Isocoumarin derivatives and use thereof in drugs

Details Isocoumarin derivatives and use thereof in drugs Isocoumarin derivatives and use thereof in drugs

1998-12-17

2000-02-01

Powers, Fiona T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549289, A61K 3135, C07D31176

Patent

active

060203633

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to isocoumarin derivatives and their use in medicines. More particularly, it relates to the use of isocoumarin derivatives for the prevention or treatment of diseases associated with an abnormality in immunological regulatory function or vascularization.


BACKGROUND ART

An isocoumarin derivative, particularly 3-hydroxymethyl-6-methoxy-8-hydroxy-1H-2-benzopyran-1-one represented by the formula ##STR2## was first found as a compound produced by Streptoverticillium eurocidicum, and has attracted attention under the name of the antibiotic MI43-37F11 because of its growth-inhibiting activity against various animal cells and human cancer cells (Japanese Patent Laid-Open No. 2177/'91). Subsequently, investigations have been made on the method for the chemical synthesis of the aforesaid antibiotic MI43-37F11 (hereinafter abbreviated as MI43). As a result, isocoumarin derivatives having a leaving group-containing methyl group (e.g., halomethyl) or benzyloxymethyl at the 3-position of an isocoumarin skeleton have been provided as intermediates (Japanese Patent Laid-Open No. 112884/'92), and isocoumarin derivatives having, at the aforesaid 3-position, a group of the formula ##STR3## wherein R.sub.3 and R.sub.4 are each independently a substituted or unsubstituted alkyl group, an alkoxy group, an alkanoyloxy group, a mono- or di-substituted amino group, a phenylthio group or N.sub.3, have been provided as compound having a pharmacological activity similar to that of MI43 (Japanese Patent Laid-Open No. 97841/'93).
On the other hand, the use of MI43 as an immunological regulator has been proposed because its oral administration can significantly inhibit adjuvant arthritis in rats and collagen-induced arthritis in mice (Japanese Patent Laid-Open No. 183966/'94). Although MI43 is considerably effective as an immunological regulator, there would still remain a need for the provision of a more effective compound or medicine.
In the case of drugs conventionally used for the treatment of autoimmune diseases, such as steroid hormones, gold preparations, D-penicillamine, levamisole and salazosulfapyridine, strict restrictions are encountered in using them, because they may sometimes produce serious side effects such as adrenal dysfunction, infection, renal disorders, hematopoietic disorders and gastrointestinal disorders.
Under the above-described background, an object of the present invention is to provide pharmaceutical preparations having no appreciable side effects and exhibiting excellent efficacy (in particular, bioavailability) in mammals including human beings.


DISCLOSURE OF THE INVENTION

In order to accomplish the above object, the present inventors have made investigations on the pharmacological effects and bioavailability of various isocoumarin derivatives. As a result, it has been found that isocoumarin derivatives having a carboxyl group attached to the 3-position, either directly or via a methylene or methine group, instead of the hydroxymethyl group attached to the 3-position of MI43, have an immunological regulatory effect equal or superior to that of, for example, MI43 and also have low toxicity and very excellent bioavailability. Moreover, it has also been found that, when administered orally to mammals, the compounds having such properties surprisingly exhibit high in vivo stability. Furthermore, it has also been found that the aforesaid compounds can significantly inhibit vascularization in mammals. The aforesaid isocoumarin derivatives having a carboxyl group attached to the 3-position via a methylene or methine group are compounds which have not been described in the literature of the prior art.
Accordingly, the present invention provides a pharmaceutical preparation comprising a pharmaceutically acceptable additive and a pharmacologically effective amount of a compound of the formula (I) ##STR4## wherein R is a hydrogen atom or a C.sub.1-6 alkyl group and n is an integer of 0 or 1, or a pharmaceutically acceptable salt thereof; and, in particular, such a pharma

REFERENCES:
patent: 5096924 (1992-03-01), Ishizuka et al.
Yamazaki et al., Chem. Pharm. Bull.,20(10), 2276-2278 (1972).

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