Use of CS-866 (olmesartan) in the manufacture of a medicament for treating arteriosclerosis

Abstract: Compound CS-866, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate, is useful in the preparation of a medicament for use in the prophylaxis or treatment of arteriosclerosis.

Description: [Technical Field of the Invention] The present invention relates to the use of CS-866 in the preparation of a medicament for use in the prophylaxis or treatment of arteriosclerosis. [Background of the Invention] The occurrence of atherosclerosis is increasing with the adoption of Western-style diet and the growth of the aged population. This disease is the main cause of such disorders as myocardial infarction, cerebral infarction and cerebral apoplexy, and there is a need for its effective prevention and treatment. Examples of risk factors which cause atherosclerosis include hyperlipemia (particularly hypercholesterolemia), hypertension and saccharometabolism disorders based on insulin resistance. In addition, there are many cases in which these risk factors occur in the form of complications (Syndrome X), and are considered to be mutually interrelated [Diabetes, 37 , 1595-1607 (1988)]. Efforts have been made for the purpose of preventing and treating atherosclerosis by suppression of various risk factors such as hyperlipemia, hypertension and insulin resistance. Although HMG-CoA reductase inhibitors like pravastatin improve hyperlipemia, their inhibitory activity on arteriosclerosis in a case of administration alone is not enough [Biochim. Biophys. Acta, 960, 294-302 (1988)]. In addition, even insulin resistance improving agents like troglitazone do not exhibit sufricient atherosclerosis inhibitory activity in a case of administration alone (Japanese Patent Application (Kokai) No. Hei 7-41423). On the other hand, among drugs for the treatment of hypertension, it has been reported that atherosclerotic lesions are suppressed when angiotensin converting enzyme (ACE) inhibitors that inhibit the renin-angiotensin system [Hypertension, 15 , 327-331 (1990)] or angiotensin II receptor antagonists [Jpn. Circ. J., 60 (Suppl. I), 332 (1996)] are administered to animals having normal blood pressure and hypercholesterolemia. Angiotensin II not only exhibits vasoconstrictive activity, but also activity that stimulates the production of growth factors such as PDGF [Hypertension, 13 , 706-711 (1989)] and activity that stimulates migration of neutrophils and macrophages [Eur. Heart J., 11 , 100-107 (1990)]. Although the mechanism in which renin-angiotensin system inhibitors suppross atherosclerosis is not clear at the present time, there is a possibility that the mechanism for suppressing atherosclerosis may be a function at the site of the lesion which is different from their blood pressure lowering action. However, since inhibitors of renin-angiotensin system are unable to lower serum lipids [J. Cardiovasc. Pharmacol., 15 , S65-S72 (1990)], their administration alone has limitations on the treatment of arteriosclerosis. In addition, although troglitazone, glibenclamide and captopril are administered concomitantly to diabetes patients, there is no suggestion indicated whatsoever relating to the prevention and treatment of arteriosclerosis [J. Clinical Therapeutic & Medicines, 9 (Supp. 3), 39-60 (1993)]. WO 95/26188 discloses angiotensin II receptor antagonists for the treatment or prevention of arteriosclerosis. In the examples, losartan is used as the angiotensin II receptor antagonist. EP 0503785 (equivalent to JP 5-078328) discloses CS-866 for the treatment or prevention of hypertension or heart and circulatory diseases, but not for the treatment of arteriosclerosis. [Disclosure of the Invention] As a result of carnestly conducting various research in consideration of the importance of the prevention and treatment of arteriosclerosis, the inventors of the present invention found a method to solve the above-mentioned problems involved in the prior art and to obtain a preventive and/or therapeutic effect on arteriosclerosis by using CS-866. The present invention provides the use of CS-866 in the preparation of a medicament for use in the prophylaxis or treatment of arteriosclerosis. The following indicates the chemical planar structural formulae of CS-866. CS-866 is described in Japanese Patent Application No. (Kokai) No. Hei 5-78328 and the like, and its chemical name is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate. The CS-866 of the present application includes its carboxylic acid derivative, pharmacologically acceptable esters of its carboxylic acid derivative (such as CS-866) and their pharmacologically acceptable salts. Moreover, hydrates of the above-mentioned compounds are also included. [Industrial Applicability] The administration route of the drug consisting of CS-866 is typically the oral administration route. The administration form can be, for example, a powder, granules, tablet or capsule and the like, and can be prepared by using conventional pharmaceutical formulation techniques. The dose of CS-866 can be varied over a wide range, in general, and the dose for adults (mg/day) is approximately 0.5 to 100 mg. In the present invention, the CS-866 is administered once a day or divided among several times per day. [Best Mode for Carrying Out the Invention] The present invention will be described more specifically by way of Examples (Example 1) Arterial sclerosis Progress Inhibitory Effect A certain amount of CS-866 was administered orally for 32 weeks to 2-3 months old WHHL rabbits [Watanabe genetically hyporlipamic rabbits: supra (Biochimica et Biophysica Acta), etc.] in groups of 4 to 7 animals each. Incidentally, food consumption was restricted to 120 g/day per animal. Blood samples were collected immediately before administration of the agent and 4, 8, 12, 16, 20, 24, 28 and 32 weeks after the start of administration to measure total cholesterol levels (mg/dl). There were no changes observed in any of the dose groups as compared with the control group to which no CS-866 was administered. The test animals were subjected to autopsy in the 32nd week to investigate the surface area of aortic lesions (%) and the incidence of xanthochromia in finger joints (%). Those results are shown in Tables 1 and 2. Surface Area of Aortic Lesions Test No. Test Compound Dose (mg/kg) No. of animals Lesion surface area (%) Arcuate region Thoracic part Abdominal region Overall 1 CS-866 1 6 68±10 26±8 19±5 34±7 Control - 7 83±6 59±7 39±4 56±4 Incidence of Xanthochromia in Finger Joints Test No. Test Compound Dose (mg/kg) No. of animals Xanthochromia incidence (%) Forelimbs Hindlimbs Overall 1 CS-866 1 6 100 100 100 Control - 7 100 100 100 (Example 2) Arterial sclerosis Progress Inhibitory Effect A certain amount of CS-866 was administered orally for 31 weeks to 2-3 months old WHHL rabbits [Watanabe genetically hyperlipemic rabbits: described supra (Biochimica et Biophysica Acta), etc.] in groups of 5 to 7 animals each. Incidentally, food consumption was restricted to 100 g/day per animal. Blood samples were collected immediately before administration of the agent and 8, 16, 24 and 31 weeks after the start of administration to measure total cholesterol levels (mg/dl). There were no changes observed in any of the dose groups as compared with the control group to which no CS-866 was administered. In addition, the test animals were subjected to autopsy in the 31st week to investigate the surface area of aortic lesions (%) and the incidence of xanthochromia in finger joints. Those results are shown in Table 3. Surface Area of Aortic Lesions Test No. Test Compound Dose (mg/kg) No. of animals Lesion surface area (%) Arcuate region Thoracic part Abdominal region Overall 2 CS-866 0.5 7 66±5 41±10 32±8 44±7 Control - 7 84±5 59±9 32±11 54±8

Claims: The use of CS-866 in the preparation of a medicament for use in the prophylaxis or treatment of arteriosclerosis.

Inventors: FUJIWARA TOSHIHIKO, MAEDA NAOYUKI, SADA TOSHIO, TSUJITA YOSHIO, FUJIWARA, TOSHIHIKO, MAEDA, NAOYUKI, SADA, TOSHIO, TSUJITA, YOSHIO
Applicants: SANKYO CO, SANKYO COMPANY LIMITED
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, A61P9