Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1985-05-13
1987-04-14
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 17, 514809, 530302, 530329, 530330, A61K 3724, C07K 706, C07K 744
Patent
active
046578927
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
In the German application DT-OS No. 29 36 099, which crresponds to U.S. Pat. No. 4,390,527, pharmacologically active peptides are described, in particular peptides with opiate-like activity, which are more potent in opiate-like activity and which have a higher stability against proteolytic enzymes (for example contained in rat plasma) when compared to the peptides described in DT-OS No. 29 21 216, corresponding to U.S. patent application Ser. No. 229,577 filed Jan. 22, 1981. The peptides of the DT-OS No. 29 36 099 have the following basic structure: D-form, L--Phe is equal to L-phenylalanine and L--Pro is equal to L-proline. It should already be mentioned now that according to the DT-OS No. 29 36 099 the amino acid in position 4 is in the L-form; the D-form is not mentioned. It has been demonstrated, that these peptides have only a determined maximal potency, especially opiate-like (see table 1, page 13).
In the German application DT-OS No. 30 34 897, which is very similar to the DT-OS No. 29 36 099 pharmacologically active peptides of the following basic structure are described: equal to phenylalanine and B is a neutral L-amino acid residue (i.e. glycine). Also here it should be mentioned that the amino 4th acid residue should be of the L-form.
In addition, it should be mentioned that the peptides of the European application No. 81305519.1 (publication No. 0053029) are essentially identical with those of the already mentioned DT-OS No. 29 21 216. The European application No. 81305519.1 has, however in the position of the 4th amino acid residue in the peptide a D-amino acid, but it was not realised, that a particular potent opiate-like effect resulted through a combination of a D--Ala residue in the second position together with a D-Proline residue in the position 4. Additionally the peptides of the Europ. application No. 8130519.1 have the disadvantage, that they are rapidly degraded in the blood and that they show by this only shortly lasting pharmacological effects in the living organism. (This degradation is prevented by introduction of a D-alanine residue in position 2). Detailed data on this are described in the DT-OS No. 29 21 216 and DT-OS No. 29 36 099.
It is an object of this invention to provide new pharmacologically active peptides, in particular opiate-like, which exhibit more potent pharmacological effects, in particular opiate-like and/or which exhibit a higher stability against proteolytic enzymes.
These objects are satisfied according to the invention in that the pharmacologically active peptides have the following formula: amino acid of the D-form, L--Phe is the amino acid residue L-phenylalanine. A and B may represent any amino acid residue. T represents OH, OR, NH.sub.2, NHR, NR.sub.2 or NH NHR', at which R has, if necessary, the following meaning: a substituted linear or branched C.sub.1-10 -alkyl, adamantyl, C.sub.1-10 -cycloalkyl or C.sub.6-8 -aralkyl, suitable phenyl, benzyl or means phenylethyl and R' hydrogen, linear or branched C.sub.1-10 -alkyl, cycloalkyl or C.sub.6-8 -aralkyl, C.sub.2-8 -alkenyl, linear, branched or cyclic aliphatic C.sub.1-16 -acyl, if appropriate substituted by OH, NH.sub.2, C.sub.1-4 -alkoxy or halogen, aromatic acyl, if appropriate substituted by OH, NH.sub.2, halogen, or C.sub.1-4 -alkoxy; linear, branched or cyclic C.sub.3-11 -aliphatic urethan or aromatic urethan and their pharmaceutically acceptable salts.
According to the invention, the peptides have in contrast to that described in the prior art a higher opiate-like activity and/or an increased stability against proteolytic enzymes (see example).
According to a further development of the invention the peptides are characterized in that the amino acid residue X is replaced by the following amino acids:
D-alanine, D-threonine, D-serine, D-methionine, D-valine, D-phenylalanine, D-leucine, D-isoleucine, D-arginine, D-histamine, D-proline, D-hydroxyproline, D-lysine, D-glutamine, D-glutamic acid, D-asparagine, D-aspartic acid and A, B are replaced by the aromatic amino acids tyrosine and phen
REFERENCES:
patent: 4254024 (1981-03-01), Stewart et al.
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