Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-31
2002-06-04
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S372000, C548S375100, C548S376100, C548S377100, C548S214000
Reexamination Certificate
active
06399644
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to aryl sulfonyls, 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
WO 95/14683 and WO 96/38426 describe isoxazoline and isoxazole fibrinogen receptor antagonists of the formula:
wherein R
1
may be a basic group, U—V may be a six-membered aromatic ring, W—X may be a variety of linear or cyclic groups, and Y is an oxy group. Thus, these compounds all contain an acid functionality (i.e., W—X—C(═O)—Y). In contrast, the presently claimed compounds do not contain such an acid functionality.
WO 94/24095 describes isoxazole immunosuppressive agents of the formula:
wherein D may be a variety of groups including H, phenyl, alkyl, and acyl, and E and G may be a variety of groups including aryl and heterocycle. However, the presently claimed aryl sulfonyls are not exemplified or discussed.
EP 0,513,387 depicts active oxygen inhibitors which are oxazoles or thiazoles of the formula:
wherein X is O or S, R
2
is preferably hydrogen, and both R
1
and R
3
are substituted cyclic groups, with at least one being phenyl. The presently claimed invention does not relate to these types of oxazoles or thiazoles.
WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula:
wherein R
1
represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.
In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula:
wherein the heterocycle may be aromatic and groups A—B—C— and F—E—D— are attached to the ring system. A—B—C— can be a wide variety of substituents including a basic group attached to an aromatic ring. The F—E—D— group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.
Illig et al, in WO 97/47299, illustrate amidino and guanidino heterocycle protease inhibitors of the formula:
R
1
—Z—X—Y—W
wherein R
1
can be a substituted aryl group, Z is a two carbon linker containing at least one heteroatome, X is a heterocycle, Y is an optional linker and W is an amidino or guanidino containing group. Compounds of this sort are not considered part of the present invention.
Jackson et al, in WO 97/32583, describe cytokine inhibitors useful for inhibiting angiogenesis. These inhibitors include imidazoles of the formula:
wherein R
1
is a variety of heteroaryl groups, R
4
is phenyl, naphthyl, or a heteroaryl group, and R
2
can be a wide variety of groups. Jackson et al do not teach inhibition of factor Xa. Furthermore, the imidazoles of Jackson et al are not considered part of the present invention.
In U.S. Pat. No. 5,082,949, Sohn et al depict phenyl-pyrazole-carboxylic acids of the formula:
wherein Y is a halogen, X is an acid or acid derivative, and R is selected from a variety of substituents. These compounds are indicated to have plant-growth regulating properties and also to be herbicide safeners. However, aryl sulfonyls, like those presently claimed, have not been described by Sohn et al, nor has the inhibition of factor Xa been described.
In U.S. Pat. No. 5,658,909, DeBernardis et al depict 1-aryl-3-piperazin-1′-yl propanones of the formula:
wherein Ar
1
can be a 5-membered heteroaryl substituted with an optionally substituted phenyl group, Y and R
24
can each be H, Z can be N or CH and Ar
2
can be phenyl or one of three heteroaryls. However, no aryl sulfonyls, like those presently claimed, have been described, nor has the inhibition of factor Xa been described.
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.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide 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.
It is another object of the present invention to provide 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.
It is another object of the present invention to provide novel compounds of formula (I) for use in therapy.
It is another object of the present invention to provide the use of novel compounds of formula (I) 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 compounds of formula (I):
or pharmaceutically acceptable salt or prodrug forms thereof, wherein D, E, and M are defined below, are effective factor Xa inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring D is absent or selected from —CH
2
N═CH—, —CH═NCH
2
—, —CH═N—CH
2
CH
2
—, —CH
2
CH
2
CH
2
—, —CH═CHCH
2
—, —CH
2
CH═CH—, a 5-6 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S;
ring D, when present, is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with 0-1 R;
R is selected from Cl, F, Br, I, OH, C
1-3
alkoxy, NH
2
, NH(C
1-3
alkyl), N(C
1-3
alkyl)
2
, CH
2
NH
2
, CH
2
NH(C
1-3
alkyl), CH
2
N(C
1-3
alkyl)
2
, CH
2
CH
2
NH
2
, CH
2
CH
2
NH(C
1-3
alkyl), and CH
2
CH
2
N (C
1-3
alkyl)
2
;
when ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with G and R′;
G is selected from F, Cl, Br, I, OH, C
1-3
alkoxy, CN, C(═NR
8
)NR
7
R
9
, NHC(═NR
8
)NR
7
R
9
, NR
8
CH(═NR
7
), C(O)NR
7
R
8
, (CR
8
R
9
)
t
NR
7
R
8
, SH, C
1-3
alkyl-S, S(O)R
3b
, S(O)
2
R
3a
, S(O)
2
NR
2
R
2a
, and OCF
3
;
R′ is selected from H, F, Cl, Br, I, SR
3
, CO
2
R
3
, NO
2
, (CH
2
)
t
OR
3
, C
1-4
alkyl, OCF
3
, CF
3
, C(O)NR
7
R
8
, and (CR
8
R
9
Jacobson Irina C.
Wexler Ruth R.
Belfield Jing S.
Patel Sudhaker B.
Raymond Richard L.
Vance David H.
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