Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-13
2003-05-20
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S425000, C514S575000, C546S300000, C548S319500, C562S621000
Reexamination Certificate
active
06566384
ABSTRACT:
FIELD OF INVENTION
This invention relates to hydroxamic and carboxylic acid derivatives, and to their use in medicine.
BACKGROUND TO THE INVENTION
Metalloproteinases, including matrix metalloproteinase (MMP), (human fibroblast) collagenase, gelatinase and TNF convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-9611209, WO-A-9712902 and WO-A-9719075, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the adamalysin family (or ADAMs) whose members include TNF convertase (TACE) and ADAM-10, which can cause the release of TNF&agr; from cells and others, which have been demonstrated to be expressed by human articular cartilage cells and also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown, such as collagenase, stromelysin and gelatinase, have been shown to inhibit the release of TNF both in vitro and in vivo. See Gearing et al (1994) Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561; GB-A-2268934; and WO-A-9320047. All of these reports inhibitors contain a hydroxamic acid zinc-binding group, as do the imidazole-substituted compounds disclosed in WO-A-9523790. Other compounds that inhibit MMP and/or TNF are described in WO-A-9513289, WO-A-96111209, WO-A-96035687, WO-A-96035711, WO-A-96035712 and WO-A-96035614.
WO-A-9718188 discloses MMP inhibitors of the formula
Ph
1
—Ph
2
—X—(CH
2
)
0-6
—(CZ)
0-1
—(CHR
1
)
0-1
—CO—NHOH
wherein Ph
1
and Ph
2
are each optionally-substituted phenyl; X is absent, O, NH or S; Z is —CONR
2
R
3
; and R
1
is H, alkyl, alkenyl, OH, optionally-substituted phenyalkyl or phenyl-SO
0-2
-alkyl, or alkyl-COOR
7
.
EP-A-0780386 discloses compounds having MMP and TNF inhibitory activity, of the formula
Y—CO—CR
1
R
2
—CR
3
R
4
—S(O)
11
R
5
wherein n i 0, 1 or 2; Y is OH or NHOH; R
1
is H or lower alkyl; R
2
is H, lower alkyl, heteroalkyl, aryl, aralkyl, arylheteroalkyl, cycloalkyl, heteroaryl, heteroaralkyl, heteroarylheteroalkyl, heterocyclo, heterocyclo-lower alkyl, heterocyclo-lower heteroaryl or NR
6
R
7
; R
3
is H, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl or lower alkoxy; R
4
is H, lower alkyl, cycloalkyl or cycaloalkylalkyl; and R
5
is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.
Compounds of EP-A-0780386 first disclosed in U.S. application No. 8939, filed Dec. 20, 1995, are of the same formula, where R
1
is H; R
2
is H, lower alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclo or NR
6
R
7
; R
3
is H, lower alkyl, cycloalkyl, cycloalkylalkyl or aralkyl; R
4
is H or lower alkyl; and R
5
is lower alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.
U.S. Pat. No. 4,325,964 discloses certain benzhydryl sulphinyl hydroxamates, as having utility in neuropsychic ailments.
Zayed et al, Zeitschrift für Naturforschung (1966)180-182, discloses 3-phenylsulphonylpropanoic acid N-hydroxyamide, as a fungicide.
SUMMARY OF THE INVENTION
The invention encompasses novel compounds of formula (I) which are useful inhibitors of matrix metalloproteinases and/or TNF&agr;-mediated diseases, including degenerative diseases and certain cancers.
Novel compounds according to the invention are of the general type represented by formula (I):
B—X—(CH
2
)
n
—CHR
1
—(CH
2
)
m
—COY (I)
wherein m and n are both independently 0 or 1, but are not both 0;
X is O, NR
3
or S(O)
0-2
;
Y is OR
2
or NHOH;
R
1
is H or a group (optionally substituted with R
9
) selected from C
1-6
alkyl, C
2-6
alkenyl, aryl, C
1-6
alkyl-aryl, heteroaryl, C
1-6
alkyl-heteroaryl, heterocycloalkyl, C
1-6
alkyl-heterocycloalkyl, cycloalkyl and C
1-6
alkyl-cycloalkyl;
R
2
is H or C
1-6
alkyl;
R
3
is H, C
1-6
alkyl, COR
2
, CON(R
2
)
2
where each R
2
is the same or different, CO
2
R
4
or SO
2
R
4
, and
R
4
is C
1-6
alkyl;
B is C
1-6
alkyl-aryl, C
1-6
alkyl, cycloalkyl, C
1-6
alkyl-cycloalkyl, cycloalkenyl, heterocycloalkenyl, C
1-6
alkyl-heteroaryl, heterocycloalkyl, C
1-6
alkyl-heterocycloalkyl, aryl or heteroaryl, any of which groups is optionally substituted by a substituent selected from R
5
, C
1-6
alkyl-R
5
, C
2-6
alkenyl-R
5
, aryl (optionally substituted with R
5
), aryl-C
1-6
alkyl-R
5
, C
1-6
alkyl-aryl (optionally substituted with R
5
), C
1-6
alkyl-heteroaryl (optionally substituted with R
5
), aryl-C
2-6
alkenyl-R
7
, heteroaryl (optionally substituted with R
5
), heteroaryl-C
1-6
alkyl-R
5
, cycloalkyl (optionally substituted with R
5
), benzofused cycloalkyl (optionally substituted with R
5
), heterocycloalkyl (optionally substituted with R
5
), benzofused heterocycloalkyl (optionally substituted with R
5
), and the groups:
provided that B is not benzhydryl when X is SO and R
1
is H;
R
5
is C
1-6
alkyl, C
2-6
alkenyl-R
7
, halogen, CN NO
2
, N(R
6
)
2
, OR
6
, COR
6
, CO
2
R
2
, CON(R
6
)
2
, NR
6
R
7
, S(O)
0-2
R
8
or SO
2
N(R
6
)
2
;
R
6
is H or a group selected from C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl, C
1-6
alkyl-heteroaryl, cycloalkyl, C
1-6
alkyl-cycloalkyl, heterocycloalkyl and C
1-6
alkyl-heterocycloalkyl, wherein said group is optionally substituted with R
8
, COR
8
, SO
0-2
R
8
, CO
2
R
8
, OR
8
, CONR
2
R
8
, NR
2
R
8
, halogen, CN, SO
2
NR
2
R
8
or NO
2
, and for each case of N(R
6
)
2
the R
6
groups are the same or different or N(R
6
)
2
is heterocycloalkyl optionally substituted with R
8
, COR
8
, SO
0-2
R
8
, CO
2
R
8
, OR
8
, CONR
2
R
8
, NR
2
R
8
, halogen, CN, SO
2
NR
2
R
8
or NO
2
;
R
7
is COR
6
, CON(R
6
)
2
, CO
2
R
8
or SO
2
R
8
;
R
8
is C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl or C
1-6
alkyl-heteroaryl; and R
9
is OR
6
, COR
6
, CO
2
R
2
, CON(R
6
)
2
, NR
6
R
7
, S(O)
0-2
R
8
, SO
2
N(R
6
)
2
, phthalimido, succinimido or the group
and the salts, solvates, hydrates, protected amino and protected carboxy derivatives thereof;
provided that the compound is not 3-phenylsulfonylpropanoic acid N-hydroxy amide.
Combinations of substituents and/or variables are only permissible if such combinations result in stable compounds.
DESCRIPTION OF THE INVENTION
Preferred compounds of the invention are those wherein any one or more of the following apply:
X is S, SO or SO
2
;
R
1
is H or a group (optionally substituted with R
9
) selected from C
1-6
alkyl, C
2-6
, alkenyl, C
1-6
alkyl-aryl, C
1-6
alkyl-heteroaryl, C
1-6
alkyl-heterocycloalkyl and C
1-6
alkyl-cycloalkyl;
B is C
1-6
alkyl-aryl, C
1-6
alkyl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, C
1-6
alkyl-heteroaryl, aryl or heteroaryl, any of which groups is optionally substituted by a substituent selected from R
5
, C
1-6
alkyl-R
5
, aryl (optionally substituted with R
5
), aryl-C
1-6
alkyl-R
5
, C
1-6
alkyl-aryl (optionally substituted with R
5
), C
1-6
alkyl-heteroaryl (optionally substituted with R
5
), heteroaryl (optionally substituted with R
5
), heteroaryl-C
1-6
alkyl-R
5
, heteroaryl-C
1-6
alkyl-R
5
cycloalkyl (optionally substituted with R
5
), benzofused cycloalkyl (optionally substituted with R
5
), heterocycloalkyl (optionally substituted with R
5
), benzofused heterocycloalkyl (optionally substituted with R
5
), and the groups:
R
5
is halogen, CN, NO
2
, N(R
6
)
2
, OR
6
, COR
6
, CON(R
6
)
2
, NR
6
R
7
, or S(O)
0-2
R
8
;
R
7
is COR
6
; and
R
9
is OR
6
, CO
2
R
2
, CON(R
6
)
2
, phthalimido, succinimido or the group
One group of compounds of the invention is represented by the formula (Ib)
B—X—(CH
2
)
n
—(CHR
1
—(CH
2
)
m
—COY (Ib)
wherein
m i 0;
n is 1;
X is SO
2
;
Y is NHOH;
R
1
is C
1-6
alkyl optionally substituted with R
9
;
R
2
is H or C
1-6
alkyl;
B is C
1-6
alkyl substituted by R
5
;
R
5
is OR
6
;
R
6
is a group selected from C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl, C
1-6
alkyl-heteroaryl, cycloalkyl, C
1-6
alkyl-cy
Baxter Andrew Douglas
Keily John Fraser
Montana John Gary
Owen David Alan
Watson Robert John
Darwin Discovery Ltd.
Gerstl Robert
Saliwanchik Lloyd & Saliwanchik
LandOfFree
Hydroxamic and carboxylic acid derivatives having MMP and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Hydroxamic and carboxylic acid derivatives having MMP and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydroxamic and carboxylic acid derivatives having MMP and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3076622