Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-02
2001-08-28
Raymond, Richard L. (Department: 1642)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S210020, C514S212030, C514S213010, C514S258100, C514S261100, C514S307000, C514S309000, C514S310000, C514S311000, C540S203000, C540S354000, C540S356000, C540S363000, C540S364000, C540S523000, C540S521000, C540S539000, C540S594000, C540S595000, C540S597000, C544S255000, C544S262000, C544S278000, C544S280000, C546S139000, C546S141000, C546S142000, C546S143000, C546S145000, C546S146000
Reexamination Certificate
active
06281227
ABSTRACT:
FIELD OF THE INVENTION
The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are Factor Xa inhibitors. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.
Factor Xa is the penultimate enzyme in the coagulation cascade. Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formula I. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme, and is therefore independent of the plasma co-factor antithrombin III. Effective factor Xa inhibition is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin.
Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, and intermittent claudication and bypass grafting (CABG) of the coronary or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems. The indications discussed above include some, but not all, of the possible clinical situations where anticoagulant therapy is warranted. Those experienced in this field are well aware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy.
SUMMARY OF THE INVENTION
This invention is directed to compounds of formula I below as well as to their pharmaceutical use for treating a patient suffering from a physiological disorder capable of being modulated by inhibiting the activity of Factor Xa:
wherein
is a monocyclic heteroaryl group containing at least one nitrogen atom, or a bicyclic heteroaryl group which includes a first proximal ring that is attached to Z and a ring distal to said first ring, said distal ring including at least one nitrogen atom;
Z is alkylenyl, —(CH
2
)
r
C(O)NR″(CH
2
)
s
—, —(CH
2
)
s
R″NC(O)(CH
2
)
r
—, —(CH
2
)
r
NR″(CH
2
)
s
— or —(CH
2
)
s
NR″(CH
2
)
r
—;
R
1
is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R′O(CH
2
)
x
—, R′O
2
C(CH
2
)
x
—, R′C(O)(CH
2
)
x
—, Y
1
Y
2
NC(O)(CH
2
)
x
—, or Y
1
Y
2
N(CH
2
)
x
—;
R′ and R″ are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
R
2
is hydrogen, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, R
3
R
4
NC(O)(CH
2
)x—, R
3
S(O)
p
— or R
3
R
4
NS(O)
p
—;
R
3
is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl or optionally substituted heteroaralkenyl, or R
1
and R
3
taken together with the —N—S(O)
p
— moiety or the —N—S(O)
p
—NR
4
— moiety through which R
1
and R
3
are linked form a 5 to 7 membered optionally substituted heterocyclyl; and
R
4
is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R
3
and R
4
taken together with the nitrogen to which R
3
and R
4
are attached form an optionally substituted 4 to 7 membered heterocyclyl;
X
1
and X
1a
are independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or X
1
and X
1a
taken together form oxo;
X
2
and X
2a
are independently H, or taken together form oxo;
X
3
is H, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or X
3
and one of X
1
and X
1a
taken together form a 4 to 7 membered cycloalkyl;
X
4
is H, optionally substituted alkyl, optionally substituted aralkyl, or hydroxyalkyl;
X
5
, X
5a
and X
5b
are independently selected from H, R
5
R
6
N—, (hydroxy)HN—, (alkoxy)HN—, or (amino)HN—, R
7
O—, R
5
R
6
NCO—, R
5
R
6
NSO
2
—, R
7
CO—, halo, cyano, nitro and R
8
(O)C(CH
2
)
q
—, and when
is a bicyclic heteroaryl group, one of X
5
, X
5a
and X
5b
is a substituent that is alpha to a nitrogen of said distal ring of
and is selected from the group consisting of H, hydroxy and H
2
N—, (optionally substituted lower alkyl)HN (hydroxy)HN—, (alkoxy)HN—, and (amino)HN—;
Y
1
and Y
2
are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y
1
and Y
2
taken together with the N through which Y
1
and Y
2
are linked form a 4 to 7 membered heterocyclyl;
R
5
and R
6
are independently H or optionally substituted lower alkyl, or one of R
5
and R
6
is H and the other of R
5
and R
6
is R
8
(O)CCH
2
— or lower acyl;
R
7
is H, optionally substituted lower alkyl, lower acyl or R
8
(O)CCH
2
—;
R
8
is H, optionally substituted lower alkyl, alkoxy or hydroxy;
m is 0, 1, 2 or 3;
p and r are independently 1 or 2;
q is 0 or 1,
s is 0, 1 or 2; and
x is 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
Definitions
“Patient” includes both humans and other mammals.
“Alkyl” means an aliphatic hydrocarbon group which may be straight- or branched- chain having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. “Lowe
Barton Jeffrey N.
Becker Michael R.
Choi-Sledeski Yong Mi
Ewing William R.
Gong Yong
Aventis Pharma Deutschland GmbH
Butch, III Peter J.
Newman Irving
Parker III Raymond S.
Raymond Richard L.
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