Phospholipid derivatives of phosphono-carboxylic acids, the prod

Details Phospholipid derivatives of phosphono-carboxylic acids, the prod Phospholipid derivatives of phosphono-carboxylic acids, the prod

1998-08-27

2000-10-24

Ambrose, Michael G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514114, 514119, 558169, 558172, 558174, 558179, 558181, A61K 3166, C07F 940, A61P 3112

Patent

active

061367974

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns new lipid derivatives of phosphonocarboxylic acids and their esters of the general formula I, ##STR2## in which R.sup.1 is a straight-chained or branched, saturated or unsaturated alkyl chain with 9-13 carbon atoms, alkyl chain with 8-12 carbon atoms with 1-6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, neopentyl, thexyl or phenyl, choline, ethanolamine, carnitine, C.sub.5 -C.sub.7 -cycloalkyl residue, benzyl or one of the following groups ##STR3## n denotes 0, 1 or 2 and m represents 0, 1, 2, or 3, organic bases as well as processes for the production thereof and pharmaceutical agents containing these compounds.
Since the compounds of the general formula I contain asymmetric carbon atoms all optically active forms and racemic mixtures of these compounds are also a subject matter of the present invention.
Compounds of formula I are also understood to include salts, tautomers, esters, optically active forms and racemic mixtures in the following.
The therapy of malignant neoplasias (carcinomas, sarcomas, haematological neoplasias), inflammatory diseases or autoimmune diseases as well as diseases caused by viruses or retroviruses such as for example AIDS, ARC (AIDS related complex), cytomegaly infections, herpes infections or hepatitis is often also accompanied by the extreme side-effects in addition to the inadequate efficacy of the therapeutic substances used. This effect can be explained by the inadequate in vivo selectivity and limited therapeutic range of the pharmacologically active substances used. The advantageous pharmacological in vitro properties of the pharmacologically active substances can often not be transferred to in vivo conditions.
It has therefore been attempted for years to provide new substances with improved properties with regard to their therapeutic range by modifying the chemical structure of pharmacologically active substances. Moreover new pharmaceutical forms of administration are often developed with the aim of transporting the active substances specifically to their site of action at which they are intended to display their therapeutic action. In this case it is particularly intended to avoid undesired interaction with healthy cells. One possibility to improve the therapeutic range is to change the physical properties of the underlying active substance in such a way that the solubility or tolerance of the active substance is improved by slight modification of the pharmacologically active substance for example by producing acid or base addition salts or by preparing pharmacological safe esters [for example fatty acid esters; J. Pharm. Sci. 79, 531 (1990]. These slightly chemically modified compounds are often denoted "prodrugs" since they are almost immediately converted into the therapeutically active agent on contact with body fluids or in the liver (first pass metabolism). Said `prodrugs` are included into the invention.
In order to improve catabolic stability, nucleosides such as e.g. ara-C and ara-A have been chemically bound to phospholipids. The corresponding derivatives exhibited less toxicity and higher stability in vivo compared to unmodified nucleosides. The absorption, and cell penetration were, however, hardly influenced. [J. Med. Chem. 32, 367 (1989), Cancer Res. 37, 1640 (1977) and 41, 2707 (1981)]. Further phospholipid derivatives of nucleosides are for example known from the following literature references:
The production and use of liponucleotides as antiviral pharmaceutical agents is described in J. Biol. Chem. 265 6112 (1990). However, in this case only dimyristoylphosphatidyl and dipamitylphosphatidyl residues coupled to the known nucleosides such as AZT and ddC with their fatty acid ester structure were investigated and synthesized.
Nucleoside conjugates of thioether lipids with cytidine diphosphate which have an antitumoral action and could be used in oncology are described in J. Med. Chem. 33, 1380 (1990).
In Chem. Pharm. Bull. 36, 209 (1988) 5'-(3-SN-phosphatidyl)-nucleo

REFERENCES:
patent: 5194654 (1993-03-01), Hostetler et al.
patent: 5696277 (1997-12-01), Hostetler et al.

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