WO2005097115A1 - Utilisation de repinotan pour inhiber la depression respiratoire induite par les opiaces/opioides - Google Patents

Utilisation de repinotan pour inhiber la depression respiratoire induite par les opiaces/opioides Download PDF

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Publication number
WO2005097115A1
WO2005097115A1 PCT/EP2005/003468 EP2005003468W WO2005097115A1 WO 2005097115 A1 WO2005097115 A1 WO 2005097115A1 EP 2005003468 W EP2005003468 W EP 2005003468W WO 2005097115 A1 WO2005097115 A1 WO 2005097115A1
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WO
WIPO (PCT)
Prior art keywords
solvates
salts
opiate
pethidine
opioid
Prior art date
Application number
PCT/EP2005/003468
Other languages
German (de)
English (en)
Inventor
Michael Friedrich BÖTTCHER
Original Assignee
Bayer Healthcare Ag
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
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Publication of WO2005097115A1 publication Critical patent/WO2005097115A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • 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
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the use of 1,2-benzisothiazol-3 (2H) -one-2- [4 - [[3,4-dihydro-2H-1-benzopyran-2-yl) methyl] ammo] butyi] -l , l-dioxide monohydrochloride (generic name: Repinotan), its salts, solvates and solvates of the salts for the manufacture of medicaments, for the inhibition of opiate / opioid-induced respiratory depression in animals and humans.
  • Respiratory depression that occurs after opiate or opioid administration is a widespread and life-threatening side effect for the patient.
  • opiate / opioid-induced respiratory depression e.g. first application, excessive dose, sudden loss of pain stimulus, etc.
  • This in turn has the consequence that the corresponding patients have to be observed longer in the wards or intensive care units or that this group of medicines is used only very slowly or not at all in the private area because the treating doctor fears respiratory depression.
  • Respiratory depression can be remedied therapeutically by the administration of an opioid antagonist (e.g. naloxone (Narcanti®, Bristol-Myers Squibb)), but this also leads to the abolition of the desired analgesic effect.
  • opioid antagonist e.g. naloxone (Narcanti®, Bristol-Myers Squibb)
  • partial agonists / antagonists e.g. pentazocin (Fortral®, Sanofi-Synthelabo), nalbuphin (Nubain, Bristol-Myers Squibb) at the opiate receptors, but ultimately cannot be excluded with these substances either ,
  • Buspirone is approved as a partial 5-HT ⁇ A agonist for use in the manufacture of medicines for human treatment (anxiolytic), but animal studies show that buspirone only has a very short-term effect on the antagonization of opiate-induced depression. Sahibzada, M. Ferreira, AM Wassermann, A.MI. Taveira-Dasila and RA Gillis; The Journal of Pharmacology and Experimental Therapeutics 292: 704-713, 2000). Buspiron's approved formulations are all administered orally.
  • Repinotan has been shown to have significant advantages over 8-OH-DPAT when used in the manufacture of a medicament for the treatment of opiate / opioid-induced respiratory depression. This may be due to a higher 5-HT- A receptor affinity for repinotan.
  • the rats showed only a slight drop in the mean arterial blood pressure when repinotan was administered alone at a dose of 0.02, 0.2, 20 or 200 ⁇ g / kg, even at higher doses.
  • a simultaneous administration of an opiate, eg morphine did not lead to a pronounced drop in the mean arterial blood pressure in the rat.
  • a slight increase in the mean arterial blood pressure was observed at low doses and a slight decrease at higher doses (biphasic course).
  • the active ingredient, its preparation, the preparation of a liquid formulation containing the active ingredient and agonistic action on the 5-HT j ⁇ receptor and the suitability as an active ingredient for treating diseases of the central nervous system are known from EP 352 613, 749 970 and 1 051 170 , Repinotan has been shown to be well tolerated in healthy subjects and patients after a stroke or craniocerebral trauma in several clinical studies. Based on the results of the receptor binding profiles on the 5-HTi A receptor, repinotan has an approx. 2-5 times higher receptor affinity compared to 8-OH-DPAT.
  • opiates or opioids are included within the scope of the invention.
  • the following opiates or opioids are named by way of example and preferably: morphine, buprenorphine, cyclazocin, dextromoramide, diamorphine, dihydrocodeine, hydromorphone, levomethadone, levallorphan, meptazinol, nalbuphine, oxycod ⁇ n, oxymorphone, pentazocimin, piritin, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, pethidine, peth
  • the invention relates to the use of 1,2-benzisothiazol-3 (2H) -one-2- [4 - [[3,4-dihydro-2H-1-benzopyran-2-yl) methyl] amino] butyl] - 1,1 -Dioxide monohydrochloride (generic name: repinotan), its salts, solvates and solvates of the salts of the formula
  • the invention also relates to the use of 1,2-benzisothiazol-3 (2H) -one-2- [4- [[3,4-dihydro-2H-1-benzopyran-2-yl) methyl] amino] butyl] -l, l-dioxide monohydrochloride (generic name: Repinotan), its salts, solvates and solvates of the salts for the production of liquid formulations for the inhibition of opiate / opioid-induced respiratory depression in animals and humans.
  • Another object of the invention is containing a kit
  • a pharmaceutical composition containing at least one opiate or opioid b) a pharmaceutical composition containing at least one opiate or opioid.
  • Another object of the invention is containing a kit
  • a pharmaceutical composition containing at least one opiate or opioid b) a pharmaceutical composition containing at least one opiate or opioid.
  • Another object of the invention is containing a kit
  • kits a) a liquid pharmaceutical composition containing 1,2-benzisothiazol-3 (2H) - one-2- [4- [[3,4-dihydro-2H-1-benzopyran-2-yl) methyl] amino] butyl] - 1,1-dioxide monohydrochloride, its salts, solvates and solvates of the salts and
  • Another preferred object of the invention is a kit as described above, wherein 1,2-benzisothiazol-3 (2H) -one-2- [4 - [[3,4-dihydro-2H-1-benzopyran-2-yl ) methyl] amino] butyl] -l, l-dioxide monohydrochloride whose salts, solvates and salts of the solvates are suitable for use in the manufacture of a medicament for the treatment of opiate / opioid-induced respiratory depression.
  • Study design randomized, open, placebo-controlled dose escalation study in crossover design on healthy young male subjects. Approximately 6 subjects take part in each dose level.
  • Study population healthy male subjects aged 18-45 years. All subjects should be phenotyped as fast metabolizers with regard to CYP450 2D6.
  • the subject is connected to the monitor system.
  • the monitor system is used to determine and document blood pressure, heart rate, respiratory rate, O 2 concentration (finger pulse oximetric), body temperature and, if possible, the oxygen and carbon dioxide concentration of the breathing air for the entire duration of the experiment.
  • venous access is placed on the right and left arm of the test subject.
  • One access is used to apply the required study medication (repinotan and one opiate, e.g.
  • remifentanil (Ultiva ® , GlaxoSmithKline) as a controllable opiate
  • the other contralateral access is used to take blood samples to determine drug concentrations (repinotan, opiate, e.g. remifentanil).
  • drug concentrations repinotan, opiate, e.g. remifentanil
  • the analgesic effect of the opiate is registered with a validated pain model.
  • Each dose level consists of two study periods in which treatment A, B and treatment C are randomized.
  • Treatment A At 0h the opiate infusion (eg Remifentanil) is started with the body weight-based initial infusion rate. After 5 minutes the infusion rate is doubled until the termination criterion (see below) is met.
  • Treatment B At time -5h, the infusion with Repinotan is started at a fixed infusion rate (1 Rep i notan ). The opiate infusion (eg remifentanil) is started at 0h. The infusion rate is identical to the treatment described under A. After 5 minutes the infusion rate is doubled until the termination criterion (see below) is met.
  • Treatment C -4h
  • the infusion of repinotan with a firmly prescribed infusion rate (- Re pi not at, for example, 75 ug / mL and 150 ug / mL) is started.
  • the opiate infusion (eg remifentanil) is started with a body weight-based initial infusion rate.
  • the infusion rate is changed so that the target plasma concentration of the paroband is doubled (eg 2.5, 5.0, 7.5, 10 ng / mL target plasma concentration) until the Abbruclikriteriu (see below) is met.
  • the study is carried out with different doses of Repinotan.
  • the Repinotan infusion starts 4 to 5 hours before the actual opiate administration in order to achieve steady state conditions for Repinotan.
  • the repinotan plasma concentrations reached under steady state conditions should be between approx. 5 and 25 ⁇ g / L.
  • the initial infusion rate of the opiates for Remifentanil can be approx. 0.1 microgram / kg / min, but is still to be defined in detail.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de monohydrochlorure de 1,2-benzisothiazol-3(2H)-one-2-[4-[[3,4-dihydro-2H-1-benzopyran-2-yl)méthyl]amino]butyl]-1,1-dioxyde (nom générique : Repinotan), ses sels, solvates et solvates des sels dans la production de médicaments destinés à inhiber la dépression respiratoire induite par les opiacés/opioïdes chez l'homme et l'animal.
PCT/EP2005/003468 2004-04-10 2005-04-02 Utilisation de repinotan pour inhiber la depression respiratoire induite par les opiaces/opioides WO2005097115A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004017627.2 2004-04-10
DE102004017627A DE102004017627A1 (de) 2004-04-10 2004-04-10 Verwendung von vollen 5-HT1A-Agonisten zur Hemmung der opiat/opioid-induzierten Atemdepression

Publications (1)

Publication Number Publication Date
WO2005097115A1 true WO2005097115A1 (fr) 2005-10-20

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PCT/EP2005/003468 WO2005097115A1 (fr) 2004-04-10 2005-04-02 Utilisation de repinotan pour inhiber la depression respiratoire induite par les opiaces/opioides

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DE (1) DE102004017627A1 (fr)
WO (1) WO2005097115A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8202895B2 (en) 2009-03-18 2012-06-19 Bayer Pharma Aktiengesellschaft Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0352613A2 (fr) * 1988-07-28 1990-01-31 Bayer Ag Aminométhyl-tétralines substituées et leurs analogues hétérocycliques
WO1999026621A1 (fr) * 1997-11-24 1999-06-03 Bayer Aktiengesellschaft Utilisation d'aminomethyl-chromanes pour empecher la degenerescence neuronale et favoriser la regeneration neuronale
WO2004045509A2 (fr) * 2002-11-18 2004-06-03 Pharmacia Corporation Methode de therapie combinee utilisant un inhibiteur de cox-2 et un modulateur du recepteur 5-ht1a

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0352613A2 (fr) * 1988-07-28 1990-01-31 Bayer Ag Aminométhyl-tétralines substituées et leurs analogues hétérocycliques
WO1999026621A1 (fr) * 1997-11-24 1999-06-03 Bayer Aktiengesellschaft Utilisation d'aminomethyl-chromanes pour empecher la degenerescence neuronale et favoriser la regeneration neuronale
WO2004045509A2 (fr) * 2002-11-18 2004-06-03 Pharmacia Corporation Methode de therapie combinee utilisant un inhibiteur de cox-2 et un modulateur du recepteur 5-ht1a

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SAHIBZADA NIAZ ET AL: "Reversal of morphine-induced apnea in the anesthetized rat by drugs that activate 5-hydroxytryptamine1A receptors", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND, US, vol. 292, no. 2, February 2000 (2000-02-01), pages 704 - 713, XP002189618, ISSN: 0022-3565 *
WILKEN B ET AL: "TREATMENT OF APNEUSTIC RESPIRATORY DISTURBANCE WITH A SEROTONIN-RECEPTOR AGONIST", JOURNAL OF PEDIATRICS, MOSBY-YEAR BOOK, ST. LOUIS, MO, US, vol. 130, no. 1, January 1997 (1997-01-01), pages 89 - 94, XP001055636, ISSN: 0022-3476 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8202895B2 (en) 2009-03-18 2012-06-19 Bayer Pharma Aktiengesellschaft Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof

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