Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-10-05
2001-09-18
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S015000, C546S016000, C546S019000, C546S020000
Reexamination Certificate
active
06291469
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel spiro compounds useful as glycoprotein IIb/IIIa antagonists for the prevention of thrombosis.
BACKGROUND OF THE INVENTION
The most prevalent vascular disease states are related to platelet dependent narrowing of the blood supply such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls.
Platelet adhesion and aggregation is believed to be an important part of thrombus formation. This activity is mediated by a number of platelet adhesive glycoproteins. The binding sites for fibrinogen, fibronectin and other clotting factors have been located on the platelet membrane glycoprotein complex IIb/IIIa. When a platelet is activated by an agonist such as thrombin the GPIIb/IIIa binding site becomes available to fibrinogen, eventually resulting in platelet aggregation and clot formation.
Heretofore it has been proposed to block these thrombus formation sites by the use of various therapeutic agents.
There is a need in the area of cardiovascular and cerebrovascular therapeutics for new agents which can be used in the prevention and treatment of thrombi.
It is a discovery of this invention that certain novel spiro compounds block the GPIIb/IIIa fibrinogen receptor, thereby inhibiting platelet aggregation and subsequent thrombus formation. Pharmaceutical formulations containing the spiro compounds of this invention inhibit aggregation and are useful for the prophylaxis and treatment of thrombogenic diseases, such as myocardial infarction, angina, stroke, peripheral arterial disease, disseminated intravascular coagulation and venous thrombosis.
SUMMARY OF THE INVENTION
The present invention covers novel spiro compounds having a Spiro nucleus formed from two fused rings, A and B, represented by the formula (I), as hereinafter defined, and all pharmaceutically-acceptable salts, solvates and prodrug derivatives thereof:
having substituents and subscripts; Q, —(L)—, A
i
, p, R
10
, m, n, R
0
, B
j
, q, and R
3
, as hereinafter defined.
Another aspect of the invention is a pharmaceutical formulation containing a novel spiro compound of the invention.
Another aspect of the invention is a method of inhibiting platelet aggregation, inhibiting fibrinogen binding, or preventing thrombosis by administering to a mammal the novel Spiro compounds of the invention.
Another aspect of this invention is a method of treating a human to alleviate the pathological effects of atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, and anastomosis of vascular grafts; wherein the method comprises administering to said human a therapeutically-effective amount of a novel spiro compound of this invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The term “spiro” refers to a compound consisting of two rings having only one carbon atom in common. Spiropentane is an exemplary compound having a spiro system. Spiro systems exclude other bicyclic compounds such as naphthalene which have two or more carbon atoms in common.
The term “alkyl” used herein refers to a monovalent straight or branched chain radical of from one to ten carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
The term “halosubstituted alkyl” as used herein refers to an alkyl group as just defined, substituted by one, two or three halogen atoms selected from fluorine, chlorine, bromine, and iodine. Examples of such groups include chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term “aryl” when used alone means a homocyclic aromatic radical whether or not fused. Preferred aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.
The term “substituted aryl” denotes an aryl group substituted with one, two, or three substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, trifluoromethyl, amino, aminomethyl, and the like. Examples of such groups are 4-chlorophenyl, 2-methylphenyl, 3-methyl-4-hydroxyphenyl, and 3-ethoxyphenyl.
The term “arylalkyl” means one, two or three aryl groups having the number of carbon atoms designated, appended to an alkyl radical having the number of carbon atoms designated. A typical arylalkyl group is the benzyl group.
The term “alkenyl” as used herein refers to a monovalent straight or branched chain radical of from two to six carbon atoms containing a carbon double bond including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
The term “alkylene” as used herein refers to a divalent straight or branched chain group of from one to ten carbon atoms, including but not limited to, —CH
2
—, —(CH
2
)
2
—. —(CH
2
)
3
—, —CH(CH
3
)—, —CH(C
2
H
5
)—, —CH(CH
3
)CH
2
—, and the like.
The term “alkenylene” as used herein refers to a divalent straight or branched chain group of from two to ten carbon atoms containing a carbon-carbon double bond, including but not limited to, —CH═CH—, —C(CH
3
)═CH—, CH═CH—CH
2
—, —CH═C(CH
3
)—CH
2
—, —CH
2
CH(CH═CH
2
)CH
2
, and the like.
The term “alkynylene” as used herein refers to a divalent straight or branched chain group of from two to ten carbon atoms containing a carbon-carbon triple bond, including but not limited to,
and the like.
The term “amidino” refers to the radical having the structural formula;
The term “basic radical” refers to an organic radical which is a proton acceptor. Illustrative basic radicals are amino and amidino. Basic radicals may also be formed from a ring nitrogen.
The term “basic group” refers to an organic group containing one or more basic radicals. A basic group may comprise only an basic radical.
The term “acid radical” refers to an organic radical which is a proton donor. Illustrative acid radicals include;
The term “acidic group” is an organic group containing one or more acid radicals. An acidic group may comprise only an acid radical.
The term “non-interfering substituent” refers to an organic radical which does not significantly reduce the therapeutic effectiveness of a compound.
COMPOUNDS OF THE INVENTION
This invention provides compounds of the general formula (I), or a pharmaceutically-acceptable salt, solvate or or prodrug thereof:
wherein;
the atoms A
i
and B
j
are independently selected from carbon, nitrogen, oxygen or sulfur, provided that at least one atom of A
i
is carbon, and at least one atom B
j
is carbon;
the rings of the spirobicycle formed by A
i
and B
j
, respectively, may optionally be partly unsaturated;
p and q are independently numbers from 2 to 6;
m is a number from zero to p;
R
10
is the same or different and is a non-interfering substituent independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, arylalkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, ═O, or ═S, with the proviso that only one R
10
may be ═O or ═S, if p is 2 or one or two R
10
may be ═O or ═S, if p is a number from 3 to 6;
n is the number from zero to q;
R
0
is the same or different and is a non-interfering substituent independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, arylalkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, ═O, or ═S, with the proviso that only one R
0
may be ═O or &boxH
Fisher Matthew J.
Jakubowski Joseph A.
Masters John J.
Mullaney Jeffrey T.
Paal Michael
Eli Lilly and Company
Knobbe Martens Olson & Bear LLP
Rao Deepak R.
Raymond Richard L.
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