The use of 2-[2-phenyl-2-(2-pyridyl)]ethyl-2-imidazoline or a salt thereof for the preparation of an antiasthmatic agent

Abstract: The invention relates to the use of 2-[2-phenyl-2-(2-pyridyl)]­ ethyl-2-imidazoline or a salt thereof for the preparation of a pharmaceutical composition for treatment and prevention of asthma.

Description: This invention relates to the use of 2-[2-phenyl-2-(2-pyridyl)]ethyl-2-imidazoline or a salt thereof for the preparation of a pharmaceutical composition for treatment and prevention of asthma. 2-[2-Phenyl-2-(2-pyridyl)]ethyl-2-imidazoline (hereinafter referred to Compound A) is known to have a hypoglycemic activity (U.S. Patent 4,138,491), an inhibitory activity on blood platelet aggregation (U.S. Patent 4,138,491), and a therapeutic effect on retinopathy (Japanese Patent Application (OPI) No. 194020/86 (the term "OPI" as used herein means an unexamined published Japanese patent application)), but has not been reported to have an effect for treatment of asthma. Muramatsu et al., in J. Pharmacol. Exp. Ther., (1983) Vol. 227, No. 1, 194 -198, discloses, that the compound as used according to the present invention shows alpha-2 blocking activity. From Goodman and Gilman's: "The Pharmacological Basis of Therapeutics", (1980) 6th edn., MacMillan Publishing Co., Inc., New York, USA, 166 - 171, 176 - 189, it is known, that for treatment of asthma either presynaptic alpha-2 receptors must be blocked or beta-2 receptors must be stimulated. The present inventors have found that Compound A and salts thereof exhibit excellent effects for treatment and prevention of asthma and completed the invention. The present invention relates to the use of Compound A or a salt thereof for the preparation of a pharmaceutical composition for treatment and prevention of asthma. The salt of Compound A includes physiologically acceptable acid addition salts formed with inorganic acids, e.g., hydrochloric acid or hydrobromic acid, and organic acids, e.g., maleic acid or fumaric acid. Pharmaceutical preparations containing Compound A or a salt thereof include tablets, capsules, powders, granules, injectable solutions, suppositories, inhalants, syrups and dermal preparations. These preparations can be prepared by known pharmaceutical techniques using appropriate additives such as excipients, e.g., corn starch or lactose, binders,e.g., hydroxypropyl cellulose or polyvinyl pyrrolidone, disintegrators, e.g., low substituted hydroxypropyl cellulose or crystalline cellulose, and lubricants, e.g., talc or magnesium stearate. If desired, the preparations of the present invention can be slow release or sustained release preparations using a known preparation technique. The asthmatic diseases, on which the preparations of the present invention are specifically effective, include bronchial asthma and cardiac asthma. The preparations according to the present invention can be administered orally or parenterally. The dose level for oral administration usually ranges from 30 to 1200 mg/day, and preferably from 50 to 400 mg/day, for adult human (50 to 60 kg body weight). Compound A and the salts thereof are of low toxicity, and LD₅₀ of dihydrochloride 3/2 hydrate of Compound A was found to be 1,137 mg/kg (p.o.) and 42 mg (i.v.) in male rats. Compound A and the salts thereof have shown excellent effects in the prevention and treatment of asthma as illustrated in the examples hereinafter. Therefore, these compounds are useful as excellent antiasthmatic agents. The present invention is hereinafter illustrated in greater detail with reference to reference example and example. The above components were mixed and compressed by a tabletting machine in a usual manner to prepare tablets each weighing 200 mg. EXAMPLE Dihydrochloride 3/2 hydrate of Compound A (200 mg) was administered to each of 6 patients suffering from intractable asthma and depending on steroids in a single dose after meal. Two out of the 6 patients successively received 200 mg of Compound A in three divided doses per day for consecutive one week. Before administration and after 1, 2 and 3 hours from the administration, the forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), and peak expiratory flow (PEF) were measured with an electronic spirometer (Nihon Koden Co., Ltd., Japan) and the respiratory resistance (Rrs) was determined with Astograph-TCK-6100-H (Chest Co., Ltd., Japan). These values are indices to the antiasthmatic effects. The results obtained are shown in Table 1 below as average ± standard error. As is apparent from Table 1, FEV₁, PEF, and FVC all increased, while Rrs decreased after 2 hours from the administration of Compound A. Further, improvements on manifestations of asthma, such as coughs, stridor and dyspnea were noted in five of the patients. Side effects causing hypoglycemosis, such as changes of blood pressure and heart beat, tremor, anxiety and palpitation were not observed at all in any of the 6 patients.

Claims: The use of 2-[2-phenyl-2-(2-pyridyl)]ethyl-2-imidazoline or a salt thereof for the preparation of a pharmaceutical composition for treatment and prevention of asthma.

Inventors: ABIKO, YASUSHI, KAMEDA, KINYA, KOBAYASHI, SETSUO, NAKAZAWA, TSUGIO, YOSHIE, YASUMASA
Applicants: DAIICHI PHARMACEUTICAL CO., LTD.
Application year: 1988
Main classification: A61K31
IPC codes: A61K31