Arylsulfonyl hydroxamic acid derivatives

Details Arylsulfonyl hydroxamic acid derivatives Arylsulfonyl hydroxamic acid derivatives

2000-11-08

2003-07-29

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S330000, C514S354000, C544S365000, C546S225000, C546S245000, C546S323000

Reexamination Certificate

active

06599890

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 (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. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (hereinafter NSAID'S) and analgesics for the treatment of arthritis, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, in the treatment of cancer.
The invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to 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. Fiers,
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;
X is carbon, oxygen, sulfur, SO, SO
2
or nitrogen;
Y is carbon, oxygen, sulfur, SO, SO
2
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, hydroxy, (C
1
—C
6
)alkyl optionally substituted by one or two groups selected from (C
1
—C
6
)alkylthio, (C
1
—C
6
)alkoxy, trifluoromethyl, halo, (C
6
—C
10
)aryl, (C
2
—C
9
)heteroaryl, (C
6
—C
10
)arylamino, (C
6
—C
10
)arylthio, (C
6
—C
10
)aryloxy, (C
2
—C
9
)heteroarylamino, (C
2
—C
9
)heteroarylthio, (C
2
—C
9
)heteroaryloxy, (C
6
—C
10
)aryl(C
6
—C
10
)aryl, (C
3
—C
6
)cycloalkyl, hydroxy, piperazinyl, (C
6
—C
10
)aryl(C
1
—C
6
)alkoxy, (C
2
—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
)alkyl)
2
amino; (C
2
—C
6
)alkenyl, (C
6
—C
10
)aryl(C
2
—C
6
)alkenyl, (C
2
—C
9
)heteroaryl(C
2
—C
6
)alkenyl, (C
2
—C
6
)alkynyl, (C
6
—C
10
)aryl(C
2
—C
6
)alkynyl, (C
2
—C
9
)heteroaryl(C
2
—C
6
)alkynyl, (C
1
—C
6
)alkylamino, (C
1
—C
6
)alkylthio, (C
1
—C
6
)alkoxy, perfluoro(C
1
—C
6
)alkyl, (C
6
—C
10
)aryl, (C
2
—C
9
)heteroaryl, (C
6
—C
10
)arylamino, (C
6
—C
10
)arylthio, (C
6
—C
10
)aryloxy, (C
2
—C
9
)heteroarylamino, (C
2
—C
9
)heteroarylthio, (C
2
—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
10
(C
1
—C
6
)alkyl or a group of the formula
wherein
n is 0 to 6;
y is 0 or 1;
W is oxygen or >NR
24
;
Z is —OR
11
, —NR
24
R
11
, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a bridged diazabicycloalyl 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
V is hydrogen, (C
1
—C
3
)alkyl, (C
1
—C
6
)alkyl(C═O)—, (C
1
—C
6
) alkoxy(C═O)—, (C
6
—C
10
)aryl(C═O)—, (C
6
—C
10
)aryloxy(C═O)—, (C
6
—C
10
)aryl(C
1
—C
6
)alkyl(C═O)—, (C
6
—C
10
)aryl-(C
1
—C
6
)alkoxy(C═O)—, or (C
1
—C
6
)alkoxy(C═O)—O—;
wherein each heterocyclic group (i.e., each Z cyclic group containing one or more heteroatoms) may optionally be independently substituted by one or two groups selected from hydroxy, (C
1
—C
6
)alkyl, (C
1
—C
6
)alkoxy, C
1
—C
10
)acyl, (C
1
—C
10
)acyloxy, (C
6
—C
10
)aryl, (C
2
—C
9
)heteroaryl, (C
6
—C
10
)aryl(C
1
—C
6
)alkyl, (C
2
—C
9
)heteroaryl(C
1
—C
6
)alkyl, hydroxy(C
1
—C
6
)alkyl, (C
1
—C
6
)alkoxy(C
1
—C
6
)alkyl, (C
1
—C
6
)acyloxy(C
1
—C
6
)alkyl, (C
1
—C
6
)alkylthio, (C
1
—C
6
)alkylthio(C
1
—C
6
)alkyl, (C
6
—C
10
)arylthio, (C
6
—C
10
)arylthio(C
1
—C
6
)alkyl, R
12
R
13
N—, R
12
R
13
NSO
2
—, R
12
R
13
N(C═O)—, R
12
R
13
N(C═O)—(C
1
—C
6
)alkyl, R
14
SO
2
—, R
14
SO
2
NH—, R
15
(C═O)—[N(R
12
)]—, R
16
O(C═O)—, or R
16
O(C═O)—(C
1
—C
6
)alkyl;
wherein R
10
is (C
1
—C
6
)acylpiperazinyl, (C
6
—C
10
)arylpiperazinyl, (C
2
—C
9
)heteroarylpiperazinyl, (C
1
—C
6
)alkylpiperazinyl, (C
6
—C
10
)aryl(C
1
—C
6
)alkylpiperazinyl, (C
2
—C
9
)heteroaryl(C
1
—C
6
)alkylpiperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, (C
1
—C
6
)alkylpiperidyl, (C
6
—C
10
)arylpiperidyl, (C
2
—C
9
)heteroarylpiperidyl, (C
1
—C
6
)alkylpiperidyl(C
1
—C
6
)alkyl, (C
6
—C
10
)arylpiperidyl(C
1
—C
6
)alkyl, (C
2
—C
9
)heteroaryl-piperidyl-(C
1
—C
6
)alkyl or (C
1
—C
6
)acylpiperidyl;
R
11
is hydrogen, (C
6
—C
10
)aryl, (C
2
-C
9
)heteroaryl, (C
6
—C
10
)aryl(C
1
—C
6
)alkyl, (C
2
—C
9
)heteroaryl(C
1
—C
6
)alkyl, (C
1
—C
6
)alkyl(C
6
—C
10
)aryl(C
1
—C
6
)alkyl(C
2
—C
9
)heteroaryl(C
1
—C
6
)alkyl, 5-indanyl, —CHR
17
O—(C═O)—R
18
or —CH
2
(C═O)—NR
19
R
20
;
R
12
and R
13
are each independently hydrogen, (C
1
—C
6
)alkyl, (C
6
—C
10
)aryl, C
2
—C
9
)heteroaryl, (C
6
—C
10
)aryl(C
1
—C
6
)alkyl or (C
2
—C
9
)heteroaryl(C
1
—C
6
)alkyl or R
12
and R
13
may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring;
R
14
is trifluoromethyl, (C
1
—C
6
)alkyl, (C
6
—C
10
)aryl, (C
2
—C
9
)heteroaryl, (C
6
—C
10
)aryl(C
1
—C
6
)alkyl or (C
2
—C
9
)heteroaryl(C
1
—C
6
)alkyl;
R
15
is hydrogen, (C
1
—C
6
)alkyl, (C
1
—C
6
)alkoxy, (C
6
—C
10
)aryl, (C
2
—C
9
)heteroaryl, (C
1
—C
6
)aryl(C
1
—C
6
)alkyl(C
6
—C
10
)aryl(C
1
—C
6
)alkoxy or (C
2
—C
9
)heteroaryl(C
1
—C
6
)alkyl;
R
16
is (C
1
—C
6
)alkyl, (C
6
—C
10
)aryl, (C
2
—C
9
)heteroaryl, (C
6
—C
10
)aryl(C
1
—C
6
)alkyl, 5-indanyl, —[CH(R
17
)]O—(C═O)—R
18
, —CH
2
(C═O)—NR
19
R
20
, or R
21
O(C
1
—C
6
)alkyl;
R
17
is hydrogen or (C
1
—C
6
)alkyl;
R
18
is (C
1
—C
6
)alkyl, (C
1
—C
6
)alkoxy or (C
6
—C
10
)aryl;
R
19
and R
20
are each independently hydrogen or (C
1
—C
6
)alkyl or may be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomopholinyl ring;
R
21
is H
2
N(CHR
22
)(C═O)—;
R
22
is the side chain of a natural D- or L-amino acid;
R
23
is hydrogen, (C
1
—C
6
)acyl, (C
1
—C
6
)alkyl, (C
6
—C
10
)aryl(C
1
—C
6
)alkyl, (C
2
—C
9
)heteroaryl(C
1
—C
6
)alkyl or (C
1
—C
6
)alkylsulfonyl;
R
24
wherever it occurs is independently hydrogen or (C
1
—C
6
)alkyl;
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,

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