Arylsulfonylamino hydroxamic acid derivatives

Details Arylsulfonylamino hydroxamic acid derivatives Arylsulfonylamino hydroxamic acid derivatives

2000-08-08

2002-04-30

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S223000, C562S430000, C562S622000

Reexamination Certificate

active

06380219

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to arylsulfonylamino 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, scleritis and other diseases characterized by matrix metalloproteinase activity, 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
or the pharmaceutically acceptable salts thereof, wherein
n is 1 to 6;
X is hydroxy, (C
1
-C
6
)alkoxy or NR
1
R
2
wherein R
1
and R
2
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
8
-C
10
)arylpiperidyl, (C
5
-C
9
)heteroarylpiperidyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkylpiperidyl, (C
5
-C
9
)heteroaryl,(C
6
-C
10
)aryl(C
1
-C
6
)alykyl,(C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl,(C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
5
-C
10
)aryl(C
6
-C
10
)aryl(C
1
-C
5
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, R
5
(C
2
-C
5
)alkyl, (C
1
-C
5
)alkyl(CHR
5
)(C
1
-C
5
)alkyl wherein R
5
is hydroxy, (C
1
-C
6
)acyloxy, (C
1
-C
6
)alkoxy, piperazino, (C
1
-C
6
)acylamino, (C
5
-C
10
)aryithio, (C
1
-C
5
)alkylsulfinyl, (C
5
-C
10
)arylsulfinyl, (C
1
-C
8
)alkylsulfoxyl, (C
6
-C
10
)arylsulfoxyl, amino, (C
1
-C
5
)alkylamino,((C
1
-C
5
)alkyl)
2
amino,(C
1
-C
5
)acylpiperazino, (C
1
-C
6
)aklylpiperazino, (C
6
-C
10
)aryl(C
1
-C
5
)alkylpiperazino, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino;R
5
(C
1
-C
6
)alkyl,(C
1
-C
5
)alkyl(CHR
5
)(C
1
-C
6
)alkyl wherein R
5
is piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
6
-C
10
)arylpiperidyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkylpiperidyl, (C
5
-C
9
)heteroarylpiperidyl or (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperidyl; and CH(R
7
)COR
8
wherein R
7
is hydrogen, (C
1
-C
5
)alkyl, (C
5
-C
10
)aryl(C
1
-C
5
)alkyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylthio (C
1
-C
5
)alkyl, (C
5
-C
10
)arylthio(C
1
-C
5
)alkyl, (C
1
-C
6
)alkylsulfinyl(C
1
-C
6
)alkyl, (C
5
-C
10
)arylsulfinyl(C
1
-C
6
)alkyl, (C
1
-C
5
)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
5
)alkylamino)
2
(C
1
-C
6
)alkyl,R
9
R
10
NCO(C
1
-C
6
)alkyl or R
9
OCO(C
1
-C
5
)alkyl wherein R
9
and R
10
are each independently selected from the group consisting of hydrogen, (C
1
-C
5
)alkyl, (C
5
-C
10
)aryl(C
1
-C
5
)alkyl and (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl; and R
8
is R
11
O or R
11
R
12
N wherein R
11
and R
12
are each independently selected from the group consisting of hydrogen, (C
1
-C
5
)alkyl, (C
5
-C
10
)aryl(C
1
-C
6
alkyl and (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl;
or R
1
and R
2
, or R
9
and R
10
, or R
11
and R
12
may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (C
1
-C
6
)acylpiperazinyl, (C
1
-C
5
alkylpiperazinyl, (C
5
-C
10
)arylpiperazinyl, (C
5
-C
9
)heterorarylpiperazinyl or a bridged diazabicycloalkyl 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 or (C
1
-C
6
)acyl;
R
3
and R
4
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, trifluoromethyl, trifluoromethyl(C
1
-C
6
)alkyl, 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
)aryl(C
1
-C
5
)alkyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl (C
5
-C
10
)aryl, (C
6
-C
10
)aryl(C
5
-C
10
)aryl(C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl (C
1
-C
5
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)acyloxy(C
1
-C
5
)alkyl, (C
1
-C
5
)alkoxy(C
1
-C
5
)alkyl, piperazinyl(C
1
-C
6
)alkyl,(C
1
-C
6
)acylamino(C
1
-C
5
)alkyl,piperidyl,(C
1
-C
6
)alkylpiperidyl, (C
5
-C
10
)aryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylthio(C
1
-C
5
)alkyl,(C
5
-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
5
)alkyl, (C
1
-C
6
)alkylsulfonyl(C
1
-C
6
)alkyl, (C
6
-C
10
)arylsulfonyl (C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, ((C
1
-C
5
)alkylamino)
2
(C
1
-C
5
)alkyl, R
13
CO(C
1
-C
5
)alkyl wherein R
13
is R
20
O or R
20
R
21
N wherein R
20
and R
21
are each independently selected from the group consisting of hydrogen, (C
1
-C
5
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
5
-C
9
)heteroaryl(C
1
-C
5
)alkyl; or R
14
(C
1
-C
5
)alkyl wherein R
14
is (C
1
-C
6
)acylpiperazino, (C
5
-C
10
)arylpiperazino, (C
5
-C
9
)heteroarylpiperazino, (C
1
-C
6
)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperidyl or (C
1
-C
6
)acylpiperidyl;
or R
3
and R
4
, or R
20
and R
21
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
15
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
)heteroary(C
1
-C
6
)alkyl or (C
1
-C
6
)alkylsulfonyl; and
Ar is (C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryl, (C
1
-C
6
)alkyl(C
6
-C
10
)aryl, (C
1
-C
5
)alkoxy (C
6
-C
10
)aryl, ((C
1
-C
6
)alkoxy)
2
(C
6
-C
10
)aryl, (C
5
-C
10
)aryloxy(C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryloxy(C
6
-C
10
aaryl, (C
1
-C
6
)alkyl(C
5
-C
9
)heteroaryl, (C
1
-C
6
)alkoxy (C
5
-C
9
)heteroaryl, ((C
1
-C
5
)alkoxy)
2
(C
5
-C
9
)heteroaryl, (C
6
-C
10
)aryloxy(C
5
-C
9
)heteroaryl, (C
5
-C
9
)heteroaryloxy(C
5
-C
9
)heteroaryl;
with the proviso that when either R
1
or R
2
is CH(R
7
)COR
8
wherein R
7
and R
8
are as defined above, the other of R
1
or R
2
is hydrogen, (C
1
-C
6
)alkyl or benzyl.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.
The term “aryl”, as used herein, unless other wise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C
1
-C
6
)alkocxy, (C
6
-C
10
)aryl

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