There is now an increasing number of patients suffering from renal dysfunction or heart diseases. This is believed to be because a development of drugs appropriate to the treatment of kidney diseases or heart diseases has lagged behind an increase in the number of senior citizens in the population or changes in the environment. Therefore, drugs appropriate to the treatment of kidney diseases or heart diseases are urgently required.
More particularly, a method for treating lesions accompanying diseases, i.e., a nosotropic treatment, is mainly used for kidney diseases such as nephritis, diabetic nephropathy or renal failure. For example, an antihypertensive agent, diuretic or anti-inflammatory agent, or a dietary treatment, kinesitherapy or the like is used. Because kidney diseases are accompanied by hypertension, and because hypertension is believed to be one of the factors that aggravate kidney diseases, antihypertensive agents are often used. Of the antihypertensive agents, in many cases those that inhibit the production or function of angiotensin II are used. This is because angiotensin II is believed to be a factor aggravating kidney diseases, as it raises the blood pressure and accelerates the growth of interstitial cells in the kidney, and an elimination of such a factor, insofar as possible, is believed to alleviate kidney diseases.
In heart diseases, such as heart failure, cardiac hypertrophy, abnormal heart rate, or valvular disease, a method for treating lesions accompanying diseases, i.e., a nosotropic treatment, also is mainly used. For example, a prevention of cardiac hypertrophy caused by an antihypertensive agent, or a dietary treatment, kinesitherapy or the like is used. Because heart diseases also are accompanied by hypertension, and because hypertension is believed to be one of the factors that aggravate heart diseases, antihypertensive agents are often used. Of the antihypertensive agents, in many cases those that inhibit the production or function of angiotensin II are used. This is because angiotensin II is believed to be a factor aggravating heart diseases, as it raises the blood pressure and accelerates the growth of interstitial cells in the heart, and an elimination of such a factor, insofar as possible, is believed to alleviate heart diseases.
Specifically, J. Clin. Pharmacol., 30: 155 to 158, 1990 reports that, when an antihypertensive agent (for example, Enalapril or Captopril) which is an inhibitor of an angiotensin converting enzyme inhibitor (ACEI), that is, a substance inhibiting an enzyme which converts angiotensin I to angiotensin II exhibiting a pressor function, i.e., angiotensin converting enzyme (ACE), is used, the blood pressure is lowered and the progress of the kidney diseases is ameliorated. U.S. Pat. No. 5,071,867 discloses that kidney diseases of a rat having kidney diseases were ameliorated by administering an antihypertensive agent at a dose higher than a usual dose used for lowering blood pressure, and this suggests that, if a dose is carefully and gradually increased, humans could tolerate a high dose and enjoy a benefit of treatment of kidney diseases. However, the necessity of careful administration is pointed out, because of side effects, such as a non-productive cough, which are characteristics of such kinds of medicaments, or because of a risk of acute heart failure accompanying a lowered blood pressure [Saishin-Igaku (Latest Medicine), 48: 1404 to 1409, 1993].
Subsequently, angiotensin II receptor antagonists (AGIIRA) are developed as an antihypertensive agent. Two subtypes of the angiotensin II receptors are known; subtype 1 and the subtype 2. Although a function exhibited by the subtype 2 has not been fully elucidated, it has been found that the receptor subtype 1 takes part in the blood pressure. Therefore, an antagonist against the receptor subtype 1 is a goal of the development of an antihypertensive agent.
As the antihypertensive agent which exhibits a strong antagonist function against the angiotensin II receptor, an imidazole derivative, 2-butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl ]methyl]imidazole (DuP753 or MK954) is known, and its function on kidney diseases also investigated. When the imidazole derivative is administered to a rat suffering from a kidney disease, it is effective in proteinuria and glomerulosclerosis, but accompanied by an explicit lowering of the blood pressure (J. Clinical Invest., 90: 766-771, 1992). Further, when the imidazole derivative is administered to a rat suffering from hyperlipemia, renal lesion is improved without a substantial influence on the blood pressure at a lower dose, but an explicit lowering of the blood pressure is accompanied by a higher dose, which is more effective in the renal lesion (Nephron, 65: 426-432, 1993).
Compounds having structures similar to that of the imidazole derivative are disclosed in, for example, Japanese Unexamined Patent Publication (Kokai) No. 63-23868, and U.S. Pat. Nos. 5,153,197, 5,128,355 and 5,155,118. More particularly, Japanese Unexamined Patent Publication (Kokai) No. 63-23868 discloses that the imidazole derivatives are effective in hypertension and congestive heart failure; U.S. Pat. No. 5,153,197 discloses that the imidazole derivatives are effective in hypertension; U.S. Pat. No. 5,128,355 discloses that the imidazole derivatives are effective in heart failure; and U.S. Pat. No. 5,155,118 discloses that the imidazole derivatives are effective in renal insufficiency caused by a non-steroid anti-inflammatory drugs. However, they are characterized by a strong angiotensin II receptor antagonist function, and exhibit a function of lowering a blood pressure.
Compounds having a benzimidazole skeleton are disclosed in, for example, Japanese Unexamined Patent Publication (Kokai) No. 4-364171 as those effective in hypertension, heart failure, cerebral apoplexy, nephritis or the like. Further, Japanese Unexamined Patent Publication (Kokai) No. 4-346978 and U.S. Pat. No. 4,880,804 disclose angiotensin II receptor antagonists having a benzimidazole skeleton. However, these compounds exhibit a strong angiotensin II receptor antagonist function, and are characterized by a pressure-lowering function. As above, the benzimidazole compounds have the function to lower the blood pressure on the basis of the subtype 1 receptor antagonist function. Therefore, an administration to a subject suffering from kidney diseases may possibly cause acute renal insufficiency or the like.
Heart failure is the terminal stage in heart diseases, and shows progressive symptoms. A survival rate for 5 years is 50%, and the prognosis is very bad. Methods for treating heart failure are distinguished between an acute phase and a chronic phase.
In the acute phase, a cataplectic failure of a cardiac pumping function is mainly coped with, and thus a treatment to administer a cardiac is mainly carried out. In the chronic phase, a treatment to retard the progress of the symptom, or to maintain the quality of life (QOL) is used. However, if the cardiac is administered as in the treatment for the acute phase, the therapeutic effectiveness is not reliable and in many cases the prognosis becomes worse. It has been found up to now that only the angiotensin converting enzyme inhibitor can improve the prognosis. However, when the angiotensin converting enzyme inhibitor is used, the blood pressure is lowered, and side effects, such as a non-productive cough and acute heart failure, may be caused.
As above, hitherto in the treatment of the kidney diseases or heart diseases, an agent having an as strong as possible pressure-lowering function is fundamentally desirable. In kidney diseases or heart diseases, the hypertension is an important symptom to be alleviated, but a mere lowering of the blood pressure is not sufficient. It is important to maintain an appropriate blood pressure, and thus, it is necessary to adjust the blood pressure by combining the kinds and doses of the antihypertensive agents in accordance with the symptoms. Nevertheless, a continuous treatment with a sufficient dose is required for kidney diseases or heart diseases per se. Therefore, as long as a conventional antihypertensive agent is used, it is fundamentally impossible to appropriately adjust the blood pressure, and at the same time, to effectively cure a kidney disease by the antihypertensive agent alone. One such problem is, for example, an acute renal failure caused by the antihypertensive agent used.
The inventors of the present invention carried out intensive studies to find compounds providing a sufficiently effective alleviation of the renal dysfunction or heart disease without any function to the blood pressure, and as a result, found novel benzimidazole derivatives which provide a sufficient effect in the alleviation of the renal dysfunction or heart disease, while the antagonism thereof to the angiotensin II receptor subtype 1 is one-hundredth (1/100) to one-thousandth (1/1000) or less that of the conventional antagonist having a standard activity as an antihypertensive agent, that is, there is no substantial antagonism. The present invention is based on this finding.
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