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WO2000056307A1 - Traitement de la hernie hiatale - Google Patents

Traitement de la hernie hiatale Download PDF

Info

Publication number
WO2000056307A1
WO2000056307A1 PCT/US2000/007112 US0007112W WO0056307A1 WO 2000056307 A1 WO2000056307 A1 WO 2000056307A1 US 0007112 W US0007112 W US 0007112W WO 0056307 A1 WO0056307 A1 WO 0056307A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
cyclobutyl
chlorophenyl
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.)
Ceased
Application number
PCT/US2000/007112
Other languages
English (en)
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
Knoll Pharmaceutical Co
Original Assignee
Knoll GmbH
Knoll Pharmaceutical Co
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
Priority to MXPA01009463A priority Critical patent/MXPA01009463A/es
Priority to EP00918070A priority patent/EP1169028A1/fr
Priority to HK02104606.6A priority patent/HK1044703A1/zh
Priority to SK1339-2001A priority patent/SK13392001A3/sk
Priority to IL14524200A priority patent/IL145242A0/xx
Priority to CA002367035A priority patent/CA2367035A1/fr
Priority to JP2000606212A priority patent/JP2002539249A/ja
Priority to PL00351081A priority patent/PL351081A1/xx
Application filed by Knoll GmbH, Knoll Pharmaceutical Co filed Critical Knoll GmbH
Priority to AU38944/00A priority patent/AU3894400A/en
Priority to BR0009160-0A priority patent/BR0009160A/pt
Publication of WO2000056307A1 publication Critical patent/WO2000056307A1/fr
Priority to NO20014476A priority patent/NO20014476L/no
Anticipated expiration legal-status Critical
Priority to BG106000A priority patent/BG106000A/xx
Ceased 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • This invention relates to a method of treating hiatial hernias and reflux esophagitis.
  • R 1 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 parenterai 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 hiatial hernias.
  • the invention further provides a pharmaceutical composition for treating hiatial hernias, comprising a compound of formula I in conjunction with a pharmaceutically acceptable diluent or carrier.
  • 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.
  • noradenaline-selective reuptake inhibitors e.g.
  • the efficacy of compounds of formula I in treating hiatial hernias is demonstrable through clinical trials in a relevant population set. Improvement in the conditions is related to weight loss.

Landscapes

  • 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)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé correspondant à la formule (I) ou un sel de celui-ci, acceptable sur le plan pharmacologique. Dans cette formule, R1 et R2 représentent indépendamment H ou méthyle (par exemple du chlorhydrate de N, N-diméthyl-1-[1-(4-chlorophényl)cyclobutyl]-3-méthylbutylamine éventuellement sous la forme de son monohydrate). Ce composé est utile dans le traitement des hernies hiatales et dans l'oesophagite par reflux.
PCT/US2000/007112 1999-03-19 2000-03-17 Traitement de la hernie hiatale Ceased WO2000056307A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
JP2000606212A JP2002539249A (ja) 1999-03-19 2000-03-17 裂孔ヘルニアの治療
HK02104606.6A HK1044703A1 (zh) 1999-03-19 2000-03-17 裂孔疝的治疗方法
SK1339-2001A SK13392001A3 (sk) 1999-03-19 2000-03-17 Použitie zlúčeniny a farmaceutická kompozícia ju obsahujúca
IL14524200A IL145242A0 (en) 1999-03-19 2000-03-17 Treatment of hiatial hernia
CA002367035A CA2367035A1 (fr) 1999-03-19 2000-03-17 Traitement de la hernie hiatale
PL00351081A PL351081A1 (en) 1999-03-19 2000-03-17 Treatment of hiatial hernia
AU38944/00A AU3894400A (en) 1999-03-19 2000-03-17 Treatment of hiatial hernia
MXPA01009463A MXPA01009463A (es) 1999-03-19 2000-03-17 Tratamiento de hernia hiatial.
EP00918070A EP1169028A1 (fr) 1999-03-19 2000-03-17 Traitement de la hernie hiatale
BR0009160-0A BR0009160A (pt) 1999-03-19 2000-03-17 Tratamento de hérnia de hiato
NO20014476A NO20014476L (no) 1999-03-19 2001-09-14 Behandling av hiatial hernia
BG106000A BG106000A (en) 1999-03-19 2001-10-10 Treatment of hiatial hernia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12511699P 1999-03-19 1999-03-19
US60/125,116 1999-03-19

Publications (1)

Publication Number Publication Date
WO2000056307A1 true WO2000056307A1 (fr) 2000-09-28

Family

ID=22418261

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/007112 Ceased WO2000056307A1 (fr) 1999-03-19 2000-03-17 Traitement de la hernie hiatale

Country Status (20)

Country Link
EP (1) EP1169028A1 (fr)
JP (1) JP2002539249A (fr)
KR (1) KR20030006909A (fr)
CN (1) CN1376061A (fr)
AU (1) AU3894400A (fr)
BG (1) BG106000A (fr)
BR (1) BR0009160A (fr)
CA (1) CA2367035A1 (fr)
CZ (1) CZ20013279A3 (fr)
HK (1) HK1044703A1 (fr)
HU (1) HUP0200498A2 (fr)
IL (1) IL145242A0 (fr)
MX (1) MXPA01009463A (fr)
NO (1) NO20014476L (fr)
NZ (1) NZ514013A (fr)
PL (1) PL351081A1 (fr)
SK (1) SK13392001A3 (fr)
TR (1) TR200102700T2 (fr)
WO (1) WO2000056307A1 (fr)
ZA (1) ZA200107679B (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103006833B (zh) * 2012-12-31 2014-02-12 代凤玲 一种食管裂孔疝术后康复的药物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4939175A (en) * 1988-03-31 1990-07-03 The Boots Co. Plc Use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4939175A (en) * 1988-03-31 1990-07-03 The Boots Co. Plc Use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine

Also Published As

Publication number Publication date
HUP0200498A2 (en) 2002-08-28
KR20030006909A (ko) 2003-01-23
HK1044703A1 (zh) 2002-11-01
IL145242A0 (en) 2002-06-30
NZ514013A (en) 2001-09-28
CZ20013279A3 (cs) 2002-07-17
BR0009160A (pt) 2002-01-29
MXPA01009463A (es) 2004-03-19
NO20014476D0 (no) 2001-09-14
PL351081A1 (en) 2003-03-10
CA2367035A1 (fr) 2000-09-28
JP2002539249A (ja) 2002-11-19
CN1376061A (zh) 2002-10-23
AU3894400A (en) 2000-10-09
SK13392001A3 (sk) 2002-04-04
BG106000A (en) 2002-06-28
ZA200107679B (en) 2003-06-18
TR200102700T2 (tr) 2002-04-22
NO20014476L (no) 2001-10-29
EP1169028A1 (fr) 2002-01-09

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