Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-22
2004-05-04
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S241000
Reexamination Certificate
active
06730689
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to novel N-[4-(1H-imidazol-1-yl)-2-fluorophenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,342,851 depicts thiazole platelet aggregation inhibitors including those of the following formula:
wherein A is a linker, B can be a linker or a ring, Q is a ring or an amino group, R, R
1
, and R
3
are a variety of groups. This patent, however, does not exemplify or suggest compounds of the present invention.
WO00/39131 describes heterobicyclic Factor Xa inhibitors of which the following is an example formula:
wherein Z is C or N, G is a mono- or bicyclic group, A is a cyclic moiety and B is a basic group or a cyclic moiety. Compounds specifically described in WO00/39131 are not considered to be part of the present invention.
WO98/28269, WO99/32454, U.S. Pat. No. 6,020,357, and U.S. Pat. No. 6,271,237 describe Factor Xa inhibitors of the following formula:
wherein ring M can be pyrazolyl, A is a ring, B can be a ring, D can be amidino, and E can be phenyl. Compounds specifically described in WO98/28269, WO99/32454, U.S. Pat. No. 6,020,357, and U.S. Pat. No. 6,271,237 are not considered to be part of the present invention.
WO98/57951 describes Factor Xa inhibitors of the following formula:
wherein ring M can be pyrazolyl and rings D—E can be amino-benzisoxazole. Compounds specifically described in WO98/57951 are not considered to be part of the present invention.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca
2+
and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation.
Thromb. Res
. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors. In addition, it is also desirable to find new compounds with improved pharmacological characteristics compared with known factor Xa inhibitors. For example, it is preferred to find new compounds with improved factor Xa inhibitory activity and selectivity for factor Xa versus other serine proteases (i.e., trypsin). It is also desirable and preferable to find compounds with advantageous and improved characteristics in one or more of the following categories, but are not limited to: (a) pharmaceutical properties (e.g., solubility, permeability, and amenability to sustained release formulations); (b) dosage requirements (e.g., lower dosages and/or once-daily dosing); (c) factors which decrease blood concentration peak-to-trough characteristics (e.g., clearance and/or volume of distribution); (d) factors that increase the concentration of active drug at the receptor (e.g., protein binding, volume of distribution); (e) factors that decrease the liability for clinical drug-drug interactions (e.g., cytochrome P450 enzyme inhibition or induction); (f) factors that decrease the potential for adverse side-effects (e.g., pharmacological selectivity beyond serine proteases, potential chemical or metabolic reactivity, and limited CNS penetration); and, (g) factors that improve manufacturing costs or feasibility (e.g., difficulty of synthesis, number of chiral centers, chemical stability, and ease of handling).
SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel N-[4-(1H-imidazol-1-yl)-2-fluorophenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
The present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
The present invention provides novel compounds for use in therapy.
The present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the compounds of the present invention are effective factor Xa inhibitors.
REFERENCES:
patent: 5342851 (1994-08-01), Sanfilippo et al.
patent: 6020357 (2000-02-01), Pinto et al.
patent: 6271237 (2001-08-01), Galemmo et al.
patent: 6339099 (2002-01-01), Lam et al.
patent: 6521614 (2003-02-01), Maduskuie, Jr. et al.
patent: WO 98/28269 (1998-07-01), None
Belfield Jing S.
Bristol--Myers Squibb Company
Ramsuer Robert W.
Vance David M.
LandOfFree
N-[4-(1H-imidazol-1-yl)-2-fluorophenyl]-3-(trifluo... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with N-[4-(1H-imidazol-1-yl)-2-fluorophenyl]-3-(trifluo..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-[4-(1H-imidazol-1-yl)-2-fluorophenyl]-3-(trifluo... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3224734