Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-08
2003-08-26
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S307000, C514S314000, C514S332000, C514S333000, C514S352000, C514S334000, C514S621000, C514S357000, C514S337000, C514S618000, C514S619000, C546S113000, C546S122000, C546S146000, C546S172000, C546S175000, C546S256000, C546S265000, C546S309000, C546S312000, C546S334000, C564S162000, C564S168000
Reexamination Certificate
active
06610701
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analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.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.
The present invention includes benzyl or pyridyl based compounds which are useful as thrombin inhibitors.
SUMMARY OF THE INVENTION
The invention includes a composition 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 compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
The invention also includes a composition 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 compositions 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 for inhibiting thrombin and treating blood coagulation and cardiovascular disorders. The invention includes compounds having the structure
wherein
u is N or CH;
A is —CH
2
C(Y)
2
R
1
or —S(O)
2
CH
2
R
1
;
R
1
is
1) a 6-membered non-heterocyclic unsaturated ring system, unsubstituted, monosubstituted or disubstituted, same or different, with R
8
,
2) a 6-membered heterocyclic saturated ring system wherein 1 or 2 ring atoms are independently selected from the group of heteroatoms consisting of N, O and S, wherein the ring is unsubstituted, monosubstituted or disubstituted, same or different, with R
8
, or
3)
R
2
is hydrogen or F;
R
3
is hydrogen or halogen;
X is hydrogen, halogen, C
1-4
alkyl, CN or CF
3
;
Y is hydrogen, C
1-4
alkyl, or F;
R
4
is
1) a 6-membered non-heterocyclic unsaturated ring system, unsubstituted, monosubstituted, or disubstituted, same or different, with R
9
,
2) a 5- or 6-membered monocyclic heteroatom-containing unsaturated ring system wherein 1 or 2 ring atoms is selected from N, wherein the ring is unsubstituted or monosubstituted with R
9
,
3) a 9- or 10-membered bicyclic heteroatom-containing unsaturated ring system wherein 1 or 2 ring atoms is selected from N, wherein the ring is unsubstituted or monosubstituted with R
9
,
4) —CH
2
C(O)NHC(NH)NH
2
;
R
8
and R
9
are independently
1) halogen,
2) C
1-8
alkyl,
3) C
1-4
alkylene C
3-7
cycloalkyl
4) (CH
2
)
1-2
NH
2
,
5) a 5-membered heterocylcic unsaturated ring having 3 or 4 N atoms, wherein the ring is unsubstituted, monosubstituted, or disubstituted, same or different, with C
1-8
alkyl, C
3-7
cycloalkyl, C
1-4
alkylene C
3-7
cycloalkyl, NH
2
, or (CH
2
)
0-4
X
2
(CH
2
)
0-3
CH
3
, wherein X
2
is a bond, S, S(O), S(O)
2
, O, or NH,
6) —OCH
2
C(O)NHR
10
, or
7) —(CH
2
)
1-2
NHC(O)OR
11
;
R
10
is C
1-4
alkyl or C
3-7
cycloalkyl;
R
11
is C
1-4
alkyl; and
R
12
and R
13
, same or different, are selected from the group consisting of hydrogen and C
1-4
alkyl,
or a pharmaceutically acceptable salt thereof.
In a class of compounds of the invention, Y is hydrogen, CH
3
, or F, and R
3
is hydrogen, Cl, or F.
In a subclass of this class of compounds, X is hydrogen, F, Cl, Br, C
1-4
alkyl, CN or CF
3
.
In a group of this subclass of compounds, R
1
is
In a subgroup of this group, R
4
is C
2
C(O)NHC(NH)NH
2
,
In a family of this subgroup, R
9
is selected from the group consisting of Cl, F, —CH
3
, —OCH
2
C(O)NHCH
2
CH
3
, —(CH
2
)
1-2
NHC(O)OC(CH
3
)
3
, —(CH
2
)
1-2
NH
2
,
In a subfamily of this family,
u is N or CH;
R
2
is hydrogen or F;
R
3
is Cl or F;
X is hydrogen, Cl or F;
R
12
is hydrogen;
R
13
is hydrogen or CH
3
;
Examples of this family are listed below. Inhibitory activity, as measured by the in vitro assay described in the specification, where indicated, is represented by “*”, indicating Ki greater than or equal to 20 nM, or “**”, indicating Ki less than 20 nM.
Additional examples include
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
Boc
2
O
di-t-butyl dicarbonate
BuLi
butyl lithium
CaCO
3
calcium carbonate
CH
2
Cl
2
dichloromethane
DAST
diethylaminosulfurtrifluoride
DBU
1,8-diazobicyclo[5.4.0]undec-7-ene
DCM
dichloromethane
DMAP
dimethylaminopyridine
DMF
dimethylformamide
DPPA
diphenylphosphoryl azide
EDC
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride
EtOAc
ethyl acetate
EtOH
ethanol
Et
3
N
triethylamine
HCl
hydrochloric acid
H
2
SO
4
sulfuric acid
HOAc
acetic acid
HOAt
1-hydroxy-7-aza-benzotriazole hydrate
HOBT
1-hydroxybenzotriazole hydrate
H
2
SO
4
sulfuric acid
LAH
lithium aluminum hydride
LDA
lithium diisopropylamide
LiCl
lithium chloride
LiOH
lithium hydroxide
MCPBA
m-chloroperoxybenzoic acid
MeI
iodomethane
MeOH
methanol
MgSO
4
magnesium sulfate
N
3
PO(Ph)
2
diphenylphosphoryl azide
NaBH
4
sodium borohydride
NaHCO
3
sodium hydrogen carbonate
NaN
3
sodium azide
NaOH
sodiumhydroxide
NaSMe
sodium thiomethoxide
Na
2
SO
4
sodium sulfate
nBuLi
n-butyllithium
NH
4
OH
ammonium hydroxide
NMM
N-methylmorpholine
PPh
3
triphenylphosphine
Pd-C
palladium on activated carbon catalyst
Pd(PPh
3
)
4
tetrakis triphenylphosphine palladium
(Ph
3
P)
2
PdCl
2
bis(triphenylphosphine)palladium dichloride
SeO
2
selenium oxide
THF
tetrahydrofuran
TMSCN
trimethylsilyl cyanide
Zn(CN)
2
zinc 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 ato
Barrow James C.
Coburn Craig
Ngo Phung L.
Selnick Harold G.
Camara Valerie J.
Huang Evelyn Mei
Merck & Co. , Inc.
Parr Richard S.
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