Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1995-09-14
1998-02-10
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
544253, 544321, 544337, 544351, 544329, 544468, 544406, 544428, 544603, 549441, 5483644, 548568, 564 86, 564168, 564184, 546197, 546226, 5462839, 5462841, 546300, A61K 31165
Patent
active
057169934
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to an anthranilic acid derivative having an excellent activity as a drug.
BACKGROUND OF THE INVENTION AND PRIOR ART
Angina pectoris which is one of ischemic heart diseases has been known as a disease which frequently attacks the aged. Although nitrate and nitrite compounds, calcium antagonist, .beta.-blocker and so forth have been used as remedies therefor, these drugs are still insufficiently effective in treating angina pectoris or in preventing the evolution thereof into myocardial infarction. Further, there have recently been observed lowering in the age of patient with angina pectoris and complication of condition of the patient owing to the change in life style and the stress increased by the complication of social mechanism, so that the development of a new type of more excellent drug has been eagerly expected.
With respect to the nitrate and nitrite compounds among the above-mentioned drugs currently used, it is believed that the action thereof relates to cyclic GMP (hereinafter abbreviated to "cGMP") which is one of the cyclic nucleotides known as intracellular second messenger. Further, it is well known that cGMP has a relaxant activity on vascular and bronchial smooth muscles. Although the mechanism of action of these drug is not always apparent, the above activity of cGMP is generally believed to be due to the synthesis of cGMP accelerated by an activated guanylate cyclase. However, these drugs exhibit low bioavailability and relatively short action time, and the occurrence of tolerance thereto has been reported, which becomes a clinical problem.
DISCLOSURE OF THE INVENTION
Under these circumstances, the inventors of the present invention started studies to develop a new type of more excellent drug.
Namely, the inventors of the present invention have directed their attention to an inhibitory activity against cGMP phosphodiesterase (hereinafter abbreviated to "cGMP-PDE") and have intensively studied on compounds having such an activity for many years. As a result of the studies, they have found that an anthranilic acid derivative which will be described below has these activity and is efficacious for various ischemic heart diseases. The present invention has been accomplished on the basis of this finding.
The present invention relates to an anthranilic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof: ##STR2## different from each other, a hydrogen atom, a halogen atom, a hydroxy group, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, a nitro group, a hydroxyalkyl group, a cyano group, a group of the formula: ##STR3## (wherein R.sup.9 and R.sup.10 represent the same or different from each other, a hydrogen atom, an optionally halogenated lower alkyl group, an arylalkyl group, a heteroarylalkyl group, an acyl group or an optionally protected carboxyl group, or alternatively R.sup.9 and R.sup.10 together with the nitrogen atom to which they are bonded may form a ring which may be substituted; and p is an integer of 0 to 6), an optionally substituted tetrazolyl group, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted pyrazolyl group, an optionally substituted imidazolyl group, a group of the formula: ##STR4## (wherein R.sup.13 represents a hydrogen atom or an optionally halogenated lower alkyl group; and q is an integer of 0 to 2), or alternatively two substituents selected from among R.sup.1, R.sup.2, R.sup.3 and R.sup.4 which are adjacent to each other may form a ring together with the carbon atoms to which they are bonded respectively;
R.sup.5 and R.sup.6 represent the same or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally halogenated lower alkyl group or an optionally halogenated lower alkoxy group; or alternatively R.sup.5 and R.sup.6 together with the carbon atoms to which they are bonded respectively may form a cyc
REFERENCES:
Database Crossfire--Beilstein Informationssysteme GmbH, Frankfurt DE *see BRN=1910632* & J. Chem. Soc., 1932, pp. 2728-2729.
Database Crossfire--Beilstein Informationssysteme GmbH, Frankfurt, DE *BRN=471803* & J. Chem. Soc., 1928, p. 539.
Database Crossfire--Beilstein Informationssysteme GmbH, Frankfurt, DE *BRN=639027* & J. Amer. Chem.Soc., vol. 76, 1954, pp. 6336-6337.
Journal of the Heterocyclic Chemicstry, vol. 12, No. 3, Jun. 1975 Provo US, pp. 565-572, G. E. Hardtmann et al., "The Chemistry of 2H-3,1-Benzoxazine-2,4(1H)dione (Isatoic Anhydrides) 1. The Synthesis of N-substituted 2H-3,1-Benzoxazine-2,4(1H)diones" *p. 568, compound 48; p. 569, compounds of 59-61, 65-69; p. 570, compounds 70-87.
Ikuta Hironori
Ishibashi Keiji
Ishihara Hiroki
Ozaki Fumihiro
Souda Shigeru
Eisai Co. Ltd.
Owens Amelia
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