Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1998-08-26
1999-09-21
Carr, Deborah D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514 89, 514 91, 514114, 514119, 514121, 514126, 514129, 514143, 514885, 540542, 546 22, 548112, 554 40, 554 41, 554 42, 554 44, 554 46, 554 61, 554 63, 554 79, 554 80, 554 84, 562 11, 562 15, 564152, 564155, 564161, 564162, 564168, 564169, 568 11, 568 17, A01N 5700
Patent
active
059554525
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 in a group --(CH.sub.2).sub.e -Cycl in which from position 3 onwards can be replaced by a heteroatom (oxygen, nitrogen or sulfur), unsaturated alkyl chain with 1-20 carbon atoms carbon atoms, preferrably 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## wherein R.sub.4 represents C.sub.1 -C.sub.6 -alkyl, benzyl or phenyl and R.sub.5 and R.sub.6 C.sub.1 -C.sub.6 -alkyl and n 1,2 or 3, carbonylamido, amidocarbonyl, a sulfinyl or a sulfonyl group, carbonylamido, amidocarbonyl, a sulfinyl or a sulfonyl group, ring carbon atom can be replaced by nitrogen and the saturated or aromatic rings can be substituted once or several times by C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 alkyl-mercapto or halogen, time has the meaning of R.sup.1, which means R.sup.1 and R.sup.2 can be exchanged in their meanings 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.
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 (ADS related complex), cytomegaly, herpes infections or hepatitis, is often also accompanied by their 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. In the case of tumour cells which have corresponding surface antigens, antibodies have for example been produced that recognize these special surface antigens and thus selectively bind to the cancer cell. The antibodies are modified with suitable toxins in such a way that the toxin is released after binding to the cancer cell is completed and the cancer cell is killed. Another alternative 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 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 enclosed by this 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, 1640 (1977) and 41
Herrmann Dieter
Opitz Hans-George
Voss Edgar
Zilch Harald
Zimmermann Gerd
Carr Deborah D.
Roche Diagnostics GmbH
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