D-mannite derivatives as starting products for the synthesis of

Details D-mannite derivatives as starting products for the synthesis of D-mannite derivatives as starting products for the synthesis of

1984-03-05

1988-03-29

Phillips, Delbert R.

Chemistry of carbon compounds

Miscellaneous organic carbon compounds

C-metal

260403, 568673, 568674, 558169, 558177, C07C 4300, C07F 900, A61K 3100

Patent

active

047342250

DESCRIPTION:

BRIEF SUMMARY
The D-mannitol derivatives according to the invention are especially well suited as starting compounds for the synthesis of (diether) phospholipids, of (monoether) phospholipids and of (ether/ester) phospholipids and make possible the preparation of structure-, stereo- and position-isomeric compounds of these classes of substances, the biological properties of which have recently been intensively investigated.
In comparison with (diacyl) phospholipids (cf. German Patent Application P No. 31 30 867.8 of the 4th Aug., 1981), the corresponding dialkylglycerol derivatives, however, scarcely occur in animal membranes. Nevertheless, mixed alkyl/acyl-glycerol phosphatides are frequent, for example, the plasmalogens which, in organs such as heart and lungs, represent important components of the membranes. Observations are also increasing that certain ether/ester phospholipids possess, in extremely small amounts (10.sup.-10 -10.sup.-11 M), hormone-like properties, such as e.g. "PEF" (platelet activating factor), the structure of which has been described as 1-octadecyl-2-acetyl-sn-glycerol-3-phosphocholine. Therefore, there is a great interest for simple syntheses which permit a specific positioning of the alkyl radicals or acyl radicals, independently of one another, in the glycerol molecule.
Although diether phospholipids scarcely occur in animal membranes, the structures related to the ester phospholipids are of great interest in cell biology. As numerous investigations were able to show (see in this regard H. Eibl, Liposomes: From Physical Structure to Therapeutic Application, Chapter 2: Phospholipid Syntheses; ed. C. G. Knight, Elsevier, Amsterdam (1981), 19), ether phospholipids scarcely differ from ester phospholipids with regard to the physical properties but strongly in their chemical stability towards pH variations and especially in their biological stability towards the phospholipases A.sub.1 and A.sub.2, which can only hydrolyse ester phospholipids. Furthermore, by variation of the phosphate-trimethylammonium distance in the phosphaditylcholines, a breakdown by phospholipase C and D can, as desired, be slowed down or completely suppressed (Eibl and Kovatchev, Methods of Enzymology (1981), 72, 632). The said structure variations permit the construction of liposomes, the biological stability of which can be controlled as desired, i.e. their biological half-life time can be objectively adjusted. For the preparation of these liposomes, there are usually employed mixtures of phospholipids, such as there also occur in natural membranes (lecithins 40-80%; cephalines 20-60% and negatively charged phospholipids 5-30%). Diether phospholipids with the mentioned structure variations in the polar region are thus especially interesting for the preparation of liposomes with increased biological half-life time.
Lysolecithin derivatives possess important biological actions. Thus, lysolecithins are suitable, for example, as immunological adjuvants, which are substances which strengthen the immune response of the organism to an antigenic stimulus, thus the antibody formation (cf. published German Patent Application No. 20 09 343); (ether) lysolecithins promote the increase of the natural resistance of the organism (cf. published German Patent Application No. 20 09 342). The lysolecithin derivatives are of great importance because of their especial effectiveness on the growth of tumours; therefore, they represent an effective antitumour agent (cf. published German Patent Application No. 26 19 686).
The lysolecithin derivatives effective as anti-tumour agents possess an asymmetric carbon atom and can, therefor, occur in two stereoisomeric forms (D- and L-form), of which, however, only one form is active. Thus, for the use as medicaments, the pure stereoisomeric biologically-active forms are superior to the racemate. However, the non-biologically-active forms are, as pure stereoisomers, also valuable reagents, especially for the determination of the activity mechanism of the (ether) lecithins; as racemate administered in admi

REFERENCES:
patent: 4159988 (1979-07-01), Eibl et al.
patent: 4163748 (1979-08-01), Eibl et al.
patent: 4382035 (1983-05-01), Eibl
patent: 4426525 (1984-01-01), Hozumi et al.

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