Sulfonated amino acid derivatives and metalloproteinase...

Details Sulfonated amino acid derivatives and metalloproteinase... Sulfonated amino acid derivatives and metalloproteinase...

2000-11-14

2002-08-27

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S496000

Reexamination Certificate

active

06441021

ABSTRACT:

TECHNICAL FIELD
This application relates to sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same.
1. Background Art
An extracellular matrix consists of collagen, proteoglycan, etc., has a function to support tissues, and plays a role in a maintaining of a cell functions, for example propagation, differentiation, adhesion, or the like. Matrix metalloproteinases (MMP) such as gelatinase, stromelysin, collagenase, and the like have an important role in degradation of an extracellular matrix, and these enzymes work for growth, tissue remodeling, etc. under physiological conditions. Therefore, it is considered that these enzymes participate in progression of various kind of diseases involving breakdown and fibrosis of tissues, such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (for example, HIV infection). At the present time, it is not clear which enzyme participates in the above diseases seriously, but it is considered that these enzymes at least participate in tissue breakdown. As metalloproteinase inhibitors of amino acid derivatives, for example hydroxamic acid derivatives of amino acids (JP-A-6-2562939), carboxylic acid derivatives of amino acid and/or their hydroxamic acid derivatives (WO95/35276), etc. are disclosed.
2. Disclosure of Invention
If it is able to inhibit the activity of MMP, it is considered that MMP inhibitors contribute to an improvement and prevention of the above diseases caused by or related to its activity. Therefore, development of MMP inhibitors has long been desired.
In the above situation, the inventors of the present invention found that a kind of sulfonamide derivatives have strong activity to inhibit MMP.
The present invention relates to a composition for inhibiting metalloproteinase which contains a compound of the formula I:
wherein R
1
is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R
2
is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R
3
is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R
4
is a bond, —(CH
2
)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(R
A
)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO
2
NH—, —SO
2
—NH—N═CH—, or tetrazol-diyl; R
5
is optionally substituted lower alkyl, optionally substituted C
3
-C
8
cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R
A
is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R
2
is hydrogen atom when Y is —NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
Mentioned in more detail, the invention relates to the following a)-b), 1)-16), and A)-C).
a) A composition for inhibiting metalloproteinase which contains a compound of the formula I:
 wherein R
1
is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R
2
is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R
3
is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R
4
is a bond, —(CH
2
)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(R
A
)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO
2
NH—, —SO
2
—NH—N═CH—, or tetrazol-diyl; R
5
is optionally substituted lower alkyl, optionally substituted C
3
-C
8
cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R
A
is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R
2
is hydrogen atom when Y is —NHOH, R
5
is optionally substituted aryl or optionally substituted heteroaryl when R
3
is optionally substituted arylene or optionally substituted heteroarylene and R
4
is CO—NH— or —NH—CO—, R
5
is optionally substituted aryl or optionally substituted heteroaryl when R
3
is optionally substituted arylene or optionally substituted heteroarylene and R
4
is tetrazol-diyl, R
5
is lower alkyl, aryl substituted by lower alkyl or optionally substituted aryl, or heteroaryl substituted by lower alkyl or optionally substituted aryl when R
3
is optionally substituted arylene and R
4
is a bond, both of R
3
and R
4
are not a bond at the same time, and R
4
is not —O— when R
3
is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
b) A composition for inhibiting metalloproteinase as mentioned above, which is a composition for inhibiting type-IV collagenase.
Preferred embodiment of the present invention are as follows.
1) A compound of the formula I:
 wherein R
1
is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R
2
is hydrogen atom, optionally substituted lower alkyl optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R
3
is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R
4
is a bond, —(CH
2
)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, N(R
A
)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO
2
NH—, —SO
2
—NH—N═CH—, or tetrazol-diyl; R
5
is optionally substituted lower alkyl, optionally substituted C
3
-C
8
cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R
A
is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R
2
is hydrogen atom when Y is —NHOH, R
5
is optionally substituted aryl or optionally substituted heteroaryl when R
3
is optionally substituted arylene or optionally substituted heterolene and R
4
is —CO—NH— or —NH—CO— (when R
3
is phenylene and R
4
is —CO—NH—, R
1
is not methyl or phenyl and R
5
is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R
5
is lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl when R
3
is alkyl, optionally substituted arylene or optionally substituted heteroarylene and R
4
is tetrazol-diyl, R
5
is lower alkyl, aryl substituted with lower alkyl or optionally substituted aryl, or heteroaryl substituted with lower alkyl or optionally substituted aryl when R
3
is optionally substituted arylene and R
4
is a bond, both of R
3
and R
4
are not a bond at the same time, and R
4
is not —O— when R
3
is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
2) A compound of the formula II:
 wherein R
6
is —CH═CH—, —C≡C—, —N═N—, —NH—CO—NH—, —S—, —SO
2
NH—, or —SO
2
—NH—N═CH—; R
7
is optionally substituted aryl or optionally substituted heteroaryl; R
8
and R
9
are each independently hydrogen atom, lower alkoxy, or nitro; R
1
, R
2
, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
3) A compound of the formula III:
 wherein R
10
is —(CH
2
)m—, —CO—, —CO—NH—, —N(R
A
)—, —NHCO—, or tetrazol-diyl; m is 1 or 2; R
1
, R
2
, R
7
, R
8
, R
9
, R
A
, and Y are as defined above, provided R
1
is not methyl or phenyl and R
7
is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when R
10
is —NH—CO—, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
4) A compound of the formula IV:

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