Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1987-03-27
1989-07-11
Chan, Nicky
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549402, 549305, 549229, 514467, 514470, A61K 3135, C07D31124
Patent
active
048472867
DESCRIPTION:
BRIEF SUMMARY
FIELD OF ART
This invention relates to cromoglycic acid derivatives and nontoxic salts thereof and pharmaceutical compositions, for example antiallergic compositions, containing the same.
BACKGROUND ART
So far, the compound of formula (II): ##STR2## [hereinafter sometimes referred to as "cromoglycic acid (II)"], which has antiallergic activity, has been used as an antiallergic agent generally in its sodium salt form.
Since it cannot be absorbed in the digestive tract, cromoglycic acid (II) has been administered generally by spraying for inhalation into the nostrils or oral cavity using a sprayer for exclusive use for that purpose.
However, this method of administration is disadvantageous in that difficulties in connection with the operation of the sprayer are encountered in the process of inhalation (especially in young children and the aged).
Therefore, development of cromoglycic acid derivatives absorbable even after oral administration has been earnestly desired.
Accordingly, it is a primary object of the invention to provide cromoglycic acid derivatives which are orally administrable and have high antiallergic activity.
A second object of the invention is to provide a method of producing the noted derivatives.
A third object of the invention is to provide pharmaceutical compositions, for example antiallergic compositions for oral application, which contain said compounds.
DISCLOSURE OF THE INVENTION
As a result of their investigation in search of orally administrable, novel cromoglycic acid derivatives, the present inventors found that the cromoglycic acid derivatives (I) defined hereinbelow are superior in absorbability through the digestive tract and, after absorption, are rapidly converted to the cromoglycic acids (II) (hereinafter sometimes referred to as "non-ester forms") as a result of in vivo enzymatic hydrolysis of the respective ester moieties, which means that oral administration of the cromoglycic acid derivatives (I) results in high blood levels of the non-ester forms which have excellent antiallergic activity, and hence results in prolonged maintenance of said antiallergic activity. The present inventors also found that conversion of the cromoglycic acid derivatives (I) to their acid addition salts increases the efficiency of absorption and at the same time contributes to the stabilization of the cromoglycic acid derivatives (I) and facilitates the isolation procedure and the manufacture of orally administrable preparations. Furthermore, they found that oral administration of the cromoglycic acid derivatives (I) in the presence of an organic acid results in substantial increases in the solubility of the cromoglycic acid derivatives (I) in the digestive tract. The above findings and the establishment of a method of producing the cromoglycic acid derivatives (I) have now led to completion of the present invention.
Thus, the present invention relates to compounds of the general formula (I) [i.e. cromoglycic acid derivatives (I)]: ##STR3## wherein R.sup.1 is an .alpha.-, .beta.- or .gamma.-amino acid residue (for ester bonding) whose amino group may optionally be substituted by at least one lower alkyl group, and each of R.sup.2 and R.sup.3 is, independently, a lower alkyloxy-substituted or an unsubstituted lower alkyl group, a 1-alkanoyloxyalkyl group, a 1-alkoxycarbonyloxyalkyl group, a phthalidyl group or a 5-methyl-1,3-dioxol-2-on-4-ylmethyl group and nontoxic salts thereof.
The invention also relates to a method of producing the cromoglycic acid derivatives (I) which comprises reacting a compound of the general formula (III) with a compound of the general formula (IV) given hereinbelow.
The invention further relates to antiallergic agents which contain the cromoglycic acid derivatives (I) or nontoxic salts thereof as active ingredients.
Referring to R.sup.1 in general formula (I), the amino acid residue forms an ester bond with the adjacent oxygen atom and is an .alpha.-, .beta.- or .gamma.-amino acid residue. The amino group of said amino acid residue may optionally be substitute
REFERENCES:
patent: 4028415 (1977-06-01), Clark
patent: 4189571 (1980-02-01), Bodor et al.
Bodor et al., C.A., 94, 180,605y (1980).
Kakeya Nobuhara
Kitagawa Masaru
Kitao Kazuhiko
Nishizawa Susumu
Tamaki Satoshi
Chan Nicky
Kyoto Pharmaceutical Industries, Ltd.
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