Arylsulfonyl Hydroxamic Acid derivatives as MMP and TNF...

Details Arylsulfonyl Hydroxamic Acid derivatives as MMP and TNF... Arylsulfonyl Hydroxamic Acid derivatives as MMP and TNF...

1998-09-17

2003-01-21

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252120, C514S255020, C514S318000, C514S330000, C544S131000, C544S159000, C544S383000, C544S384000, C546S194000, C546S225000

Reexamination Certificate

active

06509337

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to arylsulfonyl hydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (hereinafter also referred to as TNF) and as such are useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, sceritis and other diseases characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases involving the production of TNF.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor.
There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases. Matrix-degrading metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in tissue matrix degradation (e.g. collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and osteoporosis), tumor metastasis or invasion, as well as HIV-infection (
J. Leuk. Biol.,
52 (2): 244-248, 1992).
Tumor necrosis factor is recognized to be involved in many infectious and auto-immune diseases (W. Friers,
FEBS Letters,
1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al.,
Clinical Immunology and Immunopathology,
1992, 62 S11).
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula
or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond;
Y is carbon, oxygen, sulfur, sulfoxide, sulfone or nitrogen;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl optionally substituted by (C
1
-C
6
)alkylamino, (C
1
-C
6
,)alkylthio, (C
1
-C
6
)alkoxy, trifluoromethyl, (C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryl, (C
6
-C
10
)arylamino, (C
6
-C
10
)arylthio, (C
6
-C
10
)aryloxy, (C
5
-C
9
)heteroarylamino, (C
5
-C
9
)heteroarytti, (C
5
-C
9
)heteroaryloxy, (C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
3
-C
6
)cycloalykyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl(hydroxymethylene),piperazinyl,(C
6
-C
10
)aryl(C
1
-C
6
)alkoxy,(C
5
-C
9
)heteroaryl(C
1
-C
6
)alkoxy, (C
1
-C
6
)acylamino, (C
1
-C
6
)acylthio, (C
1
-C
6
)acyloxy, (C
1
-C
6
)alkylsulfinyl, (C
6
-C
10
)arylsulfinyl, (C
1
-C
6
)alkylsulfonyl, (C
6
-C
10
)arylsulfonyl, amino, (C
1
-C
6
)alkylamino or ((C
1
-C
6
)alkylamino)
2
; (C
2
-C
6
)alkenyl, (C
6
-C
10
)aryl(C
2
-C
6
)alkenyl, (C
5
-C
9
)heteroaryl(C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
6
-C
10
)aryl(C
2
-C
6
)alkynyl, (C
5
-C
9
)heteroaryl(C
2
-C
6
)alkynyl, (C
1
-C
6
)alkylamino, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkoxy, trifluoromethyl, (C
1
-C
6
)alkyl(difluoromethylene), (C
1
-C
3
)alkyl(difluoromethylene)(C
1
-C
3
)alkyl, (C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryl, (C
6
-C
10
)arylamino, (C
6
-C
10
)arylthio, (C
6
-C
10
)aryloxy, (C
5
-C
9
)heteroarylamino, (C
5
-C
9
)heteroarytthio, (C
5
-C
9
)heteroaryloxy, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkyl(hydroxymethylene), piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
1
-C
6
)acylamino, (C
1
-C
6
)acylthio, (C
1
-C
6
)acyloxy, R
13
(C
1
-C
6
)alkyl wherein R
13
is (C
1
-C
6
)acylpiperazino, (C
6
-C
10
)arylpiperazino, (C
5
-C
9
)heteroarylpiperazino, (C
1
-C
6
)alkylpiperazino, (C
1
-C
10
)aryl(C
1
-C
6
)alkylpiperazino,(C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperazino,morpholino,thiomorpholino, piperidino, pyrrolidino, piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
6
-C
10
)arylpiperidyl, (C
5
-C
9
)heteroarylpiperidyl, (C
1
-C
6
)alkylpiperidyl(C
1
-C
6
)alkyl, (C
6
-C
10
)arylpiperidyl(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroarylpiperidyl(C
1
-C
6
)alkyl or (C
1
-C
6
)acylpiperidyl;
or a group of the formula
 wherein
n is 0 to 6;
Z is hydroxy, (C
1
-C
6
)alkoxy or NR
14
R
15
wherein R
14
and R
15
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl optionally substituted by (C
1
-C
6
)alkylpiperidyl, (C
6
-C
10
)arylpiperidyl, (C
5
-C
9
)heteroarylpiperidyl, (C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl or (C
3
-C
6
)cycloalkyl; piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
6
-C
10
)arylpiperidyl, (C
5
-C
9
)heteroarylpiperidyl, (C
1
-C
6
)acylpiperidyl, (C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
3
-C
6
)cycloalkyl, R
16
(C
2
-C
6
)alkyl, (C
1
-C
5
)alkyl(CHR
16
)(C
1
-C
6
)alkyl wherein R
16
is hydroxy, (C
1
-C
6
)acyloxy, (C
1
-C,)alkoxy, piperazino, (C
1
-C
6
)acylamino, (C
1
-C
6
)alkylthio, (C
6
-C
10
)arylthio, (C
1
-C
6
)alkylsulfinyl, (C
6
-C
10
)arylsulfinyl, (C
1
-C
6
)alkylsulfoxyl, (C
6
-C
10
)arylsulfoxyl, amino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
1
-C
6
)acylpiperazino, (C
1
-C
6
)alkylpiperazino, (C
6
-C
10
)aryl(C
1
-C
6
)alkylpiperazino, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperazino,morpholino,thiomorpholino, piperidino or pyrrolidino; R
17
(C
1
-C
6
)alkyl, (C
1
-C
5
)alkyl(CHR
17
)(C
1
-C
6
)alkyl wherein R
17
is piperidyl or (C
1
-C
6
)alkylpiperidyl; and CH(R
18
)COR
19
wherein R
18
is hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylthio(C
1
-C
6
)alkyl, (C
6
-C
10
)arylthio(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfinyl(C
1
-C
6
)alkyl, (C
6
-C
10
)arylsulfinyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonyl(C
1
-C
6
)alkyl, (C
6
-C
10
)arylsulfonyl(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, ((C
1
-C
6
)alkylamino)
2
(C
1
-C
6
)alkyl, R
20
R
21
NCO(C
1
-C
6
)alkyl or R
20
OCO(C
1
-C
6
)alkyl wherein R
20
and R
21
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl and (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl; and R
19
is R
22
O or R
22
R
23
N wherein R
22
and R
23
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl and (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl;
or R
14
and R
15
, or R
20
and R
21
, or R
22
and R
23
may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (C
1
-C
6
)acylpiperazinyl, (C
1
-C
6
)alkylpiperazinyl, (C
6
-C
10
)arylpiperazinyl, (C
5
-C
9
)heteroarylpiperazinyl or a bridged diazabicydoalkyl ring selected from the group consisting of
 wherein
r is 1, 2 or 3;
m is 1 or 2;
p is 0 or 1; and
Q is hydrogen, (C
1
-C
3
)alkyl, (C
1
-C
6
)acyl or (C
1
-C
6
)alkoxy carbamoyl;
or R
1
and R
2
, or R
3
and R
4
, or R
5
and R
6
may be taken together to form a carbonyl;
or R
1
and R
2
, or R
3
and R
4
, or R
5
and R
6
, or R
7
and R
8
may be taken together to form a (C
3
-C
6
)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula
 wherein
R
24
is hydrogen, (C
1
-C
6
)acyl, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl or (C
1
-C
6
)alkylsulfonyl; and
Ar is (C
6
-C
10
)aryl or (C
5
-C
9
)heteroaryl, each of which may be optionally substituted by (C
1
-C
6
)alkyl, one or two (C
1
-C
6
)alkoxy, (C
6
-C
10
)aryloxy or (C
5
-C
9
)heteroaryloxy;
with the proviso that R
7
is other than hydrogen only when R
8
is other than hydrogen;
with the proviso that R
6
is other than hydrogen only when R
5
is other than hydrogen;
with the proviso that R
3
is other than hydrogen only when R
4
is other than hydrogen;
with the proviso that R
2
is other than hydrogen only when R

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