Thrombin inhibitors

Details Thrombin inhibitors Thrombin inhibitors

1999-10-28

2002-04-23

Bernhardt, Emily (Department: 1611)

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

06376499

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analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.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 aketo 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, useful as thrombin inhibitors and having therapeutic value in for example, preventing coronary artery disease, have the following structure:
or a pharmaceutically acceptable salt thereof, wherein b is NY
1
or O; c is CY
2
or N; d is CY
3
; e is CY
4
or N; f is CY
5
or N; g is CY
6
or N; Y
4
, Y
5
, and Y
6
are independently hydrogen, C
1-4
alkyl, or halogen; Y
1
, and Y
2
are independently hydrogen, C
1-4
alkyl, C
3-7
cycloalkyl, halogen, NH
2
, OH or C
1-4
alkoxy, and Y
3
is hydrogen, C
1-4
alky, C
3-7
cycloalkyl, halogen, NH
2
, OH, CN or C
1-4
alkoxy;
A is
W is
hydrogen,
R
1
,
R
1
OCO,
R
1
CO,
R
1
SO
2
,
R
1
(CH
2
)
n
NHCO, or
(R
1
)
2
CH(CH
2
)
n
NHCO,
wherein n is 0-4;
R
1
is
R
2
,
R
2
(CH
2
)
m
C(R
8
)
2
, where m is 0-3, and each R
8
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
8
)
2
(CH
2
)
m
, wherein m is 0-3, and each R
8
can be the same or different, wherein (R
8
)
2
can also form a ring with C represented by C
3-7
cycloalkyl,
R
2
CH
2
C(R
8
)
2
(CH
2
)
q
, wherein q is 0-2, and each R
8
can be the same or different, wherein (R
8
)
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
bicyclic 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
O(CH
2
)
p
, wherein p is 1-4,
R
2
CF
2
C(R
8
)
2
,
(R
2
CH
2
)(R
2
CH
2
)CH, or
R
2
SO
2
,
R
2
CH
2
SO
2
,
R
2
(COOR
6
)(CH
2
)
r
, where r is 1-4;
R
2
and R
5
are independently
hydrogen,
phenyl, unsubstituted or substituted with one or more of C
1-4
alkyl, C
1-4
alkoxy, halogen, hydroxy, COOH, CONH
2
, CH
2
OH, CO
2
R
7
, where R
7
is C
1-4
alkyl, or SO
2
NH
2
,
naphthyl,
biphenyl,
5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring or non-heterocyclic ring which can be saturated or unsaturated, wherein the heterocyclic ring contains from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the heterocyclic or non-heterocyclic ring is unsubstituted or 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 alkyl, or
C
10-16
tricyclic alkyl;
R
3
, R
4
and R
6
are independently selected from the group consisting of
hydrogen,
halogen,
C
1-4
alkyl,
C
3-7
cycloalkyl,
trifluoromethyl,
CN,
SCH
3
,
SOCH
3
, or
SO
2
CH
3
;
X is
hydrogen, or
halogen;
Z is CH
2
, S, or SO
2
;
R
8
is
hydrogen,
phenyl, unsubstituted or substituted with one or more of C
1-4
alkyl, C
1-4
alkoxy, halogen, hydroxy, COOH, CONH
2
,
halogen,
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,
COOH,
amino,
aryl,
heteroaryl, or
heterocycloalkyl,
CF
3
C
3-7
cycloalkyl,
C
7-12
bicyclic alkyl, or
C
10-16
tricyclic alkyl
A class of compounds of the invention, or a pharmaceutically acceptable salt thereof, includes those wherein A is
wherein R
3
is CH
3
or Cl.
A subclass of compounds of this class, or a pharmaceutically acceptable salt thereof, includes those wherein
Y
1
, Y
2
, Y
3
, Y
4
, Y
5
, and Y
6
are independently hydrogen, C
1-4
alkyl, or NH
2
; W is R
1
; R
1
is R
2
(CH
2
)
2
—; and R
2
is a 5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring or non-heterocyclic ring which can be saturated or unsaturated, wherein the heterocyclic ring contains from one to four heteroatoms selected from the group consisting of N, O, and S, and wherein the heterocyclic ring is unsubstituted.
In a group of compounds of this subclass, or a pharmaceutically acceptable salt thereof, Y
1
, Y
2
, Y
3
, Y
4
, Y
5
, and Y
6
are independently hydrogen, methyl or NH
2
; and W is
In a subgroup of this group of compounds, b is NH, N(CH
3
) or O, c is CH or N, d is CH, C(NH
2
), e is CH, f is N or CH, and g is CH or N.
Examples of this group are listed below in Table 1. Inhibitory activity of compounds of the invention is represented by “**”, indicating Ki greater than or equal to 100 nM, or “*”, indicating Ki less than 100 nM. Values are as determined according to the in vitro assay described later in the specification.
TABLE 1








The compounds of the present invention, may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. The compounds of the present invention may also have polymorphic crystalline forms, with all polymorphic crystalline forms being included in the present invention.
When any variable occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permi

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