WO2001078726A1 - Nouvelles utilisations des imidazolylmethyl-pyridines - Google Patents

Nouvelles utilisations des imidazolylmethyl-pyridines Download PDF

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Publication number
WO2001078726A1
WO2001078726A1 PCT/EP2001/004203 EP0104203W WO0178726A1 WO 2001078726 A1 WO2001078726 A1 WO 2001078726A1 EP 0104203 W EP0104203 W EP 0104203W WO 0178726 A1 WO0178726 A1 WO 0178726A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
treatment
acid addition
cell
Prior art date
Application number
PCT/EP2001/004203
Other languages
English (en)
Inventor
André Cordier
Salah-Dine Chibout
Jacky Vonderscher
Maryelle Kolopp
Anne De Brugerolle De Fraissinette
Mihael Hristos Polymeropoulos
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
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 Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Novartis Ag
Priority to AU2001258330A priority Critical patent/AU2001258330A1/en
Publication of WO2001078726A1 publication Critical patent/WO2001078726A1/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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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 present invention relates to new uses of imidazolylmethyl-pyridines of formula I,
  • R] is (C ⁇ -4)alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by (C ⁇ - 4 )alkyl, R 2 and R 3 independently of one another are hydrogen or (C* ⁇ - 4 )alkyl and R 4 is hydrogen, hydroxy, (C ⁇ - 4 )alkyl, (C ⁇ - 4 )alkoxy or halogen with an atomic number of 9 to 35, and their pharmaceutically acceptable acid addition salts, hereinafter referred to as the agents of the invention.
  • the agents of the invention as well as their production process are known, for example, from EP 534 904.
  • This patent also discloses the use of the agents of the invention for the treatment of senile dementia and other neurodegenerative diseases including Alzheimer's disease, and for the treatment of depression.
  • the agents of the invention are useful as cytoprotective and cell rescuing agents.
  • the cytoprotective and cell rescueing properties of the agents of the invention are evidenced, for example, in the following in vitro model aimed at assessing the activity of a compound on the viability of the human bilayered living skin equivalent Apligraf® in culture.
  • Apligraf® is maintained in culture for 3, 5 and 11 days in absence or in presence of up to 2% of the compound dissolved in the culture medium. Histopathological analysis of hematoxilin-eosin stained tissue slides is performed.
  • the agents of the invention increase the number of basal and epidermal layers, as well as the activation (presence of large nuclei, prominent nucleoli and basophilic cells) and differentiation of the keratinocytes up to the spinous layer. These effects are sustained (minimum of 8 days) after a short treatment (3 days) when applied in the subnatant (at the dermal site) and on the epidermal side of the skin substitute. Histological findings show remodeling and regeneration of the skin substitute. Detachment of the horny layer and upper granular cell layers are observed. Also the fibroblasts are activated.
  • pharmacogenomic investigations show significant differential regulation of genes involved in cell proliferation (e.g. Profilaggrin, GADD45, Keratin- 16, Metallothioneins and Transforming Growth Factor Beta 3) and genes/proteins involved in cell differentiation (e.g. Keratin- 1, -10 and -19). Furthermore such investigations also show a differential regulation on genes involved in tissue remodeling (e.g. mucin and elastin), some of which (e.g. metalloproteases) are known to favor tumor progression.
  • tissue remodeling e.g. mucin and elastin
  • the agents of the invention are therefore indicated as cytoprotective and cell rescuing agents.
  • the cytoprotective effect and cell rescue properties of the agents of the invention can be used in tissue bio-engineering, e.g. to increase the survival or shelf life, or increase the shipping window, of skin, epidermal or dermal equivalents of human or animal origin, e.g. Apligraf® or derivatives.
  • tissue bio-engineering e.g. to increase the survival or shelf life, or increase the shipping window, of skin, epidermal or dermal equivalents of human or animal origin, e.g. Apligraf® or derivatives.
  • applications may be anticipated in the field of solid organ transplantation, e.g. for increasing the viability time or transit time of donor organs (e.g. kidney, lungs, heart, liver) prior to transplantation into a recipient, or in the manufacture, transport and storage of other bioengineered organs or tissues.
  • the agents of the invention are also indicated for the treatment of conditions which are responsive to cytoprotective or cell rescuing agents. These include, but are not limited to, the use in promotion and/or maintenance of connective tissue repair, in the treatment of degenerative or hyperproliferative skin disease, for prevention of photoaging or photodamage, or as anti-tumor agents.
  • the agents of the invention induce cell muscle regeneration, anabolism and myogenesis.
  • the agents of the invention are therefore indicated for the treatment of myopathies, extreme exercise muscular damages (e.g. from sport), shock syndrome (infectious or cardiogenic), amyotrophy (e.g. after bone marrow traumatism), myastheny and astheny, hypothermia and neuromuscular dystrophy.
  • myopathies extreme exercise muscular damages (e.g. from sport), shock syndrome (infectious or cardiogenic), amyotrophy (e.g. after bone marrow traumatism), myastheny and astheny, hypothermia and neuromuscular dystrophy.
  • the agents of the invention induce a significant reduction of body weight as a result of reduced food intake without increased energy expenditure.
  • the agents of the invention are therefore indicated in the treatment of obesity.
  • the appropriate dosage will of course vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about lOOmg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500mg of an agent of the invention, conveniently administered, for example, in divided doses up to four times a day.
  • Preferred agents of the invention for the above-mentioned indications include [2-(2-methylimidazol-l-yl)methyl]pyridine and its pharmaceutically acceptable acid addition salts.
  • the agents of the invention may be incorporated in preservation fluids, transport or shipping media, or in cell and tissue culture media.
  • the agents of the invention may be administered in any usual manner, e.g. orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions, or topically, for example in the form of lotions, solutions, ointments or creams.
  • concentration of the agent of the invention will, of course, vary depending e.g. on the treatment desired and the nature of the form. In general, however, satisfactory results are obtained in topical application forms at concentrations of from about 0.1 to about 2%, particularly from about 0.2 to about 1% by weight.
  • the present invention also provides pharmaceutical compositions comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent, for use in the treatment of any condition mentioned above.
  • Such compositions may be manufactured in conventional manner.
  • Unit dosage forms may contain for example from about 0.25mg to about 250mg of the agent of the invention.
  • the invention further provides the use of an agent of the invention for the manufacture of a pharmaceutical composition for the treatment of any of the above-mentioned conditions.
  • the invention furthermore provides a method for the treatment of any of the above-mentioned conditions in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an agent of the invention.

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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)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un composé de formule (I), dans laquelle R1, R2, R3 et R4 sont comme définis dans la description, en tant qu'agent cytoprotecteur et de protection cellulaire ou dans le traitement de l'obésité.
PCT/EP2001/004203 2000-04-13 2001-04-11 Nouvelles utilisations des imidazolylmethyl-pyridines WO2001078726A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001258330A AU2001258330A1 (en) 2000-04-13 2001-04-11 New uses of imidazolylmethyl-pyridines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0009037.3A GB0009037D0 (en) 2000-04-13 2000-04-13 Organic compounds
GB0009037.3 2000-04-13

Publications (1)

Publication Number Publication Date
WO2001078726A1 true WO2001078726A1 (fr) 2001-10-25

Family

ID=9889785

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/004203 WO2001078726A1 (fr) 2000-04-13 2001-04-11 Nouvelles utilisations des imidazolylmethyl-pyridines

Country Status (3)

Country Link
AU (1) AU2001258330A1 (fr)
GB (1) GB0009037D0 (fr)
WO (1) WO2001078726A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005045054A2 (fr) * 2003-11-07 2005-05-19 Forschungsinstitut Für Die Biologie Landwirtschaftlicher Nutztiere Procedes pour identifier des principes actifs ayant une influence sur la masse corporelle et l'accumulation de graisse
WO2007016203A1 (fr) 2005-07-29 2007-02-08 Vanda Pharmaceuticals, Inc. Procede permettant d'ameliorer l'etat de veille
WO2009097414A1 (fr) * 2008-01-29 2009-08-06 Vanda Pharmaceuticals, Inc. Utilisation d'imidazolylalkyl-pyridines pour le traitement de troubles addictifs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4230714A (en) * 1978-08-15 1980-10-28 Pfizer Inc. Imidazole therapeutic agents
EP0534904A1 (fr) * 1991-09-23 1993-03-31 Sandoz Ltd. Imidazolylméthylpyridines
WO2000039097A1 (fr) * 1998-12-24 2000-07-06 Fujisawa Pharmaceutical Co., Ltd. Composes d'imidazole et utilisation medicinale de ces composes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4230714A (en) * 1978-08-15 1980-10-28 Pfizer Inc. Imidazole therapeutic agents
EP0534904A1 (fr) * 1991-09-23 1993-03-31 Sandoz Ltd. Imidazolylméthylpyridines
WO2000039097A1 (fr) * 1998-12-24 2000-07-06 Fujisawa Pharmaceutical Co., Ltd. Composes d'imidazole et utilisation medicinale de ces composes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 200040, Derwent World Patents Index; AN 2000-465715, XP002177687 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005045054A2 (fr) * 2003-11-07 2005-05-19 Forschungsinstitut Für Die Biologie Landwirtschaftlicher Nutztiere Procedes pour identifier des principes actifs ayant une influence sur la masse corporelle et l'accumulation de graisse
WO2005045054A3 (fr) * 2003-11-07 2005-09-22 Forsch Die Biolog Landw Licher Procedes pour identifier des principes actifs ayant une influence sur la masse corporelle et l'accumulation de graisse
WO2007016203A1 (fr) 2005-07-29 2007-02-08 Vanda Pharmaceuticals, Inc. Procede permettant d'ameliorer l'etat de veille
EP1919477A1 (fr) * 2005-07-29 2008-05-14 Vanda Pharmaceuticals Inc. Procede permettant d'ameliorer l'etat de veille
EP1919477A4 (fr) * 2005-07-29 2009-03-18 Vanda Pharmaceuticals Inc Procede permettant d'ameliorer l'etat de veille
WO2009097414A1 (fr) * 2008-01-29 2009-08-06 Vanda Pharmaceuticals, Inc. Utilisation d'imidazolylalkyl-pyridines pour le traitement de troubles addictifs

Also Published As

Publication number Publication date
AU2001258330A1 (en) 2001-10-30
GB0009037D0 (en) 2000-05-31

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