Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-17
2000-08-29
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5462817, 546207, 514336, 5143111, 514394, 514252, 514326, 5483111, 548394, 549548, 544405, 544333, A61K 31495, A61K 31435, A61K 3141
Patent
active
061109673
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel epoxysuccinamide derivatives or salts thereof, which have inhibitory activity against cathepsin, and medicines comprising such a derivative or salt.
BACKGROUND ART
On the current trend toward the aging society, abnormal acceleration of bone resorption in a human advanced in years involves many of various senile diseases. In particular, senile osteoporosis is prominent and about to become a great social problem. When the present pharmacotherapy for this senile osteoporosis is viewed, it is conducted to administer (1) estrogen, (2) protein anabolic hormones, (3) calcitonin, (4) vitamin D or (5) bisphosphonates. However, their effects are found only in improvement of subjective symptom, and hence there is no critical therapy under the circumstances.
On the other hand, it is considered that factors causing osteoporosis include two of calcification and decalcification, and abnormal decomposition of supporting tissue, collagen. However, the development of pharmaceutical agents by paying attention to the abnormal acceleration of collagen decomposition is only now under way. It is reported that a group of cathepsins takes part in this collagen decomposition to the greatest extent, and cathepsin L among the group of cathepsins, which belongs to cysteine proteases, particularly deeply involves the collagen decomposition [FEBS Letters, 269, pp. 189-193 (1990); and FEBS Letters, 280, pp. 311-315 (1991)]. It has recently be found that cathepsin K, which is a family enzyme of cathepsin L, also takes parts in bone resorption [J. Biol. Chem., 271, pp. 12517-12524 (1996)]. With respect to compounds which inhibit cysteine proteases, epoxysuccinic acid derivatives similar to those of the present application have been reported in, for example, Japanese Patent Application Laid-Open No. 104683/1996 and European Patent Publication No. 655447A1. However, these compounds inhibit both enzymes of cathepsin L and cathepsin B without any selectivity. It has been reported that cathepsin B does not take part in bone resorption [FEBS Letters, 321, pp. 247-250 (1993)], and is an enzyme related to an immune system such as antigen presenting [FEBS Letters, 324, pp. 325-330 (1993)]. It is hence apprehended that immunodeficiency may be caused if cathepsin B is inhibited. In order to inhibit bone resorption selectively, it is therefore necessary to use an inhibitor which selectively inhibits cathepsin L and family enzymes thereof. However, such a selective inhibitor has not been found yet.
It is an object of the present invention to provide a novel compound which inhibits cathepsin L and its family enzymes at a concentration lower than against other cysteine proteases, and in other words, a novel compound useful as an agent for treating and preventing metabolic osteopathy such as osteoporosis, hypercalcemia, Paget's disease, hyperparathyroidism and bone metastasis of cancer.
DISCLOSURE OF THE INVENTION
In order to achieve the above object, the present inventors have synthesized a great number of epoxysuccinamide derivatives and evaluated their action on cathepsins. As a result, the inventors have succeeded in inventing compounds which specifically inhibit cathepsin L and are useful as medicines such as agents for treating osteoporosis, thus leading to completion of the present invention.
Namely, the present invention provides an epoxysuccinamide derivative represented by a formula (I): ##STR2## wherein R.sup.1 represents a hydrogen atom, an alkyl group or an aminoalkyl group which may have a protecting group, R.sup.2 represents an aminoalkyl group which may be substituted, an aryl group which may be substituted, an aralkyl group which may be substituted, a heterocyclic group which may be substituted, or an alkyl group substituted by a heterocyclic ring which may be substituted, or R.sup.1 and R.sup.2 may form a nitrogen-containing heterocyclic ring, which may be substituted, together with the adjacent nitrogen atoms, and R.sup.3 and R.sup.4 are the same or different from each other
REFERENCES:
patent: 5556853 (1996-09-01), Tsubotani et al.
patent: 5679708 (1997-10-01), Tsubotani et al.
International Search Report.
Asao Tetsuji
Katsunuma Nobuhiko
Okajima Shigeo
Shigeno Kazuhiko
Suda Yoshimitsu
Davis Zinna Northington
Robinson Binta
Taiho Pharmaceuticals Co., Ltd.
LandOfFree
Epoxysuccinamide derivative or salt thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Epoxysuccinamide derivative or salt thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Epoxysuccinamide derivative or salt thereof will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1250458