Hydroxamic and carboxylic acid derivatives

Details Hydroxamic and carboxylic acid derivatives Hydroxamic and carboxylic acid derivatives

2001-02-06

2004-01-20

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S336000, C514S330000, C514S428000, C546S282100, C546S226000, C548S566000, C549S425000

Reexamination Certificate

active

06680338

ABSTRACT:

FIELD OF THE 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. Al of these reported 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-9611209, WO-A-96035687, WO-A-9603571 1, WO-A-96035712 and WO-A-96035714.
WO-A-9834915 (published after the earliest priority date claimed herein) discloses compounds of formula I (below) wherein B is heterocycloalkyl (optionally substituted by R
6
or R
7
) bonded through carbon to X.
WO-A-9839315 (published after the earliest priority date claimed herein) discloses compounds of formula I (below) wherein R
4
is H and R
5
is unsubstituted C
1-6
alkyl, and B is C
1-8
alkyl optionally substituted by OR
7
.
SUMMARY OF THE INVENTION
The invention encompasses compounds of formula (I), many of which are novel, which are useful inhibitors of matrix metalloproteinases and/or TNF&agr;-mediated diseases, including degenerative diseases and certain cancers.
Compounds according to the invention are of the general type represented by formula (I):
B—X—(CH
2
)
n
—CR
2
R
3
—CR
4
R
5
—COY  (I)
wherein
n=0-1;
X is S(O)
0-2
;
Y is OR
1
or NHOH;
R
2
and R
4
are independently H or a group (optionally substituted with R
10
) 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; and
R
1
, R
3
and R
5
are independently H or C
1-6
alkyl;
provided that not more than two of R
2
, R
3
, R
4
and R
5
are H; or
any of CR
2
R
3
, CR
4
R
5
and CR
2
-CR
4
is a cycloalkyl or heterocycloalkyl ring optionally substituted with R
10
or a group (optionally substituted with R
10
) selected from C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl and C
1-6
alkyl-heteroaryl;
B is heterocycloalkyl (optionally substituted by R
6
or R
7
) bonded through carbon to X, or C
1-6
alkyl-heterocycloalkyl (optionally substituted with R
6
or R
7
), or a group (substituted with R
6
) selected from C
1-8
alkyl, C
2-6
alkenyl and C
2-6
alkynyl;
R
6
is N(R
7
)
2
, OR
7
, COR
7
, C(═NOR
9
)R
7
, NR
7
R
8
, S(O)
0-2
R
9
or SO
2
N(R
7
)
2
,
R
7
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
9
, COR
9
, SO
0-2
R
9
, CO
2
R
9
, OR
9
, CONR
1
R
9
, NR
1
R
9
, halogen, CN, SO
2
NR
1
R
9
or NO
2
, and for each case of N(R
7
)
2
the R
7
groups are the same or different or N(R
7
)
2
is heterocycloalkyl optionally substituted with R
9
, COR
9
, SO
0-2
R
9
, CO
2
R
9
, OR
9
, CONR
1
R
9
, NR
1
R
9
, halogen, CN, SO
2
NR
1
R
9
or NO
2
;
R
8
is COR
7
, CON(
7
)
2
, CO
2
R
9
or SO
2
R
9
;
R
9
is C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl or C
1-6
alkyl-heteroaryl; and
R
10
is OR
7
, COR
7
, CO
2
R
1
, CON(R
7
)
2
, NR
7
R
8
, S(O)
0-2
R
9
, SO
2
N(R
7
)
2
, CN, halogen or cycloimidyl (optionally substituted with R
1
);
and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.
Combinations of substituents and/or variables are only permissible if such combinations result in stable compounds.
DESCRIPTION OF THE INVENTION
Certain compounds of the invention are preferred. The following groups and variables are particularly preferred.
One group of compounds of the invention has the formula (I) wherein X, Y, n, R
2
, R
3
, R
4
and R
5
are as defined above and B is optionally substituted C
1-8
alkyl, C
2-6
alkenyl or C
2-6
alkynyl, especially an optionally substituted C
1-8
alkyl group, in particular ethyl or propyl, especially propyl. Compounds of this type are preferably substituted with R
6
, especially where R
6
is OR
7
. Particular R
7
groups are optionally substituted aryl or heteroaryl, especially, optionally substituted phenyl, pyridyl, furanyl or thiophenyl, especially optionally substituted phenyl. R
7
when substituted, is in particular substituted with R
9
, in particular phenyl, OR
9
, in particular OCH
3
, F, Cl, Br, I or CN. Particularly preferred substituents are phenyl, OCH
3
or Cl.
Another particular group of compounds of the invention has the formula (I) wherein X, Y, n, R
2
, R
3
, R
4
and R
5
are as defined above and B is an optionally substituted C
1-6
alkyl-heterocycloalkyl group. Especially preferred are those compounds wherein B the alkyl moiety in &bgr; is ethyl or propyl, especially ethyl, and the heterocycloalkyl moiety is optionally substituted azetidinyl, pyrrolidinyl or piperidinyl, especially optionally substituted pyrrolidinyl. Compounds of this type are preferably substituted with R
7
, especially when R
7
is optionally substituted aryl or heteroaryl. Particular R
7
groups are optionally substituted phenyl, pyridyl, furanyl or thiophenyl, especially optionally substituted phenyl. R
7
when substituted, is in particular substituted with OR
9
, in particular OCH
3
, F, Cl, Br, I, NO
2
or CN.
A further useful group of compounds has the formula (I) wherein X, Y, n, R
2
, R
3
, R
4
and R
5
are as defined above and B is optionally substituted heterocycloalkyl bonded through carbon to X, in particular optionally substituted azetidinyl, pyrrolidinyl or piperidinyl, especially piperidinyl. Compounds of this type are preferably substituted with R
7
, especially when R
7
is optionally substituted aryl or heteroaryl. Particular R
7
groups are optionally substituted phenyl, pyridyl, furanyl or thiophenyl, especially optionally substituted phenyl. R
7
when substituted, is in particular substituted with OR
9
, in particular OCH
3
, F, Cl, Br, I, NO
2
or CN. In compounds of the invention when B is optionally substituted heterocycloalkyl bonded through carbon to X and CR
4
R
5
is preferably an optionally substituted heterocycloalkyl group, then the CR
4
R
5
group is a saturated heterocyclic moiety having from two to six carbon atoms and one or more heteroatoms from the group O or S (or oxidised versions thereof) which may be optionally benzofused at any available position.
In general in compounds of the invention the most preferred compounds are those wherein any one or more of the following may apply:
X is SO
2
;
Y is NHOH; and
n is O.
R
2
or R
4
is preferably optionally substituted C
1-6
alkyl, C
1-6
alkyl-heteroaryl, or C
1-6
alkyl-heterocycloalkyl. In compounds of this type, R
4
and R
5
, or R
2
and R
4
, preferably form an optionally substituted cycloalkyl or heterocycloalkyl group, in particular, a cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl or piperidinyl group, especially cyclobutyl, cyclopentyl or cyclohexy

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