EP0000559B1 - Pentapeptide-N-alkoylamides et leurs sels, procédé de préparation de ces produits et leurs compositions pharmacologiques - Google Patents

Pentapeptide-N-alkoylamides et leurs sels, procédé de préparation de ces produits et leurs compositions pharmacologiques Download PDF

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Publication number
EP0000559B1
EP0000559B1 EP78100463A EP78100463A EP0000559B1 EP 0000559 B1 EP0000559 B1 EP 0000559B1 EP 78100463 A EP78100463 A EP 78100463A EP 78100463 A EP78100463 A EP 78100463A EP 0000559 B1 EP0000559 B1 EP 0000559B1
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Prior art keywords
acid addition
peptide
addition salt
formulation according
compound
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EP78100463A
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German (de)
English (en)
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EP0000559A1 (fr
Inventor
Samuel Wilkinson
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Wellcome Foundation Ltd
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Wellcome Foundation Ltd
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Priority claimed from GB30909/77A external-priority patent/GB1604644A/en
Priority claimed from GB48980/77A external-priority patent/GB1604850A/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
    • C07K14/675—Beta-endorphins
    • C07K14/6755—Beta-endorphins with at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • 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
    • C07K14/70—Enkephalins
    • C07K14/702—Enkephalins with at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to pentapeptide-N-alkylamides and their acid addition salts; to the preparation of such compounds; to formulations containing such compounds and the preparation of such formulations; and to the use of the compounds in human and veterinary medicine.
  • the present invention more particularly relates to the peptides of the formula (I): and their acid addition salts.
  • proviso is necessary in order to exclude a compound taught as having been investigated for opiate activity in Bajusz et al., Acta Biochim. et Biophys. Acad. Sci. Hung., Vol. 11 1 (4), pages 305-309 (1976).
  • the alkyl group R may in particular have for example 1 or 2 carbon atoms.
  • amino acids and their radicals are those conventional in the art and may be found in, for example, Biochemistry, 11, 1726 (1972). In the above and throughout the following all references are to the L-amino acids and their radicals except in the case of glycine and unless otherwise stated.
  • the peptides of formula (I) and their acid addition salts when assessed by a number of standard pharmacological procedures, have been found both to induce and to maintain anaesthesia in laboratory animals including rats and mice.
  • the compounds are effective in this respect when administered by a variety of routes including parenteral, for example by intravenous or intracerebroventricular injection.
  • Illustrative of the anaesthetic effects of the compounds are the following, which should be understood to be non-limiting.
  • the activity resides in the base and the acid is of less importance although for therapeutic purposes it is preferably pharmacologically and pharmaceutically acceptable to the recipient.
  • suitable acids include
  • the peptides of formula (I) and their pharmacologically and pharmaceutically acceptable acid addition salts may be used in the fields of both human and veterinary medicine for the induction and/or maintenance of anaesthesia in a mammal.
  • a peptide or an acid addition salt thereof may be administered either alone as the sole anaesthetic agent or in combination with one or more other substances which may complement and/or supplement its activity. Such additional substances may be administered before, simultaneously with or after administration of the peptide or acid addition salt thereof and in the case of simultaneous administration the various agents may be administered either as separate doses or as a combination formulation.
  • the peptide or acid addition salt thereof may be administered subsequent to administration of a benzodiazepine tranquillizer such as chlordiazepoxide (7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide), diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one) and oxazepam (7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiaze- pin-2-one).
  • a benzodiazepine tranquillizer such as chlordiazepoxide (7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide), diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one) and oxaze
  • the peptide or acid addition salt thereof may be administered for the maintenance of anaesthesia after this has been initially induced by the previous administration of another anaesthetic agent, for example a barbiturate such as thiopental sodium (sodium 5-ethyl-5-(1-methylbutyl)-2-thiobarbiturate).
  • another anaesthetic agent for example a barbiturate such as thiopental sodium (sodium 5-ethyl-5-(1-methylbutyl)-2-thiobarbiturate).
  • a particular utility for the peptides of formula (1) and their pharmacologically and pharmaceutically acceptable acid addition salts, within the field of anaesthesia, is the induction and/or maintenance of the state referred to as "neuroleptanalgesia", a condition characterised by quiescence, psychic indifference to environmental stimuli, and analgesia (see, for example, Dorland's Illustrated Medical Dictionary, twenty-fifth edition, published by W.B. Saunders, 1974, at page 1041, and "The Pharmacological Basis of Therapeutics", Goodman, L.S. and Gilman, A. eds., fifth edition, published by MacMillan Publishing Co. Inc., 1975, especially at Chapter 8, pages 97 to 101).
  • This condition is recognised by clinicians as desirable for enabling the performance of procedures such as broncho- scopy, X-ray studies, burn dressings and cystoscopy wherein a degree of patient cooperation is of value, and a fixed-dose combination comprising the narcotic analgesic fentanyl citrate (N-(1-phenethyl-4-piperidyl)propionanilide citrate) and the neuroleptic agent droperidol (1- ⁇ 1-[3-(p-fluorobenzoyl)propyl]-1,2,3,6-tetrahydro-4-pyridyl ⁇ -2-benzimidazolinone) has found acceptance for use in such circumstances.
  • neuroleptanalgesia has been achievable only upon administration of such a narcotic analgesic plus neuroleptic drug combination as that above mentioned.
  • the peptides of formula (1) and their acceptable acid addition salts are thus an important clinical advance and valuable addition to the armamentarium of the medical and veterinary professions in alone enabling this result, without any additional medication being required.
  • a morphine agonist is a compound the biological activity of which mimics that of the natural alkaloid.
  • morphine agonist properties of the peptides of formula (I) and their derivatives as hereinbefore defined include the following, which are given solely by way of illustration and should be understood to be non-limiting.
  • the amount required of the peptide or acid addition salt thereof (hereafter referred to as the active ingredient) will vary with the route of administration and with the nature and requried extent of the desired effect, and will ultimately be at the discretion of the physician or veterinarian.
  • the dosage will be in the range 0.0025 pg to 40 mg per kilogram bodyweight of mammal, preferably 0.01 pg to 4.0 mg/kg and optimally 0.25 to 400 pg/kg (all dosages calculated with reference to the peptide base).
  • the active ingredients may be administered by any route appropriate to the effect to be achieved, suitable routes including oral, rectal, nasal, topical (buccal), vaginal and parenteral (including subcutaneous, intramuscular and intravenous). It will be appreciated that the preferred route will vary with the effect to be achieved and thus for example in the relief of obstetrical pain administration directly into the spinal cord may be advantageous.
  • active ingredients While it is possible for the active ingredients to be administered as the raw chemical it is preferable to present them as pharmaceutical formulation preparation.
  • the formulations, both veterinary and for human use, of the present invention comprise an active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Desirably the formulations should not include oxidising agents and other substances with which peptides are known to be incompatible.
  • the formulations include those suitable for oral, rectal, nasal, topical (buccal), vaginal or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend upon for example the active ingredient and the condition to be treated.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; or as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Orally ingestible formulations comprising the compounds of formula (I) may be rendered less liable to any abuse, for example, unauthorised intravenous administration, by including in the formulation an appropriate amount of a specific opiate antagonist such as naloxone (1-N-allyl-7,8-dihydro-14-hydroxy normorphinone) which is ineffective in man upon oral adminstration but which is effective upon administration by the intravenous route.
  • a specific opiate antagonist such as naloxone (1-N-allyl-7,8-dihydro-14-hydroxy normorphinone
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, while a suitable formulation for nasal administration is nasal drops comprising the active ingredient in aqueous or oily solution.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usuallyholose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • Formulations suitable for vaginal administration may be presented as pessaries, creams, pastes or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration conveniently comprise sterile aqueous solutions of the active ingredient, which solutions are preferably isotonic with the blood of the recipient.
  • Such formulations may be conveniently prepared by dissolving the solid active ingredient in water to produce an aqueous solution, and rendering said solution sterile and isotonic with the blood of the recipient.
  • the formulations may be presented in unit - or in multi-dose containers, for example sealed ampoules or vials.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • each unit thereof conveniently contains the active ingredient (as above defined) in an amount in the range 0.125 ; ng to 2 g, preferably 1.251lg to 200 mg and optimally 12.5,ug to 20 mg (all weights calculated with reference to the peptide base).
  • the peptides of formula (I) and their acid addition salts may be prepared by any of the methods known in the art for the preparation of compounds of analogous structure. Thus they may be formed by the sequential coupling of appropriate amino acids using either classical methods of peptide synthesis or solid phase procedures, or by the initial preparation and subsequent coupling of peptide sub-units.
  • Such reactions may be effected by, for example, activating the carboxlyic acid group of the ingoing amino acid and protecting the non-reacting amino and carboxylic acid groups.
  • activating and protecting (masking) groups and of suitable reaction conditions giving the minimum of racemisation may be found in the following literature, which is given purely by way of exemplification and which is intended to be neither exhaustive nor limiting.
  • the peptides of formula (!) are obtained in the form of the free base or as an acid addition salt thereof.
  • the acid addition salts may be converted into the free bases or salts of other acids, and the bases may be converted into acid addition salts thereof, by techniques well known in the art.
  • the peptides of formula (I) and acid addition salts thereof may thus be prepared by condensing a reagent (II) wherein Y 1 is selected from the radical -Tyr- and a partial radical sequence having the radical -Tyr- at its N-terminal end and from thereon corresponding to formula (I), with a reagent (III) wherein Y 2 corresponds to the balance of the above defined product, the reagents (II) and (III) being optionally protected and/or activated where and as appropriate; followed if necessary and as appropriate by one or both of the steps of deprotection of the product and conversion of the product into the base or an acid addition salt thereof.
  • peptides of formula (I) may also be prepared by reaction of a corresponding peptide alkyl ester, for example the methyl ester, with an appropriate monoalkylamine.
  • amino acid compositions of peptide hydrolysates (6N.HCI at 110° for 24 hours in evacuated sealed tubes) were determined with a Beckman-Spinco® Model 120C amino acid analyser or with a Rank Chromostak® amino acid analyser.
  • Massa Esterinum C is a commercially available suppository base consisting of a mixture of mono, di, and triglycerides of saturated vegetable fatty acids. It is marketed by Henkel International, Düssel- dorf.
  • Dissolve the compound of formula (I) in the Water for Injections Sterilise the solution by passage through a membrane filter, 0.2 ⁇ m pore size, collecting the filtrate in a sterile receiver. Fill into sterile glass vials, 2 ml/vial under aseptic conditions and freeze-dry. Close the vials with sterile rubber closures secured with an aluminium seal.
  • the injection is reconstituted prior to administration by the addition of a convenient volume of Water for Injections or sterile saline solution.
  • the weight of the compound of formula (I) is in each instance calculated with reference to the peptide base.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Peptides Or Proteins (AREA)

Claims (29)

1. Un peptide de formule (I):
Figure imgb0017
dans laquelle
X4 représente un radical L-phénylalanyle ou L-4-nitrophénylalanyle;
X5 un radical D-leucyle, D-méthionyle, D-prolyle ou L-prolyle; et
R un alkyle en C1-C5;
avec la condition que
si X4 est le radical L-phénylalanyle,
XS soit le radical D-prolyle;

ainsi que ses sels d'addition d'acides.
2. Composé selon la revendication 1 dans lequel X4 est le radical L-4-nitrophénylalanyle.
3. Composé selon la revendication 1 ou 2 dans lequel X5 est le radical L-prolyle.
4. Composé selon l'une quelconque des revendications 1 à 3 dans lequel R est un groupe méthyle ou éthyle.
5. Le H.Tyr.D-Met.Gly.Phe(4-N02).Proéthylamide ou un sel d'addition d'acide de ce peptide.
6. Le H.Tyr.D-Met.Gly.Phe.D-Pro.éthylamide ou un sel d'addition d'acide de ce peptide.
7. Le H.Tyr.D-Met.Gly.Phe(4-NO2).D-Leu.éthylamide ou un sel d'addition d'acide de ce peptide.
8. Le H.Tyr.D-Met.GIy.Phe(4-NOZ).D-Met.éthylamide ou un sel d'addition d'acide de ce peptide.
9. Sel d'addition d'acide pharmacologiquement et pharmaceutiquement acceptable d'un peptide selon l'une quelconque des revendications 1 à 4.
10. Chlorhydrate d'un peptide selon l'une quelconque des revendication 5 à 8.
11. Formule pharmaceutique comprenant un peptide ou un sel d'addition d'acide de celui-ci pharmacologiquement et pharmaceutiquement acceptable, selon l'une quelconque des revendications 1 à 10, avec un véhicule acceptable.
12. Formule selon la revendication 11 pour administration par la voie orale, rectale, nasale, buccale, vaginale ou parentérale.
13. Formule selon la revendication 11 comprenant le composé en solution dans un milieu aqueux.
14. Formule selon l'une quelconque des revendications 11 à 13 sous forme d'unités de prise (doses unitaires).
15. Formule selon la revendication 14 sous la forme d'un comprimé pour administration orale.
16. Formule selon la revendication 14 sous la forme d'un suppositoire pour administration rectale.
17. Formule selon la revendication 14 sous la forme d'un pessaire pour administration vaginale.
18. Formule selon la revendication 14 sous la forme d'une solution aqueuse injectable stérile pour l'administration parentérale.
19. Formule lyophilisée selon la revendication 18.
20. Formule selon l'une quelconque des revendications 14 à 19 dans laquelle chaque dose unitaire contient le composé actif dans une proportion de 0,125 µg à 2 g, en peptide base.
21. Formule selon l'une quelconque des revendications 11 à 20 dans laquelle le composé actif est tel que défini à l'une quelconque des revendications 5 à 8.
22. Méthode de préparation d'une formule selon l'une quelconque des revendications 11 à 21, comprenant le mélange des divers ingrédients et, si nécessaire, la mise du mélange à la forme voulue.
23. Un peptide ou un sel d'addition de celui-ci selon l'une quelconque des revendications 1 à 10 comme agent ayant une action semblable à celle de la morphine.
24. Peptide ou sel d'addition d'acide de celui-ci selon l'une quelconque des revendications 1 à 10 comme agent analgésique.
25. Peptide ou sel d'addition d'acide de celui-ci selon l'une quelconque des revendications de 1 à 10 pour le traitement ou la prophylaxie de la diarrhée.
26. Peptide ou sel d'addition d'acide de celui-ci selon l'une quelconque des revendications de 1 à 10 comme agent anti-tussif.
27. Peptide ou sel d'addition d'acide de celui-ci selon l'une quelconque des revendications 1 à 10 comme agent anesthésique.
28. Peptide ou sel d'addition d'acide de celui-ci selon l'une quelconque des revendications de 1 à 10 pour induire un état de neuroleptanalgésie.
29. Procédé de préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 10, comprenant:
(a) la réaction d'un réactif (II)
Figure imgb0018
Y' désignant le radical Tyr ou une séquence de radicaux partielle comprenant le radical Tyr à son extrémité N terminale, correspondant à la formule (I) avec un réactif (III)
Figure imgb0019
Y2 représentant la partie restante du composé ci-dessus défini, les réactifs (II) et (III) pouvant être éventuellement protégés et/ou activés si cela est approprié; puis on déprotège éventuellement le produit formé, ou bien
(b) la réaction d'un ester alkylique du peptide correspondant avec une monoalkylamine appropriée, puis, selon le cas, on transforme le produit obtenu en base ou en un sel d'addition d'acide.
EP78100463A 1977-07-22 1978-07-21 Pentapeptide-N-alkoylamides et leurs sels, procédé de préparation de ces produits et leurs compositions pharmacologiques Expired EP0000559B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB30909/77A GB1604644A (en) 1977-07-22 1977-07-22 Biologically active pentapeptide amides
GB3090977 1977-07-22
GB48980/77A GB1604850A (en) 1977-11-24 1977-11-24 Biologically active peptides
GB4898077 1977-11-24

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Publication Number Publication Date
EP0000559A1 EP0000559A1 (fr) 1979-02-07
EP0000559B1 true EP0000559B1 (fr) 1983-10-05

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EP (1) EP0000559B1 (fr)
JP (1) JPS5424850A (fr)
DE (1) DE2862327D1 (fr)
IT (1) IT1107551B (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU178001B (en) * 1976-09-16 1982-02-28 Gyogyszekutato Intezet Process for preparing new pentapeptides with morphine-like activity and derivatives thereof
FR2424253A1 (fr) * 1978-04-27 1979-11-23 Brun Lab Sa Le Nouveaux derives de peptides analogues des enkephalines, leur procede de preparation et leur application therapeutique
NL8005121A (nl) * 1979-09-20 1981-03-24 Erba Farmitalia Biologisch actieve peptiden.
JPS58501861A (ja) * 1981-12-28 1983-11-04 ベツクマン・インストルメンツ・インコ−ポレ−テツド 下垂体成長ホルモン放出活性を有する合成ペプチド
DE3369327D1 (en) * 1982-02-05 1987-02-26 Wellcome Found Pharmaceutical compounds, preparation, use and intermediates therefor and their preparation

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2703109A1 (de) * 1976-01-26 1977-08-04 Wellcome Found Biologisch wirksame amide
NZ183712A (en) * 1976-04-08 1979-10-25 Ici Ltd Polypeptide analogues of enkephalins, and pharmaceutical compositions
FR2359817A1 (fr) * 1976-07-27 1978-02-24 Reckitt & Colmann Prod Ltd Nouveaux peptides, leur procede de preparation et composition therapeutique les contenant
HU178001B (en) * 1976-09-16 1982-02-28 Gyogyszekutato Intezet Process for preparing new pentapeptides with morphine-like activity and derivatives thereof
US4259234A (en) * 1976-09-27 1981-03-31 Eli Lilly And Company Analgesic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
UNLISTED DRUGS (Edit. Special Libr. associat.) Vol. 29, page 190 n(1977) *

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IT1107551B (it) 1985-11-25
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IT7850431A0 (it) 1978-07-21
JPS5424850A (en) 1979-02-24

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