Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1990-10-19
1992-10-13
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514119, 558169, 558170, A61K 3166, C07F 940
Patent
active
051550997
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The invention relates to novel alkylphosphonoserines, processes for their preparation and their use.
A process for the preparation of alkylphosphocholines is described in R. Hirt, R. Berchthold Pharmaceutica Acta Helvetica, 33 (1958), 349-356 The cytostatic activity and the toxicity of hexadecylphophocholine is described in H. R. Scherf et al., Lipids 22, (1987), 927-929, and in C. Muschol et al. Lipids 22, (1987) 930-934.
It has now been possible to find novel alkylphosphonoserines which have an excellent cytostatic and virustatic action.
The invention relates to compounds of the formula I ##STR2## in which R denotes a straight-chain or branched, saturated or unsaturated aliphatic hydrocarbon radical having 6-30 C atoms which may optionally be substituted by halogen or the radicals OR.sub.1, SR.sub.1 or NR.sub.1 R.sub.2, where R.sub.1 and R.sub.2 in each case denote a hydrogen atom or an alkyl or acyl radical having 1-6 C atoms.
In the formula I, R denotes a straight-chain or branched, saturated or unsaturated aliphatic hydrocarbon radical having 6-30 C atoms, preferably having 10-25 C atoms. Examples of such radicals are decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, arachyl and 17-methyl-n-octadecyl radicals or the cis-9-n-octadecenyl radical.
These radicals may also be substituted by halogen, for example by Cl, Br, F or by the radicals OR.sub.1, SR.sub.1 or NR.sub.1 R.sub.2. R.sub.1 and R.sub.2 in this case independently of one another denote hydrogen or an alkyl or acyl radical having 1-6 C atoms, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, pentyl or hexyl radical or, for example, a formyl, acetyl, propionyl, butyryl or i-butyryl radical.
The alkylphosphonoserines have certain structural relationships to physiologically active naturally occurring phospholipids, for example phosphatidylserines. However, they differ from these in that they contain no glycerol component. In comparison to the naturally occurring phosphatidylserines, the alkylphosphonoserines according to the invention have a higher biostability. They are potential cytostatics and virustatics.
The novel alkylphosphonoserines can be prepared by a process in which
a) a compound of the formula II ##STR3## in which R has the abovementioned meaning and A and B denote a hydroxyl group or, if desired, the salts of these compounds are reacted with a serine derivative of the formula III ##STR4## in which X denotes benzyl, t-butyl, phthalimidomethyl, isopropyl or benzhydryl, Y denotes N-benzoyloxycarbonyl, N-t-butoxycarbonyl or N-phthaloyl, if appropriate in the presence of a condensing agent, to give compounds of the formula IV ##STR5## the protecting groups are removed and, if desired, the product is converted into a salt or
b) a compound of the formula V ##STR6## in which R has the abovementioned meaning and Z denotes an alkyl radical having 1-6 C atoms, which may optionally be substituted by Cl, Br or F or denotes the radicals ##STR7## in which C and D independently of one another denote H or methyl and E denotes methyl and n denotes 2-6, is reacted with L-serine in the presence of phospholipase D.
The compounds of the formula II used as starting compounds can be prepared in a manner known per se by first synthesizing the dimethyl alkylphosphonates from the corresponding alkyl bromide R-Br and trimethyl phosphite, converting these into the trimethylsilyl esters by reaction with a mixture of trimethylsilyl chloride and sodium iodide and hydrolyzing these by the action of water.
The reaction of the compounds of the formula II is in general carried out by converting the compounds into the salt of a base, for example pyridine, and then reacting this salt with the serine derivative. The reaction is preferably carried out in the presence of a condensing agent, for example in the presence of 2,4,6-triisopropylbenzenesulphonyl chloride under anhydrous conditions and preferably in the presence of an inert organic solvent. A suitable solvent is, for example, pyridine.
The reaction components are customarily employed
REFERENCES:
patent: 4751320 (1988-06-01), Masuda et al.
patent: 4916249 (1990-04-01), Brachwitz et al.
Doerr, I. L. et al. Chemistry and Physics of Lipids vol. 19, pp. 185-202 (1977).
Brachwitz Hans
Hermetter Albin
Langen Peter
Paltauf Friedrich
Schonfeld Reinhild
Ambrose Michael G.
Hafslund Nycomed Pharma Aktiengesellschaft
Lee Mary C.
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