Therapeutic treatment for renal dysfunction

Details Therapeutic treatment for renal dysfunction Therapeutic treatment for renal dysfunction

1999-02-22

2001-05-01

Jordan, Kimberly (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06225301

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is broadly directed to a method for inhibiting intraglomerular hypertension, glomerulosclerosis, and glomerular-interstitial fibrosis, and especially such events associated with renal dysfunctions, e.g., acute and chronic renal failure. The present invention is particularly directed to the use of a particular class of isozyme selective Protein Kinase C (PKC) inhibitors for preventing and treating renal dysfunctions, e.g., renal insufficiency, acute and chronic renal failure, and complications associated with loss of renal function.
2. Description of Related Art
Over the past three decades, dialysis and transplantation have become effective treatment modalities in prolonging the life of patients with renal insufficiency. Such treatments, however, could be responsible for the appearance of unique abnormalities not seen prior to initiation of therapy, e.g., complications of dialysis. They could alter the disease process and create new disease conditions, e.g., loss of body weight, and premature atherosclerosis. Some symptoms resulting from impaired renal function may fail to respond fully to treatment, while others may even progress despite dialysis treatment.
As one can appreciate, there remains a need for additional options to the presently available treatments for renal dysfunctions, especially renal failure. In particular, there remains a need in the art to develop improved ways to treat renal dysfunctions, especially renal failure.
SUMMARY OF INVENTION
It is an object of the invention to provide a methods for inhibiting intraglomerular hypertension.
It is another object of the invention to provide a method for inhibiting glomerulosclerosis.
It is yet another object of the invention to provide a method for inhibiting glomerular-interstitial fibrosis.
It is still another object of the invention to provide a method for treating renal dysfunctions associated with intraglomerular hypertension, glomerulosclerosis or glomerular-interstitial fibrosis.
It is another object of the invention to provide a method for treating renal failure.
These and other objects of the invention are provided by one or more of the embodiments provided below.
In one embodiment of the invention there is provided a method for inhibiting intraglomerular hypertension, glomerulosclerosis, or glomerular-interstitial fibrosis, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a particular class of protein kinase C inhibitors.
In still another embodiment of the invention there is provided a method for treating renal dysfunctions associated with intraglomerular hypertension, glomerulosclerosis, or glomerular-interstitial fibrosis, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the protein kinase C inhibitor.
In still yet another embodiment of the invention there is provided a method for treating renal failure which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the protein kinase C inhibitor.
The present invention identifies compounds which are effective in treating renal dysfunctions, especially renal dysfunctions associated with intraglomerular hypertension, glomerulosclerosis, or glomerular-interstitial fibrosis in humans.
DETAILED DESCRIPTION OF THE INVENTION
It is a discovery of the present invention that the therapeutic use of a particular class of protein kinase C inhibitors, i. e., inhibitors of the P isozyme of protein kinase C, and especially P isozyme selective inhibitors of PKC, inhibits intraglomerular hypertension, glomerulosclerosis, and glomerular-interstitial fibrosis, and especially such events associated with renal dysfunctions. Consequently, such compounds can be used therapeutically to treat renal dysfunctions, especially renal dysfunctions associated with intraglomerular hypertension and/or hyperfiltration, e.g., renal insufficiency, acute and chronic renal failure, and complications associated with loss of renal function. The compounds can also be used prophylactively to prevent the onset of renal dysfunctions.
The method of this invention preferably utilizes those protein kinase C inhibitors that effectively inhibit the P isozyme. One suitable group of compounds are generally described in the prior art as bis-indolylmaleimides or macrocyclic bis-indolylmaleimides. Bis-indolylmaleimides well recognized in the prior art include those compounds described in U.S. Pat. Nos. 5,621,098, 5,552,396, 5,545,636, 5,481,003, 5,491,242, and 5,057,614, all incorporated by reference herein. Macrocyclic bis-indolylmaleimides are particularly represented by the compounds of formula 1. These compounds, and methods for their preparation, have been disclosed in U.S. Pat. No. 5,552,396, which is incorporated herein by reference. These compounds are administered in a therapeutically effective amount to a human to inhibit intraglomerular hypertension, glomerulosclerosis, and glomerular-interstitial fibrosis, or to treat renal dysfunctions. These compounds can also be administered to patients at risk of the disease conditions mentioned above as prophylactics.
One preferred class of compounds for use in the method of the invention has the formula (I):
wherein:
W is —O—, —S—, —SO—, —SO
2
—, —CO—, C
2
-C
6
alkylene, substituted alkylene, C
2
-C
6
alkenylene, -aryl-, -aryl(CH
2
)
m
O—, -heterocycle-, -heterocycle-(CH
2
)
m
O—, -fused bicyclic-, -fused bicyclic-(CH
2
)
m
O—, —NR
3
—, —NOR
3
—, —CONH—, or —NHCO—;
X and Y are independently C
1
-C
4
alkylene, substituted alkylene, or together X, Y, and W combine to form —(CH
2
)
n
—AA—;
R
1
s are hydrogen or up to four optional substituents independently selected from halo, C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, haloalkyl, nitro, —NR
4
R
5
, or —NHCO(C
1
-C
4
alkyl);
R
2
is hydrogen, CH
3
CO—, —NH
2
, or hydroxy;
R
3
is hydrogen, —(CH
2
)
m
aryl, -C
1
-C
4
alkyl, —COO(C
1
-C
4
alkyl), —CONR
4
R
5
, —(C═NH)NH
2
, —SO(C
1
-C
4
alkyl), —SO
2
(NR
4
R
5
), or —SO
2
(C
1
-C
4
alkyl);
R
4
and R
5
are independently hydrogen, C
1
-C
4
alkyl, phenyl, benzyl, or combine with the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring;
AA is an amino acid residue;
m is independently 0, 1, 2, or 3; and
n is independently 2, 3, 4, or 5,
or a pharmaceutically acceptable salt, prodrug or ester thereof
A more preferred class of compounds for use in this invention is represented by formula I wherein the moieties —X—W—Y— contain 4 to 8 atoms, which may be substituted or unsubstituted. Most preferably, the moieties —X—W—Y— contain 6 atoms.
Other preferred compounds for use in the method of this invention are those compounds of formula I wherein R
1
and R
2
are hydrogen; and W is a substituted alkylene, —O—, S—, —CONH—, —NHCO— or —NR
3
—. Particularly preferred compounds for use in the invention are compounds of the formula Ia:
wherein Z is —(CH
2
)
p
— or —(CH
2
)
p
—O—(CH
2
)
p
—; R
4
is hydroxy, —SH, C
1
-C
4
alkyl, (CH
2
)
m
aryl, —NH(aryl), —N(CH
3
) (CF
3
), —NH(CF
3
), or —NR
5
R
6
; R
5
is hydrogen or C
1
-C
4
alkyl; R
6
is hydrogen, C
1
-C
4
alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. Most preferred compounds of the formula Ia are those wherein Z is CH
2
; and R
4
is —NH
2
, —NH(CF
3
), or —N(CH
3
)
2
, or a pharmaceutically acceptable salt, prodrug or ester thereof.
Other preferred compounds for use in the method of the present invention are compounds wherein W in formula I is —O—, Y is a substituted alkylene, and X is an alkylene. These preferred compounds are represented by formula Ib:
wherein Z is —(CH
2
)
p
—; R
4
is —NR
5
R
6
, —NH(CF
3
), or —N(CH
3
) (CF
3
); R
5
and R
6
are independently H or C
1
-C
4
alkyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. Most preferred compounds of formula Ib are those wherein p i

Affiliated with

Also associated with

Rating

Therapeutic treatment for renal dysfunction does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Therapeutic treatment for renal dysfunction, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutic treatment for renal dysfunction will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2567019