Sulfonamide derivatives having oxadiazole rings

Details Sulfonamide derivatives having oxadiazole rings Sulfonamide derivatives having oxadiazole rings

2001-10-17

2002-12-17

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S340000, C548S131000, C546S269400

Reexamination Certificate

active

06495578

ABSTRACT:

TECHNICAL FIELD
This invention relates to sulfonamide derivatives having oxadiazole rings and metalloproteinase inhibitors containing the same.
BACKGROUND ART
An extracellular matrix, consisting of collagen, fibronectin, laminin, proteoglycan, etc., has a function to support tissues, and plays a role in propagation, differentiation, adhesion, or the like in cells. Metalloproteinases which are protease having a metal ion in the active center, especially matrix metalloproteinases (MMP), are concerned with the degradation of the extracellular matrix. Many types of MMP, from MMP-1 to MMP-23, have been reported as enzymes working for the growth, remodeling of tissues, etc. under usual physiological conditions. It is reported, however, that the progression of various kinds of diseases involving breakdown and fibrosis of tissues (e.g., osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (HIV infection)) is related with increase of the manifestation or activity of the above-mentioned enzyme. A number of MMP inhibitors tend to have a TNF-&agr; production inhibiting effect.
MMP inhibitors having an oxadiazole ring skeltone are described in WO99/04780.
Compounds, having a similar side chain to those of the present invention and a MMP inhibiting effect, are described in WO97/27174 and the like.
DISCLOSURE OF INVENTION
The inhibiting of such activities of MMP is considered to contribute to the improvement and prevention of the above diseases caused by or related to the activity. Therefore, the development of MMP inhibitors has been desired.
In the above situation, the inventors of the present invention have found that certain sulfonamide derivatives having oxadiazole rings have a potent activity to inhibit MMP.
The present invention relates to:
I) A compound of the formula (I):
 wherein
R
1
and R
2
are each independently hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R
3
is optionally substituted lower alkyl, optionally substituted cycloalkyl, lower alkyloxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted non-aromatic heterocyclic group, unsubstituted or substituted amino, or halogen;
X is —CH═CH—, —O—, or —S—; and
Y is —NHOH, hydroxy, or lower alkyloxy,
its optically active substance, its pharmaceutically acceptable salt, or its solvate.
In more detail, the invention relates to the following II)-XX).
II) A compound of the formula (II):
 wherein
R
1
, R
2
, X and Y are as defined in I):
R
4
is hydrogen atom, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, optionally substituted aralkyl, lower alkylsulfonyl, guanidino group, azo group, or optionally substituted ureide; and
Z is —CH═CH—, —O—, or —S—,
its optically active substance, its pharmaceutically acceptable salt, or its solvate.
III) A compound of the formula (III):
 wherein
R
1
, R
2
, X, and Y are as defined in I); and
R
5
is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, lower alkyloxy, unsubstituted or substituted amino, or halogen,
its optically active substance, its pharmaceutically acceptable salt, or its solvate.
Preferable a compound is, wherein X is —CH═CH— or —S—; R
5
is optionally substituted alkyl or optionally substituted aralkyl; R
1
is optionally substituted lower alkyl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl; R
2
is hydrogen atom; Y is hydroxy.
IV) A compound of any one of I)~III), wherein Z and X are each independently —CH═CH— or —S—, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
V) A compound of the formula (IV):
 wherein
R
1
, R
2
, and Y are as defined in I), and R
4
is as defined in II), its optically active substance, its pharmaceutically acceptable salt, or its solvate.
VI) A compound of the formula (V):
 wherein
R
1
, R
2
, and Y are as defined in I), and R
4
is as defined in II), its optically active substance, its pharmaceutically acceptable salt, or its solvate.
VII) A compound of the formula (VI):
 wherein
R
1
, R
2
, and Y are as defined in I), and R
4
is as defined in II), its optically active substance, its pharmaceutically acceptable salt, or its solvate.
VIII) A compound of the formula (VII):
 wherein
R
1
, R
2
, and Y are as defined in I), and R
4
is as defined in II), its optically active substance, its pharmaceutically acceptable salt, or its solvate.
IX) A compound of any one of I) to VIII), wherein Y is hydroxy, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
X) A compound of any one of I) to IX), wherein R
2
is hydrogen atom, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
XI) A compound of any one of I) to X), wherein R
1
is hydrogen atom, optionally substituted lower alkyl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
XII) A compound of any one of I)~XI), wherein R
1
is hydrogen atom, methyl, isopropyl, isobutyl, n-butyl, 2-methylthioethyl, phenylmethyl, or indol-3-ylmethyl, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
XIII) A pharmaceutical composition containing a compound of any one of I)~XII).
XIV) A composition for inhibiting metalloproteinase containing a compound of any one of I)~XII).
XV) A composition for inhibiting matrix metalloproteinase containing a compound of any one of I)~XII).
XVI) A composition for treating or preventing cancer which contains a compound of any one of I)~XII).
XVII) A composition for treating or preventing nephritis which contains a compound of any one of I)~XII)
XVIII) A composition for treating or preventing osteoarthritis which contains a compound of any one of I)~XII).
XIX) A composition for treating or preventing cardiac insufficiency which contains a compound of any one of I)~XII).
XX) A composition for treating or preventing rheumatoid arthritis which contains a compound of any one of claims I)~XII).
In the present specification, the term “lower alkyl” employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having 1 to 8 carbon atom(s). Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. C1 to C6 alkyl is preferred. C1 to C3 alkyl is more preferred.
The term “alkenyl” employed alone or in combination with other terms in the present specification means a straight- or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and at least one double bond. Examples of the alkenyl include vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like. C2 to C6 alkenyl is preferred. C2 to C4 alkenyl is more preferred.
The term “lower alkynyl” used in the present specification means a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond(s). Examples of the alkynyl include ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 6-heptynyl, 7-octynyl and the like. C2 to C6 alkynyl is preferred. C2 to C4 alkynyl is more preferred.
The term “cycloalkyl” used in the present specification include

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