Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-29
2004-03-23
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S205000
Reexamination Certificate
active
06710058
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to monocyclic or bicyclic carbocycles and heterocycles, 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
U.S. Pat. No. 5,032,602 shows 2-pyridones of the following formula.
These compounds are inhibitors of HMG-COA reductase. These compounds are not described as being useful for inhibiting factor Xa and are not considered to be part of the present invention.
WO97/36900 describes inhibitors of farnesyl-protein transferase of the formula.
WO97/36900 does not consider inhibition of factor Xa however. The compounds of WO97/36900 are not considered to be part of the present invention.
WO99/31506 and WO99/31507 describe solution phase syntheses of lactams of the formula.
The lactams described in WO99/31506 and WO99/31507 are not considered to be part of the present invention.
WO95/14012 illustrates protease inhibitors of the formula.
This formula represents pyrones when Y is unsubstituted or substituted nitrogen. However, the compounds of WO95/14012 are not considered to be part of the present invention.
EP 0,908,764 depicts photographic developers of the formula below.
Careful selection of variables can lead one to pyrones. But, the compounds of EP 0,908,764 are not considered to be part of the present invention.
U.S. Pat. No. 5,252,584 shows hydroxyquinolones of the following formula.
R
1
can be a substituted pyrone. These compounds are not described as being useful for inhibiting factor Xa and are not considered to be part of the present invention.
EP 0,454,444 describes glutarimide derivatives of the following formula.
X can be O, R
1
can be an alkyl, alkoxy, or halo-substituted benzyl, and R
9
can be a cyclic moiety. These compounds are indicated to be herbicides. The compounds of EP 0,454,444 are not considered to be part of the present invention.
WO99/42455 illustrates antiviral agents of the formula.
R
1
can potentially be a cyclic amide substituted by an aryl amine. The ring containing X and Y is a 5 or 6-membered heteroaromatic ring. The compounds shown in WO99/42455 are not considered to be part of the present invention.
U.S. Pat. No. 5,998,447 shows heterocycles of the following formula.
B can be phenylene; W can be substituted phenylalkylene; c, d, e, f, g, and h can all be 0; and, E can be tetrazole. These compounds are inhibitors of leucocyte adhesion and/or antagonists of VLA-4. Tetrazole substituted compounds of this sort are not considered to be part of the present invention.
EP 0,522,606 depicts pyridine derivatives of the following formula.
R can be substituted pyridine, X can be O, A is a carbon atom that can be part of a ring (i.e., a 1,1-substituted ring), Y can be O, and R
3
and R
4
can combine for form a cyclic lactam containing an optionally substituted aralkyl. Compounds of this sort are not considered to be part of the present invention.
WO99/32477 illustrates Factor Xa inhibitors containing at least three aryl or heterocyclic groups separated by two linking groups, an example of which is shown below.
Dual linker compounds of this sort are not considered to be part of the present invention.
WO00/69826, WO00/69832, WO00/69833, and WO00/69834 relate to coagulation cascade inhibitors that are 1,3-disubsituted pyridones of the formula shown below, or aza-substituted derivatives.
B and Y
0
are preferably cyclic moieties. A, &PSgr;, K, and E
0
are preferably linkers. Pyridones and aza-pyridones of this sort are not considered to be part of the present invention.
WO01/47919 discloses factor Xa inhibitors that are substituted oxazolidinones of the formula shown below:
R
1
is thienyl or benzothienyl. Oxazolidinones of this sort are not considered to be 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 monocyclic or bicyclic carbocycles and heterocycles 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 for use in therapy.
It is another object of the present invention to provide the use of novel 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 the presently claimed monocyclic or bicyclic carbocycles and heterocycles, 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 I:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring M, including M
1
, M
2
, and M
3
, is a 5, 6, or 7 membered non-aromatic carbocycle or 5, 6, or 7 membered non-aromatic heterocycle, consisting of: carbon atoms, 0-3 N, and 0-1 heteroatoms selected from O and S(O)
p
, provided that ring M consists of a total of 0-3 O, S(O)
p
and N;
alternatively, ring M is an aromatic heterocycle selected from 2-pyridinone, 3-pyridazinone, 4-pyrimidinone, 2-pyrazinone, pyrimidine-2,4-dione, pyridazine-3,6-dione, 1H-quinolin-2-one, 1,4-dihydro-pyrrolo[3,2-b]pyridin-5-one and 1,4-dihydro-imidazo[4,5-b]pyridin-5-one;
ring M is substituted with 0-2 R
1a
, 0-1 Z, and 0-2 carbonyl groups, and, comprises: 0-2 double bonds;
provided that ring M is other than an isoxazoline, isothiazoline, pyrazoline, triazoline, tetrazoline, 3-phenyl-substituted pyrrolidine, 3-phenyl-substituted pyrroline, 3-phenyl-substituted isoxazolidine, or 4-phenyl-substituted isoxazolidine;
G is a group of formula IIa or IIb:
G
1
is selected from (CR
3a
R
3b
)
1-5
, (CR
3a
R
3b
)
0-2
CR
3a
═CR
3a
(CR
3a
R
3b
)
0-2
, (CR
3a
R
3b
)
0-2
C≡C(CR
3a
R
3b
)
0-2
, (CR
3a
R
3b
)
u
C(O)(CR
3a
R
3b
)
w
, (CR
3a
R
3b
)
u
C(O)O(CR
3a
R
3b
)
w
, (CR
3a
R
3b
)
u
OC(O)(CR
3a
R
3b
)
w
, (CR
3a
R
3b
)
u
O(CR
3a
R
3b
)
w
, (CR
3a
R
3b
)
u
NR
3e
(CR
3a
R
3b
)
w
, (CR
3a
R
3b
)
u
C(O)NR
3
(CR
3a
R
3b
)
w
, (CR
3a
R
3b
)
u
NR
3
C
Jacobson Irina C.
Smallheer Joanne M.
Wang Shuaige
Wexler Ruth R.
Belfield Jing S.
Bristol-Myers Squibb Pharma Company
Kifle Bruck
Vance David H.
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