Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-27
2001-09-11
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S258100
Reexamination Certificate
active
06288067
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions for preventing and/or treating drug-induced renal injury, comprising as an active ingredient a compound of the formula (I):
wherein R
1
and R
2
each represents a hydrogen atom or taken together with each other represent a single bond, while R
3
represents —CH(OH)CH(OH)CH
3
, —CH(OCOCH
3
)CH(OCOCH
3
)CH
3
, —CH
3
, —CH
2
OH or a phenyl group when R
1
and R
2
each represents a hydrogen atom, or —COCH(OH)CH
3
when R
1
and R
2
together represent a single bond, or a pharmaceutically acceptable salt thereof.
Clinically, drug-induced renal injury is principally manifested as nephrotic syndrome (or proteinuria in milder cases) and renal dysfunction. For example, glomerulopathy represented by membranous neuropathy induced by gold drugs is manifested as nephrotic syndrome, while tubular disorder induced by nephrotoxic agents represented by cisplatin is manifested as acute renal failure. Transport disorder specifically occurring in the renal tubules presents with clinical conditions such as Fanconi syndrome, renal tubular acidosis, renal diabetes insipidus, etc. Acute interstitial nephritis induced by methicillin or the like is manifested as renal dysfunction. Thus, drug-induced renal injury presents with various clinical conditions dependent on the type of the drug or the affected site (Medical Practice, vol. 14, No. 8, 1997, p. 1273).
For example, cyclosporin A is an immunosuppressive agent commonly used during transplantation, but causes renal injury at an incidence of 50% or more dependent on the blood concentration of the drug because of its high nephrotoxicity. Renal injury induced by cyclosporin A has various phenotypes including acute renal failure, chronic renal failure, hemolytic uremic syndrome, thrombotic microangiopathy, hypertension, electrolyte imbalance (such as hyperkalemia, metabolic acidosis, hypomagnesemia), etc. Acute renal failure is required to be identified by renal biopsy due to the difficulty in discriminating the condition from acute rejection. A decreased glomerular filtration rate (GFR) during the early stage of administration is attributed to-enhancement of the renin-angiotensin system, stimulation of the sympathetic nerve system, increased production of thromboxane A
2
and the effect of endothelin. On the other hand, patients with renal transplants often develop chronic renal failure caused by long-term administration of cyclosporin, which is difficult and sometimes impossible to discriminate from chronic rejection even by renal biopsy. Tissue injury induced by cyclosporin mainly involve endothelial cells disorder ranging from interlobar artery to afferent arterioles wherein said tissue injury principally cause renal sclerosis, interstitial cell invasion and fibrosis. Moreover, hypomagnesemia often occurs during cyclosporin administration, and extreme hypomagnesemia may cause systemic seizure under the influence of cyclosporin (“ZINZOUGAKU”, Approach from Renal Pathophysiology, ed. Kurokawa, K., Nankodo, pp. 419-428, 1995).
Vascular endothelium has been known to play an important role in vascular tonus or thrombopoiesis, and in 1980 the presence of endothelium-derived relaxing factor (EDRF) was first reported. The entity of EDRF was proved to be nitric oxide (NO) in 1987. NO is a gaseous radical and has been shown to readily pass through cell membranes and have a wide variety of effects such as circulation control, neurotransmission, inhibition of platelet aggregation, antibacterial or anticancer effect. NO not only controls metabolism by reacting with heme enzyme or SH enzyme groups, but also has physiological functions and pathological activity by crosstalking with active oxygen species such as superoxide (O
2
−
), SH compounds, ascorbic acid or the like. However, its in vivo molecular entity is still unknown in many respects because all of these molecules are unstable.
NO having a wide variety of effects as described above is produced when L-arginine is oxidized from N
G
-hydroxyl-L-arginine into L-citrulline and the reaction is catalyzed by an enzyme called NO synthase (NOS). NOS has isoforms including vascular endothelial-type, cerebellar-type, and inducible-type. The vascular endothelial-type mainly exists in the vascular endothelium and kidney, while the cerebellar-type exists in the nervous system. The inducible-type exists in macrophages or the like induced during inflammation or tissue injury. The gene for each of these isoforms has already been cloned and structurally analyzed. As a result, the gene for NOS was found to contain a binding site for (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as “BH4”) included in compounds of the formula (I) as active ingredients of the present invention, in addition to those for coenzymes such as calmodulin (CaM), flavin, NADPH. Moreover, BH4 has been suggested to actually be involved in control of the function of NOS.
Thus, the vasorelaxing effect of NO and the control of NOS functions by BH4 have been somewhat known. However, the relationship of effects of NO and NOS activity with drug-induced renal injury has not been explained, and nothing has been known about the relationship between drug-induced renal injury and endogenous BH4.
The purpose of preventing or treating drug-induced renal injury is not only to prevent or treat renal injury but also to permit the use of drugs responsible for renal injury so that patients may enjoy a prolonged and higher quality of life. However, any improvement in diseases or conditions of drug-induced renal injury can not be expected at present, because acute renal failure requires discontinuation of drug administration in order to allow renal function to recover and chronic renal failure requires dialysis or renal transplantation. Thus, no therapy for drug-induced renal injury has been established yet and neither a prophylactic or therapeutic agent therefor exists at present. As a result, drugs which are completely satisfactory in terms of side effects, safety during long-term use and improvement in QOL (quality of life) are in great demand.
Thus, therapeutic agents satisfying truly desirable conditions are required, and the development of prophylactic agents having a renal protective action is also in great demand.
The compounds of the formula (I) as active ingredients in pharmaceutical compositions of the present invention are known compounds for use in therapeutic agents against malignant hyperphenylalaninemla, depression, Parkinson's disease, etc. For example, see Japanese Patent Public Disclosure (KOKAI) Nos. 25323/84, 76086/84, 277618/86 and 267781/88.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a safe pharmaceutical composition for drug-induced renal injury without side effects, which improves circulation and organic functions by controlling the functions of endothelial cells, retards the progress of complications and improves the quality of life of patients.
The inventors have found abnormal functions of NOS in cyclosporin-induced renal injury rats prepared as a model of drug-induced renal injury. The inventors also have found an increased NOS activity level and an increased BH4 level in said cyclosporin-induced renal injury rats. As a result of various studies, we unexpectedly have found that BH4 administration recovers the functions of endothelial cells and normalizes the functions of NOS to give physiologically very natural and excellent renal protective effects, and thus accomplished the present invention. Accordingly, the present invention relates to effective prevention or treatment with BH4 preparations for drug-induced renal injury.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition for preventing or treating drug-Induced renal injury, comprising as an active ingredient a compound of the formula (I):
wherein R
1
and R
2
each represents a hydrogen atom or taken together with each other represent a single bond, while R
3
represents —CH(OH)CH(OH)CH
Kanayama Yoshiharu
Okamura Mikio
Shintaku Haruo
Yoshikawa Junichi
Krass Frederick
Pillsbury & Winthrop LLP
Suntory Limited
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