WO1999003491A1 - Nouvelle utilisation de nociceptine - Google Patents

Nouvelle utilisation de nociceptine Download PDF

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Publication number
WO1999003491A1
WO1999003491A1 PCT/DK1998/000321 DK9800321W WO9903491A1 WO 1999003491 A1 WO1999003491 A1 WO 1999003491A1 DK 9800321 W DK9800321 W DK 9800321W WO 9903491 A1 WO9903491 A1 WO 9903491A1
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WO
WIPO (PCT)
Prior art keywords
gly
arg
phe
ala
lys
Prior art date
Application number
PCT/DK1998/000321
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English (en)
Inventor
Anders Fink Jensen
Uffe Bang Olsen
Original Assignee
Novo Nordisk A/S
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU83339/98A priority Critical patent/AU8333998A/en
Publication of WO1999003491A1 publication Critical patent/WO1999003491A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—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

Definitions

  • the present invention relates to the use of compounds of the general formula I for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes.
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the com- pounds and their pharmaceutical compositions.
  • a "hot flush” is a sudden transient sensation ranging from warmth to intense heat and typically accompanied by flushing and perspiration. It is the classic sign of the menopause and the predominant complaint of menopausal women. Epidemiological studies report that the majority of menopausal women experience hot flushes, although with large variation in frequency and intensity (Treatment of the Postmenopausal Women, Basic and Clinical Aspects, Raven Press 1994, ed. R.A. Lobo).
  • Nociceptin and analogues thereof have been disclosed in WO 97/07212 and in WO 97/07208. These peptides and inhibitors thereof are said to be useful for antagonising physiologic effects of an opioid in an animal, and for treating/preventing a disease related to: hyperalgesia, neuroendocrine secretion, stress, locomotor activity, anxiety etc.
  • the present invention provides the use of a compound selected from nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
  • nociceptin and nociceptin analogues, variants or homologues inhibit cordal stimulated vasodilatation in the pithed rat (an in-vivo-model for the hot flushes, hereafter referred to as "the pithed rat") which is known to be mediated by CGRP (Nuki Y. et al. Effects of Dorsal Rhizotomy on Depressor Response to Spinal Cord Stimulation Mediated by Endogenous Calcitonin Gene-related Peptide in the Pithed Rat. J. Neurosurg. 1993; 79:899-904).
  • the present invention relates to the use of a compound selected from nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1- 15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances , in particular the peripheral vasomotor effects known as hot flushes or hot flashes or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
  • a 1 is Thr, Leu or Met
  • a 2 is Gly, Arg or Thr
  • a 3 is Ala, Arg or Ser
  • a 4 is Arg, lie Glu or Gin
  • a 5 is Lys, Arg or Phe;
  • a 6 is Ser, Pro Lys;
  • the peptide of formula I is disclosed in WO 97/07212, wherein i.a. a procedure for the preparation thereof has been described.
  • composition in a form suitable for oral, nasal, transdermal, pulmonal, or parenteral administration.
  • the compound is administered as a dose in the range from about 0.01 to about 100 g per patient per day, preferably from about 1 to about 1000 mg per patient per day, especially from about 10 to about 100 mg per patient per day, e.g. about 100 mg per patient per day.
  • the amino acids are all in either the D or L stereochemical configuration, preferably the L stereochemical configuration.
  • the compounds of the invention may comprise both L and D amino acids.
  • the invention in a second aspect relates to a method for the treatment or prevention of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes or for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs, the method comprising administering to a patient in need thereof an effective amount of nociceptin or an analogue, a variant or a homologue thereof, wherein 1 to 12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted, or a pharmaceutically acceptable salt thereof, wherein the deletion(s), addition(s) and/or substitution(s) does not substantially reduce the vasomotor disturbing effects of the analogue, variant or homologue of nociceptin.
  • the effective, such as the therapeutically effective, amount of nociceptin or an analogue, a variant or a homologue thereof will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the nociceptin or an analogue is administered as a dose with an effective amount in the range from about 0.01 to about 100 g per patient per day, preferably from about 1 to about 1000 mg per patient per day, especially from about 10 to about 100 mg per patient per day, e.g. about 100 mg per patient per day .
  • the invention includes the D and/or L stereochemical configuration of all the amino acids which constitutes nociceptin and analogs, variants or homologs hereof.
  • the term "patient” comprises any mammal which may benefit from treatment or prevention of vasomotor disturbances, such as a human, especially if the mammal is a female, such as a woman. However, “patient” is not intended to be limited to a woman.
  • the compounds intended to be embraced by the present invention are such peptides which are disclosed in WO 97/07208 and/or in WO 97/07212, as well as close analogs thereof.
  • said compounds e.g. nociceptin, analogs, variants and homologues of nociceptin as well as compounds of formula I are all together termed "nociceptins", however this term does not in any way limit the scope of the present invention.
  • Methods of preparing these nociceptins are either conventional and known to the man skilled in the art, or described in WO 97/07208 or in WO 97/07212.
  • nociceptin is intended to comprise the peptide Phe-Gly-Gly-Phe-Thr-Gly- Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn, which peptide is disclosed in both WO 97/07208 and WO 97/07212.
  • an analogue, a variant or a homologue thereof, wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted is intended to comprise nociceptin wherein 1-12 amino acid(s) have been deleted, 1-82 amino acid(s) have been added and/or 1-15 amino acid(s) have been substituted.
  • treatment is also meant to comprise profylactic treatment.
  • the nociceptins may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • Further e- xamples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66, 2 (1977) which are known to the skilled artisan.
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present nociceptins are able to form.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the nociceptins of this invention may form solvates with standard low molecular weight solvents using methods known to the man skilled in the art.
  • the nociceptins may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.
  • the present invention relates to the use of a compound, e.g. selected from the nociceptins disclosed herein, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes, the compound being characterized by inhibiting cordal stimulated vasodilatation in "the pitched rat” and/or binding to nociceptin receptors (i.e. ORL-1 receptors as disclosed in WO 97/07212 and in WO 97/07208).
  • the invention relates to the use of a compound, e.g. selected from the nociceptins disclosed herein, for the preparation of a pharmaceutical composition for alleviating symptoms of drug withdrawal in particular abstinence symptoms occuring during withdrawal from abusive drugs.
  • a pharmaceutical composition for use in accordance with the present invention comprises, one or more nociceptins as active ingredient(s), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • compositions containing nociceptins of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy. 19 th Ed., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include nociceptins or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohol's, polyethylene glycol's, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions can be sterilised and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • solubilizing agents e.g. propylene glycol
  • surfactants e.g. propylene glycol
  • absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin
  • preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydro- xylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound 100 mg Colloidal silicon dioxide (Aerosil) 1.5 mg
  • mice Male Sprague Dawley rats ( 300 ⁇ 25 g) were anaesthetised with pentobarbital sodium (50 mg/kg i.p.) and polyethylene catheters were positioned in both femoral veins for the intravenous administration of drugs, such as nociceptin and analogues, and into the left femoral artery in order to measure arterial blood pressure and heart rate.
  • drugs such as nociceptin and analogues
  • the trachea was cannulated with polyethylene tubing and the rat was pithed, ventilated and drug treated as described by Nuki Y. et al. (Effects of Dorsal Rhizotomy on Depressor Response to Spinal Cord Stimulation Mediated by Endogenous Calcitonin Gene-related Peptide in the Pithed Rat. J. Neurosurg. 1993; 79:899-904).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation de composés de formule générale (I): (Xaa)n-Phe-Gly-Gly-Phe-(A?1)-(A2)-(A3)-(A4)-(A5)-(A6)-(A7)-(A8)-(A9)-(A10)-(A11)-(A12¿)-Gln-(Xaa)¿n? pour le traitement de troubles vasomoteurs, plus particulièrement d'effets vasomoteurs périphériques connus sous le nom de bouffées de chaleur. L'invention concerne également des compositions pharmaceutiques renfermant ces composés et des procédés utilisant les composés et leurs compositions pharmaceutiques.
PCT/DK1998/000321 1997-07-15 1998-07-10 Nouvelle utilisation de nociceptine WO1999003491A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU83339/98A AU8333998A (en) 1997-07-15 1998-07-10 New use of nociceptin

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DK0866/97 1997-07-15
DK86697 1997-07-15
US5281097P 1997-07-17 1997-07-17
US60/052,810 1997-07-17

Publications (1)

Publication Number Publication Date
WO1999003491A1 true WO1999003491A1 (fr) 1999-01-28

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1998/000321 WO1999003491A1 (fr) 1997-07-15 1998-07-10 Nouvelle utilisation de nociceptine

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AU (1) AU8333998A (fr)
WO (1) WO1999003491A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009043459A1 (fr) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Utilisation d'un antagoniste d'hexapeptide de récepteur de fibrinogène de plaquettes et d'alpha-endorphine en tant qu'agent thérapeutique
WO2009043460A1 (fr) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Utilisation d'une alpha-endorphine en tant qu'agent thérapeutique
WO2009046868A1 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009039983A3 (fr) * 2007-09-11 2009-05-28 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique
US8551949B2 (en) 2009-07-27 2013-10-08 Nocicepta Llc Methods for treatment of pain
US11389473B2 (en) 2015-01-07 2022-07-19 Tonix Pharmaceuticals Holding Corp. Magnesium-containing oxytocin formulations and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007212A1 (fr) * 1995-08-11 1997-02-27 Oregon Health Sciences University Antagonistes opioides et leurs procedes d'utilisation
WO1997007208A1 (fr) * 1995-08-15 1997-02-27 Universite Libre De Bruxelles Molecules d'acide nucleique codant des peptides presentant des proprietes pronociceptives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007212A1 (fr) * 1995-08-11 1997-02-27 Oregon Health Sciences University Antagonistes opioides et leurs procedes d'utilisation
WO1997007208A1 (fr) * 1995-08-15 1997-02-27 Universite Libre De Bruxelles Molecules d'acide nucleique codant des peptides presentant des proprietes pronociceptives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIFE SCIENCES, Volume 60, No. 16, March 1997, HUNTER C. CHAMPION et al., "Nociceptin, an Endogenous Ligand for the Orl, Receptor, Has Novel Hypotensive Activity in the Rat", pages 241-245. *
PEPTIDES, Volume 18, No. 5, 1997, H.C. CHAMPION et al., "Nociceptin, an Endogenous Ligand for the ORL1 Receptor, Decreases Cardiac Output and Total Peripheral Resistance in the Rat", pages 729-732. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009043459A1 (fr) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Utilisation d'un antagoniste d'hexapeptide de récepteur de fibrinogène de plaquettes et d'alpha-endorphine en tant qu'agent thérapeutique
WO2009043460A1 (fr) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Utilisation d'une alpha-endorphine en tant qu'agent thérapeutique
WO2009046857A1 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009046868A1 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009039983A3 (fr) * 2007-09-11 2009-05-28 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique
US8551949B2 (en) 2009-07-27 2013-10-08 Nocicepta Llc Methods for treatment of pain
US9238053B2 (en) 2009-07-27 2016-01-19 Nocicepta Llc Methods for treatment of pain
US11389473B2 (en) 2015-01-07 2022-07-19 Tonix Pharmaceuticals Holding Corp. Magnesium-containing oxytocin formulations and methods of use

Also Published As

Publication number Publication date
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