Derivatives of 2'-deoxyuridine substituted in the 5-,3'-or 5'-po

Details Derivatives of 2'-deoxyuridine substituted in the 5-,3'-or 5'-po Derivatives of 2'-deoxyuridine substituted in the 5-,3'-or 5'-po

1990-08-17

1993-05-18

Brown, Johnnie R.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 282, 530327, A61K 3170, C07H 1700

Patent

active

052121615

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to novel derivatives of 2'-deoxyuridine substituted in the 5-, 3'- or 5'-position by a .alpha.-aminoacyl groups, to a process for their preparation and to pharmaceutical compositions in which they are present.
Some 2'-deoxyuridine derivatives are already known.
Thus derivatives of 2'-deoxyuridine substituted in the 5-position have been described which have the following general chemical formula: ##STR2## in which R is an alkyl or alkenyl radical having from 1 to 4 carbon atoms, an aryl radical or a halogen, it being possible for said alkyl and aryl radicals to contain at least one halogen substituent.
5'-Amino-2', 5'-dideoxy-5-methyluridine of the formula: a potential inhibitor of the herpes virus. The preparation of this compound is described in an article by Horwitz et al. in the journal "J. Org. Chem." 27 3045, (1962).
3'-Amino-2',3'-dideoxy-5-methyluridine of the formula: ##STR3## is also known, especially from a publication by LIN and PRUSOFF (J. Med. Chem. 21 109 (1978)).
Finally, 5-amino-2'-deoxyuridine of the formula: ##STR4## is known, especially from a publication by BELTZ and VISSER (J. Biol. Chem., 226, 1035, (1957)). The document J. Med. Chem. 1979, vol. 22, No. 6, pages 621 to 631 describes in general terms a process for the preparation of 5-[[.omega.-(iodoacetamido)acyl]amino]-2'-deoxyuridines using, as synthesis intermediates, compounds of the formula: ##STR5## in which R is the residue of an .omega.-amino acid.
These compounds are not presented as being capable of therapeutic application.
The present invention relates to a novel class of derivatives of 2'-deoxyuridine substituted in the 5-, 3'- or 5'-position by .alpha.-aminoacyl groups, which have the following general formula: ##STR6##
in which atoms, an aryl radical or a halogen, it being possible for said alkyl, alkenyl and aryl radicals to contain at least one halogen substituent, and a radical of the formula --NH--R.sub.1, in which R.sub.1 is an amino acid residue or a peptide residue containing from 2 to 6 amino acids; and --NH--R.sub.1, in which R.sub.1 is as defined above, that, when R is --NH--R.sub.1, R' and R" are simultaneously a hydroxyl group, and to their pharmaceutically acceptable salts.
The scope of the invention also includes all the possible optical isomers of the compounds of formula (I) and mixtures thereof.
In general formula (I), a halogen atom is preferably a chlorine or bromine atom.
The alkyl and alkenyl groups can be groups with a linear or branched chain.
An alkyl group having from 1 to 4 carbon atoms is, for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl group, preferably a methyl or ethyl group.
An alkenyl group having from 1 to 4 carbon atoms is, for example, a vinyl, propenyl or butenyl group, preferably a vinyl group.
The pharmaceutically acceptable salts of the compounds of formula (I) include those formed with a mineral acid, for example hydrochloric acid or sulfuric acid, or with an organic acid, for example citric, tartaric, malic, maleic or fumaric acid.
It has been discovered, totally surprisingly, that these novel derivatives possess the valuable pharmacological property of being inhibitors of the fetal thymidine kinase present in human cancerous tissues and are thus inhibitors of DNA synthesis in proliferating cancerous cells.
According to one particular characteristic, the invention relates to the novel class of derivatives of 2'-deoxyuridine substituted in the 5'-position, i.e. the compounds of general formula (I) in which R' is a hydroxyl group and R" is a group --NH--R.sub.1.
According to another particular characteristic, the invention relates to the novel class of derivatives of 2'-deoxyuridine substituted in the 3'-position, i.e. the compounds of general formula (I) in which R' is a group --NH--R.sub.1 and R" is a hydroxyl group.
According to yet another particular characteristic, the invention relates to the novel class of derivatives of 2'-deoxyuridine substituted in the 5-position, i.e. the compounds

REFERENCES:
patent: 3853845 (1974-12-01), Rousseau et al.
patent: 4093716 (1978-06-01), Lin et al.
patent: 4128639 (1978-12-01), Lin et al.
The Merck Index (1967) pp. 872-873.
Chem. Pharm. Bull. 25(7) 1740-1748 Azuna et al. (1977).
CA 117(5):49132t (1992) Wengel et al.
"Synthesis and Biological Activity of Several Amino Analogues of Thymidin Linn et al., Journal of Medicinal Chemistry, 1978, vol. 21, No. 1, pp. 109-112.
"Studies on the Action of Thymidine Analogues", Beltz et al., Journal of Biological Chemistry, vol. 226, pp. 1035-1045, 1957.
"Nucleoside Peptides. I. The Synthesis of 5'-Deoxy-5'-amino-5'-N-aminoacyl Peptide Derivatives of Guanosine, Adenosine, and 2'-Deoxyadenosine and Their Effect on Cell-Free Protein Synthesis", Robbins et al., J. Am. Chem. Soc., vol. 6, 1971, pp. 1474-1480.
"Nucleosides. I. 5'-Amino-5'-Deoxyuridine and 5'-Amino-5'-deoxythymidine", Horwitz et al., J. Org. Chem., 27, pp. 3045-3048.
Design of Species-or Isozyme-Specific Enzyme Inhibitors, 1. Effect of Thymidine Substitutents on Affinity for the Thymidine Site of Hamster Cytoplasmis, Thymidine Kinase, Hampton et al., J. of Org. Chem., 22, No. 6, pp. 621-631 (1979).

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