Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1993-08-03
1996-07-09
Springer, David B.
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564 91, 564 94, 514604, A61K 3118, C07C25904, C07C31130
Patent
active
055346545
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel hydroxamic acid derivatives which show activities such as cell growth inhibitory activity, vascularization inhibitory activity and the like and are useful for prophylaxis and therapy of various inflammatory diseases, tumors, arteriosclerosis, peptic ulcer, diabetic retinopathy or the like.
BACKGROUND ART
In higher animals, a lot of tissues and organs have individual unique cell growth system, which are controlled by various regulatory mechanisms.
The participation of cell growth factors capable of effecting the positive control of cell growth of various cells has been shown and there have been reports which suggest the existence of relationships between various diseases and an abnormal growth of cells induced by an excessive production of cell growth factors and/or an excessive reaction to them. For example, tumor cells release a certain substance(s) capable of accelerating vascularization to maintain their own growth. It has been revealed that the vascularizing factor has a potent growth accelerating effect on vascular endothelial cells, and such vascularization can be also observed during chronic inflammation, arteriosclerosis and peptic ulcer. Although there are some compounds known to inhibit the vascularization, for example, DS4152 and the like (see, Japanese Patent Publication (KOKAI) No. 63-119500), the activity is not sufficient.
Furthermore, lymphocytes take an important role in case of inflammation, during which an adhesion phenomenon is observed between lymphocytes and vascular wall via adhesive molecules expressed on the vascular endothelial cells. Therefore, it has been considered that inflammation can be prevented by inhibiting the expression of adhesive molecules on the vascular endothelial cells or by directly interfering the adhesive reaction.
On the other hand, the discovery of tumor genes has promoted the development of antitumor agents. The tumor gene can be classified in several groups represented by src, ras, myc gene or the like. However, conventional antitumor agents inhibited the growth of normal cells as well because they had been developed as the result of a research which uses as an index the inhibitory effects against DNA synthesis, RNA synthesis, protein synthesis or the activity of factors participating in the cell growth. Therefore, the development of antitumor agents has been carried out on the basis of a different index directed to substances that inhibit the growth of tumor cells, not normal cells. It was found that when azatyrosine is administered to normal and transformed NIH 3T3 cells, the latter having been transformed by the introduction of ras gene activated by the mutation of No. 61 amino acid glutamine to leucine, the growth of the transformed cells is specifically inhibited. It was also observed that about 85% of transformed cells were converted into flat revertant cells morphologically similar to normal cells after the administration of azatyrosin. It was proposed that, in the revertant cells, the expression of gene participating in the conversion into normal cells is activated [Cancer and Chemotherapy, vol. 17 (3): part II, 500-501, 1990].
As is easily anticipated from the above, if a drug is discovered that does not react on normal cells but specifically does react on and detransform cells transformed by, for example, ras gene, and effects the detransformation, such a drug can provide an excellent antitumor agent. Accordingly, the development of such drugs has been desired.
DISCLOSURE OF THE INVENTION
The present invention provides novel hydroxamic acid derivatives which have three kinds of activities, namely (1) inhibitory activity against the growth of vascular endothelial cells, (2) inhibitory activity against the expression of lymphocyte adhesive factors, and (3) detransforming activity of cells transformed by ras gene, and inhibit the cell growth and are effective on inflammation and tumor.
The present inventors have made an intensive research in view of the circumstances above and have found t
Arita Hitoshi
Matsuura Takaharu
Ohtani Mitsuaki
Shirahase Kazuhiro
Sugita Kenji
Shionogi & Co. Ltd.
Springer David B.
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