EP0000559A1 - 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
EP0000559A1
EP0000559A1 EP78100463A EP78100463A EP0000559A1 EP 0000559 A1 EP0000559 A1 EP 0000559A1 EP 78100463 A EP78100463 A EP 78100463A EP 78100463 A EP78100463 A EP 78100463A EP 0000559 A1 EP0000559 A1 EP 0000559A1
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EP
European Patent Office
Prior art keywords
methionyl
leucyl
acid addition
salt
peptide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP78100463A
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German (de)
English (en)
Other versions
EP0000559B1 (fr
Inventor
Samuel Wilkinson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wellcome Foundation Ltd
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Wellcome Foundation Ltd
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Filing date
Publication date
Priority claimed from GB30909/77A external-priority patent/GB1604644A/en
Priority claimed from GB48980/77A external-priority patent/GB1604850A/en
Application filed by Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Publication of EP0000559A1 publication Critical patent/EP0000559A1/fr
Application granted granted Critical
Publication of EP0000559B1 publication Critical patent/EP0000559B1/fr
Expired legal-status Critical Current

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Classifications

    • 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 peptides and derivatives thereof; 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 formula (I); and their salts and acid addition salts.
  • the alkyl group R may in particular have 1 to 5 carbon atoms, for example 1 or 2, but alkyl groups having for example 1 to 10 or 1 to 20 carbon atoms are to be understood as also included.
  • X 5 is selected from D-leucyl, D-methionyl and D-prolyl.
  • 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 a 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 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 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-I-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one) and oxazepam(7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-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-I-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one) and ox
  • the peptide or 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 (I) 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.
  • 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 compounds exhibit analgesic activity, for example they are effective in mice in the "hot plate” procedure standard in the art when tested by a modification of the method of Eddy, N.B. et al.. (J. Pharm. Exp. Therap. 107, 385 (1953)), the compounds being administered by intracerebroventricular injection, and this activity is abolished by naloxone.
  • the peptides of formula (I) are effective in mice in the abolition of acetic-acid induced writhing when screened by a modification of the method of Hendershot L.C. and Forsaith J., J. of Pharm. and Exp. Ther., 1959, Vol. 125, pg. 237; the compounds being administered orally; and the abolition being reversed by naloxone.
  • 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 required 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 ⁇ g to 40mg per kilogram bodyweight of mammal, preferably O.Olyg to 4.Omg/kg and optimally 0.25 to 400pg/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.
  • the active ingredients While it is possible for the active ingredients to be administered as the raw chemical it is preferable to present them as a 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 (l-N-allyl-7,8-dihydro-l4-hydroxy normorphinone) which is ineffective in man upon oral administration but which is effective upon administration by the intravenous route.
  • a specific opiate antagonist such as naloxone (l-N-allyl-7,8-dihydro-l4-hydroxy normorphinone) which is ineffective in man upon oral administration but which is effective upon administration by the intravenous route.
  • naloxone l-N-allyl-7,8-dihydro-l4-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, usually sucrose 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 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 inculde 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, be , flavouring agents, binders, surface active agents, thrickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional ingredients such as diluents, be , flavouring agents, binders, surface active agents, thrickeners, 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 ⁇ g. to 2g., preferably 1.25 ⁇ g. to 200 mg. and optimally 12.5 ⁇ g. 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 subunits.
  • Such reactions may be effected by, for example, activating the carboxylic 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 minimun of racemisation may be found in the following literature, all of which is incorporated herein by reference hereto, which is given purely by way of exemplification and which is intended to be neither exhaustuve nor limiting.
  • the peptides of formula (I) 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, Dusseldorf.
  • 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 volumne 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)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
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  • Pulmonology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
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

Publications (2)

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

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EP78100463A Expired EP0000559B1 (fr) 1977-07-22 1978-07-21 Pentapeptide-N-alkoylamides et leurs sels, procédé de préparation de ces produits et leurs compositions pharmacologiques

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

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2364890A1 (fr) * 1976-09-16 1978-04-14 Richter Gedeon Vegyeszet Nouveaux pentapeptides et procede pour leur preparation
EP0005658A1 (fr) * 1978-04-27 1979-11-28 Laboratoire le Brun S.A. Société dite: Nouveaux dérivés de peptides analogues des enképhalines, leur procédé de préparation et leur application thérapeutique
FR2465713A1 (fr) * 1979-09-20 1981-03-27 Erba Farmitalia Nouveaux peptides biologiquement actifs et leur emploi comme medicaments
EP0083864A3 (en) * 1981-12-28 1983-09-14 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
EP0085963A3 (en) * 1982-02-05 1983-11-23 The Wellcome Foundation Limited Pharmaceutical compounds, preparation, use and intermediates therefor and their preparation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2338925A1 (fr) * 1976-01-26 1977-08-19 Wellcome Found Nouveaux peptides et medicament contenant ces substances
FR2347336A1 (fr) * 1976-04-08 1977-11-04 Ici Ltd Derives peptidiques
FR2359817A1 (fr) * 1976-07-27 1978-02-24 Reckitt & Colmann Prod Ltd Nouveaux peptides, leur procede de preparation et composition therapeutique les contenant
FR2364890A1 (fr) * 1976-09-16 1978-04-14 Richter Gedeon Vegyeszet Nouveaux pentapeptides et procede pour leur preparation
FR2365553A1 (fr) * 1976-09-27 1978-04-21 Lilly Co Eli Derives amides de pentapeptides et tetrapeptides et leur utilisation comme medicaments

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2338925A1 (fr) * 1976-01-26 1977-08-19 Wellcome Found Nouveaux peptides et medicament contenant ces substances
FR2347336A1 (fr) * 1976-04-08 1977-11-04 Ici Ltd Derives peptidiques
FR2359817A1 (fr) * 1976-07-27 1978-02-24 Reckitt & Colmann Prod Ltd Nouveaux peptides, leur procede de preparation et composition therapeutique les contenant
FR2364890A1 (fr) * 1976-09-16 1978-04-14 Richter Gedeon Vegyeszet Nouveaux pentapeptides et procede pour leur preparation
FR2365553A1 (fr) * 1976-09-27 1978-04-21 Lilly Co Eli Derives amides de pentapeptides et tetrapeptides et leur utilisation comme medicaments

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
UNLISTED DRUGS March 1978 - ICI 116750 & Brit J Pharmacol 61:481P, Nov.'77. *
UNLISTED DRUGS March 1978 - ICI 118736 & Brit J Pharmacol 61:481P, Nov.'77. *
UNLISTED DRUGS, (Edit. Special Libr. associat.) vol. 29, page 190n (1977) & Br. J. pharmacol 59:455+523 P & 455 P, March '77. *
UNLISTED DRUGS-April 1978 - ICI 122984 & Brit J Pharmacol 61:481P, Nov.'77. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2364890A1 (fr) * 1976-09-16 1978-04-14 Richter Gedeon Vegyeszet Nouveaux pentapeptides et procede pour leur preparation
EP0005658A1 (fr) * 1978-04-27 1979-11-28 Laboratoire le Brun S.A. Société dite: Nouveaux dérivés de peptides analogues des enképhalines, leur procédé de préparation et leur application thérapeutique
FR2465713A1 (fr) * 1979-09-20 1981-03-27 Erba Farmitalia Nouveaux peptides biologiquement actifs et leur emploi comme medicaments
EP0083864A3 (en) * 1981-12-28 1983-09-14 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
EP0085963A3 (en) * 1982-02-05 1983-11-23 The Wellcome Foundation Limited Pharmaceutical compounds, preparation, use and intermediates therefor and their preparation

Also Published As

Publication number Publication date
IT7850431A0 (it) 1978-07-21
JPS5424850A (en) 1979-02-24
IT1107551B (it) 1985-11-25
DE2862327D1 (en) 1983-11-10
EP0000559B1 (fr) 1983-10-05

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