Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-02-08
1998-08-18
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514575, 544175, 502621, C07C25906, A61K 3116
Patent
active
057958912
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel acylphenylglycine derivatives or pharmaceutically acceptable salts thereof having collagenase inhibitory activity as well as to agents containing said derivatives as active ingredients for prophylaxis and treatment of diseases caused by increased collagenase activity. More specifically, the present invention relates to a novel acylphenylglycine derivative of the formula (I), ##STR2## wherein R.sup.1 represents a hydrogen atom, methyl, methylaminomethyl or morpholinomethyl; R.sup.2 represents a hydrogen atom, hydroxy, fluorine atom, or C.sub.1 -C.sub.4 linear or branched chain alkyl; and R.sup.3 represents C.sub.1 -C.sub.4 linear or branched alkyl, or a pharmaceutically acceptable salt thereof having collagenase inhibitory activity, and to an agent containing thereof as an active ingredient for prophylaxis and treatment of diseases caused by increased collagenase activity.
BACKGROUND ART
Collagenase is an enzyme involved in the metabolism of connective tissue matrix. Increased collagenase activity is considered to be a main cause of a variety of diseases including joint diseases, diseases due to bone resorption, periodontal diseases, corneal ulcer, epidermolysis bullosa and the like.
For example, in diseases of joint such as rheumatoid arthritis and osteoarthritis, increased collagenase activity has been reported by E. M. Gravallese et al. (Arthritis Rheum., 34(9): 1076 (1991)).
Diseases due to bone resorption is a class of diseases resulting from a remodeling process, which consists of formation and resorption of the bone, being biased in favor of resorption of the bone, and specific diseases such as hypercalcemia, osteoporosis are known to be included in this class. Attention has been attracted to the implication of cysteine proteases such as cathepsin L in the increased resorption of the bones in these diseases. However, a recent report by V. Everts et al. (J. Cell. Physiol., 150: 221 (1992)) indicates an additional implication of collagenase.
Thus, various compounds having collagenase inhibitory activity are investigated for they have a possibility to provide a remedy for those diseases with increased collagenase activity. See JP-A-62-103052 and JP-A-62-230757, JP-A-04-502008, and U.S. Pat. No. 5,114,953, for example. However, these compounds are not sufficient to maintain inhibitory activity in the blood after administration to a living body. Therefore, a need exists for a development of a compound which allows collagenase inhibitory activity to be maintained for a longer period of time at higher levels in the living body after administration.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a novel compound with which collagenase inhibitory activity can be maintained for a long period at higher levels in the living body after administration and to provide an agent containing the compound as an active ingredient for prophylaxis and treatment of diseases caused by increased collagenase activity.
The inventors of the present invention found that an acylphenylglycine derivative of the formula (I), ##STR3## wherein R.sup.1 represents a hydrogen atom, methyl, methylaminomethyl or morpholinomethyl; R.sup.2 represents a hydrogen atom, hydroxy, fluorine atom, or C.sub.1 -C.sub.4 linear or branched chain alkyl; and R.sup.3 represents C.sub.1 -C.sub.4 linear or branched chain alkyl, or pharmaceutically acceptable salt thereof meet the above requirements.
In this specification, the C.sub.1 -C.sub.4 linear or branched chain alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.
Among the compound of the present invention, an acylphenylglycine derivative in which R.sup.1 and R.sup.3 are both methyl and R.sup.2 is hydrogen atom in the formula (I), or a pharmaceutically acceptable salt thereof has an excellent activity in a living body, thus being particularly preferred.
Stereoisomers exist due to the chiral carbon atoms 1, 2 and 3 in the formula below when R.sup.1 in the formula (
REFERENCES:
patent: 5387610 (1995-02-01), Gray et al.
Hirayama Ryoichi
Ikeda Shoji
Matsuo Konomi
Obata Yuji
Sakamoto Fumio
Gerstl Robert
Kanebo Ltd.
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