Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-19
2004-04-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S525000, C514S269000, C514S272000, C544S319000, C544S320000, C544S321000, C544S114000, C544S238000
Reexamination Certificate
active
06716838
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of anticoagulant therapy, and specifically relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to substituted polycyclic aryl and heteroaryl uracil compounds that inhibit serine proteases of the coagulation cascade.
BACKGROUND OF THE INVENTION
Physiological systems control the fluidity of blood in mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antiplplatelet Drugs. In Hardman, J. G. and Limbird, L. E., editors: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th edition. New York, McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain fluid within the vascular systems and yet be able to undergo hemostasis, cessation of blood loss from a damaged vessel, quickly. Hemostasis or clotting begins when platelets first adhere to macromolecules in subendothelian regions of an injured and/or damaged vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets.
Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, and XII; these are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called “coagulation cascade” or chain reaction [Handin, R. I.: Bleeding and Thrombosis. In Wilson, J., et al. editors: Harrison's Principles of Internal Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1991, p. 350]. Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to XIIa to XIa to IXa and to the conversion of X to Xa. Xa with factor Va converts prothrombin (II) to thrombin (IIa) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. An extrinsic pathway is initiated by the conversion of coagulation factor VII to VIIa by Xa. The presence of Tissue Factor and VIIa accelerates formation of Xa in the presence of calcium ion and phospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrin clot as described above. The presence of one or more of these many different coagulation factors and two distinct pathways of clotting could enable the efficacious, selective control and better understanding of parts of the coagulation or clotting process.
While clotting as a result of an injury to a blood vessel is a critical physiological process for mammals such as man, clotting can also lead to disease states. A pathological process called thrombosis results when platelet aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel. Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery. When the thrombosis occurs in a coronary artery, a myocardial infarction or heart attack can result. A thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed. Thrombosis of a deep vein may be complicated by a pulmonary embolism. Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
There have been several reports of non-peptidic and peptidic uracil compounds that act as an inhibitor of a coagulation factor present in the coagulation cascade or clotting process. In U.S. Pat. No. 5,656,645, Tamura et al. describe 4,5,6-substituted-3-aminopyridonyl-acetamides, 1,6-substituted-5-aminouracinylacetamides, and 2,4-substituted-5-aminopyrimidinonyl-acetamides in which the amide substituents all have a formyl group and which reportedly have activity against thrombin. In U.S. Pat. No. 5,658,930, Tamura et al. again describe 4,5,6-substituted-3-aminopyridonyl-acetamides, 1,6-substituted-5-aminouracinylacetamides, and 2,4-substituted-5-aminopyrimidinonylacetamides in which the amide substituents all have a formyl group and which reportedly have activity against thrombin. In PCT patent application Ser. Nos. 96/18644 and 97/46207, Tamura et al. further describe 4,5,6-substituted-3-aminopyridonylacetamides, 1,6-substituted-5-aminouracinylacetamides, and 2,4-substituted-5-amino-pyrimidinonylacetamides in which the amide substituents all have a formyl group and which reportedly have activity against thrombin.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide compounds that are beneficial in anticoagulant therapy and that have a general structure:
It is another object of the present invention to provide methods for preventing and treating thrombotic conditions, such as coronary artery disease, cerebrovascular disease, and other coagulation related disorders. Such thrombotic conditions are prevented and treated by administering to a patient in need thereof an effective amount of compounds of Formula (I).
Various other objects and advantages of the present invention will become apparent from the following description of the invention.
DESCRIPTION OF THE INVENTION
The present invention relates to a class of compounds comprising Substituted Polycyclic Aryl and Heteroaryl uracils, which are beneficial in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease, as given in Formula (I):
or a pharmaceutically acceptable salt thereof, wherein;
J
a
and J
b
are independently selected from the group consisting of O and S;
J
a
is optionally selected from the group consisting of CH—R
6
and N—R
6
wherein R
6
is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of a substituent selected from the group consisting of R
4a
, R
4b
, R
14
, R
15
, R
39
, R
40
, and R
5
to form a heterocyclyl ring having 5 through 8 contiguous members;
J
b
is optionally selected from the group consisting of CH—R
6
and N—R
6
wherein R
6
is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of a substituent selected from the group consisting of R
1
, R
4a
, R
4b
, R
14
and R
15
to form a heterocyclyl ring having 5 through 8 contiguous members;
J
a
and J
b
are optionally independently selected from the group consisting of CH—R
6
and N—R
6
wherein R
6
is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the points of bonding of both R
4a
and R
4b
to form a heterocyclyl ring having 5 through 8 contiguous members;
J
a
is optionally selected from the group consisting of CH—R
6
and N—R
6
wherein R
6
is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the points of bonding of both R
39
and R
40
to form a heterocyclyl ring having 5 through 8 contiguous members;
B is formula (V):
wherein D
1
, D
2
, J
1
, J
2
and K
1
are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D
1
, D
2
, J
1
, J
2
and K
1
is O, no more than one of D
1
, D
2
, J
1
, J
2
and K
1
is S, one of D
1
, D
2
, J
1
, J
2
and K
1
must be a covalent bond when two of D
1
, D
2
, J
1
, J
2
and K
1
are O and S, and no more than four of D
1
, D
2
, J
1
, J
2
and K
1
are N with the proviso that R
32
, R
33
, R
34
, R
35
, and R
36
are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R
9
, R
10
, R
11
, R
12
, R
13
,
Jones Darin E.
Rueppel Melvin L.
South Michael S.
Balasubramanian Venkataraman
Pharmacia Corporation
Raymond Richard L.
LandOfFree
Substituted polycyclic aryl and heteroaryl uracils as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted polycyclic aryl and heteroaryl uracils as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted polycyclic aryl and heteroaryl uracils as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3192697