Pyrazinone thrombin inhibitors

Details Pyrazinone thrombin inhibitors Pyrazinone thrombin inhibitors

2000-11-21

2002-05-14

Bernhardt, Emily (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

06387911

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analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.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
A is
n=0-1;
R is
hydrogen,
C
1-4
alkyl unsubstituted or substituted with halogen, OR
9
, N(R
9
)
2
, COOR
9
; CON(R
9
)
2
aryl, or a heterocyclic ring, wherein R
9
is independently hydrogen or C
1-4
alkyl;
R
2
is
hydrogen,
C
1-4
alkyl,
CF
3
,
halogen,
cyano, or
cyclo C
3-7
alkyl;
R
3
, R
7
, R
8
, and R
13
are independently chosen from
hydrogen,
halogen,
C
1-4
alkyl;
R
14
and R
15
are independently chosen from
hydrogen,
C
1-2
alkyl, and
C
1-2
alkyl substituted with OR
16
or COOR
16
, wherein R
16
is hydrogen or C
1-4
alkyl; and
R
4
, R
5
and R
6
are independently chosen from
hydrogen,
halogen,
hydroxy,
C
1-4
alkyl,
C
1-4
alkoxy,
cyano,
CF
3
O,
CHF
2
O,
CF
3
CH
2
O,
SR
10
,
SOR
10
,
SO
2
R
10
,
OR
11
,
SR
11
,
NHR
11
wherein
R
10
is C
1-4
alkyl unsubstituted or substituted with C(CH
3
)
2
NH
2
, C(CH
3
)
2
OH, C(CH
3
)
2
NHCOCF
3
, or CF
3
, and
R
11
is 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, or CO
2
R
12
, wherein R
12
is C
1-4
alkyl.
Note that methyl substituents are conventionally indicated as bonds attached to an atom, Me, or CH
3
.
In a class of compounds, A is
In a subclass of the class of compounds, R
2
is Cl, CH
3
or CN; R
4
and R
5
are independently selected from the group consisting of hydrogen, C
1-4
alkyl, SMe, SOMe, SO
2
Me, CN, OCH
2
CF
3
, OCH
3
SCH
2
C(CH
3
)
2
NH
2
, OCF
3
, SCH
2
CH
3
, SOCH
2
CH
3
, SO
2
CH
2
CH
3
, SCH
2
CF
3
, SOCH
2
CF
3
, SO
2
CH
2
CF
3
, and halogen R
7
is hydrogen or fluoro; and R
13
is hydrogen or fluoro.
In a family of the subclass of compounds, R
4
and R
5
are independently selected from the group consisting of hydrogen, CH
3
, Cl, F, SMe, SOMe, SO
2
Me, CN, OCH
2
CF
3
, OCH
3
, SCH
2
C(CH
3
)
2
NH
2
, OCF
3
, SCH
2
CH
3
, SOCH
2
CH
3
SCH
2
CF
3
, SOCH
2
CF
3
, and SO
2
CH
2
CF
3
.
In a first subfamily of the family, A is selected from the group consisting of
In a second subfamily of the family, A is selected from the group consisting of
In a collection of the first subfamily, the compound is selected from the group consisting of
Examples of this collection include
and pharmaceutically acceptable salts thereof.
In a collection of the second subfamily, the compound is selected from the group consisting of
Examples of this collection include
and pharmaceutically acceptable salts thereof.
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 permissible only if such combinations result in stable compounds.
Some abbreviations that may appear in this application are as follows:
ABBREVIATIONS
Designation
BH
3
borane
CH
3
CH
2
OTf
ethyl triflate
Cs
2
CO
3
cesium carbonate
DAST
diethylaminosulfurtrifluoride
DBU
1,8-diazabicyclo[5.4.0]undec-7-ene
DCE
1,2-dichloroethane
DMAP
dimethylaminopyridine
DMF
dimethylformamide
DPPA
diphenylphosphoryl azide
EDC
1-ethyl-3-(3 dimethylaminopropyl)carbodiimide
hydrochioride
EtOH
ethanol
Et
3
N (TEA)
triethylamine
HCl
hydrochloric acid
HOAc
acetic acid
HOAT
1-hydroxy-7-azabenzotriazole
iPrOH
isopropyl alcohol
KOH
potassium hydroxide
K
2
CO
3
potassium carbonate
LAH
lithium aluminum hydride
LDA
lithium diisopropylamide
LiAlH
4
lithium aluminum hydride
MCPBA
meta-chloroperbenzoic acid
MeI
iodomethane
MeOH
methanol
NaBH
4
sodium borohydride
NaN
3
sodium azide
nBuLi
n-butyllithium
NH
4
OH
ammonium hydroxide
NCS
N-chlorosuccinimide
Pd-C
palladium on activated carbon catalyst
Pd(O)
palladium oxide
PhB(OH)
2
phenylboronic acid
POBr
3
phosphorous oxybromide
PPh
3
triphenylphosphine
TBAF
tetrabutylammonium fluoride
TBSCl
tert-butyldimethylsilyl chloride
TFA
trifluoroacetic acid
Tf
2
O
trifluoromethanesulfonic anhydride
THF
tetrahydrofuran
TMSCN
trimethylsilyl cyanide
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; “halogen”, 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 “cycloC
3-7
alkyl” is intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
The term “aryl” as used herein except where noted, represents a stable 6- to 10-membered mono- or bicyclic ring system such as phenyl, or naphthyl. The aryl ring can be unsubstituted or substituted with one

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