Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-12
2003-04-15
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...
C514S383000, C548S260000, C548S261000, C548S266800, C548S269200
Reexamination Certificate
active
06548525
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to nitrogen containing heteroaromatics, with ortho-substituted P1 groups, 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 95/18111 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.
Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT
1
agonists which are indole substituted five-membered heteroaromatic compounds of the formula:
wherein R
1
may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Baker et al, in WO 94/02477, discuss 5-HT
1
agonists which are imidazoles, triazoles, or tetrazoles of the formula:
wherein R
1
represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
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.
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.
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 A, B, D, E, G, J, M, R
1a
, R
1b
, and s are defined below, are effective factor Xa inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in a first embodiment, the present invention provides novel compounds of formula I:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring M contains, in addition to J, 0-3 N atoms, provided that if M contains 2 N atoms then R
1b
is not present and if M contains 3 N atoms then R
1a
and R
1b
are not present;
J is N or NH;
D is selected from 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
, and (CR
8
R
9
)
t
NR
7
R
8
, provided that D is substituted ortho to G on E;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1-2 R;
R is selected from H, Cl, F, Br, I, (CH
2
)
t
OR
3
, C
1-4
alkyl, OCF
3
, CF
3
, C(O)NR
7
R
8
, and (CR
8
R
9
)
t
NR
7
R
8
;
G is absent or is selected from NHCH
2
, OCH
2
, and SCH
2
, provided that when s is 0, then G is attached to a carbon atom on ring M;
Z is selected from a C
1-4
alkylene, (CH
2
)
r
O(CH2)
r
, (CH
2
)
r
NR
3
(CH
2
)
r
, (CH
2
)
r
C(O)(CH
2
)
r
, (CH
2
)
r
, C(O)O(CH
2
)
r
, (CH
2
)
r
OC(O)(CH
2
)
r
, (CH
2
)
r
C(O)NR
3
(CH
2
)
r
, (CH
2
)
r
NR
3
C(O)(CH
2
)
r
, (CH
2
)
r
OC(O)O(CH
2
)
r
, (CH
2
)
r
OC(O)NR
3
(CH
2
)
r
, (CH
2
)
r
NR
3
C(O)O(CH
2
)
r
, (CH
2
)
r
NR
3
C(O)NR
3
(CH
2
)
r
, (CH
2
)
r
S(O)
p
(CH
2
)
r
, (CH
2
)
r
SO
2
NR
3
(CH
2
)
r
, (CH
2
)
r
NR
3
SO
2
(CH
2
)
r
, and (CH
2
)
r
NR
3
SO
2
NR
3
(CH
2
)
r
, provided that Z does not form a N—N, N—O, N—S, NCH
2
N, NCH
2
O, or NCH
2
S bond with ring M or group A;
R
1a
and R
1b
are independently absent or selected from —(CH
2
)
r
—R
1′
, —CH═CH—R
1′
, NCH
2
R
1″
, OCH
2
R
1″
, SCH
2
R
1″
, NH(CH
2
)
2
(CH
2
)
t
R
1′
, O(CH
2
)
2
(CH
2
)
t
R
1′
, and S(CH
2
)
2
(CH
2
)
t
R
1′
;
alternatively, R
1a
and R
1b
, when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R
4
and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
R
1′
is selected from H, C
1-3
alkyl, F, Cl, Br, I, —CN, —CHO, (CF
2
)
r
CF
3
, (CH
2
)
r
OR
2
, NR
2
R
2a
, C(O)R
2c
, OC(O) R
2
, (CF
2
)
r
CO
2
R
2c
, S(O)
p
R
2b
, NR
2
(CH
2
)
r
OR
2
, CH(═NR
2c
)NR
2
R
2a
, NR
2
C(O)R
2b
, NR
2
C(O)NHR
2b
, NR
2
C(O)
2
R
2a
, OC(O)NR
2a
R
2b
, C(O)NR
2
R
2a
, C(O)NR
2
(CH
2
)
r
OR
2
, SO
2
NR
2
R
2a
, NR
2
SO
2
R
2
, C
3-6
carbocyclic residue substituted with 0-2 R
4
, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4
;
R
1″
is selected from H, CH(CH
2
OR
2
)
2
, C(O)R
2c
, C(O)NR
2
R
2a
, S(O)R
2b
, S(O)
2
Bostrom Lori L.
Galemmo, Jr. Robert A.
Pinto Donald J. P.
Rossi Karen A.
Belfield Jing S.
Bristol-Myers Squibb Pharma Company
Raymond Richard L.
Vance David H.
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