Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-17
2004-06-15
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S119000
Reexamination Certificate
active
06750225
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to 1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-ones, 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
WO95/01980 and WO96/12720 describe phosphodiesterase type IV and TNF production inhibitors of the following formula:
wherein X can be oxygen and R
2
and R
3
can a number of substituents including heterocycle, heterocycloalkyl, and phenyl. However, the presently claimed compounds do not correspond to the compounds of WO96/12720. Furthermore, WO96/12720 does not suggest Factor Xa inhibition.
WO98/52948 depicts inhibitors of ceramide-mediated signal transduction. One of the types of inhibitors described is of the following formula:
wherein Y
1
can be N—R
6
, R
6
can be unsubstituted aryl-alkyl or unsubstituted heterocyclic-alkyl and R
1
can be a substituted aryl group. WO98/52948 does not mention factor Xa inhibition or show compounds like those of the present invention.
U.S. Pat. Nos. 3,365,459, 3,340,269, and 3,423,414 illustrate anti-inflammatory inhibitors of the following formula:
wherein A is 2-3 carbon atoms, X can be O, and R
1
and R
3
can be substituted or unsubstituted aromatic groups. Neither of these patents, however, exemplify compounds of the present invention.
WO00/39131 describes heterobicyclic factor Xa inhibitors of which the following formula is an example:
wherein G can be a substituted phenyl, s can be 0, A can be phenyl, and B can be a substituted phenyl or imidazolyl.
WO01/19798 describes factor Xa inhibitors of the following formula:
A—Q—D—E—G—J—X
wherein A, D, G, and X can be phenyl or heterocycle. However, none of the presently claimed compounds are exemplified or suggested in WO01/19798.
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 1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-ones that 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 a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
It is another object of the present invention to provide a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
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 compounds of the following formula:
or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Thus, in an embodiment, the present invention provides a novel compound of formula Ia or Ib:
wherein:
R is 2-R
1
-phenyl or 2-R
1
-imidazol-1-yl;
R
1
is selected from CH
3
, CH
2
—NH
2
, CH
2
—NHCH
3
, CH
2
—NH(CH
2
CH
3
), CH
2
—NH(CH
2
CH
2
OH), CH
2
—NH(CH
2
CH
2
CH
3
), CH
2
—NH(CH(CH
3
)
2
), CH
2
—NHC(CH
3
)
3
, CH
2
—N(CH
3
)
2
, CH
2
—NCH
3
(CH
2
CH
3
), CH
2
—NCH
3
(CH
2
CH
2
OH), CH
2
—NCH
3
(CH
2
CH
2
CH
3
), CH
2
—N(CH
2
CH
3
)
2
, CH
2
—NH-pyrrolidinyl, CH
2
—NH-(3-hydroxy-pyrrolidinyl), CH
2
—NH-(3-R-hydroxy-pyrrolidinyl), CH
2
—NH-(3-S-hydroxy-pyrrolidinyl), and CH
2
—NH-(4-hydroxy-piperidinyl);
alternatively, R is 3-R
1
-pyridin-4-yl and R
1
is SO
2
NH
2
; or a pharmaceutically acceptable salt form thereof.
In a preferred embodiment, the present invention provides a compound wherein the compound is of formula Ia or Ib, R is 2-R
1
-phenyl, and R
1
is CH
2
—N—(CH
3
)
2
.
In another preferred embodiment, the present invention provides a compound wherein the compound is of formula Ia or Ib, R is 2-R
1
-phenyl, and R
1
is CH
2
—NH-(4-hydroxy-piperidinyl).
In another preferred embodiment, the present invention provides a compound wherein the compound is of formula Ia or Ib, R is 2-R
1
-phenyl, and R
1
is CH
2
—NH-(3-hydroxy-pyrrolidinyl).
In another preferred embodiment, the present invention provides a compound wherein the compound is of formula Ia or Ib, R is 2-R
1
-phenyl, and R
1
is CH
2
—NCH
3
(CH
2
CH
2
OH).
In another preferred embodiment, the present invention provides a compound wherein the compound is of formula Ia or Ib, R is 2-R
1
-phenyl, and R
1
is CH
2
—NH(CH
2
CH
2
OH).
In another preferred embodiment, the present invention provides a compound wherein the compound is of formula Ia, R is 2-R
1
-imidazol-1-yl, and R
1
is CH
2
—NH(CH
2
CH
2
CH
3
).
In another embodiment, the present invention provides a novel compound of formula IIa or IIb:
wherein:
R
a
is selected from CF
3
, C(O)NH
2
, C(O)N(CH
3
)
2
, and S(O)
2
CH
3
:
R is 2-R
1
-imidazol-1-yl;
R
1
is selected from CH
3
, CH
2
—NH
2
, CH
2
—NHCH
3
, CH
2
—NH(CH
2
CH
3
), CH
2
—NH(CH
2
CH
2
OH), CH
2
—NH(CH
2
CH
2
CH
3
), CH
2
—NH(CH(CH
3
)
2
), CH
2
—NHC(CH
3
)
3
, CH
2
—N(CH
3
)
2
, CH
2
—NCH
3
(CH
2
CH
3
), CH
2
—NCH
3
(CH
2
CH
2
OH), CH
2
—NCH
3
(CH
2
CH
2
CH
3
), CH
2
—N(CH
2
CH
3
)
2
, CH
2
—NH-cyclopropyl, CH
2
—N(CH
3
)-cyclopropyl, CH
2
—NH-cyclopentyl, CH
2
—NH-pyrrolidinyl, CH
2
—NH-(3-hydroxy-pyrrolidinyl), CH
2
—NH-(3-R-hydroxy-pyrrolidinyl), CH
2
—NH-(3-S-hydroxy-pyrrolidinyl), CH
2
—NH-(2-(pyridin-3-ylmethyl)-pyrrolidinyl), and CH
2
—NH-(4-hydroxy-piperidinyl);
alternatively, R is 3-R
1
-pyridin-4-yl and R
1
is SO
2
NH
2
; or a pharmaceutically acceptable salt form thereof.
In another preferred embodiment, the present invention provides a compound wherein the compound is of formula IIb, R
a
is CF
3
, R is 2-R
1
-imidazol-1-yl, and R
1
is CH
2
—N(CH
3
)
2
.
In another preferred embodiment, the present invention provides a compound wherein the compound is of formula IIb, R
a
is
Galemmo, Jr. Robert Anthony
Orwat Michael James
Pinto Donald Joseph Philip
Quan Mimi Lifen
Belfield Jing S.
Bristol-Myers Squibb Pharms Company
Huang Evelyn Mei
Vance David H.
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