DESCRIPTION
Therapeutic Agent for Chronic Renal Failure
TECHNICAL FIELD
The present invention relates to a therapeutic agent for chronic renal failure
which has a non-prostanoid skeleton and contains a PGl2-receptor agonist as an
effective ingredient.
BACKGROUND ART
Recently, the number of patients who need dialysis because of a decrease in
renal function tends to increase year by year. The reasons therefor include changes
in the living environment, aging and the increase in the number of patients suffering
from diabetic nephropathy due to the increase in the number of patients suffering
from diabetes mellitus in recent years.
Renal failure is the state wherein excretion of nitrogen metabolites, water
and/or electrolytes is insufficient due to blood flow obstruction in kidney, decreased
functional nephron and/or obstruclion of the urinary tract, leading to incapability to
maintain quantitative and qualita. ve homeostasis of the body fluid. Renal failure
includes acute renal failure and chronic renal failure, and both of these show
increases in blood urea nitrogen (BUN) and serum creatinine. However, since they
show large differences in the speed of progress of the diseased state and in
reversibility of the decrease in renal function, they are evidently different diseases.
Acute renal failure suddenly occurs and progresses daily (with an increase in the
serum creatinine level by not less than 0.5 mg/dl. per day as a criterion), but. by
removal of its cause, sufficient whole-body control and appropriate conservative
treatment or dialysis treatment, recovery of renal function can be basically expected
(Non-patent Document 1). On the other hand, establishment of chronic renal failure
requires a long period of time. That is, when a renal disease which may cause
glomerulonephritis or diabetic nephropathy has gradually progressed year by year
resulting in evident increases in BUN and the serum creatinine level, the patient is
diagnosed with chronic renal failure. At this time point when the increase in the
serum creatinine level is observed, the filtering function for low-molecular waste
products, which is the most important function of the kidney, is remarkably
decreased; the glomerular filtration rate is not more than 50%; and the decrease in
renal function is irreversible. After the establishment of chronic renal failure, renal
function gradually decreases for several years, and. when the glomerular filtration
rate has decreased to not more than 10%, the chronic renal failure is in the terminal
stage, and dialysis or renal transplantation is necessary. Therefore, in therapy of
chronic renal failure in the conservative stage, it is important to delay the timing of
the transition to dialysis as much as possible (Non-patent Documents 2 and 3).
Examples of the causative diseases of chronic renal failure include
nephropathic diseases such as primary renal diseases; renal disorders due to systemic
diseases; congenital renal diseases; renal infections; renal disorders due to
nephrotoxic substances; and obstructive diseases of the urinary tract. Among these,
examples of the major causative diseases include chronic glomerulonephritis.
diabetic nephropathy. chronic pyelonephritis, nephrosclerosis and cystic kidney.
Especially, the ratios of chronic glomerulonephritis, diabetic nephropathy and
nephrosclerosis are high, and. because of the drastic increase in the number of
patients suffering from diabetes mellitus in recent years, the ratio of chronic renal
failure whose causative disease is diabetic nephropathy has significantly increased.
In chronic renal failure, clinical symptoms such as pulmonary congestion and
congestive heart failure due to decreased urine output; neurological and psychotic
symptoms due to progress of uremia; anemia due to a decrease in erythropoictin
produced in the kidney; and electrolyte imbalances such as hyponatremia and
hyperkalemia; as well as digestive symptoms, abnormal bone metabolism and
abnormal sugar metabolism, are commonly observed independently of the causative
disease of the chronic renal failure.
Further, it is said that chronic renal failure has a common mechanism of
progression which is independent of its primary disease. For example, in a
commonly used textbook of internal medicine, there is the following description: "In
general, in chronic renal failure, progression of chronic renal failure is observed even
during a period when the primary disease is suppressed, so that a common
mechanism of the decrease in renal function other than the cause of each renal
disease is considered to exist." (Non-patent Document 4).
Further, chronic renal failure is known to show common clinical symptoms
even in cases where the causative underlying disease is different. That is. it is said
that "Irrespective of whether the disease is primary or secondary, most renal diseases
with a chronic process result in an irreversible decrease in renal function after
progression of the diseased state, and then become to be called chronic renal failure.
This diseased state finally leads to a type of syndrome called uremia, in which the
difference depending on the type of the underlying disease is hardly observed and
common clinical symptoms appear." i'Mon-patent Document 5).
Further, it is said that, in the pathological findings of the kidney, "kidneys of
patients suffering from temwtttl-end-stage chronic renal failure show common tissue
images in most cases even in cases where the patients have different underlying
diseases, and therefore pathological diagnosis of the underlying diseases are often
difficult." (Non-patent Document 6).
Thus, although there are various possible causative diseases of chronic renal
failure, it is a characteristic disease distinguishable from the other renal diseases,
since it shows characteristic clinical symptoms different from the other renal
diseases; it has a common mechanism of progression of the diseased state which is
different from that of the primary disease; it shows characteristic findings which do
not reflect its causative disease in the pathological findings; and its therapy requires a
therapeutic method specific to chronic renal failure.
During the conservative stage before beginning dialysis, therapy of chronic
renal failure is based on diet therapies including low protein diets and high-calorie
diets, and also includes restriction of salt and water as well as usage of an
antihypertensive drug for management of hypertension, which is a risk factor for
exacerbation of chronic renal failure. Further, to slow down progression of the
diseased state or to ameliorate uremia, oral activated carbon adsorbent preparations
may be used in some cases. However, in spite of these therapies, progression of
renal failure cannot be well prevented at present, and the number of patients who
require hemodialysis because of onset of uremic symptoms due to progression of
renal function disorder is consistently increasing. The survival rate of chronic renal
failure patients who began dialysis has been improved by virtue of the recent
progress in hemodialysis therapy, but there still remain many problems including not
only the requirement of 2 to 3 times per week of hospital visit, but also onset of
complications of long-term dialysis, infections, increased risks of onset of
cardiovascular disturbances, high medical cost and the like. Especially in cases
where the patient began dialysis because of diabetic nephropathy. the five-year
survival rate is as small as not more than 50% (Non-patent Document 7).
As mentioned above, in chronic renal failure patients, various complications
characteristic to chronic renal failure occur. Among these, anemia, which develops
and is exacerbated as renal function decreases, is especially problematic. Anemia
begins to develop when blood urea nitrogen (BUN) and blood creatinine begin to
increase, and almost all the cases of dialysis patients and the like in vho iem>m;d si • ¦.-
develop-afteRHaend-sf;ige renal failure, which then causes hypobulia. easy fatigability.
breathlessness, postural vertigo and the like, leading to remarkable decreases in QOL
of the patients.
Previously, transfusion was carried out for therapy of anemia due to chronic
renal failure, but therapy with a recombinant erythropoietin preparation (rlluliPO
preparation) has now become commonly carried out. However, problems such as
the fact that therapy with this preparation needs hospital visit and accompanies pain
because it is administered subcutaneously, and existence of drug-resistant patients
due to occurrence of autoantibody have been pointed out for this therapy. Therefore,
a prophylactic or therapeutic agent for anemia due to chronic renal failure, which can
be easily administered, whose dosing management can be carried out at home, and
whose side effects are small, is demanded.
In recent years, significant involvement of active oxygen in progression of
chronic renal failure and exacerbation of complications of chronic renal failure has
been pointed out. Superoxide dismutase (this may be hereinafter abbreviated as
SOD) is widely distributed in the living bodies of animals, plants, microorganisms
and the like, and especially important among the enzymes which decompose
superoxide anion radicals (this may be hereinafter abbreviated as (X) which are
higWy-hiuhlv-reactive active oxygens. In chronic renal failure, the SOD activity
contained in the kidney or liver decreases, and the decrease is strongly involved in
decreased renal function and onset and exacerbation of complications of chronic
renal failure such as cardiovascular disturbances, which are caused by active oxygens
(Non-patent Document 8).
In chronic renal failure, low-molecular substances (uremic substances) which
accumulate in the living body as renal function decreases cause development of
clinical symptoms characteristic to chronic renal failure, which leads to exacerbation
of cardiovascular disturbances and a further decrease in renal function. Indoxyl
sulphate is a low-molecular substance produced by the process wherein indole
produced in the intestine from tryptophan is absorbed into the living body, followed
by being metabolized in the liver. Since indoxyl sulphate is excreted mainly from
the kidney, efficient excretion is impossible in chronic renal failure because of the
decrease in renal function, so that the blood level of indoxyl sulphate increases.
Recent interest has focused on indoxyl sulphate as one of the causative substances
responsible for exacerbation of various complications of chronic renal failure and
exacerbation of cardiovascular disturbances due to endothelial dysfunction (Non-
patent Document 9). It is also known that indoxyl sulphate itself is involved in
exacerbation of renal disorders (Non-patent Document 10).
Indoxyl sulphate is actively excreted via OAT-3, which is an organic anion
transporter existing mainly in the renal tubules, and it is known that OAT-3 decreases
in chronic renal failure (Non-patent Document 11).
Further, it is known that the blood levels of various drugs, especially those of
the renal excretion type, more easily increase in chronic renal failure compared to
healthy individuals. Therefore, in many cases, in chronic renal failure patients.
occurrence of side effects of drugs is more frequent and determination of appropriate
doses of drugs is difficult. Decreases in drug transporters in the kidney are involved
in such phenomena as one of the mechanisms thereof.
Thus, in treatment of chronic renal failure patients, it is important not only to
suppress the decrease in the renal function to filtrate low-molecular substances, but
also to suppress anemia and the increase in active oxygen caused as complications of
the chronic renal failure as much as possible, as well as to prevent the decrease in the
transporters which occurs with the renal disorder as much as possible.
Prostaglandin (PG) is a group of naturally-occurring compounds which show
various physiological activities, and has the prostanoic acid skeleton in common.
The naturally-occurring PGs are grouped, based on the structural features of their
five-membered rings, into the PGAs, PGBs. PGCs. PGDs. PGEs. PGI-'s. PGGs.
PGHs, PGIs and PGJs. and further grouped into subclasses such as 1. 2 and 3 based
on the existence of unsaturation and/or oxidation. Further, their many synthetic
analogues are known. PGI2. which is typical among the PGI derivatives, is also
called prostacyclin, and known to be a substance having a strong platelet aggregation
inhibition action and peripheral vasodilator action.
It is already known that PGI2 and several compounds among the derivatives
thereof are effective for disease model animals for glomerulonephritis and diabetic
nephropathy, and are clinically effective. However, such findings on PGI? and
derivatives thereof are intended for primary diseases without onset of chronic renal
failure. At this stage, renal disorder is evaluated with the urine protein and/or the
urinary microalbumin. which increase as the barrier function of the glomerular
basement membrane in the kidney to macromolecules is deteriorated. The
pharmacological effects are also evaluated based on the decreases in these parameters.
Further, effectiveness of PGI2 derivatives in chronic renal failure has also
been reported (Patent Documents 1 to 10, Non-patent Documents 12 to 15). lor
example, results with m-phenylene PGI2 derivatives including beraprost sodium have
been reported, which results were obtained using a model rat subjected to partial
nephrectomy and a model rat suffering from chronic renal failure which was prepared
by administration of an anti-basement membrane antibody and whose primary
disease was nephritis (Patent Document 1 and Non-patent Document 12). For
accurate evaluation of renal function in chronic renal failure, glomerular filtration
rate (GFR), which is a marker of the renal function to filtrate'low-molecular
substances, or, as an alternative, eGFR (estimated GFR: estimated glomerular
filtration rate ) or creatinine clearance is used, and, in addition, the serum creatinine
level or BUN, which increases as the renal function to filtrate low-molecular
substances decreases, is used. Also in Patent Document 1 and Non-patent
Document 12, the serum creatinine level and BUN are used as indices for evaluation
of the pharmacological effects. That is, in these rat models, occurrence of chronic
renal failure defined with a serum creatinine level and BUN higher than their normal
levels was confirmed, followed by beginning administration of a compound of an m-
phenylene PGI2 derivative. Thereafter, it was shown that increases of the markers
for chronic renal failure, that is, the serum creatinine level and the BIN value, were
suppressed compared to those in the control group.
In Patent Document 13, it is described that a PGI2 derivative cicaprost
ameliorated microalbuminuria in a canine mild chronic renal failure model, but this
evaluation was carried out using the model wherein GFR was maintained at a level of
82% with respect to the normal level, so that the model had not developed chronic
renal failure, with which GFR is expected to be not more than 50%. Further, the
effect found was merely a decrease in microalbuminuria, which is a reversible change.
rather than amelioration of the renal function to filtrate low-molecular substances.
It has been reported that, in chronic renal failure patients, administration of
beraprost sodium reduced the rate of decrease in renal function, which is indicated by
decrease in the creatinine clearance or in the reciprocal of serum creatinine (Non-
patent Literature 14). It is described that a PGb derivative treprostinil ameliorated
renal function in view of urine production in chronic renal failure patients, but the
observation was carried out merely on diuresis, and whether or not chronic renal
failure is ameliorated has not been shown (Patent Document 2).
It has been shown that hypoxemia may promote production of erythropoietin
via an increased production of renal endogenous PGE2 and PGh (Non-patent
Document 15). Although the kidney is under hypoxic condition in chronic renal
failure and hence productions of endogenous PGE2 and PGI2, as well as
erythropoietin, are considered to increase, severe anemia is problematic. The reason
for this is not clear, but it is considered that, in renal failure, the ameliorating effect
by the mechanism according to this literature may not function sufficiently.
In terms of the ameliorating effect on anemia by PGI2 or a derivative [hereof.
results showing amelioration of anemia in long-term dialysis patients have been
reported only for beraprost sodium (Non-patent Document 16). However, what this
literature shows is amelioration of anemia in long-term dialysis patients wherein
most kidney cells have lost their intrinsic functions. The amelioration of anemia in
a chronic renal failure rat model in the present invention is amelioration of anemia in
chronic renal failure in the conservative stage, wherein a part of the cellular functions
in the kidney is maintained, so that the diseased state is different from that in the
above literature. Thus, the extent of the effect of beraprost sodium in chronic renal
failure in the conservative stage cannot be assumed from this literature, and there is
no disclosure about this in the literature, so that no remarkable difference in the effect
can be assumed among PGIi derivatives. Further, an ameliorating effect o\'
beraprost sodium on uremia has been reported for chronic renal failure patients.
Although anemia is described as one of the particular complications of uremia, there
is no description on a particular ameliorating effect of administration of beraprost on
anemia (Patent Document 3).
Further, administration of PGI2 or a derivative thereof increases the
erythrocytic SOD activity in gastric mucosa of rat and in human systemic sclerosis
patients having Raynaud's symptoms (Non-patent Documents 17 and 18), but there is
no suggestion at all on whether or not the administration increases the renal SOD
activity and whether or not the effect is different among PGI2 and derivatives thereof
in chronic renal failure in which the target organ and the disease are totally different.
Further, it has not been known that the administration suppresses decreases in renal
organic anion transporters in renal failure.
All of cicaprost, m-phenylene PGI2 derivatives, especially beraprost sodium.
and further, treprostinil, which are compounds used in the above-mentioned
literatures, are PGh derivatives produced by improvement of instability of naturally
occurring PGI2.
On the other hand, in recent years, PGIi-receptor agonists having a non-
prostanoid skeleton have begun to be developed.
It has been pointed out that, among these, compounds represented by the
General Formula below:
have the PGl2-receptor agonistic activity and show the antiplatelet action, vasodilator
action, bronchodilator action and the like, and that these may be useful for diseases
such as transient cerebral ischemic attack, diabetic neuropathy, diabetic gangrene and
peripheral circulatory disturbance. Further, in the Examples of this Patent
Document, it has been confirmed that the compounds have the antiplaielct action
which is an index for the PGl2-receptor agonistic activity. It is described, in this
Patent Document, that the compounds represented by the above General Formula are
useful as therapeutic agents for glomerulonephritis and diabetic nephropathy.
similarly to the other PG^-receptor agonists (Patent Document 4).
However, there is no description at all on characteristic and remarkable
effectiveness of the compounds represented by the above General Formula as
therapeutic agents for especially chronic renal failure among renal diseases.
Further, in Patent Documents 5 to 10, it is disclosed that PGIi-recepior
agonists having non-prostanoid skeletons can be used for renal failure, but there is no
description at all on characteristic and remarkable effectiveness of the agonists as
therapeutic agents for chronic renal failure.
That is, there is neither description nor suggestion on the fact that usage of the
above compounds as therapeutic agents for chronic renal failure ameliorates the renal
function to filtrate low-molecular substances; ameliorates anemia as a significant
complication of chronic renal failure; and further, increases the activity of SOI)
which plays a central role in removal of active oxygen; and/or suppresses decrease in
the organic anion transporters responsible for active excretion of urcmic substances.
PRIOR ART REFERENCES
PATENT DOCUMENTS
Patent Document 1: WO 2000/067748
Patent Document 2: WO 2005/058329
Patent Document 3: WO 2007/007668
Patent Document 4: WO 2002/088084
Patent Document 5: WO 1997/03973
Patent Document 6: WO 1999/21843
Patent Document 7: WO 1999/32435
Patent Document 8: WO 2001/016132
Patent Document 9: WO 2004/034965
Patent Document 10: .IP 2000-191523 A
NON-PATENT DOCUMENTS
Non-patent Document 1: Kenjiro Kimura et al. eds., "Lecture Transcript:
Renal Medicine, 1st Ed.", Medical View Co., Ltd., 2004, p. 270, 11. 1 to 10.
Non-patent Document 2: Kenjiro Kimura et al. eds., "Lecture Transcript:
Renal Medicine, 1st Ed.", Medical View Co., Ltd., 2004, pp. 274-275.
Non-patent Document 3: Masaomi Nangaku, Folia Pharmacol Jpn. 1 18:68-70.
2001.
Non-patent Document 4: "Hyper Reference for Internal Medicine", Nakayama
Shoten Co.t, Ltd., 1997.
Non-patent Document 5: Kiyoshi Kurokawa ed., "Nephrology - Approach
from Pathophysiology", Nankodo Co., Ltd., 1995. p. 345, left column. 11. 1 to 7.
Non-patent Document 6: Kiyoshi Kurokawa ed., "Nephrology - Approach
from Pathophysiology", Nankodo Co., Ltd., 1995. p. 347, left column. II. 3 to 5.
Non-patent Document 7: Villar E, et al., .1 Am Soc Nephrol, 18: 2125-2134.
2007.
Non-patent Document 8: Vaziri ND. et al.. Kidney Int. 63: 179-185. 2003.
Non-patent Document 9: Dou L, et al., Kidney Int, 65: 442-45 1. 2004.
Non-patent Document 10: Enomoto A. et al., Ther ApherDial. 1 1 Supple 1:
S27-31.2007.
Non-patent Document 11: Villar SR, et al., Kidney Int, 68: 2704-2713. 2005.
Non-patent Document 12: Yamada M, et al., Eur J Pharmacol. 449: 167-1 76.
2002.
Non-patent Document 13: Villa E, et al.. Am J Hypertens. 6: 253-257. 1993.
Non-patent Document 14: Fujita T, et al.. Prostaglandins Leukot EssentFatty
Acids, 65:223-227. 2001.
Non-patent Document 15: Kiyoshi Kurokawa ed., "Nephrology - Approach
from Pathophysiology". Nankodo Co., Ltd., 1995. pp. 48-49.
Non-patent Document 16: Hidekazu Moriya, Abstract for Meeting of
Japanese Society for Dialysis Therapy, 0-425, 2006.
Non-patent Document 17: Zsoldos T, et al., Acta Physiol Hung. 64: 325-330.
1984.
Non-patent Document 18: Balbir-Gurman A, et al.. Gin Rheumatol. 26:
1517-1521.2007.
DISCLOSURE OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
Since, in a chronic renal failure patient, irreversible decrease in the renal
function to filtrate low-molecular substances occurs, it is demanded to slow down the
decrease to extend the period before introduction of dialysis as much as possible.
Further, suppression of anemia as a complication which occurs with progression of
chronic renal failure, and suppression of increase in oxidative stress as a cause of
cardiovascular disturbances and vascular endothelial cell dysfunction need to be
achieved as effectively as possible. Still further, amelioration of uremia caused by
chronic renal failure and overcoming of increase in, and difficulty in control of. the
blood levels of drugs observed in chronic renal failure need to be achieved. The
present invention aims to provide a therapeutic agent for, and a method for treatment
of, chronic renal failure to improve these problems.
MEANS FOR SOLVING THE PROBLEMS
The above problems can be solved with a therapeutic agent for chronic renal
failure containing as an effective ingredient a compound represented by General
Formula (1) which is a PGh-receptor agonist, or a pharmaceutically acceptable salt
thereof.
That is, the present invention is:
[1] a therapeutic agent for chronic renal failure containing as an effective ingredient:
a compound represented by General Formula (1) below:
[wherein
R1 and R2 each independently represents aryl;
A represents NR\ O. S. SO or SO2;
Rn represents C'i-C6 alkyl, C2-C6 alkenyl or CYCfi cycloalkyl:
D represents C2-Q, alkylene or alkenylene;
G represents O, S, SO or SO2;
R3 and R4 each independently represents hydrogen or C|-C6 alkyl; and
Q represents carboxyl. C1-C6 alkoxycarbonyl. tetrazolyl or General Formula
(2) below:
(wherein R6 represents C1-C6 alkyl)]
or a pharmaceutically acceptable salt thereof;
[2] the therapeutic agent for chronic renal failure according to [1], wherein
R1 and R2 represent phenyl;
R'"1 represents C|-C6 alkyl;
D represents CVQ, alkylene;
G represents O;
R and R4 represent hydrogen; and
Q represents carboxyl or General Formula (2);
[3] the therapeutic agent for chronic renal failure according to [1] or [2], wherein
A represents NR";
R' represents CyCf, branched alkyl;
D represents butylene; and
Q represents carboxyl or General Formula (2):
[4] the therapeutic agent for chronic renal failure according to any one of [ 1 ] to 13].
wherein
R' represents isopropyl; and
Q represents carboxyl or General Formula (2):
[5] the therapeutic agent for chronic renal failure according to any one of 11 | to |4|.
wherein
Q represents carboxyl;
[6] the therapeutic agent for chronic renal failure according to any one of \ 1 ] to |5].
wherein the chronic renal failure is in the conservative stage; and
[7] a therapeutic method for treatment of chronic renal failure, which method uses
the compound according to any one of [1] to [5] or a pharmaceuticallv acceptable salt
thereof.
EFFECT OF THE INVENTION
By beginning administration of a compound represented by General Formula
(1) or a pharmaceutically acceptable salt thereof (this may be hereinafter referred to
as "compound of the present invention") after a renal disease progressed to cause
chronic renal failure, not only suppression of decrease in the renal function to filtrate
low-molecular substances, but also recovery of the function can be achieved.
Further, since the compound of the present invention has effects to improve anemia
which is a complication unique to chronic renal failure; as well as to increase the
SOD activity, which decreases in chronic renal failure; and to suppresses decrease in
OAT-3 involved in excretion of uremic substances; the compound of the present
invention can ameliorate cardiovascular disturbances and vascular endothelial cell
dysfunction due to chronic renal failure.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows serum creatinine values in a group of rats suffering from chronic
renal failure to which the sodium salt of Compound 1 was administered.
Fig. 2 shows BUN in a group of rats suffering from chronic renal failure to
which the sodium salt of Compound 1 was administered.
Fig. 3 shows creatinine clearance in a group of rats suffering from chronic
renal failure to which the sodium salt of Compound 1 was administered.
Fig. 4 shows changes in the plasma level of Compound 1 after oral
administration of Compound 1 and Compound 2.
BEST MODE FOR CARRYING OUT THE INVENTION
Examples of the "aryl" in the compound represented by General Formula (1)
include phenyl. 1-naphthyl and 2-naphthyl.
Examples of the "C|-Cc alkyl" include methyl, ethyl, n-propyl. isopropyl. n-
butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl. isopentyl. n-hexyl and isohexvl.
Examples of the "C:-C6 alkenyl" include vinyl, 1-propenyl, 2-propenyl. 1-
butenyl, 2-butenyl, 3-butenyl. 1-pentenyl, 2-pentenyl. 3-pentenyl. 4-pentenyl. 4-
methyl-3-pentenyl. 1-hexenyl. 2-hexenyl, 3-hexenyl. 4-hexenyl and 5-hexenyl.
Examples of the "CyCf, cycloalkyl" include cyclopropyl, cyclobutyl.
cyclopentyl and cyclohexyl.
Examples oi'the "C2-C6 alkylene" include ethylene, 1-methylethylene. 2-
methylethylene, propylene. butylene, pentylene and hexylene.
Examples of the "C2-Q-, alkenylene" include ethenylene. 1-propenylene. 2-
propenylene, 1-butenylene, 2-butenylene, 3-butenylene. 1-pentenylene. 2-pentenylene.
3-pentenylene, 4-pentenylene. 4-methyl-3-pentenylene. 1-hexenylene. 2-hexenylene.
3-hexenylene, 4-hexenylene and 5-hexenylene.
Examples of the "Ci-C^, alkoxy" in the "Ci-C^, alkoxycarbonyl" include
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy. tcrt-
butoxy, n-pentyloxy. isopentyloxy, n-hexyloxy and isohexyloxy.
Examples of the "pharmaceutical ly acceptable salt" of the compound oi'the
present invention include, in cases where the compound represented by General
Formula (1) is basic, salts of inorganic acids such as hydrochloric acid, sulfuric acid.
nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid: and salts of
organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid.
maleic acid, succinic acid, methanesulfonic acid, naphthalenesulfonic acid and
camphorsulfonic acid.
Examples of the "pharmaceutically acceptable salt" of the compound of the
present invention include, in cases where the compound represented by General
Formula (1) is acidic, alkaline metal salts such as the sodium salt and the potassium
salt; and alkaline earth metal salts such as the calcium salt.
Among the compounds represented by General Formula (1), Compound 1.
wherein R1 and R" represent phenyl; A represents NR/: R? represents isopropyl: 1)
represents butylene; G represents O; R and R4 represent hydrogen; and Q represents
carboxyl; or a pharmaceutically acceptable salt thereof is most suitably used.
Compound 1
Further, among the compounds described above, compounds wherein
carboxyl corresponding to Q in General Formula (1) is replaced with its equivalent
Ci-Cf, alkoxycarbonyl (e.g.. methoxycarbonyl), tetrazolyl or General Formula (2) are
also especially suitably used. In particular, General Formula (2) wherein Rfl
represents C|-C6 alkyl is preferred, and Compound 2, wherein R6 represents C| alkyl
(methyl), is especially preferably used.
Compound 2
"Chronic renal failure" in the present invention means a state wherein renal
filtration function gradually decreases for a long period of time and the functional
abnormality persists over a long time. More particularly, it can be said to be a
condition or a syndrome wherein blood urea nitrogen (BUN) and the serum
creatinine value are high or increase persistently. This definition is essential!}
equivalent to the definitions in the textbooks described in the BACKGROUND ART
section. More concretely, in the case of human, patients who show a serum
creatinine value of not less than 1.4 mg/dL based on measurement by the enzyme
method, which value is observed for not less than 1 month, can be securely diagnosed
with chronic renal failure. In other animal species, the absolute value of serum
creatinine may vary, but those can be diagnosed as having developed chronic renal
failure when the value is higher than the normal range.
"Chronic renal failure in the conservative stage" in the present invention
means, in chronic renal failure, the stage before temmaJ-end-staec" chronic renal
failure wherein maintenance of life is impossible without dialysis or renal
transplantation. The present invention can be especially effectively employed for
chronic renal failure in the conservative stage, in which most of the renal functions
are decreased but still remain.
Further, the present invention can be especially effectively employed in cases
where creatinine clearance. eGFR, or glomerular filtration rate (GFR) actually
measured by the inulin clearance method or the like is less than 60 mL/min.'1.73 n\~
in human, or in cases where these indices decreased to not more than 50% with
respect to the normal values in animals. The present invention can be preferably
employed also in cases where, in human, renal function decreased to less than 40
mL/min./1.73 m2 or less than 30 mL/min./1.73 m~.
Examples of the causative disease of chronic renal failure in the present
invention include all the nephropathic diseases such as primary renal diseases: renal
disorders due to systemic diseases; congenital renal diseases; renal infections: renal
disorders due to nephrotoxic substances; and obstructive diseases of the urinary tract.
Particular examples thereof include, but are not limited to, chronic
glomerulonephritis; diabetic nephropathy; chronic pyelonephritis; acute progressive
nephritis; gestosis; cystic kidney; nephrosclerosis; malignant hypertension: renal
disorders due to various collagen diseases such as SLE; amyloid kidney; gouty
kidney; metabolic disorder renal failure; tuberculosis; nephrolithiasis: kidney/urinary
tract malignant tumors; obstructive uropathy; myeloma; and renal hypoplasia.
The renal failure whose treatment (this may be represented as ¦'therapy") is
possible by the present invention is chronic renal failure, especially chronic renal
failure in the conservative stage. The present invention has an effect not only to
improve decreased filtration function of the kidney, but also to improve
cardiovascular disturbances and endothelial cell dysfunction which are especially
problematic in chronic renal failure, by improving anemia and increasing the SOD
activity.
"Anemia" in the present invention means anemia which occurs with chronic
renal failure. More particularly, anemia can be diagnosed by a decreased
erythrocyte count, hematocrit and/or hemoglobin content, and/or the like, and it is
known that its incidence increases as the stage progresses after the renal function
disorder stage.
Since, by the present invention, prophylaxis or therapy of anemia due to
chronic renal failure is possible, clinical symptoms such as hypobulia. easy
fatigability, breathlessness. postural vertigo and palpitation can be ameliorated.
Further, since the therapeutic agent of the present invention can be orally
administered, pain caused by subcutaneous injection can be avoided, and the agent
can be easily taken every day at home without visiting a hospital, so that anemia can
be securely ameliorated and various symptoms due to anemia can be controlled.
The ameliorating effect by the present invention on decrease in the SOD
activity which is observed in chronic renal failure was revealed for the first time.
Since SOD plays a central role in reduction/removal of oxidative stress in the living
body, amelioration of further decrease in renal function due to increased oxidative
stress can be expected in the present invention. Further, amelioration of
cardiovascular events such as vascular dysfunction and vascular endothelial cell
dysfunction, which are known to increase due to chronic renal failure, by the present
invention can be expected.
In the present invention, it was revealed that the compound of the present
invention suppresses decrease in OAT-3, an organic anion transporter in a major
excretion pathway for indoxyl sulphate which is important as a uremic substance.
Therefore, it is expected that administration of the compound of the present invention
may suppress decrease in excretion of indoxyl sulphate. Further, in cases where
anion transporters are involved in excretion of an agent, side effects of the agent can
be reduced by suppression of increase in its blood level, and an appropriate dose of
the agent can be easily determined.
Thus, since the compound of the present invention shows the effects of
amelioration of anemia, increase in renal SOD and suppression of decrease in drug
transporters in chronic renal failure, the compound of the present invention has
extremely preferable traits as an agent to be used for chronic renal failure.
The compound of the present invention can be produced by a known method,
for example, the one described in WO 2002/088084.
Further, in the present invention, the therapeutic agent may contain not less
than two kinds of compounds of the present invention, or may contain another
prostaglandin I2 derivative as mentioned above and/or a known therapeutic agent for
a renal disease. Examples of such an agent include angiotensin converting enzyme
inhibitors and angiotensin II receptor blockers, as well as antihypertensive drugs such
as calcium blockers and P blockers. Further, the therapeutic agent of the present
invention may be preferably used in combination with an antiplatelet drug such as
persantin or dipyridamole; a statin whose therapeutic effect has been reported for
renal diseases; and/or the like, or may be prepared as a mixture therewith.
Further, since the compound of the present invention can be used for
treatment of anemia due to chronic renal failure, it is also possible to use it in
combination with a rHuEPO preparation and/or an iron preparation, thereby enabling
to increase the dosing interval and to reduce the side effects of the rHuliPO
preparation and/or the iron preparation. Further, preparation of a mixture with such
preparations; and usage with another SOD preparation and/or oxidative stress
inhibitor, and preparation of a mixture therewith: are also possible.
The present invention can be used effectively especially in mammals. It can
be used in human, and can also be used for therapy of non-human mammals,
preferably pet animals such as dog, cat, rabbit, rat and guinea pig. Further, the
present invention can be used as a therapeutic method for treatment of chronic renal
failure.
In cases where the therapeutic agent of the present invention for chronic renal
failure is used in human, the suitable dose is 1 to 10000 ug/adult, preferably 5 to
5000 |ig/adult per administration in terms of the amount of the compound
represented by Formula (1) as an active ingredient, which is administered 1 to 4
times per day for 1 day or longer, preferably for not less than 3 days.
In cases where the therapeutic agent of the present invention is used in a non-
human mammal, the suitable dose is 0.1 u.g/kg to 100 mg/kg, preferably 1 ug/kg to
50 mg/kg in terms of the amount of the compound represented by Formula (1) as an
active ingredient, which is administered 1 to 4 times per day for 1 day or longer.
preferably for not less than 3 days.
The administration method may be any administration method, and examples
thereof include, but are not limited to, oral administration, subcutaneous
administration, intravenous and intravascular administration, intramuscular
administration, pulmonary administration, intraduodenal administration and
intraperitoneal administration. Further, a method wherein the drug is directly
administered to a damaged area in a tissue or organ showing an especially remarkable
damage, which administration is carried out in a direct manner or after being
impregnated in an appropriate base, is also preferably used.
In cases where the therapeutic agent of the present invention for chronic renal
failure contains a known therapeutic agent for chronic renal failure as an additional
component, the above-described dose may be reduced in consideration of the action
and effect of the additional component.
As the therapeutic agent of the present invention for chronic renal failure, one
or several kinds of derivatives may be used as they are. or these may be orally
administered in the form of a solid containing the additives described below.
Examples of the additives include excipients such as starches, lactose, sucrose,
glucose, mannitol. calcium carbonate and calcium sulfate; binders such as starches,
dextrin, gum arabic. gum tragacanth, methyl cellulose, gelatin, polyvinyl pyrrolidone
and polyvinyl alcohol; disintegrating agents such as starches, polyvinyl pyrrolidone
and crystalline cellulose; lubricants such as magnesium stearate and talc; coloring
agents; and flavoring agents.
The therapeutic agent of the present invention for chronic renal failure can be
used in various dosage forms, and particular examples thereof include dosage forms
which are conventionally used, such as tablets, sugar-coated tablets, powders,
granules, troches, capsules, balls, syrups and sprays. Further, the therapeutic agent
of the present invention may be parenterally administered in the form of a sterilized
solution, and another solute, such as sodium chloride or glucose necessary to make
the agent solution isotonic. may also be used .
Depending on the characteristics of the respective drugs, release controls such
as those attaining sustained release or delayed release may be applied. In such cases.
a wide variety administration methods may be employed for both oral and parenteral
administration, and examples thereof include a method using an implantable pump
for sustained-releasing (for example, Alzet minipump) and a method using the drug
dispersed in a biodegradable polymer which is gradually degraded in the intestinal
tract.
EXAMPLES
The present invention will now be described in more detail by way of
Examples below, but the present invention is not restricted to these Examples.
Example 1
Platelet Aggregation Inhibition Action in Rat
(Experimental Method)
To determine the dose with which the PG^-receptor agonistic activity is
equivalent between the sodium salt of Compound 1 and beraprost sodium, the
platelet aggregation inhibition action which is the major pharmacological action of
PGh-receptor agonists was used as an index for comparison. The sodium salt of
Compound 1 (30 mg/kg) or beraprost sodium (0.3 mg/kg) was orally administered to
rats fasted for 1 day, and blood was collected therefrom at the time when the plasma
level of each compound became maximum, that is, 1 hour after the administration of
the sodium salt of Compound 1 (Non-patent Document: J Pharmacol Exp Ther
322:1181-1188 2007) or 0.5 hour after the administration of beraprost sodium (Non-
patent Document: Xenobiotic Metabolism and Disposition 6:713-725 1989).
followed by measuring ADP-induced rat platelet aggregation. In the both groups,
the experiment was carried out with n=6. The sodium salt of Compound 1. which
was one of the PGh-receptor agonists used herein, was synthesized by treating a
carboxylic acid with sodium hydroxide, which carboxylic acid was synthesized
according to the method described in Patent Document 4.
(Results)
The rate of suppression of rat platelet aggregation upon stimulation with 10
uM ADP was 47.0±7.9% in the group to which the sodium salt of Compound 1 was
administered, and 64.2±8.3% in the group to which beraprost sodium was
administered, showing that beraprost sodium has a stronger tendency of suppression,
but there was no statistical difference between these (t test). As a result, it was
revealed that the sodium salt of Compound 1 at a dose of 30 mg/kg shows an almost
equivalent PG^-receptor agonistic activity with beraprost sodium at a dose of 0.3
mg/kg.
Example 2
Pharmacological Effect in Rats Suffering from Chronic Renal Failure
(Experimental Method)
Rabbit anti-rat glomerular basement membrane antiserum (14-fold diluted. 3
mL/kg) was intravenously injected to WKY rats of 8 weeks old. to induce
glomerulonephritis. Two weeks after the induction of nephritis, blood was collected.
and it was confirmed that the serum creatinine value has been significantly increased
at this time and hence that chronic renal failure has already occurred (normal group:
0.23±0.01 mg/dL, N=4; nephritis-induced group: 0.47±0.01 mg/dL. N=21: t test).
Further, creatinine clearance, which is used as an alternative to glomerular nitration
rate (GFR), was 2.63±0.07 mL/min. (N=3) in the normal group, and 1.22±0.04
mL/min. (N=21) in the nephritis-induced group. That is, creatinine clearance in the
nephritis-induced group decreased to not more than 50% with respect to that of the
normal group, and therefore it was confirmed that the nephritis-induced group
developed chronic renal failure whose primary disease was glomerulonephritis.
Thus, the time of establishment of the chronic renal failure was defined as 2 weeks
after the induction of nephritis. Six weeks after the induction of nephritis,
creatinine clearance was 0.33±0.10 mL/min. in the control group, which
corresponded to 10.2% of that of the normal group (3.24±(). 13 mL/min.). This stage
was the phase in which introduction of dialysis is considered in human, and
corresponded to the most serious phase in chronic renal failure in the conservative
stage.
Thus, 2 weeks after the induction of nephritis, based on the serum creatinine
value, the rats suffering from chronic renal failure were grouped into the normal
group (with neither induction of nephritis nor administration, n=4), the control group
(administration of only a vehicle, n=7), the group to be treated with the sodium salt
of Compound 1 (administration of 30 mg/kg twice a day, n=7) and the group to be
treated with beraprost sodium (administration of 0.3 mg/kg twice a day. n-7). after
which oral administration of the drugs were begun, followed by daily administration
thereof. As the vehicle for the drugs, 0.25% sodium carboxymethylcellulose
solution was used.
From 2 weeks after the induction of nephritis when the chronic renal failure
was established, until 6 weeks after the induction of nephritis, urine collection and
blood collection were carried out as appropriate, and the serum creatinine value.
BUN and creatinine clearance were measured for each group to evaluate renal
function. Further, the hematocrit, the hemoglobin content, and the SOD activity of
the renal tissue, which are closely linked to the diseased state of chronic renal failure,
were measured, and the expression level of mRNA of an organic anion transporter
OAT-3 was quantified. The SOD activity was measured with the SOD assay kit
WST (Dojindo Laboratories), and the expression level of mRNA of OAT-3 was
quantified using LightCycler FastStart DNA Master SYBR Green I (Roche).
Six weeks after the induction of nephritis when the chronic renal failure in the
conservative stage progressed to a serious phase in the control group, a statistical
analysis was carried out. In terms of statistical difference, homoscedastieity was
tested by the Bartlett's test between the control group and the respective drug-
administered groups. In homoscedastic cases, the parametric Dunnett's test was
carried out between the respective drug-administered groups and the control group,
while in heteroscedastic cases, the nonparametric Dunnett's test was carried out
therebetween, using a significance level of less than 5%.
(Result 1)
As shown in Fig. 1, the serum creatinine value in the group to which the
sodium salt of Compound 1 was administered kept low compared to that in the
control group until 6 weeks after the induction of nephritis. As shown in Fig. 2.
BUN in the group to which the sodium salt of Compound 1 was administered kept
low compared to that in the control group until 6 weeks after the induction of
nephritis. As shown in Fig. 3, creatinine clearance in the group to which the sodium
salt of Compound 1 was administered kept high compared to that in the control group
until 6 weeks after the induction of nephritis. Further, creatinine clearance in the
group to which the sodium salt of Compound 1 was administered was significantly
increased 6 weeks after the induction of nephritis relative to that at the beginning of
the administration (2 weeks after the induction of nephritis)(2 weeks after the
induction: 1.21±0.06 mL/min.; 6 weeks after the induction: 1.48±0.11 mL/min.; t-
test). so that it was shown that the sodium salt of Compound 1 has not only an effect
to suppress progression of the diseased state of chronic renal failure but also an
evident effect to ameliorate the renal filtration function.
The results of comparison of the actions of the respective drugs 6 weeks after
the induction of nephritis are shown in Table 1. The serum creatinine value in the
group to which the sodium salt of Compound 1 was administered was significantly
lower than that of the control group, but no statistical difference in the serum
creatinine value was found between the group to which beraprost sodium was
administered and the control group (nonparametric Dunnett's test). BUN in the
group to which the sodium salt of Compound 1 was administered was significantly
lower than that of the control group, but no statistical difference in BUN was found
between the group to which beraprost sodium was administered and the control
group (nonparametric Dunnett's test). Creatinine clearance in the group to which
the sodium salt of Compound 1 was administered was significantly higher than that
of the control group, and creatinine clearance in the group to which beraprost sodium
was administered was also significantly higher than that of the control group
(parametric Dunnett's test).
From the results above, it was shown that the sodium salt of Compound 1 has
a more excellent ameliorating effect on renal function compared to beraprost sodium.
[Table 1]
Parameters of renal function in rats suffering from chronic renal failure. 6 weeks alter
induction of nephritis
Each value in the table indicates rneantke-rtvefa^-vaiHeifl-i^-standard error calculated
from 7 cases in each group. The serum creatinine value, BUN and creatinine
clearance in the normal group (4 cases) were 0.24±0.01 mg/dL. 13.5±0.09 mg/dL and
3.24±0.13 mL/min.. respectively. The serum creatinine value and BUN were
subjected to the nonparametric Dunnett's test, and creatinine clearance was subjected
to the parametric Dunnett's test, p: *<0.05. based on comparison with the control
group.
(Result 2)
By 6 weeks after the induction of nephritis, the hematocrit (32.0±2.09%) and
the hemoglobin content (11.8±0.69 g/dL) in the control group significantly decreased
compared to those in the normal group (with a hematocrit of 44.1 ±0.34% and a
hemoglobin content of 16.0±0.09 g/dL)(t test, p<0.05). Since the values in the
control group were almost the same as those in other rats suffering from
glomerulonephritis (Non-patent Document: Mol Med 4:413-424 1998) and ICON
mice which spontaneously develop renal anemia (Non-patent Document: .1 Vet Med
Sci 66:423-431 2004), the present chronic renal failure rats were also considered to
have developed renal anemia. As shown in Table 2. the hematocrit and the
hemoglobin content in the group to which the sodium salt of Compound 1 was
administered were significantly higher than those in the control group. Although
the hematocrit and the hemoglobin content in the group to which beraprost sodium
was administered were higher than those in the control group, they did not show
statistical difference therebetween (nonparametric Dunnett's test). Thus, it was
suggested that the sodium salt of Compound 1 has an ameliorating effect on anemia.
[Table 2]
Hematocrit values and hemoglobin contents in rats suffering from chronic renal
failure, 6 weeks after induction of nephritis
Each value in the table indicates #>e-avef-age v-aluemean±t+ie standard error calculated
from 7 cases in each group. The hematocrit value and the hemoglobin content in
the normal group (4 cases) were 44.1±0.34% and 16.0±0.09 g/dl.. respectively. I he
nonparametric Dunnett's test was carried out. *p<0.05, based on comparison with
the control group.
(Result 3)
The results of measurement of the SOD activity in the renal tissue 6 weeks
after the induction of nephritis are shown in Table 3. The SOD acti\ ity in the group
to which the sodium salt of Compound 1 was administered was significantly higher
than that of the control group. Although the SOD activity in the group to which
beraprost sodium was administered was higher than that in the control group, it did
not show statistical difference therebetween (parametric Dunnett's test). Thus, it
was suggested that the sodium salt of Compound 1 has an effect to ameliorate
oxidative stress due to increase in the SOD activity.
[Table 3]
The SOD activity in the renal tissue of rats suffering from chronic renal failure. 6
weeks after induction of nephritis
Each value in the table indicates the a vet"age- - v-a h i erne a i i±the~s tan d a rd error calculated
from 7 cases in each group. The calculation was carried out taking the SOD activity
in the normal group (4 cases) as 100%.
The parametric Dunnett's test was carried out. *p<0.05, based on comparison with
the control group.
(Result 4)
The results of quantification of mRNA of the organic anion transporter OAT-
3 expressed in the renal cortex 6 weeks after the induction of nephritis are shown in
Table 4. The expression level of OAT-3 in the group to which the sodium salt of
Compound 1 was administered was significantly higher than that of the control group.
Although the expression level of OAT-3 in the group to which beraprost sodium was
administered was higher than that in the control group, it did not show statistical
difference therebetween (parametric Dunnett's test). Thus, it was suggested that the
sodium salt of Compound 1 has an effect to ameliorate excretion of uremic
substances by suppressing decrease in the transporter OAT-3.
[Table 4]
The expression level of mRNA of OAT-3 in the renal cortex of rats suffering from
chronic renal failure. 6 weeks after induction of nephritis
Each value in the table indicates tlw-average vainemcariithe-standard error calculated
from 7 cases in each group. The expression level of mRNA of OAT-3 in the normal
group (4 cases) was 1.00±0.06.
The parametric Dunnett's test was carried out: p<0.05, based on comparison with
the control group.
Example 3
Changes in Plasma Level of Compound 1 with Time after Administration of
Compound 1 and Compound 2 to Rats
Compound 1 or Compound 2 was orally administered to rats in an amount ol
5 mg/kg, and Compound 1 was intravenously administered in an amount of 1 mg/kg,
after which the concentration of Compound 1 in plasma was measured. The
experiment was carried out with n=3 in each of the both groups. Compound 2 was
converted to Compound 1 in the living body, and the bioavailability was not
statistically different from that in the case of direct administration of Compound 1
(Table 5), showing overlapping changes in the plasma level of Compound 1 between
these cases as shown in Fig. 4. Thus, it was shown that Compound 2 can be used in
a manner similar to Compound 1. Compound 1 and Compound 2 used in this
experiment was synthesized in accordance with the method described in Patent
Document 4.
[Table 5]
Bioavailability observed upon administration of Compound 1 and Compound 2 to
rats
1) Value after correction for the molecular weight.
The a-veraiifr-vakieMeanithe standard error calculated from 3 cases in each group.
As described above, the sodium salt of Compound 1 and berapmst sodium
were orally administered to rats suffering from chronic renal failure in amounts
equivalent to each other in terms of the PGh-receptor agonistic activity, to studytheir
therapeutic effects on chronic renal failure. As a result, it was revealed that the
sodium salt of Compound 1 has effects superior to beraprost sodium in terms of
amelioration of renal function, amelioration of anemia, amelioration of the SOD
activity and amelioration of decrease in OAT-3. which is involved in excretion of
uremic substances. Therefore, the compound of the present invention represented
by the sodium salt of Compound 1 was shown to be extremely useful as a therapeutic
agent for chronic renal failure compared to the other known compounds.
1. A therapeutic agent For chronic renal failure, comprising as an effective
ingredient a compound represented by General Formula (1) below:

[wherein
R1 and R2 each independently represents aryl:
A represents NR5, O, S, SO or SO2;
R3 represents C|-C(, alkyl, C2-C6 alkenyl or C3-C6 cycloalkyl;
D represents Ci-Cf, alkylene or alkenylene;
G represents O. S, SO or SO2;
R3 and R4 each independently represents hydrogen or C|-C