Lactam inhibitors of factor Xa and method

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S212080, C540S526000, C540S527000

Reexamination Certificate

active

06544981

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to lactam inhibitors of the enzyme Factor Xa which are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, novel lactam derivatives are provided which are inhibitors of the enzyme Factor Xa and have the structure I
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein n is an integer from 1 to 5;
R
1
, R
2
and R
3
are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, alkoxy, cyano, nitro, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl,
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
or R
1
, R
2
and R
3
can in pairs of two join together to form a saturated carbocylic or heterocylic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
or R
1
and R
2
can join together to form an unsaturated carbocylic or heterocylic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
wherein R
3
is optionally a bond participating in the unsaturation of said ring;
R
4
, R
6
, R
8
, R
9
, R
a
, R
b
, are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl or polycycloalkynylalkyl; all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
5
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, aminocarbonyl, substituted aminocarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynyl-alkyl, cyano, nitro, hydroxy, amino, —OR
a
, —SR
a
, —S(O)R
a
,
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
7
is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl,
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
10
and R
10a
are the same or different are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl polycycloalkynylalkyl,
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
11
and R
12
are the same or different and are independently selected from hydrogen, alkyl, aryl, cyano, nitro, heteroaryl, sulfonyl, acyl, amido, sufonamido, sulfamoyl, alkoxycarbonyl, carboxy, —C(O)
z
R
a
, —S(O)
z
R
a
,
—P(O)(OR
a
)
z
where Z is 1 or 2,
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
c
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl,
all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
d
and R
e
are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, alkoxyalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl, hydroxyalkyl, alkoxycarbonyl, or aminocarbonyl; all optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
or R
d
and R
e
can be taken together with the nitrogen to which they are attached to form a cycloheteroalkyl ring or a heteroaryl ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
Z
1
, Z
2
, Z
3
, Z
4
and Z
5
are the same or different and are independently selected from hydrogen, halo, alkyl, haloalkyl, polyhaloalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, oxo, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, C(O)H, alkylcarbonyl, arylcarbonyl, amido, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, aminosulfinyl, aminosulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylsulfonyl, alkylsulfinyl, sulfonamido, sulfonyl, amidino, guanidino,
and wherein
R
4
and R
5
can be taken together with the nitrogen to which they are attached to form a cycloheteroalkyl ring or a heteroaryl ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
5
and R
11
can be taken together to form a heteroaryl ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
5
or R
4
or R
11
or R
12
can form a ring with R
6
which can be a cycloheteroalkyl or a heteroaryl ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
10
or R
10a
can combine with R
8
or R
9
on an adjacent carbon atom to form a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z
2
, Z
3
, Z
4
, and Z
5
;
R
10
and R
10a
groups on adjacent carbon atoms can combine to form a saturated or unsaturated carbocyclic or heterocyclic ring optionally substituted through available atoms with 1, 2, 3, 4 or 5 groups selected from Z
1
, Z

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