WO2013045962A1 - Composition pharmaceutique utilisée pour prévenir et/ou traiter une atrophie musculaire - Google Patents

Composition pharmaceutique utilisée pour prévenir et/ou traiter une atrophie musculaire Download PDF

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Publication number
WO2013045962A1
WO2013045962A1 PCT/HU2012/000097 HU2012000097W WO2013045962A1 WO 2013045962 A1 WO2013045962 A1 WO 2013045962A1 HU 2012000097 W HU2012000097 W HU 2012000097W WO 2013045962 A1 WO2013045962 A1 WO 2013045962A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
muscle atrophy
muscle
acid addition
Prior art date
Application number
PCT/HU2012/000097
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English (en)
Inventor
Balázs HAZAY
Original Assignee
Hazay Balazs
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 Hazay Balazs filed Critical Hazay Balazs
Priority to EP12805748.6A priority Critical patent/EP2760448A1/fr
Publication of WO2013045962A1 publication Critical patent/WO2013045962A1/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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
    • 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

Definitions

  • the invention refers to the use of a compound of formula
  • Aryl-C N-0-CH 2 -CH-CH 2 -N
  • Aryl represents a phenyl, naphthyl or pyridyl group
  • X stands for a halo atom and then Y represents a hydroxy group
  • X is a nitrogen atom and then Y represents a valence bond between this nitrogen atom and the carbon atom adjacent to Y, thus, forming a six-membered oxadiazine ring,
  • R and Ri form together with the adjacent nitrogen atom a 5-7- membered saturated heterocyclic group
  • the skeletal muscle For lack of regular stimulation by the motorial nerves, the skeletal muscle has losses in tone and mass. The muscle becomes flaccid while containing smaller and weaker muscle fibres. This reduction of muscle size, tone and power is called muscle atrophy.
  • the muscle mass is determined by the ratio of synthesis and decomposition of muscle protein. In various conditions causing muscle atrophy, in addition to ageing, an activation of a complex biochemical and transcription system can be observed leading to the expression of an atrogenic set of genes [Glass, DJ. Molecular mechanisms modulating muscle mass. (2003) Trends Mol Med, 9(8):344-50]; Cao PR, Kim HJ, Lecker SH Ubiquitin-protein ligases in muscle wasting. (2005) Int J Biochem Cell Biol.
  • Atrogenic genes belongs to the ubiquitin-proteasome system allowing the selective degradation of regulating and structural proteins [Lecker SH, Goldberg AL, Mitch WE.: Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. (2006) J Am Soc Nephrol.;17(7):1807-19].
  • PGC-1 peroxisome proliferator-activated receptor gamma coactivator transcription factors stimulated by the physical activity protect against muscle atrophy and they are effective mainly through the inhibition of Fox03 and NF- ⁇ [Jeffrey J. Brault et al., (2010) J. Biol. Chem. 285:19460-19471].
  • the aim of the invention is the provision of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
  • the compounds of formula I are known compounds.
  • US 5,147,879 discloses compounds of formula I, wherein X represents a halo atom and Y stands for a hydroxy group, as well as acid addition salts and the manufacture thereof.
  • the known compounds have selective beta-blocking action and can be used for the treatment of diabetic angiopathy.
  • WO 00/50403 discloses the compound N-[2-hydroxy-3- (1-piperidinyl)propoxy]pyridine-1-oxide-3-carboximidoyl chloride (arimoclomol), stereoisomers thereof and use of the compound for treating insulin resistance and pathologic states connected with insulin resistance.
  • An industrially applicable preparation of the latter compound and stereoisomers thereof is discussed in WO 01/79174.
  • HU-P 226 206 and HU-P 226 617 describe the (+)- and (-)-enantiomer, respectively, of the 5-(piperidin-1-ylmethyl)-3- pyridyl-5,6-dihydro-2H-1 ,2,4-oxadiazine known from EP 801 649.
  • the enantiomers are suitable for the treatment of vascular diseases.
  • the invention provides the use of a compound of formula I or an N-oxide of the compound of formula I or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
  • the invention provides a method for the prevention and/or treatment of muscle atrophy which comprises administering to a patient exposed to or suffering from muscle atrophy an effective non-toxic dose of a compound of formula I or an N-oxide of the compound of formula I or a pharmaceutically suitable acid addition salt thereof.
  • the N- oxide of the nitrogen atom being in the pyridyl group and/or in the 5-7-membered heterocyclic group is meant.
  • the 5-7-membered heterocyclic group formed by R, Ri and the adjacent nitrogen atom is preferably a pyrrolidinyl or piperidinyl group.
  • a halo atom is a fluoro, chloro, bromo or iodo atom, preferably a chloro atom.
  • a pharmaceutically suitable acid addition salt is an acid addition salt formed with a pharmaceutically acceptable inorganic or organic acid such as a hydrochloride, acetate, fumarate, maleate, lactate, tartrate etc.
  • a preferred compound of formula I is N-[2-hydroxy-3-(1- piperidinyl)propoxy]pyridine-3-carboximidoyl chloride (bimoclomol) of formula II
  • any composition for human or veterinary use is meant, wherein the composition comprises, in addition to the active ingredient i.e. a compound of formula I or an N-oxide of the compound of formula I or a pharmaceutically suitable acid addition salt thereof, one or more carrier(s) conventionally employed in such compositions.
  • the pharmaceutical composition may include any dosage form suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
  • the solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film- coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.
  • Capsules may contain the pure active agent without any carrier, other dosage forms contain, in addition to the active agent, one or more carrier(s).
  • the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
  • suspending agents such as gelatine, carboxymethylcellulose etc.
  • emulsifiers such as sorbitane monooleate etc.
  • solvents such as water, oils, glycerol, propylene glycol, ethanol etc.
  • preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
  • compositions suitable for parenteral administration consist of sterile solutions of the active ingredients, in general.
  • the sterile solution may contain, in addition to the active agent, pH control agents and osmolarity control agents, preservatives, surfactants etc.
  • ointments for example, ointments, solutions, creames, transdermal patches etc. can be used.
  • Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).
  • the pharmaceutical composition contains dosage unit, in general.
  • the daily dose amounting generally to 1-1000 mg of the compound of formula I or an N-oxide of the compound of formula I or a pharmaceutically suitable acid addition salt thereof can be administered in one or more portions.
  • the actual dosage depends on many factors and is determined by the doctor.
  • the pharmaceutical composition is prepared by admixing the active ingredient to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se.
  • Useful methods are known from the literature, e.g. Remington's Pharmaceutical Sciences mentioned above.
  • Muscle atrophy developed by cutting the nerve in the muscle is a rapid and robust model widely used for the examination of muscle atrophy in vivo.
  • the atrophy of the muscle of one of the hind legs is achieved usually by cutting the sciatic nerve (nervus ischiadicus) [Medina, R., Wing SS., Goldberg AL: Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. Biochem. J. ,(1995), 308:631-7].
  • the experiments were carried out in male Wistar rats having a body mass of 150-200 g in narcosis with pentobarbital.
  • the sciatic nerve was exposed by excising the skin of 1 -2 cm growth at about 1 cm from the spinal column and a 5-10 mm section of the nerve was cut out. The wound was sutured.
  • Half of the animals was treated with 20 mg/kg doses of the test compounds 3 hours after the surgical intervention, then once daily for 8 days, orally.
  • the control animals obtained a similar treatment with the same amount of the carrier and tap water/T ween 80.
  • On day 8 of the experiment the animals were overnarcotized with pentobarbital, then the gastrocnemius, soleus and tibial anterior muscles were isolated from both legs, weighed and frozen in liquid nitrogen.
  • the rate of muscle atrophy developed by denervation was characterized by the weight loss in comparison with the weight of the corresponding muscle on the opposite side, in percentage.

Abstract

L'invention concerne l'utilisation d'un composé de formule (I) ou d'un N-oxyde de ce composé de formule (I) ou d'un sel d'addition d'acide pharmaceutiquement acceptable correspondant pour préparer une composition pharmaceutique conçue pour prévenir et/ou traiter une atrophie musculaire.
PCT/HU2012/000097 2011-09-26 2012-09-25 Composition pharmaceutique utilisée pour prévenir et/ou traiter une atrophie musculaire WO2013045962A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12805748.6A EP2760448A1 (fr) 2011-09-26 2012-09-25 Composition pharmaceutique utilisée pour prévenir et/ou traiter une atrophie musculaire

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP1100534 2011-09-26
HU1100534A HUP1100534A2 (en) 2011-09-26 2011-09-26 Pharmaceutical composition for the treatment of muscle atrophy

Publications (1)

Publication Number Publication Date
WO2013045962A1 true WO2013045962A1 (fr) 2013-04-04

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PCT/HU2012/000097 WO2013045962A1 (fr) 2011-09-26 2012-09-25 Composition pharmaceutique utilisée pour prévenir et/ou traiter une atrophie musculaire

Country Status (3)

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EP (1) EP2760448A1 (fr)
HU (1) HUP1100534A2 (fr)
WO (1) WO2013045962A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020044067A1 (fr) 2018-08-30 2020-03-05 N-Gene Research Laboratories, Inc. Combinaison pharmaceutique destinée à modifier l'effet des bêtabloquants et réduire les effets secondaires

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US5147879A (en) 1988-10-20 1992-09-15 Biorex Kutato-Fejleszto Kft O-(3-amino-2-hydroxypropyl)-hydroximic acid halides and process for preparing the same
EP0801649A2 (fr) 1995-11-02 1997-10-22 Biorex Kutato Es Fejlesztö Rt. Derives d'hydroxylamine utilises pour ameliorer la production de chaperons moleculaires et leur preparation.
WO2000050403A1 (fr) 1999-02-26 2000-08-31 BIOREX Kutató és Fejlesztő Rt. Chlorure de n-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxyde-3-carboximidoyl et ses utilisations dans le traitement de la resistance a l'insuline
WO2001079174A1 (fr) 2000-04-18 2001-10-25 BIOREX Kutató és Fejlesztő Rt. Derive de pyridine-1-oxyde, et processus de transformation de ce derive en composes pharmaceutiquement efficace
WO2005041965A1 (fr) * 2003-10-30 2005-05-12 Cytrx Corporation Utilisation d'un derive d'un halogenure d'acide hydroximique pour traiter des maladies neurodegeneratives
HU226206B1 (en) 1998-12-14 2008-06-30 Biorex Kutato Fejlesztoe Kft Optically active piperidinoalkyl-4h-1,2,4-oxadiazine derivative, the use thereof in the treatment of vascular diseases and pharmaceutical composition containing the compound as active ingredient
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Patent Citations (8)

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US5147879A (en) 1988-10-20 1992-09-15 Biorex Kutato-Fejleszto Kft O-(3-amino-2-hydroxypropyl)-hydroximic acid halides and process for preparing the same
EP0801649A2 (fr) 1995-11-02 1997-10-22 Biorex Kutato Es Fejlesztö Rt. Derives d'hydroxylamine utilises pour ameliorer la production de chaperons moleculaires et leur preparation.
HU226206B1 (en) 1998-12-14 2008-06-30 Biorex Kutato Fejlesztoe Kft Optically active piperidinoalkyl-4h-1,2,4-oxadiazine derivative, the use thereof in the treatment of vascular diseases and pharmaceutical composition containing the compound as active ingredient
HU226617B1 (en) 1998-12-14 2009-04-28 Cytrx Corp Optically active pyridyl-4h-1,2,4-oxadiazine derivatives, and pharmaceutical composition containing the compound as active ingredient
WO2000050403A1 (fr) 1999-02-26 2000-08-31 BIOREX Kutató és Fejlesztő Rt. Chlorure de n-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxyde-3-carboximidoyl et ses utilisations dans le traitement de la resistance a l'insuline
WO2001079174A1 (fr) 2000-04-18 2001-10-25 BIOREX Kutató és Fejlesztő Rt. Derive de pyridine-1-oxyde, et processus de transformation de ce derive en composes pharmaceutiquement efficace
WO2005041965A1 (fr) * 2003-10-30 2005-05-12 Cytrx Corporation Utilisation d'un derive d'un halogenure d'acide hydroximique pour traiter des maladies neurodegeneratives
WO2009155936A1 (fr) * 2008-06-26 2009-12-30 Orphazyme Aps Utilisation du hsp70 en tant que régulateur de l'activité enzymatique

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020044067A1 (fr) 2018-08-30 2020-03-05 N-Gene Research Laboratories, Inc. Combinaison pharmaceutique destinée à modifier l'effet des bêtabloquants et réduire les effets secondaires

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HUP1100534A2 (en) 2013-04-29
EP2760448A1 (fr) 2014-08-06

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