Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-01-02
2000-02-22
Marschel, Ardin H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
435 6, 536 231, 536 245, 536 253, 536 2533, C12Q 168, C07H 1900, C07H 2100, C07H 2102
Patent
active
060281820
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to methylphosphonic acid esters, processes for their preparation, and their use.
Phosphorylated active compound derivatives are already known which have in some cases also been employed for pharmaceutical purposes. Thus, for example, in J. Med. Chem. 1993, 36, 1048-1052 phosphoamidate esters with AZT are described. The antiviral activity of these compounds, however, is less than that of AZT by the factor 10 and the toxicity of the compounds mentioned is higher than that of AZT by the factor 5. In J. Med. Chem. 1991, 34, 1830-1837, phosphotriester derivatives with AZT are described; in these compounds too the activity is lower and the toxicity greater than in the case of AZT. Similar results are obtained with related compounds, which are reported in J. Org. Chem. 1992, 57, 7300-7307.
With the intention of obtaining phosphorylated active compound derivatives which do not have the disadvantages of relevant prior art compounds, it has now been found that the methylphosphonic acid esters according to the invention have outstanding properties. The invention accordingly relates to
1) compounds of the formula I, ##STR2## characterized in that Y has the meaning of OH, SH, OAc or SAc, where Ac.dbd.(C1-C18)-acyl, which is optionally unsaturated 1-3 times, is an optionally substituted alkyl radical or oligonucleotide where W is a radical of the formula II and R is a radical of the formula II' ##STR3## where X is oxy, sulphanediyl or methylene, B independently of one another is a nucleotide base, radical of the formula ##STR4## in which R.sup.4 is O.sup.-, S.sup.-, CH.sub.3 or CHYR', where R' and Y are as defined above and R.sup.5 is an optionally substituted alkyl radical having 1-18 carbon atoms, F, Cl, N.sub.3, NH.sub.2 or NHR.sup.6 where R.sup.3 and the adjacent phosphonyl radical can be in the 2' or 3' position.
2. Preferred compounds of the formula I are as elucidated under 1), characterized in that is optionally unsaturated 1-3 times, radicals which are independent of one another, selected from the group consisting of (C1-C4)-alkylamino, (C1-C8)-dialkylamino, where a (C3-C8)-alkylene radical in which a CH.sub.2 group can also be replaced by oxy can also be fused onto the aryl radical; from the group consisting of N, O and S; 1-3 times, optionally substituted independently of one another by up to three substituents selected from the group consisting of halogen, CN, NO.sub.2 and (C1-C3)-alkoxy, W has the meaning of a pharmaceutical active compound radical, is [lacuna] or (C1-C16)-alkyl, which can be branched or unbranched and is optionally substituted independently of one another by up to 3 radicals from the group consisting of halogen, CN, (C1-C8)-acyloxy, (C1-C18)-alkoxy or W and R, together with the phosphonate radical carrying them, form an oligonucleotide where W is a radical of the formula II and R is a radical of the formula II' where radical of the formula ##STR5## in which R.sup.4 is O, S, CH.sub.3 or CHYR', where R' and Y are as defined above and R.sup.5 is an optionally substituted alkyl radical having 1-12 carbon atoms, Cl, N.sub.3, NH.sub.2 or NHR.sup.6 where R.sup.6 is (C1-C3)-alkyl or -acyl and the curved bracket indicates that R.sup.3 and the adjacent phosphonyl radical can be in the 2' or 3' position,
3) Particularly preferred compounds of the formula I are as elucidated under 1) or 2), characterized in that is optionally unsaturated 1-3 times, radicals which are independent of one another, selected from the group consisting of (C1-C3)-alkylamino, (C1-C6)-dialkylamino, where a (C3-C8)-alkylene radical in which a CH.sub.2 group can also be replaced by oxy can also be fused onto the aryl radical; the group consisting of N, O and S; 1-3 times, optionally substituted independently of one another by up to three substituents selected from the group consisting of Cl, CN, NO.sub.2 and (C1-C3)-alkoxy, a sugar, of an inositol or of a peptide having at least one amino acid Ser or Tyr and a total of up to 20 natural amino acids, unbranched and is optionally substituted by up to 2
REFERENCES:
Meier, "5', 5'-0-Dinucleoside (alpha-hydroxybenzyl)phosphonates as a lipophilic potential prodrug of ddT," Chemical Abstracts, vol. 120, No. 25, Jun. 20, 1994, pp. 974.
Roelen, "Synthesis of alkylphosphon(othio)ate analogues of DNA," Tetrahedron Letters, vol. 33, 1992, pp. 2357-2360.
Meier, "O-Alkyl-5', 5'-dinucleoside-phosphates as combined prodrugs of antiviral and antibiotic compounds," Bioorganic Med. Chem. Lett., vol. 1, 1991, pp. 527-530.
Chris Meier et al., Lipophilic .alpha.-Hydroxybenzylphosphonates as Prodrugs of 3'-Azido-2', 3--dideoxythymidine (AZT), Liesbigs Ann. 1995, 2195-2202.
Chris Meier et al., Homo Dinucleoside-.alpha.-Hydroxyphoshonate Diesters as Prodrugs of the Antiviral Nuceloside Analogues 2', 3'-Dideoxythymidine and 3'-Azido-2', 3'-Dideoxythymidine, Nucelosides & Nucelositeda, 14(3-5), 759-762 (1995).
Chris Meier, Lipohilic 5', 5'-0-Dinucleoside-.alpha.-hydroxybenzylphophonic Acid Esters as Potential Prodrugs of 2', 3'-Dideoxythymidine (ddT), Agnew. Chemical Int. Ed. Engl 1993, vol. 32, No. 12, pp. 1704-1706.
Yoshino et al. "Organic phosphorus compounds. 2. Synthesis and coronary vasodilator activity of (benzothiazolylbenzyl)phosphonate derivatives." J. Med. Chem. vol. 32, pp. 1528-1532, 1989.
Meier Chris
Uhlmann Eugen
Hoechst Aktiengesellschaft
Marschel Ardin H.
Riley Jezia
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