Phospholipid derivatives

Details Phospholipid derivatives Phospholipid derivatives

1990-12-27

1992-03-24

Shen, Cecilia

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

549222, A61K 31665, C07F 906

Patent

active

050988980

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a novel phospholipid derivative, a method of producing the same and uses therefor, including pharmaceutical application thereof.


BACKGROUND ART

While a compound composed of ascorbic acid and alpha-tocopherol coupled together via a phosphoric acid residue is disclosed in Japanese Kokai Tokkyo Koho (published unexamined patent application) No. 59-219295, no compound comprising a phospholipid and ascorbic acid is known as yet.
It is believed that active oxygen and lipid peroxides are factors causative of aging, adult diseases and other diseases, hence are harmful to living bodies, and should be eliminated from living bodies. For inhibiting the formation or decomposing these hazardous substances, the use of antioxidants originally occurring in living organisms, for example vitamin E, ascorbic acid, ubiquinone and uric acid, has been proposed. However, none of them is fully satisfactory.


DISCLOSURE OF THE INVENTION

The present inventors made investigations concerning ascorbic acid derivatives. As a result, they succeeded in synthesizing certain phospholipid-type ascorbic acid derivatives resulting from binding a glycerol ester or ether to ascorbic acid via a phosphoric acid residue and found that said derivatives have antioxidant activity and lipid peroxide inhibiting activity, among others. The present invention has been completed based on such and other findings.
In one aspect thereof, the present invention provides phospholipid derivatives of the formula ##STR2## wherein R.sup.1 and R.sup.2 represent the same or different and each represents an alkyl or acyl group. It is to be noted that neither formula represent any specific configuration nor conformation.
In formulas [I] and [II], the alkyl or acyl group represented by R.sup.1 and/or R.sup.2 preferably contains 1 to 18 carbon atoms. The carbon chain in the alkyl group or the acyl group when it is an aliphatic acyl may be straight or branched or cyclic and may contain a cyclic portion. As examples of the alkyl group, there may be mentioned lower alkyl groups, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, sec-butyl, n-pentyl, 1-ethylpropyl and i-pentyl, as well as higher alkyl groups, such as n-decyl, n-undecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, and isomeric forms of these. As the acyl group, there may be mentioned, for instance, acyclic acyl groups, such as acetyl and propionyl, and cyclic acyl groups, such as cyclopentylcarbonyl and cyclohexylcarbonyl. The acyl group may be also be an aromatic or araliphatic acyl group, such as benzoyl or phenylacetyl.
In another aspect, the invention provides a method of producing phospholipid derivatives of the formula [I] or [II] given above which comprises reacting a glycerol halophosphate derivative of the formula ##STR3## wherein R.sup.1 and R.sup.2 represent as defined above, X represents a halogen atom and neither formula represent any particular configuration nor conformation, with ascorbic acid protected at positions 5 and 6 and then deprotecting said positions 5 and 6.
The glycerol halophosphate derivatives mentioned above can be prepared by reacting a glycerol diester, diether or monoester monoether compound of the formula ##STR4## wherein R.sup.1 and R.sup.2 represent defined above and neither formula indicates any specific steric configuration, namely a compound derived from glycerol by substitution of R.sup.1 and R.sup.2 for two of the three hydroxyl groups of glycerol, with a halophosphorylating agent, for example a phosphorous oxyhalide, such as phosphorous oxychloride or phosphorus oxybromide, in the presence of a deacidifying agent. An organic amine, such as triethylamine or pyridine, is preferred as the deacidifying agent.
The protective group for protecting the 5- and 6-position of ascorbic acid should desirably be eliminable readily after the reaction and an isopropylidene group or the like is a preferred example although an acyl group such as acetyl may also be used.
The reaction of the protected ascorbic acid and the

REFERENCES:
patent: 4647672 (1987-03-01), Seib et al.
patent: 5013850 (1991-05-01), Lee

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