Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-03-24
2000-12-05
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
283279, 546 48, 546 41, 544361, A61K 3150, A61K 3144, C07D47100, C07D40100
Patent
active
06156754&
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to glycoconjugates of camptothecin derivatives in which at least one carbohydrate component is linked via suitable spacers with the A or B ring of a camptothecin derivative. The invention furthermore relates to processes for preparing the compounds according to the invention and to their use as medicaments, in particular in connection with cancers.
20(S)-Camptothecin is a pentacyclic alkaloid which was isolated in 1966 by Wall et al. (J.Am.Chem.Soc. 88, 3888 (1966)). It has a high antitumour activity potential in numerous in vitro and in vivo tests. Unfortunately, however, the promising potential failed to be realized in the clinic because of toxicity and solubility problems.
By opening of the E ring lactone and formation of the sodium salt, a water-soluble compound was obtained which is in a pH-dependent equilibrium with the ring-closed form. Here too, clinical studies have been unsuccessful until now. ##STR1##
Approximately 20 years later, it was found that the biological activity is to be attributed to an enzyme inhibition of the topoisomerase I. Since then, the research activities have been increased again in order to find camptothecin derivatives which are more compatible and active in vivo.
To improve the water-solubility, salts of A ring- and B ring-modified camptothecin derivatives and of 20-O-acyl derivatives having ionizable groups have been described (Vishnuvajjala et al. U.S. Pat. No. 4943579). The latter prodrug concept was later also applied to modified camptothecin derivatives (Wani et al. WO 9602546). In vivo, however, the 20-O-acyl prodrugs described have a very short half-life and are very rapidly cleaved to give the parent structure.
Surprisingly, we have now found that the linkage of carbohydrate derivatives via suitable spacers on amino or hydroxyl groups which are connected to the A or B ring of camptothecin derivatives directly or via a spacer leads to a class of compounds having highly interesting properties: tumour cell lines and tumour xenografts. tolerability and tumour selectivity and improved solubility, in particular in aqueous media. stages. than the 20-O-acyl prodrugs of camptothecin described in the literature.
The present invention relates to compounds of the general formula (I) ##STR2## in which n, m and o in each case represent the number 0 or 1 and n+m+o is .gtoreq.1 where ##STR3## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently of one another may represent hydrogen, alkyl having up to 3 carbon atoms, halogen, amino, hydroxyl or nitro or ##STR4## p may have the values 1 or 2 and R.sup.5 represents --O--*, --NH* or ##STR5## or represents --*NR.sup.6, in which R.sup.6 represents arylmethyl or hetarylmethyl, ##STR6## in which R.sup.7 and R.sup.8 are as defined for R.sup.2 and R.sup.3 and may be identical or different to these, ##STR7## in which R.sup.9 represents hydrogen or --CH.sub.2 --N(CH.sub.3).sub.2 and ##STR8## in which R.sup.11 and R.sup.12 are as defined for R.sup.2 and R.sup.3 and may be identical or different to these, or ##STR9## in which R.sup.13 and R.sup.14 are as defined for R.sup.2 and R.sup.3 and may be identical or different to these, linear order, linker groupings customarily used in glycoconjugate chemistry, (see review article Lee Y.C. and Lee, R. in Lectins and Cancer 1991, 53-69; edited by Gabius M. J. and Gabius S., Springer Verlag), arylene having up to 10 carbon atoms or represent alkylene having up to 8 carbon atoms which are in each case optionally substituted, and radical of the formula (II) ##STR10## in which A represents methyl, hydroxymethyl, alkoxymethyl having up to 6 carbon atoms, acyloxymethyl having up to 6 carbon atoms or a radical of the formula --CH.sub.2 --B in which hydrogen, hydroxyl, optionally hydroxyl-substituted alkoxy having up to 6 carbon atoms, amino which is optionally substituted by alkyl or acyl having up to 6 carbon atoms, halogen, sulphate or a group of the formula ##STR11## in which R.sup.18 and R.sup.19 independently of one another each represent hydroxyl or alkoxy having u
REFERENCES:
patent: 4943579 (1990-07-01), Vishnuvajjala et al.
patent: 5340817 (1994-08-01), Wall et al.
patent: 5646159 (1997-07-01), Wall et al.
patent: 5688931 (1997-11-01), Nogusa et al.
patent: 5837673 (1998-11-01), Tsujihara et al.
patent: 5892043 (1999-04-01), Tsujihara et al.
patent: 5955100 (1999-09-01), Bosslet et al.
J. Am. Chem. Soc. 88, 3888 (1966), Wall et al.
Neoglycoconjugaates: Fundamentals and recent progresses Ubersichtsartikel Lee Y.C. and Lee, R. in Lectins and Cancer 1991, 53-69; edited by Gabius M.J. and Gabius S., Springer Verlag.
J. Med. Chem. 38 (1995), 395, Luzzio et al.
Baumgarten Jorg
Lerchen Hans-Georg
Sperzel Michael
von dem Bruch Karsten
Bayer Aktiengesellschaft
Kight John
Robinson Binta
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