Methane diphosphonic acid derivative, its production process and

Details Methane diphosphonic acid derivative, its production process and Methane diphosphonic acid derivative, its production process and

1994-06-28

1996-10-15

Dees, Jos e G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Silicon containing doai

514 96, 549 4, 549 5, 549 8, 558 89, A61K 3138, C07D33364, C07D33506, C07D33708

Patent

active

055654401

DESCRIPTION:

BRIEF SUMMARY
SPECIFICATION

This application is a 371 of PCT/JP93/01579 filed Oct. 29, 1993.
1. Technical Field
The present invention relates to novel methane diphosphonic acid derivatives, useful as pharmaceuticals such as an anti-inflammatory drug, antirheumatic drug, bone metabolic disease drug and so forth, and its production process.
2. Background Art
Compounds having a diphosphonate structure are known for use as an anti-inflammatory drug, antiarthritics and so forth according to, for example, Japanese Unexamined Patent Publication (Kokai) No. 59-42395, Japanese Unexamined Patent Publication (Kokai) No. 58-174393 and Japanese Unexamined Patent Publication (Kokai) No. 58-174394. Moreover, Japanese Unexamined Patent Publication (Kokai) No. 60-174792 contains a description to the effect that 1-substituted-amino-1-substituted-thioalkylmethylene diphosphonate is effective as an antirheumatic drug. In addition, clinical studies have-been conducted using sodium (1-hydroxyethylidene)bisphosphonate as a drug for treatment of osteoporosis. Although various other compounds having a methane diphosphonate structure have been studied for use in the treatment of inflammatory diseases and calcium metabolism disorders, these compounds are still inadequate in terms of their inhibitory effects on inflammation, thus resulting in a desire for further improvement.
On the other hand, 5-lipoxygenase inhibitor in the arachidonic acid cascade, an inhibitor for Interleukin-1 which is an important inflammatory cytokine, and an inhibitor (antioxidant) for active oxygen released by neutrophils at sites of inflammation, and so forth have recently attracted attention as a new non-steroid anti-inflammatory drug, and research has been conducted actively on these compounds. For example, 2,4-di-isobutyl-6-(N,N-dimethylaminomethyl)phenol, i.e., a compound which demonstrates both antioxidative action and action that inhibits the production of Interleukin-1, is disclosed in Japanese Unexamined Patent Publication (Kokai) No. 63-258410; 4,4-(isopropylidenedithio)bis(2,6-di-tertbutyl)phenol, as an inhibitor for the production of interleukin-1, is disclosed in Japanese Unexamined Patent Publication (Kokai) No. 63-258408; and 3,5-di-tert-butyl-4-hydroxycinnamic amide as an inhibitor for 5-lipoxygenase is disclosed in Japanese Unexamined Patent Publication (Kokai) No. 63-130570. However, in all cases, anti-inflammatory effects are either weak or not observed in vivo, thus making it difficult to say that these substances have practical efficacy.
Conventional synthetic methods employed for the hydroxymethane diphosphonates pertaining to the compounds of the present invention is described in, for example, Japanese Unexamined Patent Publication (Kokai) No. 57-31691 and Japanese Unexamined Patent Publication (Kokai) No. 58-174394.
Although a reaction is indicated in Japanese Unexamined Patent Publication (Kokai) No. 57-31691 wherein the corresponding carboxylic acid is converted directly to a diphosphonic acid without going through the phosphonic acid ester, in consideration of the use of strongly acidic compounds in the form of phosphorous trichloride and phosphorous acid as reaction reagents and a high temperature of 100.degree. C. being required to carry out the reaction, this reaction cannot be applied in cases when the target compound is decomposed or denatured under strongly acidic or high temperature conditions.
Moreover, although dialkyl phosphite is used during conversion of acyl phosphonic acid ester into the corresponding diphosphonic acid ester in the reaction indicated in Japanese Unexamined Patent Publication (Kokai) NO. 58-174394, a catalytic amount of base is essential in this reaction. Thus, in order to obtain the target diphosphonic acid ester in satisfactory yield, it is necessary to isolate and purify the acyl phosphonic acid ester as an intermediate of the reaction. When considering that acyl phosphonic acid ester is easily decomposed to carboxylic acid under acidic conditions, it is difficult to say that the process described in Japanese Un

REFERENCES:
patent: 5159108 (1992-10-01), Kieczykowski
Evans et al., "New Silicon-Phosphorus Reagents . . . " J. Am. Chem. Soc., vol. 100, No. 11, May 24, 1978, pp. 3467-3477.
Pudovik et al., "Reaction of a trimethylsilyl phosphite . . . ", Zh. Obshch. Khim., 43(3), 1973, p. 680 (Abstract Only).

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