Sulfonamide lactam inhibitors of FXa and method

Details Sulfonamide lactam inhibitors of FXa and method Sulfonamide lactam inhibitors of FXa and method

2002-01-29

2003-04-29

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S183000, C514S349000, C514S345000, C514S352000, C514S357000, C514S408000, C514S423000, C514S438000, C514S445000, C514S444000, C546S188000, C546S207000, C546S208000, C546S212000, C546S223000, C546S229000, C546S232000, C548S566000, C548S570000, C549S074000, C549S078000, C549S062000, C540S485000, C540S596000, C540S605000, C540S609000

Reexamination Certificate

active

06555542

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to sulfonamide 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
X is defined as:
—(CH
2
)
m
—
where m is an integer between 1 and 3 and which may be optionally mono- or di-substituted on 1 to 3 of the methylenes with oxo, lower alky, and aryl;
R
1
is selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl and substituted cycloheteroalkyl;
R
2
and R
3
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl;
R
4
, R
4a
, R
5
,and R
5a
are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy,
R
6
and R
6a
are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloheteroalkyl;
R
7
and R
8
are independently chosen from
—(CH
2
)
n
—H
where n is an integer between 1 and 4 and which may be optionally mono- or di-substituted on 1 to 4 of the methylenes with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;
or R
7
and R
8
together with the nitrogen atom to which they are attached may form an optionally substituted cycloheteroalkyl group;
R
a
and R
b
are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, substituted alkyl-carbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, substituted alkylaminocarbonyl, dialkylaminocarbonyl, and substituted dialkylaminocarbonyl.
Compounds within the scope of the present invention include compounds of the following formula II
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein
Y and Y
a
are independently a bond, alkyl, alkenyl or alkynyl;
X and X
a
are independently
—(CH
2
)
m
—
where m is an integer between 1 and 3 and where each methylene group of X may be optionally substituted with oxo, or mono- or di-substituted with lower alkyl or aryl;
Q is a group A or B
 where
(1) n, p, q and r are each independently 0 to 2, provided that at least one of n, p, q and r is other than zero;
(2) X
1
is —O—, —CR
14
R
15
—, —NR
14
—, or —S(O)
t
— where t is 1 or 2;
(3) the group B ring system optionally contains one or more double bonds where valence allows; and
(4) optionally fused to the group B ring system is an optionally substituted cycloalkyl ring, an optionally substituted cycloheteroalkyl ring, an optionally substituted heteroaryl ring, or an optionally substituted aryl ring;
R
1
and R
1a
are independently aryl, heteroaryl, cycloalkyl or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z
1
, Z
2
or Z
3
;
R
2
, R
2a
, R
3
and R
3a
are independently selected from
(1) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl any of which may be optionally substituted with one or more groups Z
1a
, Z
2a
or Z
3a
; or
(2) —C(O)
t
H, or C(O)
t
Z
6
where t is 1 or 2; or
(3) —Z
4
—NZ
7
Z
8
;
R
4
, R
4a
, R
4b
, R
4c
, R
5
, R
5a
, R
5b
and R
5c
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy,
 any of which may be optionally substituted with one or more groups Z
1b
, Z
2b
or Z
3b
;
R
6
and R
6a
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z
1c
, Z
2c
or Z
3c
;
R
7
and R
8
are independently chosen from optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl or
—(CH
2
)
n
—H,
where n is an integer between 1 and 4 and wherein 1 to 4 of the methylene groups may be optionally mono- or di-substituted with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;
or R
7
and R
8
together with the nitrogen atom to which they are attached may form an optionally substituted cycloheteroalkyl group;
R
a
and R
b
are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl.
R
9
is H, Z
3d
or when a group R
11
is present R
9
combines with R
11
to form a bond;
R
10
is H, Z
1f
, —Y
2
—R
11
, —Y
2
—N(R
11
)(Z
4
—Z
9a
), —Y
2
—OR
11
, —Y
2
—C(O)R
11
, —Y
2
—C(O)OR
11
, —Y
2
—OC(O)R
11
, —Y
2
—N(Z
4
—Z
9a
)—C(O)R
11
, —Y
2
—N(Z
4
—Z
9a
)—C(O)OR
11
, —Y
2
—S(O)
t
R
11
where t is 0 to 2, or —Y
2
—R
12
;
Y
2
is —(CH
2
)
u
—, —O—(CH
2
)
u
—, —C(O)—(CH
2
)
u
—, —C(O)O—(CH
2
)
u
—, —OC(O)—CH
2
)
u
— where u is 0 to 3;
R
11
when present combines with R
9
to form a bond;
R
12
is
R
13
is H, Z
2f
,
R
14
is H, Z
3f
or a group D
or R
13
and R
14
combine to form ═O or ═S;
Z
1
, Z
1a
, Z
1b
, Z
1c
, Z
1d
, Z
1e
, Z
1f
, Z
2
, Z
2a
, Z
2b
, Z
2c
, Z
2d
, Z
2e
, Z
2f
, Z
3
, Z
3a
, Z
3b
, Z
3c
, Z
3d
, Z
3e
, Z
3f
, Z
13
and Z
14
are each independently
(1) hydrogen or Z
6
, where Z
6
is
(i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl;
(ii) (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of Z
1
through Z
3f
,
(2) —OH or —OZ
6
,
(3) —SH or —SZ
6
,
(4) —C(O)
t
H, —C(O)
t
Z
6
, or —O—C(O)Z
6
,
(5) —SO
3
H, —S(O)
t
Z
6
, or S(O)
t
N(Z
9
)Z
6
,
(6) halo,
(7) cyano,
(8) nitro,
(9) —Z
4
—NZ
7
Z
8
,
(10) —Z
4
—N(Z
9
)—Z
5
—NZ
7
Z
8
,
(11) —Z
4
—N(Z
10
)—Z
5
—Z
6
,
(12) —Z
4
—N(Z
10
)—Z
5
—H,
(13) oxo,
Z
4
and Z
5
are each independently
(1) a single bond,
(2) —Z
11
—S(O)
t
—Z
12
—,
(3) —Z
11
—C(O)—Z
12
—,
(4) —Z
11
—C(S)—Z
12
—,
(5) —Z
11
—O—Z
12
—,
(6) —Z
11
—S—Z
12
—,
(7) —Z
11
—O—C(O)—Z
12
—,
(8) —Z
11
—C(O)—O—Z
12
—,
(9) —Z
11
—C(═NZ
9a
)—Z
12
—, or
(10) —Z
11
—C(O)—C(O)—Z
12
—
Z
7
, Z
8
, Z
9
, Z
9a
and Z
10
(1) are each independently hydrogen or a group provided in the definition of Z
6
,
(2) Z
7
and Z
8
may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the defintion of Z
1
through Z
3
,
(3) Z
7
or Z
8
, together with Z
9
, may be alkylene or alkenylene completing a 3- to 8-membered saturated or

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