Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1981-01-22
1987-07-21
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 16, 514 17, 514 18, 530328, 530329, 530330, 530331, A61K 3702, C07K 508, C07K 510, C07K 706
Patent
active
046818715
DESCRIPTION:
BRIEF SUMMARY
The invention deals with new pharmacologically active peptides, in particular, peptides with opiate-like activity, methods for their activation and/or isolation, methods for their synthetic manufacture, as well as pharmacologically active peptides manufactured according to these methods.
Pharmacologically active peptides have been known which in special biological testing systems display a specific opiate-like activity. They are, in particular, those pentapeptides isolated from the brain by Hughes et al. (Nature 258, 577, 1975): methionine cephalin and the leucine cephalin as well as their longer chain analogs. These known peptides and their synthetic derivatives have the disadvantage that they lose their pharmacological activity, in this case an opiatelike activity, after treatment in vitro with proteases (for example, Pronase E.Merck) after a short incubation period. On in vivo administration these peptides are only slightly attacked and destroyed by proteases naturally present in the body.
It is an object of the present invention to create new pharmacologically active peptides, in particular, ones with opiate-like activity, which have a new, special amino acid sequence, and which have, based on this sequence, a surprisingly increased stability against the peptide-splitting enzymes (proteases, for example, Pronase E. Merck). It is furthermore an object of the invention to put those skilled in the art in a position so they can manufacture the peptide in any desired amount using customary methods, by disclosing the amino acid sequence of the pharmacologically active peptides.
This object is satisfied according to the invention in that the pharmacologically active peptides have the following formula: Tyr-Pro-A-Pro-B-Pro-C-Pro-D . . . etc., in which Tyr is equal to the amino acid tyrosine, and Pro is equal to the amino acid proline. A, B, C, D, . . . etc., can be any amino acid (also Pro/Tyr).
According to a further development of the invention, one of the peptide chain ends has the grouping Tyr-Pro-A-Pro-B-Pro-C-Pro-D . . . etc., in which the proline residues have been entirely or partially substituted by amino acid residues of tryptophan, leucine, alanine, glycine, isoleucine, tyrosine, phenylalanine, valine, histidine, hydroxyproline, asparagine and/or methionine. A, B, C, D . . . etc., can be any amino acid.
According to an advantageous further development, the pharmacologically active peptides have the following formulas:
According to a particularly advantageous further development the letters, A, B, C, D of the peptides listed up to now are:
According to another further development, the optically-active amino acids and/or amino acid residues of the peptides have been replaced by those which have a D-, L-or D/L stereochemical configuration.
According to a preferred further development, all amino acids of the peptide are present in L-form.
According to another further development
(a) the end-positioned tyrosine has the general formula: ##STR1## and is substituted by:
R.sub.1 for hydrogen or an alkyl group with 1 to 4 C-atoms,
R.sub.2 for hydrogen or together with R.sub.1 for an ethylene bond,
R.sub.3 for hydrogen, an alkyl group with 1 to 4 C-atoms or an R.sub.4 CO-group,
R.sub.4 for a saturated or unsaturated straight or branched chain alkyl residue with 1 to 17 C-atoms, a phenyl residue or a phenyl alkyl residue with 7 to 12 C-atoms, whereby the phenyl residues can be substituted by 1 or 2 substitutents from the halogen series, alkyl with 1 to 4 C-atoms or alkoxy with 1 to 4 C-atoms, whereby the R.sub.3 O-group is in the meta position or para position to ##STR2##
W for the hydrogen, alkyl with 1 to 5 C-atoms, alkenyl with 3 to 5 C-atoms, cyclopropylmethyl, cyclobutylmethyl, R.sub.4 CO-, H-Lys-, H-Phe- or H-Tyr.
(b) The phenylalanine of the general formula: ##STR3## is substituted by:
R.sub.5 for hydrogen or alkyl with 1 to 4 C-atoms,
R.sub.6 for hydrogen, fluorine, chlorine, bromine, nitro, alkyl with 1 to 4 C-atoms or alkoxy with 1 to 4 C-atoms,
Z for one or two substituents.
(c) the proline of the ge
REFERENCES:
patent: 3793304 (1974-02-01), Wieland et al.
patent: 4028318 (1977-06-01), Aurell et al.
patent: 4119620 (1978-10-01), Nagatsu et al.
patent: 4247454 (1981-01-01), Af Ekenstan et al.
patent: 4252715 (1981-02-01), Aurell et al.
patent: 4254106 (1981-03-01), Wilkinson
patent: 4390527 (1983-06-01), Brantl et al.
Unlisted Drugs, Feb. 1980, edit Spec. Library Association, Naunym Schmied Arch. Pharmacol 308 (Suppl.): R39 (155 Abs), 1979 Casomorphins siehe Zusammenfassung.
Brantl Victor
Henschen Agnes
Lottspeich Friedrich
Teschemacher Hansjorg
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