Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-12-09
1998-08-04
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546156, 546159, A61K 347, C07D21558
Patent
active
057894191
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/01118, filed on 6 Jun. 1995.
1. Technical Field
The present invention relates to a 4-quinolinone derivative or a salt thereof, which is useful as a medicine, in particular, as a prophylactic and therapeutic agent for diseases of circulatory and bronchial systems, an N-amino-4-quinolinone derivative or a salt thereof, which is an intermediate useful for the preparation thereof, and a medicinal composition comprising the 4-quinolinone derivative as an active ingredient.
2. Background Art
Drugs having a smooth muscle-activating effect, for example, direct smooth muscle relaxants, calcium antagonists, .beta.-blockers, .alpha.-blockers, etc., have heretofore been widely used as prophylactic and therapeutic agents for diseases of circulatory system, such as ischemic heart diseases such as angina pectoris and myocardial infarction, and hypertension, bronchial asthma, and the like. However, all of these drugs involve such problems that their pharmacological effects are insufficient, and they cause many side effects. There is hence a demand for development of a therapeutic agent which is more effective and safer.
Therefore, smooth muscle relaxants having a new mechanism called the "potassium channel-activating action" on smooth muscle cells have been developed in recent years and attracted considerable attention as therapeutic agents for diseases of circulatory and bronchial systems. As compounds having a potassium channel-activating effect, which are active ingredients in such remedies, there have been known Cromakalim -1-benzopyran-3-ol! and the like.
However, the conventional compounds having a potassium channel-activating effect cannot be said to be fully satisfactory medicines in view of both effectiveness and safety. It is therefore an object of the present invention to provide a compound having a potassium channel-activating effect, which is excellent in both effectiveness and safety.
DISCLOSURE OF THE INVENTION
Thus, the present inventors have synthesized a great number of compounds and screened such compounds by using a potassium channel-activating effect as an index. As a result, it has been found that a 4-quinolinone derivative or a salt thereof, which has a specific structure, has a strong potassium channel-activating effect and is also useful as a medicine for treating circulatory diseases and bronchial diseases, thus leading to completion of the present invention.
According to the present invention, there is thus provided a 4-quinolinone derivative represented by the following general formula (1): ##STR2## wherein R.sup.1 and R.sup.2 may be the same or different from each other and mean individually a hydrogen atom; a halogen atom; a cyano group; a lower alkyl, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio or lower alkoxy group which may be substituted by halogen atom; or a phenylsulfonyl, phenylsulfinyl or phenylthio group which may have a substituent; and R.sup.3 and R.sup.4 may be the same or different from each other and denote individually a hydrogen atom; a lower alkyl or cycloalkyl group which may be substituted by halogen atom; or a pyridyl, furanyl or phenyl group which may have a substituent, or R.sup.3 and R.sup.4 may form a 4-, 5- or 6-membered heterocyclic ring, which may be substituted by a lower alkyl group, together with the adjacent carbon atom and nitrogen atom, or a salt thereof.
According to the present invention, there is also provided a medicinal composition comprising the 4-quinolinone derivative or the salt thereof and a pharmaceutically acceptable carrier.
According to the present invention, there is further provided use of the 4-quinolinone derivative or the salt thereof for a medicine.
According to the present invention, there is still further provided an N-amino-4-quinolinone derivative represented by the following general formula (2): ##STR3## wherein R.sup.1 and R.sup.2 may be the same or different from each other and mean individually a hydrogen atom; a halogen atom; a cyano group; a lower alkyl, lower alkylsulfonyl, l
REFERENCES:
patent: 5175151 (1992-12-01), Afonso
David W. Robertson et al. , Journal of Medicinal Chemistry, "Potassium Channel Modulators: Scientific Applications and Therapeutic Promise," vol. 33, No. 6, Jun. 1990, pp. 1529-1541.
Gillian Edwards et al., "Structur-Activity Relationships of K+ Channel Openers," vol. 11, No. 10, Oct. 1990, pp. 417-422.
Valerie A. Ashwood et al., "Synthesis and Antihypertensive Activity of Pyran Oxygen and Amide Nitrogen Replacement Analoges of the Potassium Channel Activator Cromakalim," Journal of Medicinal Chemistry, vol. 34, No. 11, Nov. 1991, pp. 3261-3267.
Susan D. Longman et al., "Potassium Channel Activator Drugs: Mechanism of Action, Pharmacological Properties, and Therapeutic Potential," Medicinal Research Reviews, vol. 12, No. 2, Mar. 1, 1992, pp. 73-148.
Karnail S. Atwal, "Modulation of Potassium Channels by Organic Molecules," Medicinal Research Reviews, vol. 12, No. 6, Nov. 1992, pp. 569-591.
Adegawa Shigeru
Kuraishi Tadayuki
Matsuda Hideaki
Ogawa Yoichiro
Yamazaki Kazuo
M. Mach D. Margaret
Rotman Alan L.
SS Pharmaceutical Co., Ltd.
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