Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-06-27
1997-07-01
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142365, 514252, 544114, 544224, 544238, 544236, 548229, 560 81, 560157, 560158, 560190, 560197, A61K 3150, C07D23704, C07D40312, C07D41312
Patent
active
056439083
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP92/01420 filed Nov. 2, 1992.
TECHNICAL FIELD
The present invention relates to novel piperazic acid derivatives having excellent collagenase inhibiting activity.
BACKGROUND ART
Collagenase degrades collagen, which is one of the main components of the connective tissues. Of the collagenases, type IV collagenases degrade type IV collagen, which is a main component of the basement membranes. It is known that the activity of type IV collagenases is raised at the time of angiogenesis accompanied by cancer growth and at the time of cancer invasion and metastasis, and that these enzymes play an important role in the degradation of the basement membranes [William G. Stetler-Stevenson; Cancer and Metastasis Reviews, Vol. 9, 289-303 (1990)]. Accordingly, a collagenase inhibitor may be useful for the prevention and treatment of these diseases.
Hitherto, there have been reports concerning low molecular weight substances showing collagenase inhibiting effects, including peptide compounds containing a mercapto group [Robert D. Gray, Hossain H. Saneii and Arno F. Spatola: Biochemical and Biophysical Research Communications, Vol. 101, No. 4, 1251-1258 (1981); Charles F. Vencill, David Rasnick, Katherine V. Crumley, Norikazu Nishino and James C. Powers: Biochemistry, Vol. 24, 3149-3157 (1985)]; peptide compounds containing a carboxyl group [Jean-Marie Delaisse, Yves Eeckhout, Christopher Sear, Alan Galloway, Keith McCullagh and Gilbert Vaes: Biochemical and Biophysical Research Communications, Vol. 133, 483-490 (1985)]; benzyloxycarbonyl propyl-leucyl-glycylhydroxamic acid [William M. Moore and Curtis A. Spilburg: Biochemical and Biophysical Research Communications, Vol. 136, 390-395 (1986)]; and hydroxylamine derivatives (Japanese Patent Kokai Application Hei No. 1-160997). Furthermore, SC 44463 has been reported [Reuven Reich, Erik W. Thompson, Yukihide Iwamoto, George R. Martin, James R. Deason, George C. Fuller and Ruth Miskin: Cancer Research, Vol. 48, 3307-3312 (1988)] as an inhibitor relatively specific to type IV collagenases. SC 44463 has been confirmed to exhibit an inhibitory activity on cancer metastasis in an animal experiment. The above compounds, however, are synthetic ones and are not yet put to practical use.
On the other hand, the tissue inhibitor of metalloproteinase (TIMP) and related substances are known as collagenase inhibitors of the protein type. It becomes possible to prepare TIMP on a large scale by recombinant DNA technology, but it has not yet been put to practical use [A. J. P. Docherty, A. Lyons, B. J. Smith, E. M. Wright, P. E. Stephens, T. J. R. Harris, G. Murghy and J. J. Reynolds: Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity; Nature, Vol. 318, 66-69 (1985)].
As a compound having a hydroxylamino-substituted 2-pentylsuccinic acid structure, actinonin has been isolated from the culture filtrate of actinomycetes. This compound has been reported to inhibit aminopeptidase M at low concentrations [H. Umezawa, T. Aoyagi, T. Tanaka, T. Suda, A. Okuyama, H. Naganawa, M. Hamada and T. Takeuchi: J. Antibiotics, Vol. 38, 1629-1630 (1985)], however, it has not been investigated whether or not it inhibits type IV collagenases.
Furthermore, a natural product having the following chemical structure has been isolated from a strain which belongs to streptomyces and is known to have antibacterial and collagenase inhibiting activities (Japanese Patent Kokai Application Hei 3-157372). ##STR2##
In addition, in Japanese Patent Kokai Application Hei 3-53891, the formula ##STR3## of the compound is described, and the compound is said to have antibacterial activity, however, there is no disclosure of its inhibitory activity on type IV collagenases.
DISCLOSURE OF INVENTION
The present inventors have eagerly studied the synthesis of derivatives having better inhibitory activity against type IV collagenases and the pharmacological activities of these derivatives. The study resulted in the finding that new matlyst
REFERENCES:
patent: 4604407 (1986-08-01), Haslanger et al.
patent: 4659711 (1987-04-01), Huang et al.
patent: 5387610 (1995-02-01), Gray et al.
Abstract for JP 3-157372 (Jul. 5, 1991).
Abstract for JP 3-53891 (Mar. 7, 1991).
Reich et al, Cancer Research 48 pp. 3307-3312 (1988).
Advanced Organic Chemistry by Jerry March (2nd. Ed.) pp. 363-365, 384-385 (1977).
Protective Groups in Organic Chemistry, J.F.W. McOmie (Editor), pp. 43-50, 183-198 (1973).
Kobayashi Tomowo
Sugimura Yukio
Tamaki Kazuhiko
Tanzawa Kazuhiko
Bernhardt Emily
Sankyo Company Limited
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