EP1218008A2 - New use of 1,2,4-triazolo[1,5-a]pyrimidines - Google Patents

New use of 1,2,4-triazolo[1,5-a]pyrimidines

Info

Publication number
EP1218008A2
EP1218008A2 EP00947848A EP00947848A EP1218008A2 EP 1218008 A2 EP1218008 A2 EP 1218008A2 EP 00947848 A EP00947848 A EP 00947848A EP 00947848 A EP00947848 A EP 00947848A EP 1218008 A2 EP1218008 A2 EP 1218008A2
Authority
EP
European Patent Office
Prior art keywords
triazolo
ethyl
pyrimidine
chlorophenoxy
compound
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Withdrawn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
EP00947848A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ian Charles Kilpatrick
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 EP1218008A2 publication Critical patent/EP1218008A2/en
Withdrawn legal-status Critical Current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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to 1 ,2,4-triazolo[1 ,5-a]pyrimidines which are useful in the treatment and/or prophylaxis of obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
  • eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
  • represents H or optionally substituted alkyl, alkoxy or alkanoyl
  • R 2 and R 3 independently represent H or optionally substituted alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl or sulphonyl
  • R and R 5 independently represent H, alkyl or together with the carbon atom to which they are attached represent optionally substituted cycloalkylidene
  • R 6 , R and R 8 independently represent H, halo hydroxy, mercapto, cyano or optionally substituted alkyl, alkanoyl, aikoxy, alkoxycarbonyl, carboxy, alkanoyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, sulphamoyl, carbamoyl, alkylcarbamoyl or alkanoylamino; processes for their preparation, and their use in the
  • the present invention provides a method of treating obesity comprising the administration of a therapeutically effective amount of a compound of formula I including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
  • R-i represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C 1-6 alkyl, C-
  • R 2 and R 3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkyltf ⁇ io, C 1-6 alkylsulphinyl, C -6 alkylsulphonyl or hydroxy;
  • R 4 and R 5 independently represent H, C -6 alkyl or R 4 and R 5 combined together with the carbon atom to which they are attached represent C 3-6 cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C 1-6 alkyl); and
  • RQ, R 7 and R 8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C-
  • any group mentioned herein which contains a chain of three or more carbon atoms signifies a group in which the chain may be straight or branched.
  • an alkyl group may comprise propyl which includes n-propyl and isopropyl and butyl which includes n-buty I, sec-butyl, isobutyl and tert-butyl.
  • the total number of carbon atoms is specified herein for certain substituents, for example C 1-6 signifies an alkyl group having from 1 to 6 carbon atoms.
  • the term ' halo' as used herein signifies fluoro, chloro, bromo and iodo.
  • Optionally substituted as used herein, unless immediately followed by a list of substituent groups, means optionally substituted with one or more group or groups selected from halo, cyano, hydroxy and amino.
  • substituents R 6 , R 7 and R 8 are other than H, the substituent may replace any H attached to a carbon atom in the ring and may be located at any such position of the ring, ie up to three of positions 2, 3, 4 and/or 5.
  • stereoisomers of compounds of formula I are:
  • Preferred compound of formula I are 7-[1-(4-chlorophenoxy)ethyl]-1 ,2,4- triazolo[1 ,5-a]pyrimidine and 7-[1-(4-chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]- pyrimidin-5-ol including the racemates, enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof.
  • More preferred compounds of formula I are ( ?)-7-[1-(4-chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidine and (S)-7-[1-(4- chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidine and pharmaceutically acceptable salts thereof.
  • a most preferred compound of formula I is ( )-7-[1-(4- chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidine and pharmaceutically acceptable salts thereof.
  • the compounds of formula I may be prepared as described in WO95/10521 (Knoll AG) and WO98/07724 (Knoll AG).
  • 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 1000 mg preferably 1 to 500 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 500 mg of the active compound.
  • the tablets and capsules each contain 5, 10, 15, 20, 25, 30, 50, 100 ,250 or 500mg.
  • 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 of 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 in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the present invention also comprises a compound of Formula I for use as a medicament.
  • compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress in mammals particularly humans, and as an aid to smoking cessation in human beings.
  • eating disorders such as bulimia, anorexia, snacking and binge eating
  • non-insulin dependent diabetes mellitus such as hyperglycaemia, hyperlipidaemia, and stress in mammals particularly humans
  • the amount of active compound administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
  • the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
  • eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
  • the present invention also provides a method of treating obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia and stress which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • the present invention also provides a method of reducing the craving to smoke in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • the present invention also provides a method of reducing weight gain after smoking cessation in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • the compounds of the present invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate.
  • the compounds of the present invention may be useful in preventing cardiovascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation. Accordingly the present invention further provides a method for, and the use of a compound of formula I in the manufacture of the medicament for, thetreament of obesity. The present invention also provides a method for, and the use of a compound of formula I in the manufacture of a medicament for, the prophylaxis of obesity.
  • the present invention provides a pharmaceutical composition for the treatment and/or the prevention of obesity comprising a therapeutically effective amount of a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof in conjunction with a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a method for the prophylaxis of obesity comprising the administration of a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof in conjunction with a pharmaceutically acceptable diluent or carrier to a mammal in need thereof.
  • the invention is illustrated by the following Examples which are given by way of example only.
  • the final product of each of these Examples was characterised by one or more of the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
  • This derivative was boiled under reflux with methanol (400 ml) for 6 hours and then left to stand at ambient temperature for 66 hours with methanolic hydrogen chloride solution (10 ml). The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated off, washed with saturated sodium bicarbonate solution, brine and then dried and evaporated under reduced pressure to give an oil which was distilled under high vacuum. The distillate was purified by flash column chromatography on silica using petroleum ether, b.p. 60-80°C / ethyl acetate
  • Guanidine hydrochioride (1.87 g) was added with stirring to a solution of sodium (0.41 g) in ethanol (15 ml). The mixture was stirred for 15 minutes and then to this mixture was added a solution of methyl 4-(4-chlorophenoxy)- 3-oxopentanoate (5.0 g) in ethanol (15 ml). The mixture was stirred and boiled under reflux for 16 hours. The mixture was cooled and then evaporated to dryness under reduced pressure to give a solid. The solid was triturated with water (10 ml) containing glacial acetic acid (2 ml) and dichloromethane (20 ml) for 1 hour and then filtered.
  • active compound denotes any compound of the invention but particularly any compound which is the final product of one of the preceding
  • capsules 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
  • Tablets are prepared from the following ingredients.
  • the active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinyl- pyrrolidone in ethanol.
  • the dry granulate is blended with the magnesium stearate and the rest of the starch.
  • the mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
  • Tablets are prepared by the method described in (b) above.
  • the tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1 :1).
  • suppositories 100 parts by weight of active compound is incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Addiction (AREA)
  • Anesthesiology (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP00947848A 1999-06-24 2000-06-16 New use of 1,2,4-triazolo[1,5-a]pyrimidines Withdrawn EP1218008A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9914743 1999-06-24
GBGB9914743.1A GB9914743D0 (en) 1999-06-24 1999-06-24 Therapeutic agents
PCT/EP2000/005543 WO2001000186A2 (en) 1999-06-24 2000-06-16 New use of 1,2,4-triazolo'1,5-a! pyrimidines

Publications (1)

Publication Number Publication Date
EP1218008A2 true EP1218008A2 (en) 2002-07-03

Family

ID=10855954

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00947848A Withdrawn EP1218008A2 (en) 1999-06-24 2000-06-16 New use of 1,2,4-triazolo[1,5-a]pyrimidines

Country Status (7)

Country Link
EP (1) EP1218008A2 (ja)
JP (1) JP2003503343A (ja)
AU (1) AU6150200A (ja)
CA (1) CA2376886A1 (ja)
GB (1) GB9914743D0 (ja)
MX (1) MXPA01013421A (ja)
WO (1) WO2001000186A2 (ja)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2743299A1 (en) 2008-11-12 2010-05-20 Schering Corporation Inhibitors of fatty acid binding protein (fabp)
US8759357B2 (en) 2009-10-08 2014-06-24 Merck Sharp & Dohme Corp. Inhibitors of fatty acid binding protein (FABP)
KR101775682B1 (ko) * 2015-11-30 2017-09-06 주식회사 대웅 보툴리눔 독소의 제조방법

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9321162D0 (en) * 1993-10-13 1993-12-01 Boots Co Plc Therapeutic agents
GB9906124D0 (en) * 1999-03-18 1999-05-12 Knoll Ag Therapeutic agent
GB9906126D0 (en) * 1999-03-18 1999-05-12 Knoll Ag Pharmaceutical formulations
GB9906130D0 (en) * 1999-03-18 1999-05-12 Knoll Ag Compounds for use in therapy

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0100186A2 *

Also Published As

Publication number Publication date
GB9914743D0 (en) 1999-08-25
AU6150200A (en) 2001-01-31
MXPA01013421A (es) 2002-07-30
WO2001000186A3 (en) 2002-05-10
WO2001000186A2 (en) 2001-01-04
JP2003503343A (ja) 2003-01-28
CA2376886A1 (en) 2001-01-04

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