Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-25
2004-03-23
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S224000
Reexamination Certificate
active
06710061
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to certain novel compounds, methods for preparing the compounds, compositions, intermediates and derivatives thereof and for treating serine protease mediated disorders. More particularly, the aminopyrrolidine sulfonamide compounds of the present invention are selective serine protease or dual-serine protease inhibitors of Factor Xa and tryptase useful for treating serine protease or dual-serine protease mediated disorders.
BACKGROUND OF THE INVENTION
Thrombotic disorders are a major cause of mortality in industrialized countries (Kaiser, Brigitte, Thrombin and Factor Xa Inhibitors,
Drugs of the Future
, 1998, 23(4), 423-436). Thrombin has been a target for the development of anticoagulation agents because it occupies a central position in the coagulation cascade (Kunitada, S., et al., Factor Xa Inhibitors,
Current Pharmaceutical Design
, 1996, 2, 531-542). Since Factor Xa (FXa) is responsible for the formation of thrombin, a FXa inhibitor has become an alternative strategy to selectively prevent thrombin production and clot formation.
Like thrombin, FXa is a member of the serine protease superfamily. In the blood coagulation cascade, FXa links the intrinsic and extrinsic activation pathways for the production of thrombin. In the intrinsic pathway, Factor IXa converts Factor X to FXa in the presence of Factor VIIIa, Ca
2+
and phospholipid. In the extrinsic pathway, Factor VIIa converts Factor X to FXa in the presence of tissue factor. Once formed, FXa binds to Factor Va on phospholipid surfaces in the presence of Ca
2+
ions to form the prothrombinase complex, which is responsible for converting prothrombin to thrombin. Thrombin in turn converts fibrinogen to fibrin, which ultimately results in the production of a fibrin clot.
Potential advantages for FXa inhibitors as anticoagulants stem from the inhibition of thrombin formation rather than inhibition of its catalytic activity. For example, it is expected that thrombin-induced platelet activation could still occur under FXa inhibition, thus minimizing bleeding risk. The thrombin/thrombomodulin complex downregulates thrombin production, thus functioning as an endogenous anticoagulant. It has been postulated that FXa inhibition would supply sufficient thrombin for this interaction, which might minimize the “thrombotic rebound” effect observed in the clinical use of direct thrombin inhibitors.
A comprehensive review of FXa inhibitors has recently appeared (
Drugs of the Future
1999, 24(7), 771-787).
PCT application WO 96/10022 to Faull, et. al., describes sulfonylpiperazine-derived FXa inhibitors of the formula:
PCT application WO 98/54164 to Tawada, et. al., describes sulfonylpiperazine-derived FXa inhibitors of the formula:
Accordingly, it is an object of the invention to provide aminopyrrolidine sulfonamide-derived compounds that are serine protease inhibitors; in particular, selective serine protease or dual-serine protease inhibitors of Factor Xa and tryptase. It is another object of the invention to provide a process for preparing aminopyrrolidine sulfonamide compounds, compositions, intermediates and derivatives thereof. It is a further object of the invention to provide methods for treating serine protease or dual-serine protease mediated disorders.
SUMMARY OF THE INVENTION
This invention is directed to aminopyrrolidine sulfonamide compounds selected from the group consisting of Formula (I) and Formula (II):
wherein
R
1
is selected from the group consisting of hydrogen, C
1-8
alkyl, C
3-7
cycloalkyl, aryl, aryl(C
1-8
)alkyl, aryl(C
2-8
)alkenyl, heteroaryl(C
1-8
)alkyl, heteroaryl(C
2-8
)alkenyl and R
4
C(O)CH
2
—; wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from R
4
;
R
2
is selected from the group consisting of hydrogen, hydroxy, C
1-8
alkoxy, aryloxy and aryl(C
1-8
)alkoxy; with the proviso that R
2
is bonded to the heterocyclyl ring by a single bond; alternatively, R
2
is oxo; with the proviso that R
2
is bonded to the heterocyclyl ring by a double bond;
R
3
is selected from the group consisting of aryl, aryl(C
1-8
)alkyl, aryl(C
2-8
)alkenyl, heteroaryl(C
1-8
)alkyl, heteroaryl(C
2-8
)alkenyl; wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of halogen, C
1-8
alkyl, C
1-8
alkoxy, amino, (C
1-4
alkyl)amino, di(C
1-4
alkyl)amino, trihalo(C
1-8
)alkyl and trihalo(C
1-8
)alkoxy;
R
4
is selected from the group consisting of hydroxy, amino, C
1-8
alkyl, (C
1-4
alkyl)amino, di(C
1-4
alkyl)amino, C
1-8
alkoxy, carboxy, carboxy(C
1-8
)alkyl, carboxy(C
1-8
)alkoxy, (carboxy)amino, (carboxy(C
1-4
)alkyl)amino, (carboxyaryl)amino, (carboxyaryl(C
1-4
)alkyl)amino, (carboxy(C
1-4
)alkylaryl)amino, aryloxy, aryl(C
1-8
)alkoxy, (aryl)amino, (aryl(C
1-4
)alkyl)amino, (C
1-4
alkylaryl)amino, (arylcarboxy)amino, di(aryl)amino, di(aryl(C
1-4
)alkyl)amino, C
1-8
alkoxycarbonyl, C
1-8
alkoxycarbonyl(C
1-8
)alkoxy, aminocarbonyl, (C
1-8
alkyl)aminocarbonyl, (carboxy(C
1-8
)alkyl)aminocarbonyl, (C
1-8
alkoxycarbonyl(C
1-8
)alkyl)aminocarbonyl and guanidino; and,
G is selected from the group consisting of hydrogen, halogen, hydroxy, C
1-4
alkyl, C
1-8
alkoxy, aryl, aryloxy, aryl(C
1-8
)alkyl, aryl(C
1-8
)alkoxy, amino, carboxy, alkylaminocarbonyl, alkylcarbonylamino, trihalo(C
1-8
)alkyl and trihalo(C
1-8
)alkoxy;
n is 1 or 2;
and pharmaceutically acceptable salts thereof.
The aminopyrrolidine sulfonamide compounds of the present invention are selective serine protease or dual-serine protease inhibitors useful for treating serine protease mediated disorders. An embodiment of the invention includes compounds that are selective or dual-inhibitors of Factor Xa and tryptase.
The present invention includes a method for preparing instant compounds, compositions, intermediates and derivatives thereof and a method for treating selective serine protease or dual-serine protease mediated disorders.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the instant compounds are those wherein, preferably, R
1
is selected from the group consisting of hydrogen, aryl(C
1-8
)alkyl and heteroaryl(C
1-8
)alkyl, wherein aryl, heteroaryl and the aryl and heteroaryl portion of arylalkyl and heteroarylalkyl are optionally substituted with a substituent selected from R
4
. More preferably, R
1
is selected from the group consisting of hydrogen, benzyl, phenethyl, phenylpropyl and benzofurylmethyl, wherein phenyl, the phenyl portion of benzyl and the benzofuryl portion of benzofurylmethyl are optionally substituted with a substituent selected from R
4
. Most preferably, R
1
is selected from the group consisting of hydrogen, benzyl, phenylpropyl and benzofurylmethyl, wherein phenyl, the phenyl portion of benzyl and the benzofuryl portion of benzofurylmethyl are optionally substituted with a substituent selected from R
4
.
An embodiment of the instant compounds also include those wherein, preferably, R
2
is hydrogen.
An embodiment of the instant compounds further includes those wherein, preferably, R
3
is aryl(C
2-8
)alkenyl, wherein aryl is optionally substituted with one to three substituents independently selected from halogen. More preferably, R
3
is independently selected from the group consisting of phenethenylene and phenylpropenylene, wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chlorine and fluorine. Most preferably, R
3
is phenethenylene, wherein phenyl is substituted with one to three substituents selected from chlorine.
Embodiments of the instant compounds include those wherein, preferably, R
4
is selected from the group consisting of hydroxy, di(C
1-4
alkyl)amino, C
1-8
alkoxy, carboxy, carboxy(C
1-8
)alkoxy, aryl(C
1-8
)alkoxy, C
1-8
alkoxycarbonyl, C
1-8
alkoxycarbonyl(C
1-8
)alkoxy, aminocarbonyl, (C
1-8
alkyl)aminocarbonyl, (carboxy(C
1-8
)alkyl)aminocarbonyl and C
1-8
alkoxycarbonyl(C
1-8
)alkyl)aminocarbonyl.
More preferably, R
4
is select
Boyd Robert E.
Greco Michael N.
Hawkins Michael J.
Maryanoff Bruce E.
McKane Joseph K.
Ortho-McNeil Pharamceutical, Inc.
Small Andrea D.
Woodrow Hal B.
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