Thrombin inhibitors

Details Thrombin inhibitors Thrombin inhibitors

2001-12-18

2003-02-04

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S538000, C548S528000, C548S518000, C546S111000, C546S279100, C514S422000, C514S343000, C514S290000

Reexamination Certificate

active

06515011

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analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.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. U.S. Pat. Nos. 5,536,708, 5,672,582, 5,510,369 and 5,741,485 describe proline-based thrombin inhibitors having cyclohexylamino end groups. The present invention includes proline-based thrombin inhibitors having phenyl ring end groups substituted with ammonioethyl or ammoniomethyl moieties, which have been found to provide therapeutically effective thrombin inhibitors having desirable potency and pharmacokinetic properties.
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.
This invention includes compounds of the general formula
or a pharmaceutically acceptable salt thereof, wherein
m is 0, 1, or 2;
R
w
and R
v
are independently selected from the group consisting of hydrogen, C
1-4
alkyl, and halogen;
R
t
is C
1-6
alkyl or C
3-7
cycloalkyl;
R
1
is selected from the group consisting of
1)
wherein
R
4
and R
5
are independently selected from the group consisting of hydrogen, halogen, C
1-4
alkoxy, C
1-6
alkyl, —OH, and cyano, and
X is a bond, O, or S, and
wherein
R
6
is selected from the group consisting
a) hydrogen,
b) C
1-6
alkyl,
c) —OH,
d) —NR
24
R
25
, where R
24
and R
25
are independently hydrogen, or C
1-6
alkyl unsubstituted or substituted with one or more of —OH, —COOH, C
3-7
cycloalkyl, or COOR
17
, where R
17
is C
1-6
alkyl,
e) NHC(O)OR
18
,
f) NHC(O)R
18
,
g) NHC(O)NHR
18
,
h) NHSO
2
R
18
,
i) NHC(O)NH
2
, and
j) NHCN,
 wherein R
18
is selected from the group consisting of C
1-6
alkyl, aryl, and C
3-7
cycloalkyl;
R
7
and R
8
are independently selected from the group consisting of
a) hydrogen,
b) —CF
3
,
c) C
1-6
alkyl,
d) phenyl, unsubstituted or substituted with C
1-6
alkyl, COOR
26
or halogen, where R
26
is C
1-6
alkyl or hydrogen,
f) C
3-7
cycloalkyl,
 where R
27
is C
1-6
alkyl or C
3-7
cycloalkyl,
 wherein R
x
and R
y
are independently selected from the group consisting of hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl, unsubstituted phenyl or phenyl substituted with halogen, C
1-4
alkyl, OH, or C
1-4
alkoxy, and
 wherein n is 0, 1, 2 or 3,
i) C
1-6
alkyl substituted with one or two of the group consisting of
i) C
3-7
cycloalkyl, either unsubstituted or substituted with C
1-4
alkyl,
ii) —COOH,
iii) —OH,
 wherein R
9
and R
10
are independently selected from the group consisting of
aa) hydrogen,
bb) halogen,
cc) C
1-4
alkoxy,
dd) C
1-4
alkyl,
ee) hydroxy,
ff) CF
3
,
gg) cyano,
hh) COOR
28
, where R
28
is C
1-6
alkyl or hydrogen;
or R
7
and R
8
are joined to form a C
3-7
carbocyclic ring which is unsubstituted or independently substituted with one or two C
1-6
alkyl groups;
R
3
is selected from the group consisting of
1) —C(R
11
)(R
12
)C(R
13
)(R
14
)N(R
15
)(R
16
),
2) —C(R
13
)(R
14
)N(R
15
)(R
16
), and
 where n is 0, 1 or 2,
wherein
R
11
and R
12
are independently selected from the group consisting of
a) hydrogen,
b) F,
c) C
1-4
alkyl,
d) CF
3
,
e) CHF
2
,
f) C
3-7
cycloalkyl,
 or R
11
and R
12
together form a 3-7 membered carbocyclic ring,
R
13
and R
14
are independently selected from the group consisting of
a) hydrogen,
b) C
1-4
alkyl
c) —CF
3
,
d) —CHF
2
,
e) —CH
2
OH,
f) C
3-6
cycloalkyl, or R
13
and R
14
together form a 3-7 membered carbocyclic ring,
R
15
and R
16
are independently selected from the group consisting of
a) hydrogen,
b) C
1-6
alkyl, unsubstituted or substituted with —OH, C
3-7
cycloalkyl, or C(O)OR
19
, wherein R
19
is selected from the group consisting of hydrogen and C
1-6
alkyl,
c) C
3-7
cycloalkyl, and
d) —C(O)R
20
, wherein R
20
is selected from the group consisting of C
1-6
alkyl, —OR
21
and —NHR , and wherein R
21
is hydrogen, C
1-6
alkyl or benzyl,
or R
15
and R
16
are joined to form a 4-7 membered heterocyclic ring which is unsubstituted or substituted with hydroxyl or halogen.
In a class of these compounds or pharmaceutically acceptable salts thereof, the compound has the formula
and R
3
is —C(R
11
)(R
12
)C(R
13
)(R
14
)N(R
15
)(R
16
) or —C(R
13
)(R
14
)N(R
15
)(R
16
).
In a subclass of this class, R
3
is —C(R
11
)(R
12
)C(R
13
)(R
14
)N(R
15
)(R
16
).
In a group of this subclass, R
3
is —C(R
11
)(R
12
)C(R
13
)(R
14
)NH
2
.
In a subgroup of this group, R
3
is —CH
2
CH
2
NH
2
, —CH
2
CH(CHF
2
)NH
2
, or —CH
2
CH(CF
3
)NH
2
.
In a family of this subgroup,
x is a bond;
R
6
is hydrogen, —OH, —CH
3
or —NH
2
;
R
7
is hydrogen, —CH
3
, phenyl, 3-chlorophenyl, cyclopropyl or —CH
2
CH
3
; and
R
8
is phenyl, 3-chlorophenyl, cyclohexyl, —CH
3
, —CF
3
, —CH
2
CH
3
, —CH(CH
3
)
2
, —CH(CH
3
)(CH
2
CH
3
), —C(CH
3
)
3
, 2-pyridyl, 3-pyridyl,
 or C
1-6
alkyl substituted with
In a subfamily of this family, R
9
is hydrogen or Cl and R
10
is hydrogen.
In a collection of this subfamily, R
1
is selected from the group consisting of
Examples of this collection are selected from the group consisting of
In a second subclass of the class, R
3
is —C(R
13
)(R
14
)N(R
15
)(R
16
).
In a group of the second subclass, R
3
is —CH
2
N(R
15
)(R
16
), —CH(CHF
2
)N(R
15
)(R
16
), —CH(CH
2
OH)N(R
15
)(R
16
), or —CH(CH
3
)N(R
15
)(R
16
).
In a subgroup of this group, R
3
is —CH
2
NH
2
, —CH
2
NHC(O)OC(CH
3
)
3
, —CH(CHF
2
)NH
2
, —CH(CH
2
OH)NH
2
, or —CH(CH
3
)NH
2
.
In a family of this subgroup,
x is a bond;
R
6
is hydrogen, —OH or —NH
2
;
R
7
is hydrogen, —CH
3
, phenyl, 3-chlorophenyl, cyclopropyl or —CH
2
CH
3
; and
R
8
is phenyl, 3-chlorophenyl, cyclohe

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