Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-14
2003-03-04
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C548S953000, C546S268100, C514S340000
Reexamination Certificate
active
06528503
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 &agr;-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analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.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 &agr;-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 thrombin inhibitors having phenyl ring end groups substituted with aminomethyl 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
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
R
1
and R
2
are independently selected from the group consisting of
1) hydrogen,
2) C
1-6
alkyl,
3) C
1-6
alkyl substituted with one, two or three members, same or different, selected from the group consisting of
i) hydroxyl,
ii) halogen,
iii) C
3
,
iv) phenyl,
v) phenyl, substituted with one, two or three members, same or different, selected from the group consisting of
a) hydroxyl,
b) halogen,
c) CF
3
,
d) C
1-6
alkyl,
e) C
1-4
alkoxyl,
f) amino,
g) C
1-4
alkylamino, and
h) CH
3
C(O)NH—,
vi) pyridyl,
vii) pyridyl substituted with one or two members, same or different, selected from the group consisting of
a) halogen,
b) C
1-4
alkoxyl, and
c) C
1-6
alkyl,
viii) pyridyl N-oxide
ix) pyridyl N-oxide substituted with one or two members, same or different, selected from the group consisting of
a) halogen,
b) C
1-4
alkoxyl, and
c) C
1-6
alkyl,
x) C
3-6
cycloalkyl, and
xi) C
3-6
cycloalkyl substituted with C
1-4
alkyl or halogen,
4) C≡C—R
8
,
5) phenyl,
6) phenyl substituted with one, two or three members, same or different, selected from the group consisting of
i) hydroxyl,
ii) halogen,
iii) CF
3
,
iv) C
1-6
alkyl,
v) C
1-4
alkoxyl,
vi) amino,
vii) C
1-4
alkylamino, and
viii) CH
3
C(O)NH—,
7) pyridyl,
8) pyridyl substituted with one or two members, same or different, selected from the group consisting of
i) halogen,
ii) C
1-4
alkoxyl, and
iii) C
1-6
alkyl,
9) pyridyl N-oxide,
10) pyridyl N-oxide substituted with one or two members, same or different, selected from the group consisting of
i) halogen,
ii) C
1-4
alkoxyl, and
iii) C
1-6
alkyl,
11) C
3-6
cycloalkyl, and
12) C
3-6
cycloalkyl substituted with C
1-4
alkyl or halogen;
R
3
is hydrogen or halogen;
R
4
is halogen;
R
8
is selected from the group consisting of
1) hydrogen,
2) C
1-6
alkyl,
3) C
3-6
cycloalkyl, and
4) C
3-6
cycloalkyl substituted with C
1-4
alkyl or halogen,
provided that when R
3
is hydrogen, R
4
is Cl.
In a class of compounds or pharmaceutically acceptable salts thereof of the invention, R
3
is hydrogen or F, and R
4
is Cl or F, provided that when R
3
is hydrogen, R
4
is Cl.
In a subclass of the class of compounds or pharmaceutically acceptable salts thereof, R
2
is hydrogen or C
1-6
alkyl.
In a group of this subclass or pharmaceutically acceptable salts thereof, R
1
is
1) C
1-6
alkyl, unsubstituted or substituted with one, two, or three members, same or different, selected from the group consisting of
i) cyclopropyl, and
ii) cyclopropyl substituted with C
1-4
alkyl,
C≡CC(CH
3
)
3
, or
phenyl substituted with Cl.
Examples of this group of compounds are listed below:
1(3,3-Dimethyl-2(R)-hydroxybutanoyl)azetidine-2(S)-N-(2-aminomethyl-5-chlorobenzyl)carboxamide (1)
1-(4,4-Dimethyl-2(R)-hydroxypentanoyl)azetidine-2(S)-N-(2-aminomethyl-5-chlorobenzyl)carboxamide (2)
1-(3-(1-Methylcyclopropyl)-2(R)-hydroxypropanoyl)azetidine-2(S)-N-(2-aminomethyl-5-chlorobenzyl)carboxamide (3)
1-(3(S)-Cyclopropyl-2(R)-hydroxybutanoyl)azetidine-2(S)-N-(2-aminomethyl-5-chlorobenzyl)carboxamide (4)
1-(3-Cyclopropyl-3-methyl-2(R)-hydroxybutanoyl)azetidine-2(S)-N-(2-aminomethyl-5-chlorobenzyl)carboxamide (5)
1-(3(R)-Cyclopropyl-2(R)-hydroxybutanoyl)azetidine-2(S)-N-(2-aminomethyl-5-chlorobenzyl)carboxamide (4)
1-(2-hydroxy-2,5,5-trimethyl-3-hexynoyl)azetidine-2(S)-N-(2-aminomethyl-5-chlorobenzyl)carboxamide (7)
1-(2(R)-hydroxy(3-chlorophenyl)acetyl)azetidine-2(S)-N-(2-aminomethyl-5-chlorobenzyl)carboxamide (8)
1-(3-Cyclopropyl-3-methyl-2(R)-hydroxybutanoyl)azetidine-2(S)-N-(2-aminomethyl-6-fluoro-5-chlorobenzyl)carboxamide (9)
1-(3,3-Dimethyl-2(R)-hydroxybutanoyl)azetidine-2(S)-N-(2-aminomethyl-5,6-difluorobenzyl)carboxamide (10)
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:
Designation
Boc
tert-butyloxycarbonyl
DBU
1,8-diazabicyclo[5.4.0]undec-7-ene
DMF
dimethylformamide
DPPA
diphenylphosphoryl azide
EDC
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
EtOAc
ethyl acetate
Fmoc
9-fluorenylmethoxycarbonyl
HCl
hydrochloric acid
HOBT
1-hydroxybenzotriazole
HPLC
high pressure liquid chromatography
LiAlH
4
lithium aluminum hydride
LCMS
liquid chromatography mass spectrum
Lyle Terry A.
Morrissette Matthew M.
Staas Donnette D.
Tran Lekhanh O.
Williams Peter D.
Aulakh Charanjit S.
Camara Valerie J.
Merck & Co. , Inc.
Parr Richard S.
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