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EP1169027A1 - Traitement de l'arthrose - Google Patents

Traitement de l'arthrose

Info

Publication number
EP1169027A1
EP1169027A1 EP00918058A EP00918058A EP1169027A1 EP 1169027 A1 EP1169027 A1 EP 1169027A1 EP 00918058 A EP00918058 A EP 00918058A EP 00918058 A EP00918058 A EP 00918058A EP 1169027 A1 EP1169027 A1 EP 1169027A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
chlorophenyl
cyclobutyl
methylbutylamine
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Withdrawn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
EP00918058A
Other languages
German (de)
English (en)
Other versions
EP1169027A4 (fr
Inventor
Carl M. Mendel
Timothy B. Seaton
Steve P. Weinstein
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 GmbH and Co KG
Original Assignee
Knoll 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 Knoll GmbH filed Critical Knoll GmbH
Publication of EP1169027A1 publication Critical patent/EP1169027A1/fr
Publication of EP1169027A4 publication Critical patent/EP1169027A4/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Withdrawn legal-status Critical Current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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

Definitions

  • This invention relates to a method of treating osteoarthritis and gout.
  • R and R 2 are independently H or methyl, is administered in conjunction with a pharmaceutically acceptable diluent or carrier to a human in need thereof.
  • a preferred compound of formula I is N,N-dimethyl-1-[1-(4- chlorophenyl)cyclobutyl]-3-methylbutylamine or a salt thereof, for example the hydrochloride salt.
  • a preferred form of this hydrochloride is its monohydrate.
  • N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutylamine hydrochloride in the treatment of obesity is described in published PCT application WO90/06110.
  • a particularly preferred form of this compound is N, N-dimethyl-1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate (sibutramine hydrochloride) which is described in European Patent Number 230742.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer- specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • Preferred compounds of formula I are N, N-dimethyl-1 -[1-(4-chlorophenyl)- cyclobutyl]-3-methylbutylamine, N- ⁇ 1 -[1 -(4-chlorophenyl)cyclobutyl]-3- methylbutyl ⁇ -N- methylamine, and 1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutylamine including racemates, individual enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof.
  • the individual enantiomers can be prepared by enantioselective synthesis from optically active precursors, or by resolving the racemic compound which can be prepared as described above.
  • Enantiomers of secondary amines of the formula I can also be prepared by preparing the racemate of the corresponding primary amine, resolving the latter into the individual enantiomers, and then converting the optically pure primary amine enantiomer into the required secondary amine by methods described in British Patent Specification 2098602.
  • the hydrochloride salts are preferred in each case, but the free bases and other pharmaceutically acceptable salts are also suitable.
  • the compound of formula I may be administered in any of the known pharmaceutical dosage forms.
  • the amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 50 mg preferably 1 to 30 mg per day given in one or more doses.
  • Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions.
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
  • Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
  • the tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate.
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
  • the tablets and capsules may conveniently each contain 1 to 50 mg of the active compound.
  • Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy- methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
  • the active compound may be formulated into granules with or without additional excipients.
  • the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion.
  • the granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
  • the therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
  • Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
  • Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
  • Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
  • a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
  • the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base.
  • the amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
  • the therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity.
  • Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
  • the therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
  • Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused.
  • the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
  • the amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
  • the compounds of the present invention may be beneficial to use in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the invention further provides the use of compounds of formula I in the manufacture of a medicament for treating osteoarthritis or gout.
  • the invention further provides a pharmaceutical composition for treating osteoarthritis or gout, comprising a compound of formula I in conjunction with a pharmaceutically acceptable diluent or carrier.
  • Obesity is associated with the development of osteoarthritis and gout and, in obese middle -aged women at or after menopause, pain at the medial aspect of the knee (adiposa dolorosa juxtarticularis).
  • Possible mechanisms underlying the relationship between obesity and osteoarthritis include mechanical stresses related to increased load of obesity, metabolic changes associated with increased fatness, and dietary elements that are related to the development of obesity.
  • the increased risk of gout associated with obesity may be related to the accompanying hyperuhcaemia although central fat distribution may also be involved, particularly in women.
  • Monoamine reuptake inhibitors have been used to treat certain of the disorders described in the present invention.
  • these compounds are known to suffer from a number of disadvantages. Firstly such compounds are not effective in all patients. Secondly where the compounds are effective they may not provide a complete cure of the disorder. Thirdly, there are many undesirable side-effects known with this type of compound. Such side-effects include nausea, sexual dysfunction, light headedness, somnolence, sweating, tremor, dry mouth, asthenia, insomnia, diarrhoea, headache, vomiting, anxiety, drowsiness, dizziness, fever, rash or allergic reactions, arthralgia, myalgia, convulsions, hypomania and mania.
  • ⁇ -HT serotonin

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un composé de formule (I) ou d'un sel de celui-ci pharmaceutiquement acceptable. R1 et R2 sont de manière indépendante H ou méthyle ( par exemple l'hydrochlorure d'amine N,N-diméthyle-1-[1-(4-chlorophényle)cyclobutyl]-3-méthylbutyl éventuellement sous la forme de son monohydrate). Ledit composé permet de traiter l'arthrose ou la goutte.
EP00918058A 1999-03-19 2000-03-17 Traitement de l'arthrose Withdrawn EP1169027A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12530099P 1999-03-19 1999-03-19
US125300P 1999-03-19
PCT/US2000/007072 WO2000056306A1 (fr) 1999-03-19 2000-03-17 Traitement de l'arthrose

Publications (2)

Publication Number Publication Date
EP1169027A1 true EP1169027A1 (fr) 2002-01-09
EP1169027A4 EP1169027A4 (fr) 2004-10-20

Family

ID=22419072

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00918058A Withdrawn EP1169027A4 (fr) 1999-03-19 2000-03-17 Traitement de l'arthrose

Country Status (20)

Country Link
EP (1) EP1169027A4 (fr)
JP (2) JP2002539248A (fr)
KR (1) KR20020038567A (fr)
CN (1) CN1352552A (fr)
AU (1) AU773490B2 (fr)
BG (1) BG105999A (fr)
BR (1) BR0009081A (fr)
CA (1) CA2366660A1 (fr)
CZ (1) CZ20013284A3 (fr)
HK (1) HK1044702A1 (fr)
HU (1) HUP0200494A2 (fr)
IL (1) IL145238A0 (fr)
MX (1) MXPA01009461A (fr)
NO (1) NO20014477L (fr)
NZ (1) NZ514016A (fr)
PL (1) PL365463A1 (fr)
SK (1) SK13342001A3 (fr)
TR (1) TR200102699T2 (fr)
WO (1) WO2000056306A1 (fr)
ZA (1) ZA200107682B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6476078B2 (en) 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6974838B2 (en) 1998-08-24 2005-12-13 Sepracor Inc. Methods of treating or preventing pain using sibutramine metabolites
US6399826B1 (en) 1999-08-11 2002-06-04 Sepracor Inc. Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain
WO2002083631A1 (fr) 2001-04-13 2002-10-24 Sepracor Inc. Procedes permettant la preparation de didesmethylsibutramine et d'autres derives de sibutramine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998013033A1 (fr) * 1996-09-25 1998-04-02 Knoll Aktiengesellschaft Traitement medical

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA821577B (en) * 1981-04-06 1983-03-30 Boots Co Plc Therapeutic agents
ZA836848B (en) * 1982-09-30 1984-05-30 Boots Co Plc Therapeutic agents
GB8531071D0 (en) * 1985-12-17 1986-01-29 Boots Co Plc Therapeutic compound
JP2675573B2 (ja) * 1988-03-31 1997-11-12 科研製薬株式会社 脳機能改善剤
IE61928B1 (en) * 1988-11-29 1994-11-30 Boots Co Plc Treatment of obesity
EP0647134A4 (fr) * 1992-06-23 1997-07-30 Sepracor Inc Procedes et compositions utilises pour traiter la depression et d'autres affections avec de la sibutramine (-) optiquement pure.
AU4542993A (en) * 1992-06-23 1994-01-24 Sepracor, Inc. Methods and compositions for treating depression and other disorders using optically pure (+) sibutramine
JP3862295B2 (ja) * 1993-09-30 2006-12-27 独立行政法人理化学研究所 抗肥満剤
US5459164A (en) * 1994-02-03 1995-10-17 Boots Pharmaceuticals, Inc. Medical treatment
AU2764495A (en) * 1994-06-01 1995-12-21 Arris Pharmaceutical Corporation Compositions and methods for treating mast-cell mediated conditions
MA24500A1 (fr) * 1997-03-21 1998-10-01 Lg Life Sciences Ltd Derive du sel d'acide carboxylique de naphthyridine .

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998013033A1 (fr) * 1996-09-25 1998-04-02 Knoll Aktiengesellschaft Traitement medical

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0056306A1 *

Also Published As

Publication number Publication date
CZ20013284A3 (cs) 2002-10-16
NO20014477D0 (no) 2001-09-14
BR0009081A (pt) 2003-03-05
EP1169027A4 (fr) 2004-10-20
MXPA01009461A (es) 2004-03-19
HK1044702A1 (zh) 2002-11-01
BG105999A (en) 2002-06-28
HUP0200494A2 (en) 2002-08-28
JP2012051904A (ja) 2012-03-15
KR20020038567A (ko) 2002-05-23
AU773490B2 (en) 2004-05-27
PL365463A1 (en) 2005-01-10
JP2002539248A (ja) 2002-11-19
CN1352552A (zh) 2002-06-05
TR200102699T2 (tr) 2002-03-21
NO20014477L (no) 2001-11-01
SK13342001A3 (sk) 2002-04-04
IL145238A0 (en) 2002-06-30
WO2000056306A1 (fr) 2000-09-28
ZA200107682B (en) 2003-06-18
AU3893200A (en) 2000-10-09
NZ514016A (en) 2001-09-28
CA2366660A1 (fr) 2000-09-28

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