Thrombin inhibitors

Details Thrombin inhibitors Thrombin inhibitors

2001-03-22

2003-03-18

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S405000, C544S408000

Reexamination Certificate

active

06534510

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analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.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
The invention is a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, wherein
T is selected from the group consisting of
D, E, F, G, H, I, and J are independently N or CY
1
provided that the number of such variables D, E, F, G, H, I, and J representing N is 0, 1, or 2;
K, L, M and Q are independently NH or CY
1
Y
2
, provided that the number of such variables D, E, F, K, L, M, and Q representing N is 0, 1, or 2;
Y
1
and Y
2
are independently selected from the group consisting of
hydrogen,
C
1-4
alkyl,
halogen,
amino, or
hydroxy;
A is
W is
hydrogen
R
1
,
R
1
OCO,
R
1
CO,
R
1
SO
2
,
R
1
(CH
2
)
n
NHCO,
wherein n is 0-4;
R
1
is
R
2
,
R
2
(CH
2
)
m
C(R
12
)
2
, where m is 0-3, and each R
12
can be the same or different,
(R
2
)(OR
2
)CH(CH
2
)
p
, where p is 1-4,
where m is 0-3,
R
2
C(R
12
)
2
(CH
2
)
m
, wherein m is 0-3, and each R
12
can be the same or different, wherein (R
12
)
2
can also form a ring with C represented by C
3-7
cycloalkyl,
R
2
CH
2
C(R
12
)
2
(CH
2
)
q
, wherein q is 0-2, and each R
12
can be the same or different, wherein (R
12
)
2
can also form a ring with C represented by C
3-7
cycloalkyl,
(R
2
)
2
CH(CH
2
)
r
, where r is 0-4 and each R
2
can be the same or different, and wherein (R
2
)
2
can also form a ring with CH represented by C
3-7
cycloalkyl, C
7-12
bicylic alkyl, C
10-16
tricylic alkyl, or a 5- to 7-membered mono- or 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,
R
2
(CH
2
)
t
O(CH
2
)
p
, wherein t is 0 or 1 and p is 1-4,
R
2
CF
2
C(R
12
)
2,
(R
2
CH
2
)(R
2
CH
2
)N—,
(R
2
CH
2
)(R
2
CH
2
)CH, or
R
2
(COOR
3
)(CH
2
)
r
, where r is 1-4;
R
2
and R
4
are independently
phenyl, unsubstituted or substituted with one or more of C
1-4
alkyl, C
1-4
alkoxy, halogen, hydroxy, COOH, CONH
2
, CH
2
H, CO
2
R′, where R′ is C
1-4
alkyl, or SO
2
NH
2
,
naphthyl,
biphenyl,
pyridine N-oxide,
a 5- to 7-membered mono- or a 9- to 10-membered bicyclic
a) non-heterocyclic ring system, which is saturated or unsaturated, and which is unsubstituted or substituted with halogen or hydroxy, or
b) heterocyclic ring system, which is saturated or unsaturated, having carbon ring atoms and heteroatom ring atoms, wherein the ring system contains i) from one to four heteroatoms selected from the group consisting of N, O, and S, and wherein the ring system is unsubstituted, or ii) from one to four nitrogen atoms, wherein one or more of the carbon and nitrogen ring atoms are substituted with halogen or hydroxy.
C
1-7
alkyl, unsubstituted or substituted with one or more of hydroxy,
COOH,
amino,
aryl,
C
3-7
cycloalkyl,
CF
3
,
N(CH
3
)
2
,
—C
1-3
alkylaryl,
heteroaryl, or
heterocycloalkyl,
CF
3
C
3-7
cycloalkyl, unsubstituted or substituted with aryl,
C
7-12
bicyclic alky, or
C
10-16
tricyclic alkyl;
R
3
, R
5
and R
6
are independently selected from the group consisting of
hydrogen,
halogen,
C
1-4
alkyl,
C
3-7
cycloalkyl, or
trifluoromethyl;
X is
hydrogen, or
halogen;
Z is CH
2
, S, or SO
2
;
R
12
is
hydrogen,
phenyl, unsubstituted or substituted with one or more of C
1-4
alkyl, C
1-4
alkoxy, halogen, hydroxy, COOH, CONH
2
,
naphthyl,
biphenyl,
a 5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to four heteroatoms selected from the group consisting of N, O and S,
C
1-4
alkyl, unsubstituted or substituted with one or more of hydroxy,
OH,
COOH,
amino,
—N(CH
3
)
2
,
—NH(CH
3
),
—N(CH
2
)COOH,
aryl,
heteroaryl, or
heterocycloalkyl,
CF
3
C
3-7
cycloalkyl,
C
7-12
bicyclic alkyl, or
C
10-16
tricyclic alkyl.
In one class of compounds of the invention, Y
1
and Y
2
are hydrogen or amino. In a subclass of this class of compounds, A is
In a group of this subclass, R
5
and R
6
are independently selected from —CH(CH
3
)
2
and —CH
2
CH
3
, and W is selected from the group consisting of:
Examples of this group are listed below. Inhibitory activity of compounds of the invention is represented by “**” indicating Ki greater than or equal to 20 nM, or “*”, indicating Ki less than 20 nM. Values are as determined according to the in vitro assay described later in the specification.
The term “alkyl” means branched or straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, “C
1-10
” denotes alkyl having 1 to 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like.
The term “alkenyl” means hydrocarbon chains of either a straight of branched configuration and one or more unsaturated carbon—carbon bonds which may occur at an stable point along the chain, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl radicals and the like.
The term, “alkynyl” means hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, e.g., ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term “alkoxy” means an alkyl group of indicated number of carbon atoms attached through an oxy

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