EP1517688A2 - Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph - Google Patents

Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph

Info

Publication number
EP1517688A2
EP1517688A2 EP03760622A EP03760622A EP1517688A2 EP 1517688 A2 EP1517688 A2 EP 1517688A2 EP 03760622 A EP03760622 A EP 03760622A EP 03760622 A EP03760622 A EP 03760622A EP 1517688 A2 EP1517688 A2 EP 1517688A2
Authority
EP
European Patent Office
Prior art keywords
diseases
bicarbonate
proteins
intracellular
activity
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.)
Withdrawn
Application number
EP03760622A
Other languages
German (de)
English (en)
Inventor
Heinz Rupp
Bernd Eisele
Dieter Ziegler
Bodo JÄGER
Bernhard Maisch
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.)
Abbott Products GmbH
Original Assignee
Solvay Pharmaceuticals GmbH
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 Solvay Pharmaceuticals GmbH filed Critical Solvay Pharmaceuticals GmbH
Priority to EP03760622A priority Critical patent/EP1517688A2/fr
Publication of EP1517688A2 publication Critical patent/EP1517688A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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

Definitions

  • DIDS 4,4'-diisothiocyanostilbene-4,4'-disulfonate
  • the AE proteins are activated by extracellular acidosis or intracellular alkalosis.
  • the AE proteins In response to a drop in extracellular pH, the AE proteins begin to export bicarbonate ions; as a result there is a decrease in the intracellular pH. If the pH inside the cell is increased, the activity of the AE proteins normalizes the intracellular pH again.
  • inhibition of AE proteins in the ventricular myocytes is very useful, since the consequent reduction in the export of intracellular bicarbonate ions prevents intracellular acidosis with its negative consequences for the cells.
  • selective imidazoline receptor agonists and their physiologically tolerable acid addition salts have very advantageous pharmacological properties.
  • selective imidazoline receptor agonists are inhibitors of the proteins which regulate intracellular pH and belong to the superfamily of bicarbonate transporters and one of the compound 4,4'-diisothiocyanostilbene-4,4'-disulfonate (DIDS), a standard inhibitor of bicarbonate transporters have similar inhibitory effects.
  • the bicarbonate ions are discharged via the AE protein located on the other cell side of the osteoclast through the simultaneous absorption of chloride ions. Electroneutrality is maintained by the transport of the CI ions on the bone side, which takes place parallel to the proton transport. A reduction in the activity of the AE protein has been shown to reduce the process of bone resorption [Teti et al. (1989) Cytoplasmic pH regulation and chloride / bicarbonate exchange in avian osteociasts. J Clin Invest. 83: 227-33; Hall et al. (1989) Optimal bone resorption by isolated rat osteociasts requires chloride / bicarbonate exchange. Calcif Tissue Int. 45: 378-80].
  • solid preparations which can be formulated for the direct or delayed release of active ingredient are preparations which can be administered orally, such as tablets, dragées, capsules, powders or granules, or suppositories and plasters (transdermal therapeutic systems).
  • These solid preparations can contain pharmaceutically customary inorganic and / or organic carriers such as milk sugar, talc or starch in addition to pharmaceutically customary auxiliaries, for example lubricants or tablet disintegrants.
  • the active substance is accommodated in an active substance reservoir, in particular, for example, an active substance matrix (eg a polymer matrix).
  • composition of the bicarbonate solution 1 18 mmol / l NaCI, 4.7 mmol / l KCI, 2.5 mmol / l CaCI2 x 2 H2O, 1 .6 mmol / l MgCI2 x 7 H2O, 24.9 mmol / l NaHCO3, 1.2 mmol / l KH2PO4 , 5.6 mmol / l glucose and either 0.4% or 10% FCS, equilibrated with 20% O2 and 5% CO2 for at least 30 min to ensure a pH of 7.4.
  • the effect of moxonidine, DIDS and guanabenz on the change in intracellular pH after alkalization of the cells by an NH 4 CI pulse is determined.
  • the BCECF-loaded cardiac fibroblasts are preincubated with a bicarbonate test solution which contained one of the compounds mentioned above for 30 min.
  • the response of the intracellular pH of the pretreated cells to a 5 mmol / l NH 4 CI pulse is measured over time.
  • the change in pH during the subsequent washout of the NH CI (intracellular acidification) was also measured over time.
  • the activity of the Na + - / bicarbonate (Na + / HCO 3 " ) cotransporter (NBC) protein and / or the Na + -dependent chloride / bicarbonate (CI “ / HCO 3 " ) exchanger (NDAE and N ( D) CBE) proteins can be determined on the basis of their activation due to intracellular acidification using the ammonium method [Boron & De Weer (1976) Intracellular pH transients in squid giant axons caused by CO2, NH3, and metabolic inhibitors. J Gen Physiol. 67:91 -1 12]. Pharmacological test for the effect of the compounds on pathological changes in the bones
  • the inhibitory effect of the test substances on the absorption of bone material is examined in an in vitro test. Osteoclasts isolated from newborn rats are brought into direct contact with slices of bone material derived from cattle and incubated together for at least 6 h in the presence and absence of the test substances. Following the incubation, each slice of bone is examined microscopically to determine the extent of bone resorption [Chambers et al. (1985) The effect of calcium-regulating hormones and prostaglandins on bone absorption by osteociasts disaggregated from neonatal rabbit bones. Endocrinology 1 16: 234-9].
  • the inhibitory effect of the test substances on gastric acid secretion is tested on a culture of parietal cells from rabbits.
  • the activity of the AE protein and the associated acid secretion is determined in the presence and absence of the test substances both under basal conditions and after stimulation of the Acid production measured by adding known stimulating compounds [Muallem et al. (1988) Activation of the Na + / H + and CI- / HCO3- exchange by stimulation of acid secretion in the parietal cell. J Biol Chem. 263: 14703-1 1].
  • the inhibitory effect of the test substances on the development of stress-induced gastrointestinal ulcers is tested on rats.
  • rats are exposed to stress by immobilization and partial immersion in water at 22 ° C for 6 h.
  • the development of gastric lesions and their severity are compared in control rats and rats that were treated preventively with the test substances 30 min before exposure to stress [Takagi & Okabe (1968)

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation d'agonistes du récepteur d'imidazoline sélectifs, notamment moxonidine, rilménidine, LNP-509, S-23515, PMS-812, PMS-847 et BU-98008, ainsi que leurs sels d'addition d'acide physiologiquement compatibles, pour produire des préparations pharmaceutiques pour traiter et/ou assurer la prophylaxie de troubles et/ou de pathologies fonctionnels chez les grands mammifères ou chez l'homme, qui impliquent une inhibition ou une baisse de l'activité de protéines régulant le pH intracellulaire et font partie de la superfamille des transporteurs de bicarbonate, notamment les agents pathogènes des os, dus à une proportion indésirable de résorption osseuse, en particulier l'ostéoporose, les affections du tractus gastro-intestinal, notamment les ulcères de l'estomac, et les pathologies neuronales et/ou neuropsychiatriques s'accompagnant d'une activité neuronale modifiée sur le plan pathologique, de préférence une activité neuronale augmentée, de préférence la dépression, la maladie d'Alzheimer, les troubles de l'alimentation et la schizophrénie.
EP03760622A 2002-06-19 2003-06-16 Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph Withdrawn EP1517688A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP03760622A EP1517688A2 (fr) 2002-06-19 2003-06-16 Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP02013387 2002-06-19
EP02013387 2002-06-19
EP03760622A EP1517688A2 (fr) 2002-06-19 2003-06-16 Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph
PCT/EP2003/006319 WO2004000312A2 (fr) 2002-06-19 2003-06-16 Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph

Publications (1)

Publication Number Publication Date
EP1517688A2 true EP1517688A2 (fr) 2005-03-30

Family

ID=29797127

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03760622A Withdrawn EP1517688A2 (fr) 2002-06-19 2003-06-16 Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph

Country Status (6)

Country Link
US (1) US7309706B2 (fr)
EP (1) EP1517688A2 (fr)
AU (1) AU2003257418A1 (fr)
CA (1) CA2487541A1 (fr)
PL (1) PL372695A1 (fr)
WO (1) WO2004000312A2 (fr)

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EP2612854B1 (fr) * 2005-10-25 2015-04-29 Shionogi&Co., Ltd. Dérivés d'aminothiazolidine et d'aminotétrahydrothiazepine comme inhibiteurs de BACE 1
TW200902526A (en) * 2007-04-24 2009-01-16 Shionogi & Amp Co Ltd Aminodihydrothiazin derivative substituted with a cyclic group
WO2008133273A1 (fr) * 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Composition pharmaceutique pour le traitement de la maladie d'alzheimer
WO2009151098A1 (fr) * 2008-06-13 2009-12-17 塩野義製薬株式会社 DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DU SOUFRE AYANT UNE ACTIVITÉ INHIBANT LA β-SÉCRÉTASE
US12246013B2 (en) 2008-08-01 2025-03-11 Eye Therapies Llc Vasoconstriction compositions and methods of use
ES2518418T3 (es) 2008-08-01 2014-11-05 Eye Therapies Llc Composiciones de vasoconstricción y métodos de uso
US8952011B2 (en) 2008-08-01 2015-02-10 Eye Therapies Llc Compositions and methods for the treatment of nasal conditions
US20100203165A1 (en) * 2008-08-01 2010-08-12 Gerald Horn Compositions and methods for treatment of disorders or conditions of the eye
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US8987270B2 (en) 2009-07-27 2015-03-24 Eye Therapies Llc Formulations of selective alpha-2 agonists and methods of use thereof
UA110467C2 (uk) 2009-12-11 2016-01-12 Шионогі Енд Ко., Лтд. Похідні оксазину
WO2011075621A1 (fr) * 2009-12-17 2011-06-23 Alpha Synergy Development, Inc. Compositions et méthodes d'administration ophtalmique de décongestionnants nasals
CN103261199A (zh) 2010-10-29 2013-08-21 盐野义制药株式会社 萘啶衍生物
EP2634188A4 (fr) 2010-10-29 2014-05-07 Shionogi & Co Dérivé d'aminodihydropyrimidine fusionnée
US8445526B2 (en) 2011-02-03 2013-05-21 Glaucoma & Nasal Therapies Llc Compositions and methods for treatment of glaucoma
WO2012147763A1 (fr) 2011-04-26 2012-11-01 塩野義製薬株式会社 Dérivé d'oxazine et inhibiteur de bace 1 le contenant
EP2912035A4 (fr) 2012-10-24 2016-06-15 Shionogi & Co Dérivés de dihydrooxazine ou d'oxazépine ayant une activité inhibitrice de bace1
US8999938B2 (en) 2013-06-21 2015-04-07 Gnt Llc Ophthalmic lipophilic drug delivery vehicle formulations
KR20160042039A (ko) 2013-08-09 2016-04-18 알데릭스, 인코포레이티드 인산염 수송을 억제하기 위한 화합물 및 방법
CN110358723A (zh) * 2019-05-08 2019-10-22 广州医科大学附属第二医院 一种成年小鼠心脏成纤维细胞的培养方法
EP3735974A1 (fr) * 2019-05-10 2020-11-11 Rottapharm Biotech S.r.l. Utilisation de quinazoline 2-phényl-6-(1h-imidazol-1-yl) pour le traitement de maladies neurodégénératives, de préférence la maladie d'alzheimer
WO2021158059A1 (fr) * 2020-02-07 2021-08-12 건국대학교 글로컬산학협력단 Composition comprenant un composé de rilmenidine en tant que principe actif pour le traitement du syndrome de l'x fragile ou de la déficience développementale associée
KR20250145285A (ko) * 2024-03-28 2025-10-13 건국대학교 글로컬산학협력단 릴메니딘을 포함하는 정서장애의 예방, 개선 또는 치료용 조성물

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Also Published As

Publication number Publication date
US7309706B2 (en) 2007-12-18
US20050165080A1 (en) 2005-07-28
AU2003257418A1 (en) 2004-01-06
WO2004000312A3 (fr) 2004-02-19
WO2004000312A2 (fr) 2003-12-31
PL372695A1 (en) 2005-07-25
CA2487541A1 (fr) 2003-12-31

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