Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1994-01-14
1997-04-08
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514105, 558161, 562 21, A61K 3166, C07F 938, C07F 940
Patent
active
056188048
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel methanediphosphonic acid derivative which inhibits actions of interleukin-1 that mediates pyrexia-inducing reactions, inflammation-inducing reactions, activates various blood cells and has bone destructive action, while simultaneously having an action to inhibit active oxygen that cause cell damage and fat denaturation, as well as an action to inhibit bone destruction during osteoporosis and chronic articular rheumatism.
BACKGROUND ART
Many of the diphosphonic acid compounds that have been developed mainly as drugs for treatment of bone metabolic diseases thus far have an action to inhibit bone destruction, and have been expected to inhibit bone destruction during the occurrence of arthritis such as chronic articular rheumatism. Although compounds having a diphosphonic acid structure are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 59-42395, Japanese Unexamined Patent Publication (Kokai) No. 2-22285, Japanese Unexamined Patent Publication (Kokai) No. 3-77894 and Japanese Unexamined Patent Publication (Kokai) No. 60-174792, these diphosphonic acid compounds are primarily focused on inhibition of bone resorption. Although these compounds are effective as therapeutic drugs for bone metabolic disorders, they are still not adequate for treatment of chronic articular rheumatism.
In order for diphosphonic acid compounds to be used in the treatment of chronic articular rheumatism and so forth, a new drug is desired that, in addition to having an action to inhibit bone resorption, also has other, more effective actions, including inhibition of Interleukin-1 (abbreviated as IL-1), which is a mediator of inflammations, as well as inhibition of cell damage caused by activated neutrophils and macrophages.
IL-1 is known to be a mediator involved in pyrexia and inflammation, and its inhibitory agent is expected to be useful as an antiinflammatory drug. However, similar to many other cytokines, IL-1 is considered to mainly act locally. Although numerous substances have been reported to inhibit IL-1 in vitro, antiinflammatory drugs having action that allows adequate improvement of the disease state by actually inhibiting IL-1 in vivo have not yet been developed. In addition, invasion of activated neutrophils and macrophages at the site of inflammation have been observed during inflammations. Although the active oxygen produced by these blood cells has an action of heterogenous digestion, in cases where an inflammation has become chronic, these cells are known to damage normal tissue as well. Thus, compounds having both an IL-1 inhibiting action and antioxidative action are considered to be useful as not only antiinflammatory drugs, but also against autoimmune diseases such as chronic articular rheumatism, as well as organ disorders, such as those in the brain and liver, which occur during ischemia.
DISCLOSURE OF THE INVENTION
The present inventors conducted research on diphosphonic acid compounds that demonstrate excellent anti-inflammatory action, by giving to a diphosphonic acid derivatives not only action as therapeutic drugs for treatment of bone metabolic diseases, but also IL-1 inhibitory action and antioxidative action. During the course of this research, it was found that, if a naphthalene skeleton is given to a phosphonic acid structure, IL-1 inhibitory action and antioxidative action are provided that are not found in existing drugs.
The object of the present invention is to provide a useful, novel compound having an action to inhibit Interleukin-1, antioxidative action, and an action to inhibit bone destruction.
Namely, the present invention relates to the methane diphosphonic acid derivatives shown in general formula (I): ##STR2## [wherein, X and Y represent substituent groups on the naphthyl group, and represent a halogen atom, nitro group, nitrile group, alkyl group, alkoxy group, trifluoromethyl group, the group: ##STR3## (wherein Z.sup.1 and Z.sup.2 represent independently hydrogen atom or alkyl group, or Z.sup.1 and Z.sup.2
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Funaba Yuriko
Kawabe Norio
Nakadate Teruo
Tanahashi Masahiko
Uchiro Hiromi
Ambrose Michael
Richter Johann
Toray Industries Inc.
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