GB2166139A - Biologically active penta- and heptapeptides - Google Patents

Biologically active penta- and heptapeptides Download PDF

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Publication number
GB2166139A
GB2166139A GB08427027A GB8427027A GB2166139A GB 2166139 A GB2166139 A GB 2166139A GB 08427027 A GB08427027 A GB 08427027A GB 8427027 A GB8427027 A GB 8427027A GB 2166139 A GB2166139 A GB 2166139A
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Prior art keywords
tyr
phe
ala
arg
ser
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GB08427027A
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GB8427027D0 (en
GB2166139B (en
Inventor
Giuseppe Perseo
Renzo Mena
Castiglione Roberto De
Antonietta Cervini
Alessandro Rossi
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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Priority to GB08427027A priority Critical patent/GB2166139B/en
Publication of GB8427027D0 publication Critical patent/GB8427027D0/en
Priority to DE19853537405 priority patent/DE3537405A1/en
Priority to JP60233569A priority patent/JPS61103898A/en
Priority to BE0/215758A priority patent/BE903493A/en
Publication of GB2166139A publication Critical patent/GB2166139A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

5 and 7 residue peptides of formula: <IMAGE> wherein X is hydrogen, a protecting group or an amidino group, Y is hydrogen atom or a protecting group, A is a D-aminoacid, B and E are optionally substituted D or L aminoacid, C is Gly or Sar or a D or L amino acid, F is a valency bond or a Pro-Ser residue; and pharmaceutically acceptable salts thereof; are useful as analgesic, antipsychotic and neuroendocrinological agents.

Description

SPECIFICATION Biologically active penta- and heptapeptides The invention relates to biologically active peptides, their pharmaceutically acceptable salts, processes for their preparation and their application as therapeutic agents.
The invention provides peptides of general formula (I):
wherein X represents a hydrogen atom, a group of formula
or a terminal amino protecting group selected from formyl, acetyl, trifluoroacetyl, propionyl, benzoyl, benzyloxycarbonyl, 2 ,4-dichlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, t-butoxycarbonyl, 1 -methyl-cyclobutoxycarbonyl, adamantyloxycarbonyl, methyl, ethyl, isopropyl, benzyl and trityl; Y represents a hydrogen atom or a phenolic hydroxy protecting group selected from formyl, acetyl, trifluoroacetyl, benzoyl, methyl. t-butyl, trityl, benzyl and 2,4-dichlorobenzyl, t-butoxycarbonyl, benzyloxycarbonyl and 2 ,4-dichlorobenzyloxycarbonyl;; A represents a D-Ala, D-Val, D-lle, D-Leu, D-Pro, D-Ser, D-Thr, D-Met, D-MetO, D-Arg, D-Lys or D-Orn residue; B represents a Phe residue unsubstituted or substituted at the p-position of the benzene ring by Cl, F, NO2, NH2 or SO2NH2 or B represents a Trp or Phg residue; C represents a Me-Ala, Me-Phe, Phg, Npg, Ala, Val, lle, Leu, Met, Ser, Thr, Phe, Trp or Tyr residue either of L- or D-configuration or a Gly or Sar residue; E represents a Tyr, Ser, Thr, Met, MetO, Leu, Nle, Ape, Phe or substituted Phe residue either of L- or D-configuration, the substituent on the substituted Phe residue being chlorine, bromine, fluorine, amino or nitro and being located at the p-position of the benzene ring; and F represents a valency bond or the dipeptide residue Pro-Ser.The invention further provides that, when X is a hydrogen atom or a terminal amino protecting group, A is a basic amino acid residue or B is not a Phe residue or C is an amino acid residue having a D-configuration.
Salts of peptides according to the invention with pharmaceutically acceptable acids are within the scope of the invention. Such acid addition salts can be derived from a variety of inorganic and organic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, nitric, sulfamic, citric, lactic, pyruvic, oxalic, maleic, succinic, tartaric, cinnamic, acetic, trifluoroacetic, benzoic, salicylic, gluconic, ascorbic and related acids.
The present invention also provides a process for the preparation of a peptide or pharmaceutically acceptable salt thereof according to the invention, which process comprises condensing suitable protected aminoacids, aminoacid derivatives or peptides, in the order of the aminoacids of the desired peptide, optionally reacting the resultant peptide with the appropriate guanylating agent, as required removing the protecting groups and optionally converting the resulting peptide into a pharmaceutically acceptable salt thereof, the reaction conditions being selected to avoid racemisation at chiral centers.
The synthesis consists essentially in appropriate successive condensations of protected amino acids or peptides. The condensation is carried out so that the resulting peptide has the desired sequence of 5- or 7-amino acid residues. The amino acids and peptides, which can be condensed according to methods known in themselves in polypeptide chemistry, have their amino and carboxyl groups, which are not involved in the formation of the peptide linkage, blocked by a suitable protecting group. The protecting groups are capable of being removed by acid or alkali treatment and by hydrogenolysis.For the protection of the amino group the following protective groups may, for example, be employed: benzyloxycarbonyl, t-butoxycarbonyl, trityl, formyl, trifluoroacetyl, o-nitrophenylsulphenyl, 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 3 ,5-dimethoxy-a-a'-dimethylbenzyloxycarbonyl or methylsulphonylethoxycarbonyl.
For the protection of the carboxyl group the following protective groups may, for example, be employed: methyl, ethyl, t-butyl, benzyl, p-nitrobenzyl or fluorenylmethyl.
The hydroxy functions of hydroxy amino acids may be protected by suitable protecting groups (throughout all the synthesis or only during a few steps) or may be unprotected.
De-protecting reactions are carried out according to methods known per se in polypeptide chemistry.
The condensation between an amino group of one molecule and a carboxyl group of another molecule to form the peptidic linkage may be carried out through an activated acyl-derivative such as a mixed anhydride, an azide or an activated ester, or by direct condensation between a free amino group and a free carboxyl group, in the presence of a condensing agent such as dicylohexylcarbodiimide, alone or together with a racemization preventing agent, such as Nhydroxysuccinimide or 1-hydroxybenzotriazole. The condensation may be carried out in a solvent such as dimethylformamide, dimethylacetamide, pyridine, acetonitrile, tetrahydrofuran or N-methyl-2-pyrrolidone.
The reaction temperature may be from -30"C to ambient temperature. The reaction time is generally from 1 to 120 hours. The scheme of synthesis, the protecting groups and the condensing agents are selected so as to avoid the risk of racemization.
The preparation of the compounds of general formula I wherein X is an amidino group can be achieved by reacting the corresponding compounds of formula I wherein X is a hydrogen atom with a guanylating agent such as 1-guanyl-3,5-dimethylpyrazole.
The compounds according to the invention are useful in methods of treatment of the human or animal body by therapy or surgery or in methods of diagnosis. They show interesting pharmacological activities, particularly on the central nervous system as analgesics, antipsychotics, and neuroendocrinologicals, in tests carried out on laboratory animals.
Analgesic activity has been assessed in rats by the tail-pinch test according to Bianchi C. and Franceschini J. in Br. J. Pharmacol. 9, 280, 1954, and the by tail4lick test according to D'amour F.E. and Smith D.L. in J. Pharmacol. Exp. Ther. 72, 74, 1941. The tested substances were administered intravenously, subcutaneously, intraperitoneally or orally. When administered intravenously or subcutaneously, the tested products displayed on unusually long-lasting (over 120 min) analgesic effect at doses generally from 0.1 to 20 mg/kg.
The compounds according to the invention show very high affinities to central analgesic receptors when tested "in vitro" on the rat brain according to the procedure described by Pert and Snyder in Molec. Pharmacol., 10, 878, 1974.
Activity on the central nervous system with the characteristic properties of antipsychotic drugs is also displayed by the compounds according to the invention, as shown by tests carried out on rats according to the procedure described by Janssen, Jageneau and Schellekens in Psychopharmacologia (were.), 1, 389, 1960. Active doses are generally from 0.2 to 60 mg/kg.
Furthermore, the compounds according to the invention stimulate the release of growthhormone and prolactin as shown by radio-immuno assays in the rat, carried out according to the procedure described by Niswender, Chen, Midgley, Mettes, Ellis, Proc. Soc. Exp. Biol. Med., 130, 793, 1968. Active doses are generally from 0.01 to 10 mg/kg. Accordingly, the invention further provides a pharmaceutical composition comprising a peptide according to the invention or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
Preferred compounds according to the invention are reported below H-Tyr-D-Ala-Phe-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phe(Cl)-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phe(F)-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Trp-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phg-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe(Cl)-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe(F)-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Trp-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phg-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe(CI)-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe(F)-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Trp-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phg-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe(CI)-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe(F)-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Trp-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phg-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe(Cl)-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe(F)-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Trp-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phg-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe(CI)-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe(F)-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Trp-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phg-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe(CI)-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe(F)-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Trp-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phg-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phe(CI)-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phe(F)-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Trp-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phg-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phe-D-Ala-Tyr-NH2 H-Tyr-D-Ala-Phe-D-Ala-Met-NH2 H-Tyr-D-Ala-Phe-D-Ala-MetO-NH2 H-Tyr-D-Ala-Phe-D-Ala-Ser-NH2 H-Tyr-D-Ala-Phe-D-Ala-Thr-NH2 H-Tyr-D-Ala-Phe-D-AIa-Leu-NH2 H-Tyr-D-Ala-Phe-D-Ala-Phe-NH2 H-Tyr-D-Ala-Phe-D-Ala-Phe(Cl)-NH2 H-Tyr-D-Arg-Phe-D-AIa-Tyr-NH2 H-Tyr-D-Arg-Phe-D-Ala-Met-NH2 H-Tyr-D-Arg-Phe-D-Ala-MetO-NH2 H-Tyr-D-Arg-Phe-D-Ala-Ser-NH2 H-Tyr-D-Arg-Phe-D-Ala-Thr-NH2 H-Tyr-D-Arg-Phe-D-Ala-Leu-NH2 H-Tyr-D-Arg-Phe-D-Ala-Phe-NH2 H-Tyr-D-Arg-Phe-D-Ala-Phe(CI)-NH2 G-Tyr-D-Arg-Phe-D-Ala-Tyr-NH2 G-Tyr-D-Arg-Phe-D-Ala-Met-NH2 G-Tyr-D-Arg-Phe-D-Ala-MetO-NH2 G-Tyr-D-Arg-Phe-D-Ala-Ser-NH2 G-Tyr-D-Arg-Phe-D-Ala-Thr-NH2 G-Tyr-D-Arg-Phe-A-Ala-Leu-NH2 G-Tyr-D-Arg-Phe-D-Ala-Phe-NH2 G-Tyr-D-Arg-Phe-D-Ala-Phe(CI)-NH2 G-Tyr-D-Arg-Phe-Gly-D-Tyr-NH2 G-Tyr-D-Arg-Phe-Gly-D-Met-NH2 G-Tyr-D-Arg-Phe-Gly-D-MetO-NH2 G-Tyr-D-Arg-Phe-Gly-D-Ser-NH2 G-Tyr-D-Arg-Phe-Gly-D-Thr-NH2 G-Tyr-D-Arg-Phe-Gly-D-Leu-NH2 G-Tyr-D-Arg-Phe-Gly-D-Phe-NH2 G-Tyr-D-Arg-Phe-Gly-D-Phe(Cl)-NH2 G-Tyr-D-Ala-Phe-Gly-D-Tyr-NH2 G-Tyr-D-Ala-Phe-Gly-D-Met-NH2 G-Tyr-D-Ala-Phe-Gly-D-MetO-NH2 G-Tyr-D-Ala-Phe-Gly-D-Ser-NH2 G-Tyr-D-Ala-Phe-Gly-D-Thr-NH2 G-Tyr-D-Ala-Phe-Gly-D-Leu-NH2 G-Tyr-D-Ala-Phe-Gly-D-Phe-NH2 G-Tyr-D-Ala-Phe-Gly-D-Phe(Cl)-NH2 H-Tyr-D-Arg-Phe-Gly-D-Tyr-NH2 H-Tyr-D-Arg-Phe-Gly-D-Met-NH2 H-Tyr-D-Arg-Phe-Gly-D-MetO-NH2 H-Tyr-D-Arg-Phe-Gly-D-Ser-NH2 H-Tyr-D-Arg-Phe-Gly-D-Thr-NH2 H-Tyr-D-Arg-Phe-Gly-D-Leu-NH2 H-Tyr-D-Arg-Phe-Gly-D-Phe-NH2 H-Tyr-D-Arg-Phe-Gly-D-Phe(Cl)-NH2 H-Tyr-D-Arg-Phe-Gly-Tyr-NH2 H-Tyr-D-Arg-Phe-Gly-Met-NH2 H-Tyr-D-Arg-Phe-Gly-MetO-NH2 K-Tyr-D-Arg-Phe-GIy-Ser-NH2 H-Tyr-D-Arg-Phe-Gly-Thr-NH2 H-Tyr-D-Arg-Phe-Gly-Leu-NH2 H-Tyr-D-Arg-Phe-Gly-Phe-NH2 H-Tyr-D-Arg-Phe-Gly-Phe(Cl)-NH2 H-Tyr-D-Arg-Phe-Sar-Tyr-NH2 H-Tyr-D-Arg-Phe-Sar-Met-NH2 H-Tyr-D-Arg-Phe-Sar-MetO-NH2 H-Tyr-D-Arg-Phe-Sar-Ser-NH2 H-Tyr-D-Arg-Phe-Sar-Thr-NH2 H-Tyr-D-Arg-Phe-Sar-Leu-NH2 H-Tyr-D-Arg-Phe-Sar-Phe-NH2 H-Tyr-D-Arg-Phe-Sar-Phe-(Cl)-NH2 H-Tyr-D-Arg-Phe-Sar-D-Tyr-NH2 H-Tyr-D-Arg-Phe-Sar-D-Met-NH2 H-Tyr-D-Arg-Phe-Sar-D-MetO-NH2 H-Tyr-D-Arg-Phe-Sar-D-Ser-NH2 H-Tyr-D-Arg-Phe-Sar-D-Thr-NH2 H-Tyr-D-Arg-Phe-Sar-D-Leu-NH2 H-Tyr-D-Arg-Phe-Sar-D-Phe-NH2 H-Tyr-D-Arg-Phe-Sar-D-Phe(Cl)-NH2 G-Tyr-D-Ala-Phe-Sar-D-Tyr-NH2 G-Tyr-D-Ala-Phe-Sar-D-Met-NH2 G-Tyr-D-Ala-Phe-Sar-D-MetO-NH2 G-Tyr-D-Ala-Phe-Sar-D-Ser-NH2 G-Tyr-D-Ala-Phe-Sar-D-Thr-NH2 G-Tyr-D-Ala-Phe-Sar-D-Leu-NH2 G-Tyr-D-Ala-Phe-Sar-D-Phe-NH2 G-Tyr-D-Ala-Phe-Sar-D-Phe(Cl)-NH2 G-Tyr-D-Arg-Phe-Sar-D-Tyr-NH2 G-Tyr-D-Arg-Phe-Sar-D-Met-NH2 G-Tyr-D-Arg-Phe-Sar-D-MetO-NH2 G-Tyr-D-Arg-Phe-Sar-D-Ser-NH2 G-Tyr-D-Arg-Phe-Sar-D-Thr-NH2 G-Tyr-D-Arg-Phe-Sar-Leu-NH2 G-Tyr-D-Arg-Phe-Sar-Phe-NH2 G-Tyr-D-Arg-Phe-Sar-Phe(Cl)-NH2; and their pharmaceutically acceptable salts.
In this specification symbols and abbreviations are those commonly used in peptide chemistry (see Eur. J. Biochem. (1984) 138, 9-37). Other symbols and abbreviations used are: AcOEt, ethyl acetate; AcOH, acetic acid; n-BuOH, n-butyl alcohol; DMF, dimethylformamide; ECC, ethylchloroformate; Et2O, diethyl ether; EtOH, ethyl alcohol; FC, flash chromatography on silica gel 0.040-0.063 mm (Merck); G,
HCI/AcOH, dry hydrogen chloride in glacial acetic acid; HCI/THF, dry hydrogen chloride in anhydrous tetrahydrofuran; MeOH, methyl alcohol; NMM, N-methylmorpholine; Npg, neopentylglycine; PE, petroleum ether; Phe(CI), p-chloro-phenylalanine; Phe(F), p-fluoro-phenylalanine; Phg, phenylglycine; iPr2O, diisopropyl ether; iPrOH, isopropyl alcohol; Sar, N-methylgylcine; THF, tetrahydrofuran; TLC, thin layer chromatography.The following Examples intend to illustrate the invention without limiting it. The R, are determined on pre-coated plates of silica gel 60 F254 (Merck), layer thickness 0.25 mm, length 20 cm, using the following development systems: System A: benzene/benzine (60-80)/ethyl acetate=70/10/40 by volume.
System B: benzene/ethyl acetate/acetic acid/water= 100/100/20/10 by volume (upper phase).
System C: benzene/ethyl acetate/acetic acid/water= 100/100/40/15 by volume (upper phase).
System D: n-butanol/acetic acid/water=4/1/1 by volume.
System E: methylene chloride/methanol=97/3 by volume.
System F: methylene chloride/methanol=95/5 by volume.
System G: chloroform/methanol/32 MO ammonium hydroxide=55/45/20 by volume.
Merck is a trade-mark.
TLC analysis are carried out at a temperature ranging from 18 to 25"C: the R, values can therefore change+5%. Melting points are determined in open capillaries with a Tottoli apparatus and are uncorrected. Most of the derivatives soften and decompose before melting. Solvents for crystallization, precipitation or grinding are reported in brackets.
High voltage paper electrophoresis is carried out with a Pherograph-Original-Frankfurt Type 64 apparatus on Schleicher and Scull paper No. 2317 at pH 1.2 (formic acid : acetic acid water=123:100:777) at 1600 V (40 V/cm), and at pH 5.8 (pyridine : acetic acid water=450:50:4500) at 1400 V (32.5 V/cm). The products were characterized by their mobilities at pH 1.2 (E,2) and pH 5.8 (Es8) relative to Glu. Optical rotations are measured with a Jasco DIP-140 Digital Polarimeter at a concentration c= 1 in methanol unless otherwise stated.
Example 1 Preparation of H-Tyr-D-Ala-Phe-D-Ala-Tyr-Pro-Ser-NH2 (IX) Step 1. Boc-Phe-D-Ala-OBzl (I) To a solution of 2.65 g (10 mmol) of Boc-Phe-OH in 30 ml of anhydrous THF,1.12 ml (10 mmol) of NMM and 0.99 ml (10 mmol) of ECC were successively added at a temperature of -12"C.
After stirring at this temperature for 2 minutes, a cold solution of 2.16 g (10 mmol) of HCI.D Ala-OBzl (G. Harris and l.C. MacWilliam (1963) J. Chem. Soc. 5552) and 1.12 ml of NMM (10 mmol) in 25 ml of DMF was added.
The reaction mixture was stirred for 45 minutes -120C and for 2 minutes at 0-15 C, then filtered from salts and evaporated in vacuo.
The residue was dissolved in ethyl acetate and washed several times successively with sodium chloride saturated solutions of 1M citric acid, 1M sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate and the solvent removed in vacuo, obtaining a partially purified compound as an oil. Purification was completed by FC eluting with CH2CI2:MeOH=98:2 to give from iPr2O/PE 2.86 g (67% yield) of compound I. m.p. 87-89"C; [a]2,4+18.5"; RfE 0.56; RfF 0.79.
Step 2. HCl.H-Phe-D-Ala-OBzl (II) 2.76 g (6.47 mmol) of Boc-Phe-D-Ala-OBzl (I) were dissolved at room temperature in 28 ml of a saturated solution of HCI/AcOH. After 30 minutes Boc-removal was complete and the solvent removed in vacuo. The residue was dissolved in iPrOH and concentrated to dryness. 2.04 9 (87% yield) of compound II were obtained from iPrOH/iPr2O. m.p. 167-172"C; [a]2,4+71.2"; Ref,0.74; E12 0.94.
Step 3. Boc-D-Ala-Phe-D-Ala-OBzl (Ill) Boc-D-Ala-OH (1.01 g, 5.35 mmol) and HCl.H-Phe-D-Ala-OBzl (Il) (1.94 g, 5.35 mmol) were coupled as described in Step 1 of this Example, but using iso-butylchloroformate as activating agent, to give 2.40 g (90% yield) of compound Ill from iPrOH/iPr2O. [a]2,4+15.7"; RfE 0.30; RfF 0.44.
Step 4. HCl.H-D-AIa-Phe-D-Ala-OBzl (IV) Boc-D-Ala-Phe-D-Ala-OBzl (Ill) (2.30 g, 4.63 mmol) was deblocked as described in the preceding Step 2, to give 1.91 g (95% yield) of compound IV from iPrOH/iPr2O/PE. [a]2,4+17.3"; RfD 0.67; ear2 0.84.
Step 5. Boc-Tyr-D-Ala-Phe-D-Ala-OBzl (V) Boc-Tyr-OH (1.19 g, 4.22 mmol) and HCl.H-D-Ala-Phe-D-Ala-OBzl (IV) (1.83 g, 4.22 mmol) were coupled as described in Step 1 of this Example to give 2.64 9 (95% yield) of compound V from iPrOH/iPR2O. [a]2,4+22.0"; Ref,0.55; RfB 0.71.
Step 6. Boc-Tyr-D-Ala-Phe-D-Ala-OH (Vl) 2.52 g (3.81 mmol) of Boc-Tyr-D-Ala-Phe-D-Ala-OBzl (V) dissolved in 30 ml of MeOH were hydrogenated at room temperature and atmospheric pressure in the presence of 0.63 g of 10% palladium-on-charcoal. The catalyst was removed by filtration and the solution concentrated in vacuo. The product was purified by FC eluting with AcOEt:MeOH=93:7, to give 1.30 g (60% yield) of compound VI from iPrOH/iPr2O. [a]2,4+20.6", Ref,0.29; Rfc 0.55; Es8 0.41.
Step 7. Boc-Tyr-D-Ala-Phe-D-Ala-Tyr(Bzl)-Pro-Ser-NH2 (VII) Boc-Tyr-D-Ala-Phe-D-Ala-OH (1.21 g, 2.12 mmol) (Vl) and HCl.H-Tyr(Bzl)-Pro-Ser-NH2 (1.04 9, 2.12 mmol) (de Castiglione et al., Int. J. Peptide Protein Res. (1981) 17, 263) were condensed as described in this Example, Step 1, but using a different isolation procedure.After the completion of the reaction, removal of salts by filtration and evaporation of the solvent, the oily residue was dissolved in 20 ml of DMF and poured dropwise in 200 ml of a 10% citric acid aqueous solution cooled to O"C. The product was filtered and washed to neutrality with water, dissolved in DMF and the resulting solution evaporated in vacuo. 1.50 g of a partially purified compound VII was obtained from iPrOH/iPr2O. The purity was increased by FC eluting with CH2CI2 containing increasing amount, from 5 to 10%, of methanol. 1.07 g (50% yield) of compound VII were obtained from iPrOH/iPr2O. [a]29.0"; Rf, 0.36; RfD 0.87.
Step 8. Boc-Tyr-D-Ala-Phe-D-Ala-Tyr-Pro-Ser-NH2 (VIII) Boc-Tyr-D-Ala-Phe-D-Ala-Tyr(Bzl)-Pro-Ser-NH2 (1.00 g, 0.99 mmol) (VII) was hydrogenated as described in this Example, Step 6, to give 0.84 g (93% yield) of compound VIII from iPrOH/i Pr2O. [a]2g+5.0 ; Rf, 0.17; Rf,2 0.82.
Step 9. HCl.H-Tyr-D-Ala-Phe-D-Ala-Tyr-Ser-NH2 (IX) 0.80 g (0.87 mmol) of Boc-Tyr-D-Ala-Phe-D-Ala-Tyr-Pro-Ser-NH2 (VIII) were dissolved at room temperature in a mixture of 8 ml of a solution 3.5 M of HCl/THF and 0.8 ml of anisole. After 30 minutes Boc-removal was complete and the solvents removed in vacuo. 0.71 g of partially pure compound IX were obtained from iPrOH/iPr2O. The purification was completed by countercurrent distribution using as eluent system H20/n-BuOH/AcOH/EtOH=64/40/4/5. 0.52 g (702/o yield) of compound IX were obtained from MeOH/Et2O. m.p. 175-180"C(d); [a]2D+18.5"; Ref,) 0.49; E,2 0.56.
Example 2 Preparation of HCl.G-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (X) Step 1. HCl.G-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (X) 0.84 g (1.00 mmol) of HCl.H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (de Castigione et al., Int. J.
Peptide Protein Res. (1981) 17, 263) were dissolved in 10 ml of absolute ethanol and heated at 65"C. 0.35 ml of triethyalmine (2.50 mmol) and 0.30 9 (1.50 mmol) of 1-guanyl-3,5-dimethylpyrazole nitrate were successively added and the mixture was allowed to react, under mechanical stirring, at 65"C for 6 hours. The solvent was removed in vacuo and the crude product obtained as an oil was purified by FC eluting with a mixture of CH2CI2:MeOH=6:4 containing increasing amount of a 33% aqueous solution of ammonia from 10 to 15%. After desalting on Sephadex G-10 eluting with EtOH/H2O=7/3, 0.35 g (40% yield) of compound X were obtained from AcOEt/EtOH. RfG 0.25; E12 0.51.
Results of tests for analgesic activity are reported in Table 1.
Table 1. Analgesia after subcutaneous administration (tail-pinch test in the rat) % Inhibition ED"(mg/kg) at 4 mg/kg H-Tyr-D-Ala-Phe-D-Ala-Tyr-Pro-Ser-NH 90 1.3 G-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 100 0.4

Claims (10)

1. A peptide of general formula (I)
wherein X represents a hydrogen atom, a group of formula
or a terminal amino protecting group selected from formyl, acetyl, trifluoroacetyl, propionyl, benzoyl, benzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, t-butoxycarbonyl, 1 -methyl-cyclobutoxycarbonyl, adamantyloxycarbonyl, methyl, ethyl, isopropyl, benzyl and trityl; Y represents a hydrogen atom or a phenolic hydroxy protecting group selected from formyl, acetyl, trifluoroacetyl, benzoyl, methyl, t-butyl, trityl, benzyl and 2,4-dichlorobenzyl, t-butoxycarbonyl, benzyloxycarbonyl and 2,4-dichlorobenzyloxycarbonyl; A represents a D-Ala, D-Val, D-lle, D-Leu, D-Pro, D-Ser, D-Thr, D-Met, D-MetO, D-Arg, D-Lys or D-Orn residue;; B represents a Phe residue unsubstituted or substituted at the p-position of the benzene ring by CI, F, NO2, NH2 or SO2NH2 or B represents a Trp or Phg residue; C represents a Me-Ala, Me-Phe, Phg, Npg, Ala, Val, lle, Leu, Met, Ser, Thr, Phe, Trp or Tyr residue either of L- or D-configuration or a Gly or Sar residue; E represents a Tyr, Ser, Thr, Met, MetO, Leu, Nle, Ape, Phe or substituted Phe residue either of L- or D-configuration, the substituent on the substituted Phe residue being chlorine, bromine, fluorine, amino or nitro and being located at the p-position of the benzene ring; and F represents a valency bond or the dipeptide residue Pro-Ser; with the proviso that, when X is a hydrogen atom or a terminal amino protecting group, A is a basic amino acid residue or B is not a Phe residue or C is an amino acid residue having a D-configuration; and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 which is H-Tyr-D-Ala-Phe-D-Ala-Tyr-Pro-Ser-NH2 or its hydrochloride.
3. A compound according to claim 1 which is G-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 or its hydrochloride.
4. A compound according to claim 1 which is H-Tyr-D-Ala-Phe(CI)-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phe(F)-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Trp-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phg-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe(Cl)-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe(F)-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Trp-D-Ala-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phg-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe(CI)-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe(F)-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Trp-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phg-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe(CI)-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe(F)-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Trp-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phg-D-Ala-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe(CI)-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phe(F)-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Trp-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Arg-Phg-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe(CI)-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phe(F)-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Trp-Gly-Tyr-Pro-Ser-NH2 G-Tyr-D-Ala-Phg-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe-Giy-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe(Cl)-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phe(F)-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Trp-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Arg-Phg-Gly-Tyr-Pro-Ser-NH, H-Tyr-D-Ala-Phe(CI)-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phe(F)-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Trp-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phg-Gly-Tyr-Pro-Ser-NH2 H-Tyr-D-Ala-Phe-D-Ala-Tyr-NH2 H-Tyr-D-Ala-Phe-D-Ala-Met-NH2 H-Tyr-D-Aia-Phe-D-Ala-MetO-NH2 H-Tyr-D-Ala-Phe-D-AIa-Ser-NH2 H-Tyr-D-Ala-Phe-D-Ala-Thr-NH2 H-Tyr-D-AIa-Phe-D-Ala-Leu-NH2 H-Tyr-D-Ala-Phe-D-AIa-Phe-NH2 H-Tyr-D-Ala-Phe-D-Ala-Phe(Cl)-NH2 H-Tyr-D-Arg-Phe-D-AIa-Tyr-NH2 H-Tyr-D-Arg-Phe-D-Ala-Met-NH2 H-Tyr-D-Arg-Phe-D-Ala-MetO-NH2 H-Tyr-D-Arg-Phe-D-Ala-Ser-NH2 H-Tyr-D-Arg-Phe-D-Ala-Thr-NH2 H-Tyr-D-Arg-Phe-D-Ala-Leu-NH2 H-Tyr-D-Arg-Phe-D-Ala-Phe-NH2 H-Tyr-D-Arg-Phe-D-Ala-Phe(Cl)-NH2 G-Tyr-D-Arg-Phe-D-Ala-Tyr-NH2 G-Tyr-D-Arg-Phe-D-Ala-Met-NH2 G-Tyr-D-Arg-Phe-D-Ala-MetO-NH2 G-Tyr-D-Arg-Phe-D-Ala-Ser-NH2 G-Tyr-D-Arg-Phe-D-Ala-Thr-NH2 G-Tyr-D-Arg-Phe-D-Ala-Leu-NH2 G-Tyr-D-Arg-Phe-D-Ala-Phe-NH2 G-Tyr-D-Arg-Phe-D-Ala-Phe(CI)-NH2 G-Tyr-D-Arg-Phe-Gly-D-Tyr-NH2 G-Tyr-D-Arg-Phe-Gly-D-Met-NH2 G-Tyr-D-Arg-Phe-Gly-D-MetO-NH2 G-Tyr-D-Arg-Phe-Gly-D-Ser-NH2 G-Tyr-D-Arg-Phe-GIy-D-Thr-NH2 G-Tyr-D-Arg-Phe-Gly-D-Leu-NH2 G-Tyr-D-Arg-Phe-GIy-D-Phe-NH2 G-Tyr-D-Arg-Phe-Gly-D-Phe(CI)-NH2 G-Tyr-D-AIa-Phe-Gly-D-Tyr-NH2 G-Tyr-D-Ala-Phe-Gly-D-Met-NH2 G-Tyr-D-Ala-Phe-GIy-D-MetO-NH2 G-Tyr-D-AIa-Phe-Gly-D-Ser-NH2 G-Tyr-D-Ala-Phe-Gly-D-Thr-NH2 G-Tyr-D-AIa-Phe-Gly-D-Leu-NH2 G-Tyr-D-Ala-Phe-GIy-D-Phe-NH2 G-Tyr-D-Ala-Phe-GIy-D-Phe(Cl)-NH2 H-Tyr-D-Arg-Phe-Gly-D-Tyr-NH2 H-Tyr-D-Arg-Phe-Gly-D-Met-NH2 H-Tyr-D-Arg-Phe-Gly-D-MetO-NH2 H-Tyr-D-Arg-Phe-Gly-D-Ser-NH2 H-Tyr-D-Arg-Phe-GIy-D-Thr-NH2 H-Tyr-D-Arg-Phe-GIy-D-Leu-NH2 H-Tyr-D-Arg-Phe-GIy-D-Phe-NH2 H-Tyr-D-Arg-Phe-Gly-D-Phe(Cl)-NH2 H-Tyr-D-Arg-Phe-Gly-Tyr-NH2 H-Tyr-D-Arg-Phe-GIy-Met-NH2 H-Tyr-D-Arg-Phe-Gly-MetO-NH2 H-Tyr-D-Arg-Phe-Gly-Ser-NH2 H-Tyr-D-Arg-Phe-GIy-Thr-NH2 H-Tyr-D-Arg-Phe-Gly-Leu-NH2 H-Tyr-D-Arg-Phe-Gly-Phe-NH2 H-Tyr-D-Arg-Phe-Gly-Phe(CI)-NH2 H-Tyr-D-Arg-Phe-Sar-Tyr-NH2 H-Tyr-D-Arg-Phe-Sar-Met-NH2 H-Tyr-D-Arg-Phe-Sar-MetO-NH2 H-Tyr-D-Arg-Phe-Sar-Ser-NH2 H-Tyr-D-Arg-Phe-Sar-Thr-NH2 H-Tyr-D-Arg-Phe-Sar-Leu-NH2 H-Tyr-D-Arg-Phe-Sar-Phe-NH2 H-Tyr-D-Arg-Phe-Sar-Phe(cl)-NH2 H-Tyr-D-Arg-Phe-Sar-D-Tyr-NH2 H-Tyr-D-Arg-Phe-Sar-D-Met-NH2 H-Tyr-D-Arg-Phe-Sar-D-MetO-NH2 H-Tyr-D-Arg-Phe-Sar-D-Ser-NH2 H-Tyr-D-Arg-Phe-Sar-D-Thr-NH2 H-Tyr-D-Arg-Phe-Sar-D-Leu-NH2 H-Tyr-D-Arg-Phe-Sar-D-Phe-NH2 H-Tyr-D-Arg-Phe-Sar-D-Phe(Cl)-NH2 G-Tyr-D-Ala-Phe-Sar-D-Tyr-NH2 G-Tyr-D-Ala-Phe-Sar-D-Met-NH2 G-Tyr-D-Ala-Phe-Sar-D-MetO-NH2 G-Tyr-D-Ala-Phe-Sar-D-Ser-NH2 G-Tyr-D-Ala-Phe-Sar-D-Thr-NH2 G-Tyr-D-AIa-Phe-Sar-D-Leu-NH2 G-Tyr-D-Ala-Phe-Sar-D-Phe-NH2 G-Tyr-D-Ala-Phe-Sar-D-Phe(Cl)-NH2 G-Tyr-D-Arg-Phe-Ser-D-Tyr-NH2 G-Tyr-D-Arg-Phe-Sar-D-Met-NH2 G-Tyr-D-Arg-Phe-Sar-D-MetO-NH2 G-Tyr-D-Arg-Phe-Sar-D-Ser-NH2 G-Tyr-D-Arg-Phe-Sar-D-Thr-NH2 G-Tyr-D-Arg-Phe-Sar-Leu-NH2 G-Tyr-D-Arg-Phe-Sar-Phe-NH2 or G-Tyr-D-Arg-Phe-Sar-Phe(cl)-NH2
5. A peptide according to any one of claims 2 to 4 in the form of a pharmaceutically acceptable salt.
6. A peptide as claimed in any one of claims 1 to 5 or a pharmacutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy or surgery or in a method of diagnosis.
7. A peptide or salt according to claim 6 for use an as analgesic, antipsychotic or neuroendocrinological agent.
8. A process for the preparation of a peptide as claimed in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises condensing suitable protected aminoacids, aminoacid derivatives or peptides, in the order of the aminoacids of the desired peptide, optionally reacting the resultant peptide with the appropriate guanylating agent, as required removing the protecting groups and optionally converting the resulting peptide into a pharmaceutically acceptable salt thereof, the reaction conditions being selected to avoid racemisation at chiral centers.
9. A process for the preparation of a pharmaceutically acceptable salt of a peptide of formula (I) as claimed in claim 1, said process being substantially as hereinbefore described in Example 1 or 2.
10. A pharmaceutical composition comprising as active ingredient a peptide or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 together with a pharmaceutically acceptable diluent or carrier.
GB08427027A 1984-10-25 1984-10-25 Biologically active penta-and heptapeptides Expired GB2166139B (en)

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DE19853537405 DE3537405A1 (en) 1984-10-25 1985-10-21 BIOLOGICALLY ACTIVE PENTA AND HEPTAPEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM
JP60233569A JPS61103898A (en) 1984-10-25 1985-10-21 Biologically active pentapeptide and heptapeptide
BE0/215758A BE903493A (en) 1984-10-25 1985-10-22 BIOLOGICALLY ACTIVE PENTA-AND HEPTA-PEPTIDES

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0755942A1 (en) * 1994-03-11 1997-01-29 Daiichi Pharmaceutical Co., Ltd. Peptide derivative
EP0850950A1 (en) * 1995-09-11 1998-07-01 Daiichi Pharmaceutical Co., Ltd. Peptide derivatives
US6051685A (en) * 1994-03-11 2000-04-18 Daiichi Pharmaceuticals Co., Ltd. Peptide derivatives
US20110052519A1 (en) * 2008-01-30 2011-03-03 Carreno Serraima Cristina Peptide derivatives useful in the treatment, care or cleansing of the skin, mucosae, scalp or nails

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2070618A (en) * 1979-09-20 1981-09-09 Erba Farmitalia Polypeptides
WO1985001292A1 (en) * 1983-09-19 1985-03-28 Victor Brantl Pharmacologically active peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2070618A (en) * 1979-09-20 1981-09-09 Erba Farmitalia Polypeptides
WO1985001292A1 (en) * 1983-09-19 1985-03-28 Victor Brantl Pharmacologically active peptides

Non-Patent Citations (1)

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Title
CHEMICAL ABSTRACTS (1981) 95: 43634P *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0755942A1 (en) * 1994-03-11 1997-01-29 Daiichi Pharmaceutical Co., Ltd. Peptide derivative
EP0755942A4 (en) * 1994-03-11 1997-05-21 Daiichi Seiyaku Co Peptide derivative
US6051685A (en) * 1994-03-11 2000-04-18 Daiichi Pharmaceuticals Co., Ltd. Peptide derivatives
EP0850950A1 (en) * 1995-09-11 1998-07-01 Daiichi Pharmaceutical Co., Ltd. Peptide derivatives
EP0850950A4 (en) * 1995-09-11 1999-05-19 Daiichi Seiyaku Co Peptide derivatives
US20110052519A1 (en) * 2008-01-30 2011-03-03 Carreno Serraima Cristina Peptide derivatives useful in the treatment, care or cleansing of the skin, mucosae, scalp or nails
AU2009209601B2 (en) * 2008-01-30 2014-07-10 Diverdrugs S.L. Peptide derivatives useful in the treatment, care or cleansing of the skin, mucosae, scalp or nails
US8815266B2 (en) * 2008-01-30 2014-08-26 Lipotech, S.A. Peptide derivatives useful in the treatment, care or cleansing of the skin, mucosae, scalp or nails
EP2245045B1 (en) * 2008-01-30 2017-09-06 Lipotec, S.A. Peptide derivatives useful in the treatment, care or cleansing of the skin, mucosae, scalp or nails

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DE3537405A1 (en) 1986-04-30
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BE903493A (en) 1986-04-22

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