Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-30
2002-07-23
Gersil, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S131000
Reexamination Certificate
active
06423729
ABSTRACT:
TECHNICAL FIELD
This invention relates to a composition for treating or preventing glomerulopathy, especially glomerulonephritis and diabetic nephropathy, having a superior antiproteinuric effect and to a novel compound having superior inhibitory activity for type IV collagenase and an antiproteinuric effect and a composition containing it for treating or preventing.
BACKGROUND ART
A glomerulus is organized by epithelial cells, mesangial cells, endothelial cells, and epithelial cells of Bowman's capsule. The glomerulus filtrates blood to produce a glomerular filtrate containing substantially the same components as plasma components of which molecular weight is 10,000 or less. Generally, the filtration is controlled not to leak essential substances in blood, especially serum protein, to urine.
Glomerulus damage causes the growth of mesangial cells which are one of the glomerulus component cells and the expansion of a neighbor extracellular matrix to increase the amount of urinary protein excretion. It is known that the increase of urinary protein excretion further lowers the renal function by leading glomerulopathy to damage of renal tubules. Therefore, the inhibition of the urinary protein excretion is expected to improve various diseases associated with glomerulopathy. Such damage is derived from not only a primary disease but also a systemic disease such as diabetes. However, initiation and progression mechanisms remain uncertain and a fundamental method for treatment is not established.
As the present treating method, symptomatic therapies are carried out, but they have many problems. For example, the immunosuppressants are used for patients of nephritis because many types of nephritis are considered to be caused by immunologic mechanism, but nephrotoxicity occurs by the prolonged administration. Though steroids are also administered to the patients of nephritis, some nephritis are resistant to them. Recently, it is proved that angiotensin converting enzyme inhibitors (antihypertensive agents) are useful for nephritis. However, the medicament for nephritis without a hypotensive effect is required.
Accordingly, pharmacotherapy of glomerulopathy has been in a trial and error stage. The treatment of glomerulopathy is made more difficult by the fact that the cause of glomerulopathy is not all alike and clinical course full of variety can not easily be prospected.
As a treating agent for nephritis other than the above mentioned medicament, compounds described in JP-A-9-87176 are exemplified.
Compounds similar to those of the present invention are described in WO97/27174, EP0757984 A1, EP0757037 A2, WO97/45402, WO97/44315, WO96/00214, WO95/35276, and WO97/05865.
DISCLOSURE OF INVENTION
In the above situation, the inventors of the present invention have studied on the medicament which can inhibit the initiation and progression of glomerulopathy such as glomerulonephritis and diabetic nephropathy or decrease urinary protein excretion.
The inventors of the present invention made glomerulopathy model rats which leak urine proteins by using a nephritogenic antibody and searched for compounds inhibiting the initiation and progression of the damage of model rats. In result, the inventors of the present invention found that some sulfonamide derivatives inhibited the initiation and progression of glomerulopathy, especially glomerulonephritis and diabetic nephropathy through the inhibition of protein excretion and they are useful treating or preventing them.
The present invention relates to i) to xxxiv) represented below.
i) A composition for treating or preventing glomerulopathy which contains 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 heteroayl, or optionally substituted heteroarylalkyl;
R
3
is 1,4-phenylene or 2,5-thiophendiyl;
R
4
is a substituent represented by the formula:
wherein R
5
is hydrogen atom, hydroxy, optionally substituted lower alkyloxy, mercapto, lower alkylthio, cycloalkyl, halogen, carboxy, lower alkyloxycarbonyl, nitro, cyano, lower holoalkyl, aryloxy, optionally substituted amino, guanidino, optionally substituted lower alkyl, lower alkenyl, lower alkynyl, acyl, acyloxy, —CONR
A
R
B
, —N(R
C
)COR
D
(wherein R
A
, R
B
, and R
C
are the same or different selected from hydrogen atom, lower alkyl, or aralkyl; R
D
is lower alkyl, aryl, and aralkyl), optionally substituted non-aromatic heterocyclic group, or optionally substituted heteroaryl;
R
6
is optionally substituted lower alkyl, cycloalkyl, lower alkyloxy, halogen, lower alkylthio, optionally substituted amino, carboxy, lower alkyloxycarbonyl, aryloxy, phenyl, optionally substituted non-aromatic heterocyclic group, or optionally substituted heteroaryl; and
Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
ii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (II):
wherein R
1
, R
2
, and R
3
are as defined above:
R
7
is a substitution represented by the formula:
wherein R
8
is hydrogen atom, hydroxy, lower alkyloxy, mercapto, lower alkylthio, cycloalkyl, halogen, carboxy, lower alkyloxycarbonyl, nitro, cyano, lower haloalkyl, aryloxy, optionally substituted amino, guanidino, optionally substituted lower alkyl, lower alkenyl, lower alkynyl, alkanoyl, acyloxy, or optionally substituted heteroaryl;
R
9
is optionally substituted lower alkyl, cycloalkyl, carboxy, lower alkyloxycarbonyl, aryloxy, or phenyl; and
Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
iii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (I):
wherein R
1
, R
2
, and R
3
are as defined above;
R
4
is a substituent represented by the formula:
wherein R
10
is hydrogen atom, optionally substituted lower alkyloxy, lower alkylthio, halogen, optionally substituted amino, optionally substituted lower alkyl, or optionally substituted non-aromatic heterocyclic group;
R
11
is optionally substituted lower alkyl, lower alkylthio, halogen, optionally substituted amino, phenyl, optionally substituted non-aromatic heterocyclic group, or optionally substituted heteroaryl; and
Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
iv) A composition for treating or preventing glomerulopathy which contains a compound of the formula (II):
wherein R
1
, R
2
, and R
3
are as defined above;
R
7
is a substituent represented by the formula:
wherein R
12
is hydrogen atom, halogen, nitro, optionally substituted lower alkyl, lower alkyloxy, or lower alkylthio;
R
13
is optionally substituted lower alkyl or phenyl; and
Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
v) A composition for treating or preventing glomerulopathy which contains a compound of the formula (III):
wherein R
1
, R
10
, and Y are as defined above; and R
14
is hydrogen atom or lower alkyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
vi) A composition for treating or preventing glomerulopathy which contains a compound of the formula (IV):
wherein R
1
, R
12
, R
14
, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
vii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (V):
wherein R
1
, R
10
, R
14
, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
viii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (VI):
wherein R
1
, R
12
, R
14
, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
ix) A composition for treating or preventing glomerul
Kurihara Hidetake
Sinosaki Toshihiro
Tamura Yoshinori
Watanabe Fumihiko
Foley & Lardner
Gersil Robert
Shionogi & Co. Ltd.
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