Nitrogen containing heterobicycles as factor Xa inhibitors

Details Nitrogen containing heterobicycles as factor Xa inhibitors Nitrogen containing heterobicycles as factor Xa inhibitors

2000-07-13

2002-08-06

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S213010, C514S221000, C514S230500, C514S312000, C514S314000, C514S379000, C514S406000, C540S460000, C540S468000, C540S480000, C544S105000, C544S353000, C546S156000, C546S165000, C548S364700, C548S241000

Reexamination Certificate

active

06429205

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to nitrogen containing heterobicycles, 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
WO98/28269 describes factor Xa inhibitors of the formula:
wherein ring M contains, in addition to J, 0-3 N atoms, J is N or NH, and D is substituted meta or para to G on E.
However, WO98/28269 does not disclose compounds containing heterobicycles like those of the present invention.
WO98/57951 describes factor Xa inhibitors of the formula:
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 E contains 0-2 N atom and M is a variety of rings including pyrazole and triazole. WO98/57951 does not, however, disclose compounds containing heterobicycles like those of the present invention.
WO98/57937 describes factor Xa inhibitors of the formula:
wherein ring D is phenyl or pyridyl and M is a variety of rings including pyrazole and triazole. However, WO98/57937 does not disclose compounds containing heterobicycles like those of the present invention.
PCT/US98/26427 describes factor Xa inhibitors of the formula:
wherein ring M contains, in addition to J, 0-3 N atoms and J is N or NH and D is substituted ortho to G on E. However, PCT/US98/26427 does not disclose compounds containing heterobicycles like those 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 heterobicycles 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 bicyclic compounds for use in therapy.
It is another object of the present invention to provide the use of novel bicyclic 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 compounds of Formulas A and B
or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in an embodiment, the present invention provides a novel compound of formula A or B:
or a stereoisomer or pharmaceutically acceptable salt thereof;
G is a group of formula I or II:
ring D is selected from —(CH
2
)
3
—, —(CH
2
)
4
—, —CH
2
N═CH—, —CH
2
CH
2
N═CH—, and 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
;
alternatively, ring D is absent;
when ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with R
a
and R
b
;
R
a
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
)
t
NR
7
R
8
;
R
b
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
, OCF
3
, and a 5-6 membered heteroaromatic system containing from 1-4 heteroatoms selected from the group N, O, and S and substituted with R
c
;
alternatively, R
a
and R
b
combine to form methylenedioxy or ethylenedioxy;
R
c
is selected from OH, SH, C
1-3
alkoxy, C
1-3
thioalkoxy, 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
;
Z is N or CR
1a
;
R
1a
is absent or selected from —(CH
2
)
r
—R
1c
, —CH═CH—R
1c
, NCH
2
R
1d
, OCH
2
R
1d
, SCH
2
R
1d
, NH(CH
2
)
2
(CH
2
)
t
R
1c
, O(CH
2
)
2
(CH
2
)
t
R
1c
, and S(CH
2
)
2
(CH
2
)
t
R
1c
;
R
1b
is absent or selected from —(CH
2
)
r
—R
1c
, —CH═CH—R
1c
, NCH
2
R
1d
, OCH
2
R
1d
, SCH
2
R
1d
, NH(CH
2
)
2
(CH
2
)
t
R
1c
, O(CH
2
)
2
(CH
2
)
t
R
1c
, and S(CH
2
)
2
(CH
2
)
t
R
1c
;
alternatively, R
1a
and R
1b
, when both are present, 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
1c
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
2b
, 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
1d
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
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
, a C
1-6
carbocyclic-CH
2
— 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
1-6
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

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