Disubstituted pyrazolines and triazolines as factor Xa...

Details Disubstituted pyrazolines and triazolines as factor Xa... Disubstituted pyrazolines and triazolines as factor Xa...

1999-03-26

2001-02-20

Tsang, Cecilia (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S407000, C514S247000, C514S252010, C514S255030, C514S256000, C514S269000, C514S315000, C514S326000, C514S336000, C514S341000, C514S360000, C514S362000, C514S363000, C514S364000, C514S365000, C514S372000, C514S374000, C514S378000, C514S383000, C514S385000, C514S396000, C514S402000, C514S406000, C514S422000, C514S427000, C514S444000, C514S461000, C544S140000, C544S238000, C544S242000, C544S333000, C544S336000, C544S371000, C546S211000

Reexamination Certificate

active

06191159

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to disubstituted pyrazolines and triazolines 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.
WO 97/47299 describes amidino and guanidino heterocyclic protease inhibitors of the formula:
R
1
—Z—X—Y—W
wherein W contains an amidino, guanidino, or imino group attached to a variety of moieties including phenyl and piperidinyl, Y is a O, N, S, or C linker or is absent, X is a heterocycle, Z is a two atom linker containing at least one heteroatom, and R
1
is a variety of groups including cycloalkyl, aryl, heteroaryl, and araalkyl all of which are optionally substituted. A variety of proteases are described as possible targets for these compounds including Factor Xa. The presently claimed compounds differ in that they do not contain the combination R
1
—Z or Y—W.
WO 97/23212 describes isoxazolines, isothiazolines, and pyrazolines of the formula:
wherein X is O, S or NR
15
. Though the pyrazolines of WO 97/23212 are indicated to be factor Xa inhibitors, they 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 disubstituted pyrazolines and triazolines 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 formulae I and II:
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, D, E, G, M, Z, 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 formulae I or II:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
M
1
is N or CR
1c
;
M
2
is NR
1a
or CR
1a
R
1a
, provided that only one of M
1
and M
2
is a N atom;
D is selected from 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
NR
7
R
8
;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1 R;
alternatively, D—E—G together represent pyridyl substituted with 1 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 selected from NHCH
2
, OCH
2
, and SCH
2
, provided that when s is 0, then G is absent;
Z is selected from a 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 group A;
R
1a
and R
1b
are, at each occurrence, independently selected from H, —(CH
2
)
r
—R
1′
, NCH
2
R
1″
, OCH
2
R
1″
, SCH
2
R
1″
, N(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′
;
R
1c
is selected from H, —(CH
2
)
q
—R
1′
, C
1-3
alkyl, C(O)R
2c
, (CF
2
)
r
CO
2
R
2c
, C(O)NR
2
R
2a
, 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, C
1-3
alkyl, halo, (CF
2
)
r
CF
3
, 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
, NR
2
C(O)R
2b
, NR
2
C(O)NHR
2b
, NR
2
C(O)
2
R
2a
, OC(O)NR
2b
, C(O)NR
2
R
2a
, SO
2
NR
2
R
2a
, NR
2
SO
2
R
2b
, 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, C(O)R
2b
, C(O)NR
2
R
2a
, S(O)R
2b
, S(O)
2
R
2b
, and SO
2
NR
2
R
2a
;
R
2
, at each occurrence, is selected from H, CF
3
, C
1-6
alkyl, benzyl, C
3-6
carbocyclic residue substituted with 0-2 R
4b
, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4b
;
R
2a
, at each occurrence, is selected from H, CF
3
, C
1-6
alkyl, benzyl, C
3-6
carbocyclic residue substituted with 0-2 R
4b
, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4b
;
R
2b
, at each occurrence, is selected from CF
3
, C
1-4
alkoxy, C
1-6
alkyl, benzyl, C
3-6
carbocyclic residue substituted with 0-2 R
4b
, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4b
;
R
2c
, at each occurrence, is selected from CF
3
, OH, C
1-4
alkoxy, C
1-6
alkyl, benzyl, C
3-6
carbocyclic residue substituted with 0

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