Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-01-27
1997-10-21
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 49, 536 284, 536 285, 536 2851, A61K 31505, C07H 1906
Patent
active
056796528
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new amphiphilic nucleosidephosphate analogues, the production of these, and means for treating cancer-type diseases and infectious diseases. Nucleoside analogues that have specific structural features are proven medications used in the therapies applied for cancer and infectious diseases caused by viruses (AIDS Res. Human Retroviruses 8, 119 (1992)). The therapeutic effect of cytosine nucleoside analogues, for example, araC is limited in that the body's cytosine desaminases desaminate the amino group of the nucleo-base too rapidly and the uracile nucleoside analogues that are formed thereby are, as a rule, therapeutically ineffective (Biochem. Pharmacol. 33, 2159 (1984)). In order to achieve a therapeutic effect, cytosinenucleoside analogues thus have to be applied in large doses that are associated with serious side effects for the patient. Attempts are being made to optimize the therapeutic effect with cytosinenucleoside analogues, the amino groups of which have protective groups. examples of the virostatics that are most frequently used for chemotherapy in the case of AIDS. The anti-retroviral effect is based on the fact that AZT and ddC are anabolized to the 5'-triphosphate derivate after cell absorption and these then selectively bind the reverse-transkriptase of the human immune deficiency virus (HIV), by which AIDS is triggered (Proc. Natl. Acad. Sci. U.S.A. 1986, 38, 8333-8337). Attempts have been made to increase the anti-HIV effect of AZT by using AZT derivatives, which are better absorbed by the infected cells or only liberate AZT after a delay (depot effect) because of inhibited hydrolysis, and to reduce the serious toxic side effects. According to another concept, attempts are being made to deliberately neutralize the large HIV reservoir of macrophages that have encapsulated AZT or glycerophospholipid-AZT-congugates in their lipid membrane. It is hoped that the macrophages will consume the greater part of the applied liposomes before they hydrolyse, so that only a small quantity of liberated AZT is absorbed by other cells, the toxic side effects being reduced by this. In a new therapy schema, with which the therapeutic index of AZT can be improved, AZT is being administered with 2',3'-didesoxycytidine (ddC). However, attempts are also being made to achieve the advantage of such a combination therapy using dinucleosidephosphate analogues, in which AZT is bound covalently with other anti-retroviral didesoxynucleoside analogues, although, however, the most effective nucleosides AZT and ddC have still not yet been coupled (AIDS Res. Human. Retro. 198, 4, 449-4547 Antimicrob. Agents Chemother. 1990, 34, 1061-1067). However, the dimerisation of different anti-retrovirally effective compounds is only useful if both reagents develop their effect in approximately equal concentrations. A considerable disadvantage of the dimers that have been described is their excessively hydrophilic character. Because of this, passage through the cell membrane and the stable incorporation in liposomes is made more difficult and enzymatic hydrolysis is not delayed.
It is the task of the present invent ion to describe new nucleosidephosphate analogues with which cancerous diseases and infections can be combatted more effectively.
This problem has been solved by new amphiphilic nucleosidephosphate analogues that combine the advantages of the various concepts referred to above, and are accessable in preparative quantities at reasonable cost. Lipophilic nucleotide derivatives have been covalently bonded to hydrophillc therapeutically effective nucleoside analogues through phosphodiester bridges or lipophilic and therapeutically effective nucleoside analogues are coupled to hydrophilic nucleotide derivatives.
Thus, the object of the present invention are amphiphilic nucleosidephosphate analogues of Formula I ##STR3## wherein
R.sup.1 stands for a hydroxyl-, amino-, acylated, or alkylized amino group or one substituted by polyoxyethylene, whose acyl- or alkyl rest is linear or branched, have 1
REFERENCES:
Furman et al., "Phosphorylation of 3'-azido-3'-deooxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase," Proc. Natl. Acad. Sci. USA, vol. 83, pp. 8333-8337, Nov. 1986.
CA85: 103772, 1996.
Cancer Res., 1976, 36(8) 2726-32.
Piet Herdewijn et al., "Synthesis and Anti-HIV Activity of Different Sugar-Modified Pyrimidine and Purine Nucleosides," J. Med. Chem., 1988, 31, 2040-2048.
Guerin Frederique
Schott Herbert
Schwendener Albert Reto
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