Thrombin inhibitors

Details Thrombin inhibitors Thrombin inhibitors

2000-04-18

2001-05-29

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S091000

Reexamination Certificate

active

06239132

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analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.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, 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 A is
R
5
is hydrogen, C
1-4
alkyl, C
3-7
cycloalkyl, halogen, NH
2
, OH or C
1-4
alkoxy;
R
4
is hydrogen, Cl, F, C
1-4
alkyl or NH
2
;
Y is hydrogen, Cl, or F;
R
1
and R
2
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
8
, where R
8
is C
1-4
alkyl, or SO
2
NH
2
,
CHR
6
R
7
wherein R
6
and R
7
are independently
hydrogen,
unsubstituted C
1-4
alkyl,
C
1-4
alkyl substituted with OH, COOH, NH
2
, aryl, CF
3
,
C
3-7
cycloalkyl,
CF
3
CH
2
C
3-7
cycloalkyl, unsubstituted or substituted with aryl,
C
7-12
bicyclic alkyl, or
C
10-16
tricyclic alkyl; and
R
9
is C
1-4
alkyl or SO
2
NH
2
.
A class of compounds of the invention, or a pharmaceutically acceptable salt thereof, includes those wherein R
4
is Cl, R
5
is hydrogen and Y is hydrogen.
A group of this class of compounds, or a pharmaceutically acceptable salt thereof, includes those wherein A is
R
1
and R
2
are independently
—CH
3
,
—CH
2
CH(CH
3
)
2
,
—CH
2
CH
3
,
—CH(CH
3
)
2
, or
R
9
is CH
3
.
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.
The invention also includes compounds having the following structure:
which are useful for preparing thrombin inhibitors, wherein
R
1
and R
2
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
8
, where R
8
is C
1-4
alkyl, or SO
2
NH
2
,
CHR
6
R
7
wherein R
6
and R
7
are independently
hydrogen,
unsubstituted C
1-4
alkyl,
C
1-4
alkyl substituted with OH, COOH, NH
2
, aryl, CF
3
,
C
3-7
cycloalkyl,
CF
3
CH
2
C
3-7
cycloalkyl, unsubstituted or substituted with aryl,
C
7-12
bicyclic alkyl, or
C
10-16
tricyclic alkyl.
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 permissible only if such combinations result in stable compounds.
As used herein except where noted, “alkyl” is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); “alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; “Halo”, as used herein, means fluoro, chloro, bromo and iodo; and “counterion” is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.
The term “C
3-7
cycloalkyl” is intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
The term “C
7-12
bicyclic alkyl” is intended to include bicyclo[2.2.1]heptyl (norbornyl), bicyclo[2.2.2]octyl, 1,1,3-trimethylbicyclo[2.2.1]heptyl (bornyl), and the like.
The term “aryl” as used herein except where noted, represents a stable 6- to 10-membered mono- or bicyclic ring system. The aryl ring can be unsubstituted or substituted with one or more of C
1-4
lower alkyl; hydroxy; alkoxy; halogen; amino. Examples of “aryl” groups include phenyl and naphthyl.
The term “heterocycle” or “heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 9- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Bicyclic unsaturated ring systems include bicyclic ring systems which may be partially unsaturated or fully unsaturated. Partially unsaturated bicyclic ring systems include, for example, cyclopentenopyridinyl, benzodioxan, methylenedioxyphenyl groups. Especially useful are rings containing one oxygen or sulfur, one to four nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include piperidin

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