Arylsulfonylamino hydroxamic acid derivatives

Details Arylsulfonylamino hydroxamic acid derivatives Arylsulfonylamino hydroxamic acid derivatives

1999-07-22

2001-10-16

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S210030, C546S225000, C548S953000

Reexamination Certificate

active

06303636

ABSTRACT:

The present invention relates to arylsulfonylamino 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, scieritis 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.
This 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. comeal, 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).
The present invention relates to a compound of the formula
or the pharmaceutically acceptable salts thereof, wherein
R
1
and R
2
are each independently selected from (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
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl or R
1
and R
2
may be taken together to form a (C
3
-C
6
)cycloalkyl or benzo-fused (C
3
-C
6
)cycloalkyl ring or a group of the formula
wherein n and m are independently 1 or 2 and X is CF
2
, S, O or NR
3
wherein R
3
is 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, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonyl, (C
6
-C
10
)arylsulfonyl or acyl; and
Q is (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl, (C
6
-C
10
)aryloxy(C
6
-C
10
)aryl, (C
5
-C
10
)aryl(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryloxy(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl(C
6
-C
10
)aryl, (C
1
-C
6
)alkyl(C
6
-C
10
)aryl, (C
1
-C
6
)alkoxy(C
6
-C
10
)aryl,(C
1
-C
10
)aryl(C
1
-C
6
)alkoxy(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryloxy(C
6
-C
10
)aryl, (C
1
-C
6
)alkyl(C
2
-C
9
)heteroaryl, (C
1
-C
6
)alkoxy(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryloxy(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryloxy(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryloxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl(C
6
-C
10
)aryloxy(C
6
-C
10
)aryl, (C
1
-C
6
)alkyl(C
2
-C
9
)heteroaryloxy(C
6
-C
10
)aryl, (C
1
-C
6
)alkyl(C
6
-C
10
)aryloxy(C
2
-C
9
)heteroaryl, (C
1
-C
6
)alkoxy(C
6
-C
10
)aryloxy(C
6
-C
10
)aryl, (C
1
-C
6
)alkoxy(C
2
-C
9
)heteroaryloxy(C
6
-C
10
)aryl or (C
1
-C
6
)alkoxy(C
6
-C
10
)aryloxy(C
2
-C
9
)heteroaryl wherein each aryl group is optionally substituted by fluoro, chloro, bromo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy or perfluoro(C
1
-C
3
)alkyl.
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 0-alkyl groups wherein “alkyl” is defined above.
The term “aryl”, as used herein, unless otherwise 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
)alkoxy, (C
6
-C
10
)aryloxy, trifluoromethoxy, difluoromethoxy and (C
1
-C
6
)alkyl.
The term “heteroaryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C
1
-C
6
)alkoxy, (C
6
-C
10
)aryloxy, trifluoromethoxy, difluoromethoxy and (C
1
-C
6
)alkyl.
The term “acyl”, as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms “alkyl” or “aryl” are as defined above.
The term “acyloxy”, as used herein, includes O-acyl groups wherein “acyl” is defined above.
The compound of formula I may have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
Preferred compounds of formula I include those wherein R
1
and R
2
are taken together to form a (C
3
-C
6
)cycloalkyl or benzo-fused (C
3
-C
6
)cycloalkyl ring or a group of the formula
wherein n and m are independently 1 or 2 and X is CF
2
, S, O or NR
3
wherein R
3
is 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, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonyl, (C
6
-C
10
)arylsulfonyl or acyl.
Other preferred compounds of formula I include those wherein R
1
and R
2
are taken together to form a (C
3
-C
6
)cycloalkyl or benzo-fused (C
3
-C
6
)cycloalkyl ring.
Other preferred compounds of formula I include those wherein Q is (C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
6
-C
10
)aryloxy(C
6
-C
10
)aryl, (C
6
-C
10
)aryloxy(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
2
-C
9
)heteroaryl (C
2
-C
9
)heteroaryl(C
5
-C
10
)aryl or (C
2
-C
9
)heteroaryloxy(C
6
-C
10
)aryl.
Other preferred compounds of formula I include those wherein Q is (C
6
-C
10
)aryloxy(C
6
-C
10
)aryl.
Other preferred compounds of formula I include those wherein R
1
and R
2
are each independently (C
1
-C
6
)alkyl.
More preferred compounds of formula I include those wherein R
1
and R
2
are taken together to form a (C
3
-C
6
)cycloalkyl or benzo-fused (C
3
-C
6
)cycloalkyl ring or a group of the formula
wherein n and m are independently 1 or 2 and X is CF
2
, S, O or NR
3
wherein R
3
is 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, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonyl, (C
6
-C
10
)arylsulfonyl or acyl; and Q is (C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryloxy(C
6
-C
10
)aryloxy(C
6
-C
10
)aryl, (C
6
-C
10
)aryloxy-(C
2
-C
9
)het

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