Pyrazinone thrombin inhibitors

Details Pyrazinone thrombin inhibitors Pyrazinone thrombin inhibitors

2000-06-01

2002-09-24

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...

C544S405000

Reexamination Certificate

active

06455532

ABSTRACT:

BACKGROUND OF THE INVENTION
Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.
Edwards et al., J. Amer. Chem. Soc., (1992) vol. 114, pp. 1854-63, describes peptidyl a-ketobenzoxazoles which are reversible inhibitors of the serine proteases human leukocyte elastase and porcine pancreatic elastase.
European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.
Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or a-keto carboxyl derivatives.
R. J. Brown et al., J. Med. Chem., Vol. 37, pages 1259-1261 (1994) describes orally active, non-peptidic inhibitors of human leukocyte elastase which contain trifluoromethylketone and pyridinone moieties.
H. Mack et al., J. Enzyme Inhibition, Vol. 9, pages 73-86 (1995) describes rigid amidino-phenylalanine thrombin inhibitors which contain a pyridinone moiety as a central core structure.
SUMMARY OF THE INVENTION
The invention includes compounds for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compounds may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. The compounds can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
The invention also includes a compound for preventing or treating 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, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compounds may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
The invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
Compounds of the invention are useful as thrombin inhibitors and have therapeutic value in for example, preventing coronary artery disease, and have the following structure:
wherein
W is selected from the group consisting of
1) hydrogen,
2) a 5- to 7-membered mono- or a 9- to 10-membered fused bicyclic heterocyclic ring having carbon ring atoms and heteroatom ring atoms which ring can be saturated or unsaturated, wherein the ring contains
a) from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the ring is unsubstituted, or
b) from one to four N atoms, and where one or more of the ring atoms are substituted with one or more of
i) C
1-4
alkyl,
ii) hydroxy,
iii) COOR′, where R′ is hydrogen or C
1-4
alkyl,
iv) CONH
2
,
v) CH
2
OH,
i) SO
2
NH
2
,
vii) halogen,
viii) amino,
ix) aryl,
x) C
3-7
cycloalkyl,
xi) CF
3
,
xii) OCF
3
xiii) N(CH
3
)
2
,
xiv) —C
1-3
alkylaryl,
xv) heterocyclic ring,
xvi) C
1-4
alkoxy,
xvii) F
w
H
x
C(CH
2
)
0-1
O—, wherein w and x are either 1 or 2, provided that when w is 1, x is 2, and when w is 2, x is 1,
xviii) C
1-4
thioalkoxy, or
xix) cyano,
3) a 5- to 7-membered mono- or a 9- to 10-membered fused bicyclic non-heterocyclic saturated ring which is unsubstituted or substituted with one or more of
a) C
1-4
alkyl,
b) hydroxy,
c) COOR′, where R′ is hydrogen or C
1-4
alkyl,
d) CONH
2
,
e) CH
2
OH,
f) SO
2
NH
2
,
g) halogen,
h) amino,
i) aryl,
j) C
3-7
cycloalkyl,
k) CF
3
,
l) OCF
3
m) N(CH
3
)
2
,
n) —C
1-3
alkylaryl,
o) heterocyclic ring,
p) C
1-4
alkoxy,
q) F
w
H
x
C(CH
2
)
0-1
O—, wherein w and x are either 1 or 2, provided that when w is 1, x is 2, and when w is 2, x is 1,
r) C
1-4
thioalkoxy,or
s) cyano,
4) a 6-membered mono or 9- to 10-membered fused bicyclic non-heterocyclic unsaturated ring which is unsubstituted or substituted with one or more of
a) C
1-4
alkyl,
b) hydroxy,
c) COOR′, where R′ is hydrogen or C
1-4
alkyl,
d) CONH
2
,
e) CH
2
OH,
f) SO
2
NH
2
,
g) halogen,
h) amino,
i) aryl,
j) C
3-7
cycloalkyl,
k) CF
3
,
l) OCF
3
,
m) N(CH
3
)
2
,
n) —C
1-3
alkylaryl,
o) heterocyclic ring,
p) C
1-4
alkoxy,
q) F
w
H
x
C(CH
2
)
0-1
O—, wherein w and x are either 1 or 2, provided that when w is 1, x is 2, and when w is 2, x is 1,
r) C
1-4
thioalkoxy, or
s) cyano,
5) CF
3
,
6) C
3-7
cycloalkyl, unsubstituted, monosubstituted with halogen or aryl, or disubstituted with halogen,
7) C
7-12
bicyclic alkyl,
8) C
10-16
tricyclic alkyl,
9)
 where m is 0-3, and each R
12
can be the same or different,
10)
 where p is 1-4,
11)
 where mis 0-3,
12)
13)
 where mis 0 or 1,
14)
15)
 wherein m is 0-3, and each R
12
can be the same or different, wherein the R
12
substituents can together form a ring, with the C to which they are bonded, represented by C
3-7
cycloalkyl,
16)
 wherein q is 0-2, and each R
12
can be the same or different, wherein the R
12
substituents can together form a ring, with the C to which they are bonded, represented by C
3-7
cycloalkyl,
17)
 wherein r is
0-4
, and each R
2
can be the same or different, wherein the R
2
substituents can together form a ring, with the C to which they are bonded, represented by C
3-7
cycloalkyl, C
7-12
bicyclic alkyl, C
10-16
tricyclic alkyl, or a 5- to 7-membered mono- or 9- to 10-membered fused bicyclic heterocyclic ring, which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S,
18)
 wherein n and p are independently 1-4,
19)
 wherein each R
12
can be the same or different,
20)
 and
21)
 wherein t is 1-4 and q is independently 0-2;
R
2
is selected from the group consisting of
1) hydrogen,
2) a 5- to 7-membered mono- or a 9- to 10-membered fused bicyclic heterocyclic ring having carbon ring atoms and heteroatom ring atoms which ring can be saturated or unsaturated, wherein the ring contains
a) from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the ring is unsubstituted, or
b) from one to four N atoms, and where one or more of the ring atoms are substituted with one or more of
i) C
1-4
alkyl,
ii) hydroxy,
iii) COOR′, where R′ is hydrogen or C
1-4
alkyl,
iv) CONH
2
,
v) CH
2
OH,
vi) SO
2
NH
2
,
vii) halogen,
viii) amino,
ix) aryl,
x) C
3-7
cycloalkyl,
xi) CF
3
,
xii) OCF
3
,
xiii) N(CH
3
)
2
,
xiv) —C
1-3
alkylaryl,
xv) heterocyclic ring,
xvi) C
1-4
alkoxy,
xvii) F
w
H
x
C(CH
2
)
0-1
O—, wherein w and x are either 1 or 2, provided that when w is 1, x is 2, and when w is 2, x is
xviii) C
1-4
thioalkoxy, or
xix) cyano,
3) a 5- to 7-membered mono- or a 9- to 10-membered fused bicyclic non-heterocyclic saturated ring which is unsubstituted or substituted with one or more of
a) C
1-4
alkyl,
b) hydroxy,
c) COOR′, where R′ is hydrogen or C
1-4
alkyl,
d) CONH
2
,
e) CH
2
OH,
f) SO
2
NH
2
,
g) halogen,
h) amino,
i) aryl,
j) C
3-7
cycloalkyl,
k) CF
3
,
l) OCF
3
,
m) N(CH
3
)
2
,
n) —C
1-3
alkylaryl,
o) heterocyclic ring,
p) C
1-4
alkoxy,
q) F
w
H
x
C(CH
2
)
0-1
O—, wherein w and x are either 1 or 2, provided that when w is 1, x is 2, and when w is 2, xis 1,
r) C
1-4
thioalkoxy, or
s) cyano,
4) a 6-membered mono or 9- to 10-membered fused bicyclic non-heterocyclic unsaturated ring which is unsubstituted or substituted with one or more of
a) C
1-4
alkyl,
b) hydroxy,
c) COOR′, where R′ is hydrogen or C
1-4
alkyl,
d

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