Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1989-08-10
1992-05-05
Wax, Robert A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 18, 514261, 530331, A61K 3702, A61K 3162, C07K 506
Patent
active
051107988
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to purine derivatives having an immunomodulating, antiviral activity and on Central Nervous System, to a process for the preparation thereof and to pharmaceutical compositions containing them.
The derivatives according to the invention can be presented by the following tautomeric general formula I ##STR2## wherein R.sub.1 is OH or NH.sub.2 and R.sub.2 is hydrogen or NH.sub.2, with the proviso that R.sub.1 and R.sub.2 cannot be both NH.sub.2 groups, R is hydrogen or C.sub.1 -C.sub.6 alkyl, A is a group of formula II ##STR3## wherein X is oxygen, sulphur or selenium m is an integer from 0 to 4; tri-peptide residue in which the amino acids which compose it are selected from the group consisting of alanine, arginine, glycine, isoglutamine, leucine, lysine, methionine, ornithine, proline and serine, with the proviso that, when A is a residue of formula III, B is always a di- or tri-peptide residue as above defined.
In case amino acid B or N-terminal amino acid of the di- or tri-peptide is a basic amino acid (arginine, ornithine, lysine), the carbamate bond can involve either the amino group which is at the l-position to the carboxy group or the amino group at the w-position to the carboxy group.
The present invention also relates to non toxic salts of compounds of formula I.
European patent N. 0 077 660 discloses purine derivatives in which an amino acid is linked to the purine ring at the 9-position by means of carbonyloxyalkyl or carbonylethylcarbonyloxyalkyl bridges.
The derivatives according to the present invention show, in comparison to the known compounds, a different and surprising pharmacological activity range, particularly immunostimulating activity, antiviral activity and activity on Central Nervous System, so that they are valuable for use in human therapy.
Preferred compounds according to the invention are: is 0 or 1, X is oxygen, n is 2 and B is an amino acid residue selected from the group consisting of arginine, methionine, leucine or the residue of a di- or tri-peptide selected from the group consisting of leucyl-methionine, ornithyl-ornithine, glycyl-leucyl-methionine, leucyl-seryl-arginine, lysyl-arginine, alanyl-isoglutamine, lysyl-lysine, histidyl-leucyl-methionine, propyl-arginine; which p is 2 or 3, R.sub.3 is hydrogen and B is a di- or tri-peptide selected from the above defined group.
Compounds I are prepared by reaction of a compound of formula IV: ##STR4## wherein R.sub.1, R.sub.2, R and A are as above defined, with phosgene and subsequent condensation with an amino acid or dior tri-peptides of formula H.sub.2 NB according to per se known procedures.
Compounds of formula IV in which R.sub.1 is OH, R.sub.2 is hydrogen or NH.sub.2 and A is a residue of formula III wherein R and R.sub.3 are hydrogen, are prepared according to the procedures described in EP-B-77460. Compounds IV wherein R.sub.1 is OH, R.sub.2 is hydrogen and A is a residue of formula III can be prepared according to the process described in Italian Pat. Application N. 19083 A/87.
Compounds IV in which R.sub.1 is OH and R.sub.2 is NH.sub.2 can be obtained according to the following reaction scheme: ##STR5## wherein Q is a residue of formula ##STR6## in which R and A are as above defined.
Compounds IV in which R.sub.2 is hydrogen and R.sub.1 is NH.sub.2, on the contrary, are obtained from compounds of formula V ##STR7## wherein R and A are as above defined, by reaction with liquid NH.sub.3 at high temperature.
For the preparation of compounds IV in which A is a residue of formula II, reaction schemes analogous to the ones reported above and the ones known for the preparation of purine systems can be conveniently used. Thus, for example, 4,6-dichloro-5-amino-pyrimidine can be reacted with a compound for formula H.sub.2 N(CH.sub.2).sub.m --X--(CH.sub.2).sub.n OH wherein X, m and n are as above defined, to obtain the intermediates of formula VI: ##STR8## which can then be transformed into corresponding compounds I by means of an appropriate combination of known reactions, analogous to the above r
REFERENCES:
patent: 4548819 (1985-10-01), De Clercq et al.
G. Migliorati et al., Cancer Detection and Prevention 16: 1-3, 16 Apr. 1991.
Ferraris Paolo C.
Stradi Riccardo
Co Pharma Corporation S.r.l.
Walsh Stephen
Wax Robert A.
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