Prophylactic or therapeutic drug for renal diseases

Details Prophylactic or therapeutic drug for renal diseases Prophylactic or therapeutic drug for renal diseases

2002-08-26

2004-02-03

Spivack, Phyllis G. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S361000, C514S364000, C514S394000

Reexamination Certificate

active

06686383

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a prophylactic or therapeutic drug containing an angiotensin II antagonistic compound or salt thereof as the active constituent, for diabetic nephropathy or glomerulonephritis.
BACKGROUND OF THE INVENTION
The kidneys are a major target organ of hypertension. Prolonged hypertension induces various renal impairments, mainly through renovascular lesions. Among them, contraction of renal vessels and degenerative lesions of elastic fibers lead to further elevation of the blood pressure. It is generally believed that hypertension raises renal intraglomerular pressure, which overloads the glomeruli, stimulating fibrosis and enlargement of the mesangial region, which advances to hardening of the glomeruli. In diabetic nephropathy as well, elevation in intraglomerular pressure is followed by trace albuminuria, progressing to the sclerosis of the glomeruli. Eventually, renal functions decline, resulting in chronic renal failure requiring artificial dialysis therapy. In recent years, 20% of patients with end-stage renal failure who commence artificial dialysis have diabetic nephropathy as the underlying disease. The number of patients likely to receive artificial dialysis tends to increase year after year, posing a critical problem in the medical care system. At present, it is said that there are few ideal pharmaceutical therapies for chronic renal failure, and even that blood-pressure-lowering therapy may aggravate rather than improve renal failure.
Angiotensin II antagonistic compounds are known as a therapeutic drug for cardiovascular diseases, e.g., hypertension, cardiac diseases (heart enlargement, heart failure, myocardial infarction, etc.), apoplexy, nephritis, etc. (European Patent Official Gazette (EPO) 459136A). The mechanism of their action is considered to be based on inhibition of binding to the angiotensin II receptor of angiotensin II, which possesses intense vasoconstrictive action. EP 459136A
1
describes the availability of angiotensin II antagonists in the treatment of nephropathy or nephritis.
Many data of clinical and experimental studies have been reported on the relation between renal diseases and hypertension. It is now established that the kidneys are directly or indirectly involved in the onset of hypertension, and also are apt to be affected by hypertension. However, hypertension in chronic glomerulonephritis has been poorly elucidated, particularly as to causative factors, effects of hypertension on the course of nephritis, and prophylactic effects of blood pressure lowering therapy.
Currently, nephritis is considered to be a clinical picture of different diseases with different entities. In accordance with the popularization of renal biopsy, renal diseases have been reviewed, resulting in their redefinition as a wide range of diseases characterized by proteinuria (“Shibata's Internal Medicine of the Kidneys,” by Seiichi Shibata, Bunkodo, 1988). Glomerulonephritis, once regarded as a single disease, has been differentiated into glomerulonephritis, chronic pyelonephritis, IgA nephropathy, periarteritis nodosa, gout, diabetes, systemic lupus erythematosus (SLE), hepatic infarction, hereditary renal disease, amyloidosis, and Wegener's sarcoma.
Diabetes associated with hypertension facilitates cardiovascular impairment and/or other organ complications, greatly affecting life expectancy. Accordingly, it is important to control blood pressure within the normal range during treatment, along with the control of diabetes and the improvement or prevention of arteriosclerosis.
OBJECT OF THE INVENTION
This invention provides a prophylactic or therapeutic drug for diabetic nephropathy or glomerular nephritis.
SUMMARY OF THE INVENTION
Under the above-mentioned circumstances, the inventors intensively studied to develop a drug for the prophylaxis or treatment of nephropathy or nephritis. Ultimately, they found that compounds possessing angiotensin II antagonistic action, represented by a particular structural formula, are very effective in the prophylaxis or treatment of diabetic nephropathy or glomerulonephritis. The present invention was thus accomplished.
Namely, this invention relates to a prophylactic or therapeutic drug for diabetic nephropathy or glomerulonephritis, containing, as the active constituent, a compound or salt thereof represented by formula (I):
(wherein R
1
stands for H or an optionally substituted hydrocarbon residue; R
2
stands for an optionally esterified carboxyl group; R
3
stands for a group actually or potentially capable of forming an anion; X shows that the phenylene and phenyl groups bind to each other directly or through a spacer having an atomic chain length of two or less; n stands for 1 or 2; ring A stands for a benzene ring having one or two optional substituents in addition to R
2
; Y stands for a bond, —O—, —S(O)
m
— (wherein m stands for 0, 1 or 2), or —N(R
4
)— (wherein R
4
stands for H or an optionally substituted alkyl group)).
DETAILED DESCRIPTION OF THE INVENTION
The invented compounds used for prophylactic or therapeutic purposes, as represented by formula (I), are structurally very prominently characterized by the coexistence of R
2
, standing for an optionally esterified carboxyl group, and R
3
, standing for a group actually or potentially capable of forming an anion. This structural characteristic contributes to the onset of very intense prophylactic or therapeutic effect on diabetic nephropathy or glomerulonephritis.
The compounds of this invention, possessing angiotensin II antagonistic action, represented by formula (I), can be favorably used in the prophylaxis or treatment of diabetic nephropathy or glomerulonephritis.
In formula (I), R
1
stands for H or an optionally substituted hydrocarbon residue.
Examples of the hydrocarbon residue represented by R
1
include alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl groups. Among them alkyl, alkenyl and cycloalkyl groups are preferable.
The alkyl group represented by R
1
is a straight chain or branched lower alkyl group having 1 to about 8 carbon atoms, as exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl or octyl.
The alkenyl group represented by R
1
is a straight chain or branched lower alkenyl group having 2 to about 8 carbon atoms, as exemplified by vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl or 2-octenyl.
The alkynyl group represented by R
1
is a straight chain or branched lower alkynyl group having 2 to about 8 carbon atoms, as exemplified by ethynyl, 2-propinyl, 2-butynyl, 2-pentynyl or 2-octynyl.
The cycloalkyl group represented by R
1
is a lower cycloalkyl group having 3 to about 6 carbon atoms, as exemplified by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The above mentioned alkyl, alkenyl, alkynyl or cycloalkyl group may optionally be substituted with hydroxyl group, an optionally substituted amino group (e.g. amino, N-lower (C
1-4
) alkylamino or N,N-dilower (C
1-4
) alkylamino), halogen, a lower (C
1-4
) alkoxy group, a lower (C
1-4
) alkylthio group.
The aralkyl group represented by R
1
is, for example, a phenyl-lower (C
1-4
) alkyl such as benzyl or phenethyl, and the aryl group represented by R
1
is, for example, phenyl.
The above mentioned aralkyl or aryl group may optionally have, on any position of its benzene ring, for example, halogen (e.g. F, Cl or Br), nitro, an optionally substituted amino group (e.g. amino, N-lower (C
1-4
) alkylamino or N,N-dilower (C
1-4
) alkylamino), lower (C
1-4
) alkoxy (e.g. methoxy or ethoxy), lower (C
1-4
) alkylthio (e.g. methylthio or ethylthio) or lower (C
1-4
) alkyl (e.g. methyl or ethyl).
Among the above mentioned groups represented by R
1
, optionally substituted alkyl, alkenyl or cycloalkyl groups (e.g. a lower (C
1-5
) alkyl, lower (C
2-5
) alkenyl or lower (C
3-6
) cycloalkyl group optionally substituted with hydroxyl group, amino group, halogen or a lower (C
1-4
) alkoxy group) are preferable.
Y stands for a bond, —O—, —S(O)
m
— (wherein m is 0, 1 or 2) or —N(R

Affiliated with

Also associated with

Rating

Prophylactic or therapeutic drug for renal diseases does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Prophylactic or therapeutic drug for renal diseases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Prophylactic or therapeutic drug for renal diseases will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3298981