WO2000056323A1 - Treatment of certain cancers associated with weight gain - Google Patents

Treatment of certain cancers associated with weight gain Download PDF

Info

Publication number
WO2000056323A1
WO2000056323A1 PCT/US2000/007361 US0007361W WO0056323A1 WO 2000056323 A1 WO2000056323 A1 WO 2000056323A1 US 0007361 W US0007361 W US 0007361W WO 0056323 A1 WO0056323 A1 WO 0056323A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
cyclobutyl
chlorophenyl
cancer
Prior art date
Application number
PCT/US2000/007361
Other languages
English (en)
French (fr)
Inventor
Carl M. Mendel
Timothy B. Seaton
Steve P. Weinstein
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
Priority to PL00351958A priority Critical patent/PL351958A1/xx
Application filed by Knoll Gmbh filed Critical Knoll Gmbh
Priority to EP00915015A priority patent/EP1171106A1/en
Priority to MXPA01009470A priority patent/MXPA01009470A/es
Priority to SK1337-2001A priority patent/SK13372001A3/sk
Priority to IL14523900A priority patent/IL145239A0/xx
Priority to CA002367045A priority patent/CA2367045A1/en
Priority to AU36320/00A priority patent/AU3632000A/en
Priority to BR0009161-8A priority patent/BR0009161A/pt
Priority to JP2000606228A priority patent/JP2002539255A/ja
Priority to KR1020017011855A priority patent/KR20010113765A/ko
Publication of WO2000056323A1 publication Critical patent/WO2000056323A1/en
Priority to NO20014478A priority patent/NO20014478L/no
Priority to BG105998A priority patent/BG105998A/xx

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Definitions

  • This invention relates to a method of treating certain cancers associated with weight gain.
  • 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.
  • Cancers which may advantageously be treated with a compound of formula I include colon cancer, breast cancer, endometrial cancer and gallbladder cancer.
  • 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.
  • N, N-dimethyl-1 -[1 -(4- chlorophenyl)cyclobutyl]-3-methyibutylamine and salts thereof for improving the glucose tolerance of humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus is described in published PCT application WO95/20949.
  • I contain a chiral centre.
  • a compound of formula I may exist in two enantiomeric forms.
  • the present invention includes the use of the individual enantiomers and mixtures of the enantiomers.
  • 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, ⁇ dimethyl-1-[1-(4-chlorophenyl)- cyclobutyl]-3-methylbutylamine, N- ⁇ 1-[1-(4-chlorophenyl)cyciobutyl]-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.
  • 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 microcrystaliine cellulose or polyvinylpyrroiidone 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.
  • 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 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 certain cancers associated with obesity, for example colon cancer, breast cancer, endometrial cancer and gallbladder cancer.
  • the invention further provides a pharmaceutical composition for treating colon cancer, breast cancer, endometrial cancer and gallbladder cancer, 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, arthraigia, myalgia, convulsions, hypomania and mania.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/US2000/007361 1999-03-19 2000-03-17 Treatment of certain cancers associated with weight gain WO2000056323A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
CA002367045A CA2367045A1 (en) 1999-03-19 2000-03-17 Treatment of certain cancers associated with weight gain
EP00915015A EP1171106A1 (en) 1999-03-19 2000-03-17 Treatment of certain cancers associated with weight gain
MXPA01009470A MXPA01009470A (es) 1999-03-19 2000-03-17 Tratamiento de ciertos canceres asociados con el aumento de peso.
SK1337-2001A SK13372001A3 (sk) 1999-03-19 2000-03-17 Použitie zlúčeniny a farmaceutická kompozícia ju obsahujúca
IL14523900A IL145239A0 (en) 1999-03-19 2000-03-17 Treatment of certain cancers associated with weight gain
PL00351958A PL351958A1 (en) 1999-03-19 2000-03-17 Treatment of some tumours associated with gain in weight
AU36320/00A AU3632000A (en) 1999-03-19 2000-03-17 Treatment of certain cancers associated with weight gain
KR1020017011855A KR20010113765A (ko) 1999-03-19 2000-03-17 체중 증가와 관련된 특정 암의 치료방법
JP2000606228A JP2002539255A (ja) 1999-03-19 2000-03-17 体重増加に関係する癌の治療
BR0009161-8A BR0009161A (pt) 1999-03-19 2000-03-17 Tratamento de certos cânceres associados a ganho de peso
NO20014478A NO20014478L (no) 1999-03-19 2001-09-14 Behandling av visse kreftformer forbundet med vektökning
BG105998A BG105998A (en) 1999-03-19 2001-10-10 Treatment of certain cancers associated with weight gain

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12525099P 1999-03-19 1999-03-19
US60/125,250 1999-03-19

Publications (1)

Publication Number Publication Date
WO2000056323A1 true WO2000056323A1 (en) 2000-09-28

Family

ID=22418838

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/007361 WO2000056323A1 (en) 1999-03-19 2000-03-17 Treatment of certain cancers associated with weight gain

Country Status (19)

Country Link
EP (1) EP1171106A1 (ja)
JP (1) JP2002539255A (ja)
KR (1) KR20010113765A (ja)
CN (1) CN1399545A (ja)
AU (1) AU3632000A (ja)
BG (1) BG105998A (ja)
BR (1) BR0009161A (ja)
CA (1) CA2367045A1 (ja)
CZ (1) CZ20013281A3 (ja)
HU (1) HUP0200497A2 (ja)
IL (1) IL145239A0 (ja)
MX (1) MXPA01009470A (ja)
NO (1) NO20014478L (ja)
NZ (1) NZ514012A (ja)
PL (1) PL351958A1 (ja)
SK (1) SK13372001A3 (ja)
TR (1) TR200102692T2 (ja)
WO (1) WO2000056323A1 (ja)
ZA (1) ZA200107687B (ja)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096202A1 (en) * 2003-04-28 2004-11-11 Cipla Limited Pharmaceutical formulation comprising anti-obesity agent and acidulant

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5068440A (en) * 1985-12-17 1991-11-26 Boots Company, Plc Process for the manufacture of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate
US5459164A (en) * 1994-02-03 1995-10-17 Boots Pharmaceuticals, Inc. Medical treatment

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5068440A (en) * 1985-12-17 1991-11-26 Boots Company, Plc Process for the manufacture of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate
US5459164A (en) * 1994-02-03 1995-10-17 Boots Pharmaceuticals, Inc. Medical treatment

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096202A1 (en) * 2003-04-28 2004-11-11 Cipla Limited Pharmaceutical formulation comprising anti-obesity agent and acidulant

Also Published As

Publication number Publication date
JP2002539255A (ja) 2002-11-19
IL145239A0 (en) 2002-06-30
CN1399545A (zh) 2003-02-26
BR0009161A (pt) 2002-01-22
PL351958A1 (en) 2003-07-14
TR200102692T2 (tr) 2002-03-21
NO20014478D0 (no) 2001-09-14
HUP0200497A2 (en) 2002-08-28
MXPA01009470A (es) 2004-03-19
NZ514012A (en) 2001-09-28
CZ20013281A3 (cs) 2002-07-17
AU3632000A (en) 2000-10-09
NO20014478L (no) 2001-10-29
BG105998A (en) 2002-06-28
CA2367045A1 (en) 2000-09-28
SK13372001A3 (sk) 2002-07-02
KR20010113765A (ko) 2001-12-28
ZA200107687B (en) 2002-12-18
EP1171106A1 (en) 2002-01-16

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