carbocyclic or heterocyclic ring system containing
4 to 8 members in the ring.
[0129] B is a fluorenyl-type group of the structure: 25
[0130] B is an indenyl-type group of the structure 26
[0131] R.sup.x is H, alkyl or aryl;
[0132] R.sup.1 is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or
aryl).sub.3Si (where each alkyl or aryl group is independent),
cycloalkyl, cycloalkenyl, substituted alkylamino, substituted
arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl,
heteroarylamino, heteroaryloxy, arylsulfonylamino,
hetero-arylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl,
alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio,
heteroarylsulfinyl, heteroarylsulfonyl, --PO(R.sup.13) (R.sup.14),
(where R.sup.13 and R.sup.14 are independently alkyl, aryl, alkoxy,
aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl,
cycloheteroalkoxy, or cycloheteroalkylalkoxy); R.sup.1 can also be
aminocarbonyl (where the amino may optionally be substituted with
one or two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl
or aryloxy).sub.2alkyl (where the two aryl or alkyl substituents
can be independently defined, or linked to one another to form a
ring, such as 1,3-dioxane or 1,3-dioxolane, connected to L.sup.1
(or L.sup.2 in the case of R.sup.2) at the 2-position); 1,3-dioxane
or 1,3-dioxolane connected to L.sup.1 (or L.sup.2 in the case of
R.sup.2) at the 4-position.
[0133] The R.sup.1 group may have from one to four substituents,
which can be any of the R.sup.3 groups or R.sup.1 groups, and any
of the preferred R.sup.1 substituents set out below.
[0134] R.sup.1 may be substituted with the following preferred
substituents: alkylcarbonylamino, cycloalkylcarbonyl-amino,
arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino,
aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where
the uriedo nitrogens may be substituted with alkyl, aryl or
heteroaryl), heterocyclylcarbonylamino (where the heterocycle is
connected to the carbonyl group via a nitrogen or carbon atom),
alkylsul-fonylamino, arylsulfonylamino, heteroarylsulfonylamino,
27
[0135] where
[0136] J is: CHR.sup.23, 28
[0137] R.sup.23, R.sup.24 and R.sup.25 are independently hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
[0138] R.sup.20, R.sup.21, R.sup.22 are independently hydrogen,
halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl,
heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these
preferred substituents may either be directly attached to R.sup.1,
or attached via an alkylene chain at an open position.
[0139] R.sup.2 is the same or different from R.sup.1 and is
independently any of the groups set out for R.sup.1, H,
polyhaloalkyl (such as CF.sub.3CH.sub.2, CF.sub.3CF.sub.2CH.sub.2
or CF.sub.3) or cycloheteroalkyl, and may be substituted with one
to four of any of the groups defined for R.sup.3, or any of the
substituents preferred for R.sup.1.
[0140] L.sup.1 is a linking group containing from 1 to 10 carbons
in a linear chain (including alkylene, alkenylene or alkynylene),
which may contain, within the linking chain any of the following:
one or two alkenes, one or two alkynes, an oxygen, an amino group
optionally substituted with-alkyl or aryl, an oxo group; and may be
substituted with one to five alkyl or halo groups (preferably
F).
[0141] L.sup.2 may be the same or different from L.sup.1 and may
independently be any of the L.sup.1 groups set out above or a singe
bond.
[0142] R.sup.3, R.sup.3', R.sup.4 and R.sup.4' may be the same or
different and are independently selected from H, halogen, CF.sub.3,
haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy,
alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio,
alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl,
aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,
cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO,
Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl,
Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or
heteroaryl and Ar may optionally include 1, 2 or 3 additional rings
fused to Ar;
[0143] R.sup.3a and R.sup.3b are the same or different and are
independently any of the R.sup.3 groups except hydroxy, nitro,
amino or thio; 29
[0144] are the same or different and independently represent a 5 or
6 membered heteroaryl ring which may contain 1, 2, 3 or 4
heteroatoms in the ring which are independently N, S or O; and
including N-oxides.
[0145] X (in the fluorenyl type ring) is a bond, or is one of the
following groups: 30
[0146] wherein
[0147] Y is O, N--R.sup.6 or S;
[0148] n' is 0, 1 or 2;
[0149] R.sup.6 is H, lower alkyl, aryl, --C(O)--R.sup.11 or
--C(O)--O--R.sup.11;
[0150] R.sup.7 and R.sup.8 are the same or different and are
independently H, alkyl, aryl, halogen, --O--R.sup.12, or
[0151] R.sup.7 and R.sup.8 together can be oxygen to form a
ketone;
[0152] R.sup.9, R.sup.10, R.sup.9' and R.sup.10' are the same or
different and are independently H, lower alkyl, aryl or
--O--R.sup.11;
[0153] R.sup.9" and R.sup.10" are the same or different and are
independently H, lower alkyl, aryl, halogen or --O--R.sup.11;
[0154] R.sup.11 is alky or aryl;
[0155] R.sup.12 is H, alkyl or aryl.
[0156] The various provisos for compounds set out in U.S.
application Ser. No. 472,067, filed Jun. 6, 1995 (file DC21e) and
U.S. application Ser. No. 08/767,923, filed Dec. 17, 1996 (file
HX79c) are not applicable here.
[0157] The MTP inhibitors disclosed in U.S. provisional application
No. 60/017,253, filed May 10, 1996, (file HX82*) are pyrrolidine
compounds and have the structure X 31
[0158] XI
[0159] where
[0160] Q is 32
[0161] W is H,H or O;
[0162] X is: CHR.sup.8, 33
[0163] R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
[0164] R.sup.1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
arylalkyl (wherein alkyl preferably has at least 2 carbons, more
preferably at least 3 carbons), diarylalkyl, arylalkenyl,
diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl,
heteroarylalkyl (wherein alkyl preferably has at least 2 carbons,
more preferably at least 3 carbons), cycloalkyl, or cycloalkylalkyl
(wherein alkyl preferably has at least 2 carbons, more preferably
at least 3 carbons); all of the aforementioned R.sup.1 groups being
optionally substituted through available carbon atoms with 1, 2, 3
or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy,
aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl,
cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or
oxo; or
[0165] R.sup.1 is a fluorenyl-type group of the structure 34
[0166] R.sup.1 is an indenyl-type group of the structure 35
[0167] Z.sup.1 and Z.sup.2 are the same or different and are
independently a bond, O, S, 36
[0168] with the proviso that with respect to B, at least one of
Z.sup.1 and Z.sup.2 will be other than a bond;
[0169] R.sup.11 is a bond, alkylene, alkenylene or alkynylene of up
to 10 carbon atoms, arylene (for example 37
[0170] or mixed arylene-alkylene (for example 38
[0171] where n is 1 to 6;
[0172] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl,
trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl,
arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or
cycloalkylalkyl; with the provisos that (1) when R.sup.12 is H,
aryloxy, alkoxy or arylalkoxy, then Z.sup.2 is 39
[0173] or a bond;
[0174] and (2) when Z.sup.2 is a bond, R.sup.12 cannot be
heteroaryl or heteroarylalkyl;
[0175] Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or
alkenylene of from 1 to 5 carbon atoms;
[0176] R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are independently
hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl,
cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino,
thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio,
aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino,
alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or
aryloxy;
[0177] R.sup.15a and R.sup.16a are independently any of the
R.sup.15 or R.sup.16 groups except hydroxy, nitro, amino or
thio;
[0178] or R.sup.1 is 40
[0179] wherein p is 1 to 8 and R.sup.17 and R.sup.18 are each
independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of
R.sup.17 and R.sup.18 being other than H;
[0180] or R.sup.1 is 41
[0181] wherein
[0182] R.sup.19 is aryl or heteroaryl;
[0183] R.sup.20 is aryl or heteroaryl;
[0184] R.sup.21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,
cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
[0185] R.sup.2, R.sup.3, R.sup.4 are independently hydrogen, halo,
alkyl, alkenyl; alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
heteroarylalkyl, hydroxy or haloalkyl;
[0186] R.sup.5 is alkyl , alkenyl, alkynyl, aryl, alkoxy, aryloxy,
arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl,
cycloheteroalkyl, heteroaryloxy, cycloalkylalkyl, polycycloalkyl,
polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino,
alkylamino, arylamino, heteroarylamino, cycloalkyloxy,
cycloalkylamino, all of the R.sup.5 substituents and R.sup.6
substituents (set out hereinafter) being optionally substituted
through available carbon atoms with 1, 2, 3 or 4 groups selected
from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,
cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl,
arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy,
arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl,
heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino
(wherein the amino includes 1 or 2 substituents which are alkyl,
aryl or heteroaryl, or any of the other aryl compounds mentioned in
the definitions), thiol, alkylthio, arylthio, heteroarylthio,
arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl,
alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl,
alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,
arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl,
heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl. Where R.sup.5
is phenyl, aryl, heteroaryl or cycloalkyl; this group preferably
includes an ortho hydrophobic substituent such as alkyl, haloalkyl
(with up to 5 halo groups), alkoxy, haloalkoxy (with up to 5 halo
groups), aryl, aryloxy or arylalkyl;
[0187] R.sup.6 is hydrogen or C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkenyl; 42
[0188] are the same or different and are independently selected
from heteroaryl containing 5- or 6-ring members; and
[0189] including N-oxides of the formulae I and II compounds, that
is 43
[0190] including pharmaceutically acceptable salts thereof.
[0191] The MTP inhibitors disclosed in U.S. provisional application
No. 60/017,254, filed May 10, 1996, (file HX84*) are azetidine
compounds which have the structure 44
[0192] where
[0193] Q is 45
[0194] X is: CHR.sup.8, 46
[0195] R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
[0196] R.sup.1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
arylalkyl (wherein alkyl preferably has at least 2 carbons, more
preferably at least 3 carbons), diarylalkyl, arylalkenyl,
diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl,
heteroarylalkyl (wherein alkyl preferably has at least 2 carbons,
more preferably at least 3 carbons), cycloalkyl, or cycloalkylalkyl
(wherein alkyl preferably has at least 2 carbons, more preferably
at least 3 carbons); all of the aforementioned R.sup.1 groups being
optionally substituted through available carbon atoms with 1, 2, 3
or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy,
aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl,
cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or
oxo; or
[0197] R.sup.1 is a fluorenyl-type group of the structure 47
[0198] R.sup.1 is an indenyl-type group of the structure 48
[0199] Z.sup.1 and Z.sup.2 are the same or different and are
independently a bond, O, S, 49
[0200] with the proviso that with respect to B, at least one of
Z.sup.1 and Z.sup.2 will be other than a bond;
[0201] R.sup.11 is a bond, alkylene, alkenylene or alkynylene of up
to 10 carbon atoms, arylene (for example 50
[0202] or mixed arylene-alkylene (for example 51
[0203] where q is 1 to 6;
[0204] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl,
trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl,
arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or
cycloalkylalkyl; with the provisos that (1) when R.sup.12 is H,
aryloxy, alkoxy or arylalkoxy, then Z.sup.2 is 52
[0205] or a bond;
[0206] and (2) when Z.sup.2 is a bond, R.sup.12 cannot be
heteroaryl or heteroarylalkyl;
[0207] Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or
alkenylene of from 1 to 5 carbon atoms;
[0208] R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are independently
hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl,
cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino,
thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio,
aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino,
alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or
aryloxy;
[0209] R.sup.15a and R.sup.16a are independently any of the
R.sup.15 or R.sup.16 groups except hydroxy, nitro, amino or
thio;
[0210] or R.sup.1 is 53
[0211] wherein p is 1 to 8 and R.sup.17 and R.sup.18 are each
independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of
R.sup.17 and R.sup.18 being other than H;
[0212] or R.sup.1 is 54
[0213] wherein
[0214] R.sup.19 is aryl or heteroaryl;
[0215] R.sup.20 is aryl or heteroaryl;
[0216] R.sup.21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,
cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
[0217] R.sup.2, R.sup.3, R.sup.4 are independently hydrogen, halo,
alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
heteroarylalkyl, hydroxy or haloalkyl;
[0218] R.sup.5 is alkyl , alkenyl, alkynyl, aryl, alkoxy, aryloxy,
arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl,
cycloheteroalkyl, heteroaryloxy, cycloalkylalkyl, polycycloalkyl,
polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino,
alkylamino, arylamino, heteroarylamino, cycloalkyloxy,
cycloalkylamino, all of the R.sup.5 substituents and R.sup.6
substituents (set out hereinafter) being optionally substituted
through available carbon atoms with 1, 2, 3 or 4 groups selected
from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,
cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl,
arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy,
arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl,
heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino
(wherein the amino includes 1 or 2 substituents which are alkyl,
aryl or heteroaryl, or any of the other aryl compounds mentioned in
the definitions), thiol, alkylthio, arylthio, heteroarylthio,
arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl,
alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl,
alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,
arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl,
heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl. Where R.sup.5
is phenyl, aryl, heteroaryl or cycloalkyl; this group preferably
includes an ortho hydrophobic substituent such as alkyl, haloalkyl
(with up to 5 halo groups), alkoxy, haloalkoxy (with up to 5 halo
groups), aryl, aryloxy or arylalkyl;
[0219] R.sup.6 is hydrogen or C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkenyl; 55
[0220] are the same or different and are independently selected
from heteroaryl containing 5- or 6-ring members; and
[0221] including N-oxides of the formulae I and II compounds, that
is 56
[0222] including pharmaceutically acceptable salts thereof.
[0223] Compounds disclosed as preferred in each of the above
applications are preferred for use in the present invention.
[0224] Most preferred MTP inhibitors to be employed in accordance
with the present invention include preferred MTP inhibitors as set
out in U.S. patent application Ser. No. 548,811, filed Jan. 11,
1996 (file DC21h) and in U.S. application Ser. No. 08/767,923,
filed Dec. 17, 1996 (file HX79c).
[0225] Thus, preferred compounds in U.S. patent application Ser.
No. 548,811 (file DC21h) for use herein are compounds designated VI
above
[0226] where Z is a bond;
[0227] X.sup.1 and X.sup.2 are H;
[0228] R.sup.5 is aryl such as phenyl substituted with
[0229] (1) aryl such as phenyl, 57
[0230] (2) heteroaryl such as 58
[0231] (3) halo such as Cl
[0232] R.sup.5 is heteroaryl such as 59
[0233] substituted with
[0234] (1) aroyl such as 60
[0235] (2) arylthio such as 61
[0236] wherein the R.sup.5 substituent is preferably in the
position adjacent to the carbon linked to 62
[0237] (CH.sub.2).sub.x is --(CH.sub.2).sub.4-- or 63
[0238] Most preferred is
[0239]
9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]but-
yl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide 64
[0240] Preferred compounds in U.S. application Ser. No. 08/767,923
(file HX79c) for use herein are MTP inhibitor compounds of formula
I that is 65
[0241] wherein
[0242] A is NH,
[0243] B is 66
[0244] X is a bond, oxygen or sulfur; R.sup.3 and R.sup.4 are
independently H or F.
[0245] Preferred R.sup.1 groups are aryl, preferably phenyl,
heteroaryl, preferably imidazoyl or pyridyl (preferably substituted
with one of the preferred R.sup.1 substituents: arylcarbonylamino,
heteroarylcarbonylamino, cycloalkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, arylsulfonylamino,
heteroarylsulfonylamino), PO(OAlkyl).sub.2, heteroarylthio,
benzthi-azole-2-thio, imidazole-2-thio, alkyl, or alkenyl,
cycloalkyl such as cyclohexyl, or 1,3-dioxan-2-yl.
[0246] Preferred R.sup.2 groups are alkyl, polyfluoroalkyl (such as
1,1,1-trifluoroethyl), alkenyl, aryl or heteroaryl (preferably
substituted with one of the preferred R.sup.1 substituents above),
or PO(OAlkyl).sub.2.
[0247] If R.sup.2 is alkyl, 1,1,1-trifluoroethyl, or alkenyl, it is
preferred that R.sup.1 is other than alkyl or alkenyl.
[0248] It is preferred that L.sup.1 contains 1 to 5 atoms in the
linear chain and L.sup.2 is a bond or lower alkylene.
[0249] Preferred embodiments of formula IA and formula IB compounds
of the invention include those where B, L.sup.1, L.sup.2, R.sup.1
and R.sup.2 are as set out with respect to the preferred
embodiments of the formula I compounds, q is 0 or 2 and R.sup.x is
H.
[0250] Thus, preferred MTP inhibiting compounds for use herein and
disclosed in U.S. application Ser. No. 08/767,923, filed Dec. 17,
1996, include the following 67
[0251] or a pharmaceutically acceptable salt thereof.
[0252] The squalene synthetase inhibitors suitable for use herein
include, but are not limited to, .alpha.-phosphonosulfonates
disclosed in U.S. application Ser. No. 08/266,888, filed Jul. 5,
1994 (HX59b), 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
68including the triacids thereof, triesters thereof and
tripotassium and trisodium salts thereof as well as other squalene
synthetase inhibitors disclosed in U.S. Pat. Nos. 4,871,721 and
4,924,024 and in Biller et al, J. Med. Chem., 1988, Vol. 31, No.
10, pp 1869 to 1871.
[0253] 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, phosphinylphosphonates reported by
McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes
reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med.
Chem. U. of Utah, Abstract, Table of Contents, pp. 16, 17, 40-43,
48-51, Summary.
[0254] All of the above U.S. applications are incorporated herein
by reference.
[0255] Other cholesterol lowering drugs suitable for use herein
include, but are not limited to, antihyperlipo-proteinemic agents
such as fibric acid derivatives, such as fenofibrate, gemfibrozil,
clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,
probucol, and related compounds as disclosed in U.S. Pat. No.
3,674,836, probucol and gemfibrozil being preferred, bile acid
sequestrants such as cholestyramine, colestipol and DEAE-Sephadex
(Secholex.RTM., Polidexide.RTM.), as well as clofibrate, lipostabil
(Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine
derivative), imanixil (HOE-402), tetrahydrolipstatin (THL),
istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin
(Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide
(Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and
CL-283,546 (disubstituted urea derivatives), nicotinic acid,
acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,
poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat.
No. 4,759,923, quaternary amine poly(diallyldimethylammonium
chloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009,
and other known serum cholesterol lowering agents.
[0256] Preferred combinations in accordance with the invention are
clopidogrel and ifetroban and optionally pravastatin, atorvastatin,
simvastatin, lovastatin, cerivastatin or fluvastatin.
[0257] In carrying out the method of the present invention, the
ADP-receptor blocking antiplatelet drug in combination with the
thromboxane A.sub.2 receptor antagonist and optionally the
cholesterol lowering drug may be administered to mammalian species,
such as monkeys, dogs, cats, rats, humans, etc., and, as such, may
be incorporated in a conventional systemic dosage form, such as a
tablet, capsule, elixir or injectable. The above dosage forms will
also include the necessary carrier material, excipient, lubricant,
buffer, antibacterial, bulking agent (such as mennitol),
anti-oxidants (ascorbic acid of sodium bisulfite) or the like. Oral
dosage forms are preferred, although parenteral forms are quite
satisfactory as well.
[0258] The dose administered must be carefully adjusted according
to age, weight and condition of the patient, as well as the route
of administration, dosage form and regimen and the desired
result.
[0259] Clopidogrel will be employed in an oral daily dosage within
the range from about 10 to about 1000 mg and preferably from about
25 to about 600 mg, and most preferably from about 50 to about 100
mg.
[0260] Ticlopidine may be employed in a daily dosage as set out in
the 1997 PDR (250 mg) although daily dosages of from about 10 to
about 1000 mg, preferably from about 25 to about 800 mg may be
employed in accordance with the present invention.
[0261] The thromboxane A2 receptor antagonist alone or in
combination with one or more components of the combination of the
invention may be incorporated in a conventional dosage form, such
as a tablet, capsule, elixir, cream, suppository, aerosol spray or
injectable. The above dosage forms will also include the necessary
carrier material, excipient, lubricant, buffer, antibacterial,
bulking agent (such as mannitol), antioxidants (ascorbic acid of
sodium bisulfite) or the like. Oral dosage forms are preferred,
although parenteral forms are quite satisfactory as well.
[0262] The thromboxane A.sub.2 receptor antagonist may be employed
in a separate dosage form from the ADP-receptor blocking
antiplatelet drug and optional cholesterol lowering drug, such as
separate injections and/or tablets or they may be employed in a
single dosage form, such as a single injection and/or tablet.
[0263] With regard to such systemic formulations, where the
thromboxane A.sub.2 receptor antagonist is to be employed alone,
single or divided doses of from about 0.1 to about 2500 mg
preferably from about 2 to about 2000 mg, one to eight times daily,
may be administered in systemic dosage forms as described
above.
[0264] With regard to combinations of the thromboxane A.sub.2
receptor antagonist with ADP-receptor blocking antiplatelet drug,
and optional cholesterol lowering drug, single or divided doses of
from 0.1 to about 2500 mg of thromboxane A.sub.2 receptor
antagonist, preferably 2 to 2000 mg thromboxane A.sub.2 receptor
antagonist, and from about 2 to about 2000 mg ADP-receptor blocking
antiplatelet drug and preferably from about 5 to about 1500 mg
ADP-receptor blocking antiplatelet drug may be administered one to
eight times daily.
[0265] With regard to the optional cholesterol lowering drug, for
oral administration, a satisfactory result my be obtained employing
the HMG CoA reductase inhibitor in dosages employed, for example,
for pravastatin, simvastatin, fluvastatin, lovastatin, atorvastatin
or cerivastatin, as indicated in the Physician's Desk Reference,
such as in an amount within the range of from about 1 to 2000 mg,
and preferably from about 4 to about 200 mg.
[0266] For oral administration, a satisfactory result may be
obtained employing the optional MTP inhibitor in an amount within
the range of from about 0.01 mg/kg to about 100 mg/kg and
preferably from about 0.1 mg/kg to about 75 mg/kg.
[0267] A preferred oral dosage form, such as tablets or capsules,
will contain the MTP inhibitor in an amount of from about 5 to
about 500 mg, preferably from about 10 to about 400 mg, and more
preferably from about 20 to about 250 mg.
[0268] For parenteral administration, the MTP inhibitor will be
employed in an amount within the range of from about 0.005 mg/kg to
about 10 mg/kg and preferably from about 0.005 mg/kg to about 8
mg/kg.
[0269] The optional squalene synthetase inhibitor may be employed
in dosages in an amount within the range of from about 10 mg to
about 2000 mg and preferably from about 25 mg to about 200 mg.
[0270] A preferred oral dosage form, such as tablets or capsules,
will contain clopidogrel or ticlopidine in an amount of from about
10 to about 500 mg, the thromboxane A.sub.2 receptor antagonist in
an amount from about 1 to about 1500 mg, preferably from about 2 to
about 100 mg, the optional HMG CoA reductase inhibitor in an amount
of from about 0.1 to about 100 mg, preferably from about 5 to about
80 mg, and more preferably from about 10 to about 50 mg, and/or the
optional MTP inhibitor in an amount from about 10 to about 400
mg.
[0271] The optional cholesterol lowering drugs when present will be
employed in dosages normally employed as indicated in the
Physician's Desk Reference, for each of such agents such as in an
amount within the range of from about 2 mg to about 7500 mg and
preferably from about 2 mg to about 4000 mg.
[0272] Aspirin may also be optionally present and may be employed
in daily dosages within the range from about 20 mg to about 5000
mg, preferably from about 40 mg to about 500 mg, and in a weight
ratio to the ADP-receptor blocking antiplatelet drug within the
range from about 50:1 to about 0.5:1, preferably from about 25:1 to
about 1:1.
[0273] The ADP-receptor blocking antiplatelet drug, thromboxane
A.sub.2 receptor antagonist and the optional cholesterol lowering
agent and optionally aspirin may be employed together in the same
oral dosage form or in separate oral dosage forms taken at the same
time.
[0274] The compositions described above may be administered in the
dosage forms as described above in single or divided doses of one
to four times daily. It may be advisable to start a patient on a
low dose combination and work up gradually to a high dose
combination.
[0275] Tablets of various sizes can be prepared, e.g., of about 2
to 2000 mg in total weight, containing one or both of the active
substances in the ranges described above, with the remainder being
a physiologically acceptable carrier of other materials according
to accepted pharmaceutical practice. These tablets can, of course,
be scored to provide for fractional doses. Gelatin capsules can be
similarly formulated.
[0276] Liquid formulations can also be prepared by dissolving or
suspending one or the combination of active substances in a,
conventional liquid vehicle acceptable for pharmaceutical
administration so as to provide the desired dosage in one to four
teaspoonsful.
[0277] Such dosage forms can be administered to the patient on a
regimen of one to four doses per day.
[0278] According to another modification, in order to more finely
regulate the dosage schedule, the active substances may be
administered separately in individual dosage units at the same time
or carefully coordinated times. Since blood levels are built up and
maintained by a regulated schedule of administration, the same
result is achieved by the simultaneous presence of the two
substances. The respective substances can be individually
formulated in separate unit dosage forms in a manner similar to
that described above.
[0279] Fixed combinations of the ADP-receptor blocking antiplatelet
drug, thromboxane A.sub.2 receptor antagonist and optional
cholesterol lowering drug and optionally aspirin are more
convenient and are preferred, especially in tablet or capsule form
for oral administration.
[0280] In formulating the compositions, the active substances, in
the amounts described above, are compounded according to accepted
pharmaceutical practice with a physiologically acceptable vehicle,
carrier, excipient, binder, preservative, stabilizer, flavor, etc.,
in the particular type of unit dosage form.
[0281] Illustrative of the adjuvants which may be incorporated in
tablets are the following: a binder such as gum tragacanth, acacia,
corn starch or gelatin; an excipient such as dicalcium phosphate or
cellulose; a disintegrating agent such as corn starch, potato
starch, alginic acid or the like; a lubricant such as stearic acid
or magnesium stearate; a sweetening agent such as sucrose,
aspartame, lactose or saccharin; a flavoring agent such as orange,
peppermint, oil of wintergreen or cherry. When the 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 otherwise modify the physical form
of the dosage unit. For instance, tablets or capsules may be coated
with shellac, sugar or both. A syrup of elixir may contain the
active compound, water, alcohol or the like as the carrier,
glycerol as solubilizer, sucrose as sweetening agent, methyl and
propyl parabens as preservatives, a dye and a flavoring such as
cherry or orange.
[0282] Some of the active substances described above form commonly
known, pharmaceutically acceptable salts such as alkali metal and
other common basic salts or acid addition salts, etc. References to
the base substances are therefore intended to include those common
salts known to be substantially equivalent to the parent
compound.
[0283] The formulations as described above will be administered for
a prolonged period, that is, for as long as the potential for acute
coronary syndrome, including myocardial infarction, stable or
unstable angina, reocclusion after PTCA, restenosis after PTCA, as
well as intermittent claudication, TIA, stroke and reversible
ischemia neurological deficit remains or the symptoms continue.
Sustained release forms of such formulations which may provide such
amounts biweekly, weekly, monthly and the like may also be
employed. A dosing period of at least one to two weeks are required
to achieve minimal benefit.
[0284] The following Examples represent preferred embodiments of
the present invention.
[0285] Formulations suitable for oral administration for inhibiting
platelet aggregation and thrombus formation are prepared as
described below.
EXAMPLES 1
[0286] Capsules are prepared each containing about 98 mg
clopidogrel (as described below) and 35 mg ifetroban.
1 Example 1 Amount (mg/ Ingredient Capsule) Clopidogrel hydrogen
sulfate 98 Lactose, Hydrous, NF ca. 108 ca. Microcrystalline
Cellulose, 13 NF ca. Pregelatinized Starch, NF 10.5 Polyethylene
glycol 6000 NF 7.5 Hydrogenated castor oil, NF 3.3
[0287] The above clopidogrel tablet is prepared by blending
anhydrous lactose, clopidogrel hydrogen sulfate, pregelatinized
starch, polyethylene glycol 6000 in a bin-type blender for about 15
minutes at 7 rpm.
[0288] The blended mix is then screened (1.25 mm screen) and
blended for about 30 minutes at 7 rpm in a bin-type blender. The
blend is compacted using a roller compactor fitted with milling
equipment. The milled granulation which contains particles ranging
from 1 mm to less than 20 mm is blended with microcrystalline
cellulose (screen through 1.25 mm screen) and hydrogenated castor
oil in a bin-type blender for about 30 minutes at 7 rpm. The blend
is compressed into 240 mg tablets.
[0289] A formulation containing the sodium salt of ifetroban, in
the form of tablets, having the following composition, was prepared
by the direct compression manufacturing process as described in
U.S. Pat. No. 5,506,248 which is incorporated herein by
reference.
2 Percent by Ingredient weight Na Salt of Ifetroban 35 Mannitol 50
Microcrystalline Cellulose 8 Crospovidone 3.0 Magnesium Oxide 2.0
Magnesium Stearate 1.5 Colloidal Silica 0.3
[0290] Na salt of ifetroban, magnesium oxide, mannitol,
microcrystalline cellulose, and crospovidone were mixed together
for 2 to 10 minutes employing a suitable mixer. The resulting
mixture was passed through a #12 to #40 mesh size screen.
Thereafter, magnesium stearate and colloidal silica were added and
mixing was continued for 1 to 3 minutes.
[0291] The resulting homogeneous mixture was then compressed into
tablets each containing 35 mg, ifetroban sodium salt.
[0292] The clopidogrel tablets and ifetroban tablets are ground
into powders and filled into a single capsule.
EXAMPLE 2
[0293] Capsules each containing 250 mg ticlopidine (tablets as
described in 1997 PDR) or 98 mg clopidogrel (Example 1) 35 mg
ifetroban tablets (as described in Example 1), and optionally 40 mg
pravastatin (tablets as described in 1997 PDR) are prepared by
grinding up the ticlopidine tablet, and ifetroban tablet, and
optionally the pravastatin tablet and filling the resulting powders
into a single capsule.
EXAMPLE 3 and 4
[0294] Clopidogrel tablets (25 mg, 50 mg or 98 mg) or ticlopidine
tablets (250 mg) and ifetroban tablets (5.25 mg 10 mg and 20 mg as
per U.S. Pat. No. 5,506,248) and optionally pravastatin tablets
(10, 20 or 40 mg as described in the 1997 PDR) may be administered
as a combination in accordance with the teachings of the present
invention to inhibit platelet aggregation and thrombus formulation.
In addition, the clopidogrel and ifetroban and optionally
pravastatin tablets may be ground up into powders and used together
in a single capsule.
EXAMPLE 5
[0295] The following experiment was carried out to demonstrate
inhibition of vessel injury-induced venous thrombosis by
clopidogrel plus ifetroban in relation to antiplatelet
activity.
[0296] The risk of pulmonary embolism after orthopedic surgery
represents an unmet medical need. Clopidogrel was tested in the
FeCl.sub.2 model to establish its potential therapeutic utility. In
these experiments ex vivo indices of platelet activation were
determined to correlate antithrombotic and antiplatelet activities.
The antiplatelet agent ifetroban, which acts by blockade of
thromboxane receptors, was also tested. In addition, antithrombotic
efficacy of the combination of treatments with clopidogrel and
ifetroban was evaluated.
Methods
[0297] Thrombosis Procedure. Male Sprague Dawley rats (350-450 g)
were anesthetized with sodium pentobarbital (50 mg/kg i.p.). A
jugular vein was cannulated for drug infusion or anesthetic
supplementation, and the trachea was intubated to ensure airway
patency. The vena cava was isolated by a midline abdominal incision
and cleared of connective tissue. A fiberoptic probe (model
P-433-10, 0.8 mm tip diameter) was placed on the dorsal surface of
the vena cava distal to the renal veins and attached to a laser
doppler blood perfusion monitor (model BPM 430-2, Vasamedics, St.
Paul, Minn.). When baseline flow had stabilized, a 2 mm.times.5 mm
strip of filter paper was saturated in 15% FeCl.sub.2 and placed on
the vena cava downstream from the flow probe for 1 min. The vena
cava was dissected free 60 min after filter paper application and
opened lengthwise. The thrombus was removed to determine wet and
dry thrombus weights on a Sartorius R-160P balance (Brinkmann
Instruments Inc., Westbury, N.Y.). Blood flow was monitored on an
R-611 physiological recorder (Sensor Medics, Anaheim, Calif.).
Total blood flow was calculated by planimetry and normalized as
percent of baseline flow (0 min=100%) over 60 min.
[0298] Ex Vivo Platelet Function and Coagulation Testing. Male
Sprague Dawley rats (350-450 g) were anesthetized with sodium
pentobarbital (50 mg/kg i.p.) The vena cava was isolated by a
midline abdominal incision and 5 to 8 ml of blood was withdrawn
into a {fraction (1/10)}.sup.th volume of 3.8% Na citrate. A
portion of each blood sample was centrifuged for 3 sec in a
Microcentrifuge E (Beckman, Palo Alto, Calif., USA) to prepare
platelet rich plasma (PRP) and for 3 min to prepare platelet poor
plasma (PPP). The PRP was adjusted to a count of
.about.450.times.10.sup.- 3 platelets per .mu.l by adding PPP.
[0299] Platelet aggregation responses of PRP to ADP (1,3 and 10
.mu.M; Chrono-Log Corp., Havertown, Pa., USA) were determined using
the photometric technique described for a model 540 aggregometer
(Chrono-Log Corp.).
[0300] A modified activated clotting time (ACT) was determined in a
BBL Fibrometer (Becton Dickinson, Cockeysville, Md., USA) by
incubating blood (100 .mu.l) with celite (30 .mu.l of 1% celite
suspension +70 .mu.l saline) for 3 min at 37.degree. C. and
recalcifying (100 .mu.l of 20 mM CaCl.sub.2). Celite (Haemoscope,
Skokie, Ill., USA) is a contact activator used to shorten control
clotting times in plastic reaction vessels. The development of clot
tensile strength as a function of time was determined in a model
3000 computerized thrombelastograph (Haemoscope) by activating 284
.mu.l of whole blood with 28 .mu.l of 1% celite suspension and 18
.mu.l of 150 mM CaCl.sub.2.
[0301] Drug treatments. There were 3 separate studies. In the first
study rats were dosed once daily for 3 days with an oral gavage of
either saline (n=6) or clopidogrel 3 (n=5), 10 (n=5), 20 (n=4)
mg/kg). One hour after the last dose, rats were anethetized for the
thrombosis protocol or blood was obtained for ex vivo testing of
platelet function and whole blood coagulation. In the second study
a continuous i.v. infusion of either saline or ifetroban (150
.mu.g/kg/min) was administered starting 15 min before FeCl2-induced
injury of the vena cava. In the third study, rats were treated with
saline or clopidogrel (2 mg/kg per day for 3 days) and administered
either saline or ifetroban (150 .mu.g/kg/min) starting 15 min
before FeCl2 application.
Results
[0302] The benefit of prophylactic clopidogrel treatment on vessel
injury-induced venous thrombosis was characterized by a reduction
in thrombus weight and improvement in vessel patency and blood
flow. Thrombus weight was decreased by 46, 72, and 84% at
clopidogrel doses of 3, 10 and 20 mg/kg daily for 3 days,
respectively. In contrast, ifetroban was inactive in this model
even though the dose used had been shown previously to
block.gtoreq.99% of rat platelet thromboxane A.sub.2 receptors
(Schumacher et al., J. Cardiovasc. Pharmacol., 22:526-533, 1993).
Doses of clopidogrel which were antithrombotic inhibited ex vivo
platelet aggregation responses to ADP. This result was dependent on
both the dose of clopidogrel and the concentration of ADP. In
vehicle-treated rats, threshold maximal aggregation was achieved
with 3 .mu.M ADP, and the 10-mg/kg dose of clopidogrel inhibited
this activity by 50%. A near maximal 86% inhibition of ADP-induced
aggregation was achieved with the 20-mg/kg clopidogrel dose.
However, the platelet shape change response to ADP was unaffected
by even this high dose of clopidogrel. The ex vivo whole blood
coagulation tests were also unaffected by clopidogrel.
[0303] In rats, the clopidogrel dose (2 mg/kg per day for 3 days)
was not sufficient to inhibit thrombus formation, and ifetroban
alone produced no significant effect. However, the combination of
clopidogrel pretreatment plus acute ifetroban treatment
significantly reduced thrombus weight by 43%. The ratio of dry to
wet thrombus weights did not differ among treatment groups and
averaged 0.27.+-.0.003.
Discussion
[0304] Clopidogrel is well recognized as a potent inhibitor of
ADP-induced platelet aggregation in humans and rats. Clopidogrel
has produced dose-dependent activity in rat models of carotid
artery thrombosis induced by transmural vessel injury and vena cava
thrombosis induced by either transmural vessel injury or partial
stasis of blood flow combined with mild vessel injury. These models
are reminders of the inadequacy of current anticoagulant therapy in
situations where thrombosis is complicated by severe vessel injury,
especially venous thrombosis accompanying orthopedic surgery.
Potent inhibition (.gtoreq.75%) of stasis-induced vena cava
thrombosis was achieved using doses of heparin and a
low-molecular-weight heparin (fragmin) which increased APTT by only
1.8-fold, and using a dose of warfarin which produced a PT ratio
(INR) of 2.2. These results are consistent with the well
established effectiveness of these indirect thrombin inhibitors in
settings of uncomplicated venous thrombosis. In contrast,
comparable inhibition of vessel injury-induced venous thrombosis
necessitated higher doses which caused APTT increases of>10-fold
(heparin) and 6.6-fold (fragmin) and an INR of 9.5 (warfarin).
Inhibition of platelet-dependent carotid artery thrombosis by these
drugs also required higher doses exerting equal or greater effects
on blood coagulation (Schumacher et al., J. Cardiovasc. Pharmacol.,
28:19-25, 1996).
[0305] The dose-dependent antithrombotic activity of clopidogrel in
each of the thrombosis models was as follows. Unlike the indirect
thrombin inhibitors, clopidogrel was least effective against
stasis-induced venous thrombosis. This profile would be expected
for an antiplatelet drug, because the model is not considered to be
platelet-dependent. It is the near equivalent efficacy of
clopidogrel against vessel injury-induced venous and arterial
thrombosis that was unexpected. The 10-mg/kg dose of clopidogrel
showed good activity in all three models. The potential uniqueness
of clopidogrel is further underscored by the failure of both
ifetroban and aspirin (Schumacher et al., 1993a, Schumacher and
Steinbacher, J. Cardiovasc. Pharmacol. 22:526-533, 1993) in the
vessel injury-induced venous thrombosis model.
[0306] In order to compare clopidogrel doses that were effective in
experimental venous thrombosis to the dose used in clinical
studies, platelet aggregation was used as an ex vivo indicator of
pharmacodynamic activity. Clopidogrel exerted significant
inhibition of both venous and arterial thrombosis at a dose causing
50% inhibition of ex vivo platelet function. Clinical studies have
demonstrated the efficacy of clopidogrel against arterial
thrombosis at a dose that inhibits human platelet aggregation to 5
.mu.M ADP by 40 to 50%. Although ifetroban alone was effective in
the uncomplicated venous thrombosis model, in the vessel injury
induced venous thrombosis model it was not effective. This suggests
that the thromboxane mechanism does not play the key role in
platelet involvement in this platelet-dependent model. Aspirin,
which also inhibits the thromboxane mechanism, was inactive in both
venous thrombosis models. The activity of clopidogrel in these
models implicates the ADP receptor as an initiating platelet
receptor mechanism in thrombogenesis involving low shear forces,
vessel injury and the development of platelet-poor thrombi.
[0307] Clopidogrel has not been reported to affect coagulation in
classical clotting tests that use plasma that is devoid of
platelets. This suggests that the mechanism whereby clopidogrel
inhibits venous thrombosis is probably related to platelet
inhibition separate from a direct action on in vitro blood
coagulation.
[0308] The efficacy of ifetroban in animals treated with a
sub-threshold dose of clopidogrel is particularly surprising.
Clopidogrel and ifetroban show synergistic antiplatelet activity.
They act by antagonizing separate receptor-mediated mechanisms of
platelet aggregation: clopidogrel blocks ADP-induced platelet
aggregation, and ifetroban antagonizes thromboxane receptor
dependent platelet activation. These mechanisms represent two of
the three most important pathways for recruitment of platelets into
growing thrombi; thrombin receptor activation is the third key
platelet pathway that is not blocked effectively by either
clopidogrel or ifetroban. The synergistic efficacy of clopidogrel
and ifetroban in this model of vessel-injury induced venous
thrombosis attests to the pivotal role of platelets in the model.
Clearly, high doses of clopidogrel are optimally effective in this
model, but it may not be practical to use such high doses in
patients. These results suggest that optimal efficacy might be
achieved with moderate doses of clopidogrel plus ifetroban. One
potential mechanism for the synergistic activity of clopidogrel and
ifetroban in this model involves the role of activated platelets as
a platform for thrombin generation.
Conclusions
[0309] Clopidogrel is a potent inhibitor of ADP-induced aggregation
with well-established utility in experimental arterial thrombosis;
however, its effectiveness against venous thrombosis is less well
understood. The thromboxane receptor antagonist, ifetroban, also
produced intermediate efficacy in this model. In contrast,
inhibition of vena cava thrombosis induced by topical application
of FeCl.sub.2 requires super-therapeutic doses of anticoagulants
and is more representative of platelet-dependent venous thrombosis
complicated by severe vessel injury during major knee and hip
surgery. Clopidogrel and ifetroban were tested in this rat model of
vessel injury-induced thrombosis. Clopidogrel, dosed orally once
daily for 3 days at 3, 10 and 20 mg/kg, inhibited acute thrombus
formation by 46, 72, and 84%, respectively. At 2 mg/kg clopidogrel
had no effect on thrombus formation. In vehicle-treated rats, 3
.mu.M ADP caused threshold maximal platelet aggregation, and the
10-mg/kg clopidogrel dose inhibited this activity by 50%, which
is-in the activity range of the clinical dose. Ifetroban (and
aspirin in previous experiments) failed to inhibit thrombosis in
this model. However, the combination of ifetroban and the
sub-threshold dose of clopidogrel (2 mg/kg) reduced thrombus
formation by 43% (p<0.0l). Thus, ifetroban and clopidogrel may
appear to produce synergistic antithrombotic activity.
* * * * *