Antithrombotic agents

Details Antithrombotic agents Antithrombotic agents

1999-08-11

2001-01-30

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252020, C514S255050, C514S255010, C514S252110, C544S120000, C544S238000, C544S295000, C544S357000, C544S405000

Reexamination Certificate

active

06180627

ABSTRACT:

This application is filed claiming priority from co-pending British Provisional Application No. 9900801.3 filed Jan. 14, 1999 and British Provisional Application No. 9817819.7 filed Aug. 14, 1998.
This invention relates to a series of indole, indazole and benzimidazole derivatives, which are antithrombotic agents, having utility in a variety of therapeutic areas including the prevention and/or treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisation trauma, application of lower limb plaster casts, or fractures of the lower limbs or pelvis; recurrent DVT; DVT during pregnancy when there is a previous history thereof; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable fangina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; disseminated intravascular coagulation; coagulation in extra-corporeal circuits; occlusion of arterio-venous shunts and blood vessel grafts (including coronary artery by-pass grafts); and restenosis and occlusion following angioplasty. They also have utility as an adjunct to thrombolytic therapy.
The compounds of the invention are potent and selective inhibitors of thrombin, which is the final serine protease enzyme in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to produce fibrin which forms linear insoluble polymers which, in turn, are cross-linked by factor XIIIa, itself activation of factors V and VIII earlier in the cascade. It also has important actions at the cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in haemostasis and thrombus formation.
Clearly then, potent, selective and orally bioavailable thrombin inhibitors represent an attractive target for the convenient therapeutic control of thrombosis. In addition, thrombin potently causes neurite retraction and therefore a thrombin inhibitor is of potential therapeutic utility in the treatment of acute and chronic neurodegenerative disorders. Furthermore, the compounds disclosed herein are of potential value in the treatment of inflammatory disorders and scarring, and in wound healing.
Because of their potential as substrate mimics, arginine derivatives have (see Cardiovascular Drug Rev., 1991, 9, 247). In turn, other research groups have sought to express the basic arginine function in alternative structures; for example, WO-A-95/13274 discloses amidinophenylalanine and amidinopyridylalanine derivatives as antithrombotic agents. Further variations on the theme of arginine mimicry amongst thrombin inhibitors are represented by, inter alia, the guanidinyl- and amidinyl-substituted heterocyclic compounds disclosed in EP-A-0623595. In general, however, compounds containing the basic arginine, amidine or guanidine function have poor oral bioavailability and are poorly selective since they inhibit trypsin as well as thrombin.
Thrombin inhibitors containing a 3-amino-2-pyridone acetamide template have been disclosed by Corvas Int Inc in PCT patent reference WO 96/18644 and COR Therapeutics Inc in WO 98/16547. Compounds of the type disclosed within WO 96/18644 and WO 98/16547 contain a guanidino function as an arginine mimic and are likely to be irreversible inhibitors of thrombin by virtue of the presence of an aldehyde or an activated carbonyl fragment.
Thrombin inhibitors containing a 3-amino-2-pyridone or pyrazinone acetamide fragment and an arginine mimic which is not a guanidine or amidine have been disclosed by Merck in PCT patent reference WO 97/40024, WO 97/01338, WO 97/30708, WO 98/09987, WO 99/11267 and in Bioorg Med Chem, Letters. 1997, 7, p1497; 1998, 8, p1719, 1998, 8, p817.
The present inventors have now found a class of non basic or weakly basic bicyclic heterocyclic arginine mimics which are highly potent, selective, reversible thrombin inhibitors with good oral bioavailability.
Accordingly, the present invention provides compound of formula (I):
wherein:
R
1
is hydrogen, C
1
-C
4
alkyl, perfluoro C
1
-C
4
alkyl, OC
1
-C
4
alkyl, fluoro or chloro;
R
2
is hydrogen, CH
3
,or CF
3
;
R
3
is hydrogen, C
1
-C
4
alkyl, perfluoro C
1
-C
4
alkyl, OC
1
-C
4
alkyl, fluoro or chloro;
R
4
is hydrogen or C
1
-C
4
alkyl;
R
5
is hydrogen or C
1
-C
4
alkyl;
R
6
is hydrogen, fluoro or chloro;
C
1
-C
6
alkyl, C
3
-C
6
carbocyclic (eg cyclopropyl), C
3
-C
6
carbocyclicC
1
-C
4
alkyl wherein the alkyl and carbocyclic may optionally be substiututed by C
1
-C
4
alkyl or fluoro (eg perfluoro C
1
-C
4
alkyl), and wherein the carbocycle contains zero, one or more double bonds;
or R
5
and R
6
together form a bridging chain containing 2 or 3 carbon atoms;
Y is hydrogen, chloro, fluoro, bromo, methyl or CF
3
;
W and X are independently CH, CF, CCl or N;
V is C or N;
B—A— is any one of the following fragments:
B—C(R
8
)(R
9
)—
B—CH
2
—C(R
8
)(R
9
)—
B—C(R
8
)(R
9
)—CH
2
—
B—CH
2
—C(R
8
)(R
9
)—CH
2
—
B—C(R
8
)(R
9
)—CH
2
—CH
2
—
B—CH
2
—CH
2
—C(R
8
)(R
9
)—
 wherein:
R
8
and R
9
are independently hydrogen, —(CH
2
)
m
N(R
10
)(R
11
), —CH
2
O—(CH
2
)
2
N(R
10
)(R
11
), or R
8
and R
9
together form a 4 to 6 membered ring containing a nitrogen atom present as N(R
12
); and
m is 0, 1 and 2 (preferably m=1) except where A represents —C(R
8
)(R
9
)— when m is 1 or 2;
R
10
and R
11
are independently selected from hydrogen or C
1
-C
4
alkyl optionally containing an oxygen atom in the chain or at the end of the chain;
or R
10
and R
11
together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring wherein when the ring is six membered it may optionally contain one oxygen atom or a nitrogen atom present as N(R
12
);
R
12
is hydrogen or C
1
-C
4
alkyl optionally containing an oxygen atom in the chain or at the end of the chain;
B is phenyl or a 5 to 6 membered aromatic heterocyclic ring containing up to two heteroatoms independently selected from oxygen, sulphur and nitrogen;
R
7
(when B is phenyl or an aromatic heterocycle) is one or more of hydrogen, C
1
-C
6
alkyl, perfluoro C
1
-C
6
alkyl, C
1
-C
6
alkyl, perfluoro C
1
-C
6
alkyl, fluoro, chloro, or any one of the following fragments: (CH
2
)
p
—O—(CH
2
)
2
N(R
10
)(R
11
) where R
10
and R
11
are as defined above, and p is 0 or 1;
where Q, together with the C atom to which it is joined, is a 5 or 6 membered heterocyclic ring (preferably saturated) containing one nitrogen atom, said heterocyclic ring being optionally substituted by C
1
-C
4
alkyl, and q is 1 or 2;
—(CH
2
)
r
—C(R
13
)(R
14
)—(CH
2
)
s
—N(R
15
)(R
16
) where r and s are independently 0, 1 or 2 and R
13
and R
14
are independently hydrogen or C
1
-C
4
alkyl optionally containing one oxygen atom in the chain or at the end of the chain, or R
13
and R
14
together with the carbon atom to which they are bonded for a 4 to 6 membered carbocyclic saturated ring;
R
15
and R
16
are independently selected from hydrogen or C
1
-C
4
alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or R
15
and R
16
together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring;
or one of R
13
or R
14
and one of R
15
or R
16
together with the carbon and nitrogen atoms to which they are bonded form a 4 to 6 membered saturated heterocyclic ring in which case the other of R
13
or R
14
is hydrogen or C
1
-C
4
alkyl, and the other of R
15
or R
16
is hydrogen or C
1
-C
4
alkyl optionally containing an oxygen atom in the chain or at the end of the chain;
or wherein R
7
—B represents any one of the following bicyclic fragments where R
12
is as defined above
 with the proviso that R
7
, R
8
and R
9
cannot all be hydrogen, and only one of R
7
, R
8
and R
9
contains one nitrogen atom or, when R
8
and R
9
together form a ring, said ring contains only one nitrogen atom with the proviso that one of R

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