Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-03-13
2003-12-09
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S092000, C564S168000, C514S331000, C514S335000, C514S400000, C514S604000, C514S616000, C514S619000, C544S338000, C546S234000, C546S337000
Reexamination Certificate
active
06660885
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 polycyclic aryl and heteroaryl substituted benzene 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 Antiplatelet 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 benzene compounds that act as an inhibitor of a coagulation factor present in the coagulation cascade or clotting process. In PCT Patent Applications WO 99/00121 and WO 99/00128, Beight et al. describe certain aroylamido, aroyloxy, and N-arylamidocarbonyl and certain heteroaroylamido, heteroaroyloxy, and N-heteroarylamidocarbonyl benzenes that may be further substituted at the other benzene ring carbons by other groups and that are reported to have inhibitory activity against factor Xa. In U.S. Pat. No. 5,872,138 and PCT Patent Application WO 98/10763, Naylor-Olsen et al. describe disubstituted benzenes having a group linked through an oxygen, nitrogen or sulfur heteroatom, any one of six basic heterocycles linked to the ring through linker group, and, optionally, an additional alkyl, alkenyl, alkoxy, amino, or arylmethylenesulfonamido group and claimed to inhibit human thrombin. In PCT Patent Application WO 99/26920, Semple et al. disclose 1-oxy-2,3,4,5-tetrasubstituted-phenylacetamides having an acyl function in the group substituting the amide nitrogen and having activity against thrombin. In PCT Patent Application WO 96/39380, Lu and Soll describe bis-(sulfonamido substitutedbenzoyl) derivatives of diamines claimed to have utility as inhibitors of thrombotic disorders. In PCT Patent Application WO 96/40100, Illig et al. describe sulfonamido substitutedbenzoyl and benzyl derivatives of amines directed to non-peptidic factor Xa and claimed to have utility as inhibitors of thrombotic disorders. In PCT Patent Applications WO 00/039102, Wexler et al. describe certain 3-(amino substituted bicyclo heteroaryl)-propoxy, -propylamino, and -propanoylamido benzene compounds that may be further substituted at the other two benzene ring carbons by other groups and that are reported to be inhibitors of trysin-like serine protease enzymes, especially factor Xa and thrombin.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel 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 Polycyclic Aryl and Heteroaryl Substituted Benzenes, 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 is selected from the group consisting of hydrido, halo, hydroxy, hydroxyalkyl, amino, aminoalkyl, cyano, alkyl, alkenyl, haloalkyl, haloalkenyl, carboxy, carboxyalkyl, carboalkoxy, amidocarbonyl, acyl, phosphono, sulfo, O—R
6
, NH—R
6
, S—R
6
, S(O)—R
6
, and S(O)
2
—R
6
, wherein R
6
is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, haloalkenyl, acyl, aroyl, and heteroaroyl;
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
can be O, no more than one of D
1
, D
2
, J
1
, J
2
and K
1
can be 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
can be 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
32
, R
33
, R
34
, R
35
, and R
36
can independently be Q
b
;
R
9
, R
10
, R
11
, R
12
, R
13
, R
16
, R
17
, R
18
, R
19
, R
32
Parlow John J.
South Michael S.
Kumar Shailendra
Pharmacia Corporation
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