Guanidine mimics as factor Xa inhibitors

Details Guanidine mimics as factor Xa inhibitors Guanidine mimics as factor Xa inhibitors

1998-06-18

2002-01-15

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S379000, C514S399000, C548S304700, C548S364400, C548S311400

Reexamination Certificate

active

06339099

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to novel guanidine mimics 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 96/28427 describes benzamidine anticoagulants of the formula:
wherein Z
1
and Z
2
are O, N(R), S or OCH
2
and the central ring may be phenyl or a variety of heterocycles. The presently claimed compounds do not contain the Z
1
linker or the substitution pattern of the above compounds.
WO 95/13155 and PCT International Application U.S. 96/07692 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.
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.
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. But, Baker et al do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Tidwell et al, in
J. Med. Chem.
1978, 21(7), 613-623, describe a series of diarylamidine derivatives including 3,5-bis(4-amidinophenyl)isoxazole. This series of compounds was tested against thrombin, trypsin, and pancreatic kallikrein. The presently claimed invention does not include these types of compounds.
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 guanidine mimics 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 D, E, and M 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 D is selected from —CH
2
N═CH—, —CH
2
CH
2
N═CH—, a 5-6 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S;
ring D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;
ring E contains 0-2 N atom and is substituted by 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
;
M is selected from the group:
J is O or S;
J
a
is NH or NR
1a
;
Z is selected from a bond, C
1-4
alkylene, (CH
2
)
r
O(CH
2
)
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 saturated ring substituted with 0-2 R
4
and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
alternatively, when Z is C(O)NH and R
1a
is attached to a ring carbon adjacent to Z, then R
1a
is a C(O) which replaces the amide hydrogen of Z to form a cyclic imide;
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
, C

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