Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-10-10
1999-03-16
O'Sullivan, Peter
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514825, 514895, 514903, 564138, 564141, 564159, C07C23114, C07C23118, A61K 3116
Patent
active
058831320
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates, by way of novel industrial products, to compounds whose structure is related to that of 15-deoxyspergualin, which has the nomenclature -hydroxy-2-oxoethyl!heptanamide. It further relates to their method of preparation and to their use in therapeutics.
PRIOR ART
15-Deoxyspergualin (DSG), also known by the international non-proprietary name "Gusperimus", is known to possess a valuable activity in the field of immunosuppression. Numerous publications refer to this activity: in particular, a series of articles on this subject may be found in "Immunomodulating Drugs"--Annals of the New York Academy of Sciences, vol. 685, pages 123 to 201.
However, 15-deoxyspergualin does not have a satisfactory chemical stability and attempts have been made to obtain compounds of greater stability, for example (i) by replacing the .alpha.-hydroxyglycine group of 15-deoxyspergualin with various .alpha.- or .omega.-amino acids, (ii) by modifying the structure of the central portion of the chain, or else (iii) by modifying the portion of the chain carrying the guanidine group. Examples of such modifications are described in EP-A-0 181 592, EP-A-0 105 193 and FR-A-2 698 628.
The modifications involving the spermidine portion of the chain were studied essentially in J. Antibiot. 40, pages 1303-1315, and most of the compounds prepared were inactive. None of the proposed structures showed an activity which was at least equivalent to that of DSG, and the authors concluded that the presence of the spermidine linkage was essential.
The present invention relates to compounds which are analogous to 15-deoxyspergualin but in which the spermidine linkage has been modified, said compounds having a greater activity than the known products.
SUBJECT OF THE INVENTION
The present invention proposes novel compounds whose general structure is related to that of 15-deoxyspergualin and which have a greater activity than the known products of the prior art in the field of immunosuppression.
The difference between the products according to the invention and the known products of the prior art derives especially from the presence of a methyl group on the carbon atom carrying the primary amine group of the spermidine portion of the molecule. The choice of a particular configuration for this asymmetric carbon atom (denoted by **C hereafter) also makes it possible to improve the activity of these novel compounds.
The 15-deoxyspergualin analogs according to the invention are characterized in that they are selected from the group consisting of: ##STR2## in which: R is a hydrogen atom, a group OH, a group OCH.sub.3 or a group CH.sub.2 OH, atom of (R, S), (R) or (S) configuration, and configuration; and
According to the invention, a method of preparing the compounds of formula (I) and their addition salts is also recommended, said method comprising the deprotection of a compound of the formula ##STR3## in which: R is a hydrogen atom, a group OCH.sub.3, a group OH, a group CH.sub.2 OH, a group OR' or a group CH.sub.2 OR', protecting group for the amine group, (R) or (S) configuration, and more reaction treatments known to those skilled in the art, in order to effect the replacement of all the protecting groups R.sub.1, R.sub.2, R.sub.3 and R' with a hydrogen atom.
According to the invention, a method of preparing the compounds of formula (I) in which *C is of determined (R) or (S) configuration and R is OH, and their addition salts, is also recommended, said method being applicable to the preparation of 11-(S)-15-DSG (S isomer of 15-deoxyspergualin) and comprising the step which consists in obtaining, as an intermediate, a mixture of diastereoisomers of the formula ##STR4## in which: Ar is an aromatic substituent, especially a naphthalenyl (i.e. naphthyl) group and preferably the 2-naphthalenyl group, --N(R.sub.2)--(CH.sub.2).sub.2 --CH(CH.sub.3)--NH(R.sub.3), amino-protecting group, especially of the benzyloxycarbonyl type, and separating the two isomers by methods known to those skilled in the art, f
REFERENCES:
patent: 4525299 (1985-06-01), Umezawa et al.
patent: 5061787 (1991-10-01), Saino et al.
The Journal of Antibiotics, vol. XL, No. 9, "Synthesis and Antitumor Activity . . . ", pp. 1303-1315, Sep. 1987.
Annals New York Academy of Sciences, "Synthesis and Background Chemistry . . . ", pp. 123-201, vol. 685.
Durand Philippe
Lebreton Luc
Renaut Patrice
Fournier Industrie et Sante
O'Sullivan Peter
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