EP1070066A1 - 1,2,4-TRIAZOLO 3,4-a]PYRIDAZINE SUBSTITUEE - Google Patents

1,2,4-TRIAZOLO 3,4-a]PYRIDAZINE SUBSTITUEE

Info

Publication number
EP1070066A1
EP1070066A1 EP99905069A EP99905069A EP1070066A1 EP 1070066 A1 EP1070066 A1 EP 1070066A1 EP 99905069 A EP99905069 A EP 99905069A EP 99905069 A EP99905069 A EP 99905069A EP 1070066 A1 EP1070066 A1 EP 1070066A1
Authority
EP
European Patent Office
Prior art keywords
compound
triazolo
methyloxy
methylisoxazol
cognition
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Withdrawn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
EP99905069A
Other languages
German (de)
English (en)
Inventor
William Robert Terlings Park CARLING
Tamara Ladduwahetty
Angus Murray Terlings Park MACLEOD
Kevin John Terlings Park Eastwick Road MERCHANT
Kevin William Terlings Park MOORE
Francine Sternfeld
Leslie Joseph Terlings Park STREET
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.)
Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme Ltd
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 claimed from GBGB9803992.8A external-priority patent/GB9803992D0/en
Priority claimed from PCT/GB1998/001307 external-priority patent/WO1998050385A1/fr
Priority claimed from GBGB9824896.6A external-priority patent/GB9824896D0/en
Application filed by Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of EP1070066A1 publication Critical patent/EP1070066A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a substituted triazolo-pyridazine derivative, to its use in therapy, to compositions containing it and to a process for its manufacture.
  • European Patent Applications 0085840 and 0134946 describe related series of l,2,4-triazolo[3,4-a]phthalazine derivatives which are stated to possess antianxiety activity. However, there is no disclosure nor any suggestion in either of these publications of the compounds of the present invention, nor that the compounds disclosed in the Applications have any cognition enhancing properties.
  • the present invention provides a compound which is: 3-(5-methylisoxazol-3-yl)-6-(l-methyl-l,2,3-triazol-4-yl)methyloxy- 1,2,4- triazolo[3,4-a]phthalazine.
  • the Cognition enhancement can be shown by testing the compound in the Morris watermaze as reported by McNamara and Skelton, Psychobiology, 21: 101- 108.
  • the functional efficacy at the various receptor subtypes can be calculated using the method disclosed in WO-A-9625948.
  • the compound of the present invention can be used in a variety of disorders of the central nervous system. Such disorders include delirium, dementia and amnestic and other cognitive disorders. Examples of delirium are delirium due to substance intoxication or substance withdrawal, delirium due to multiple etiologies and delirium NOS (not otherwise specified).
  • dementia examples include: dementia of the Alzheimer's type with early onset which can be uncomplicated or with delirium, delusions or depressed mood; dementia of the Alzheimer's type, with late onset, which can be uncomplicated or with delirium, delusions or depressed mood; vascular dementia which can be uncomplicated or with delirium, delusions or depressed mood; dementia due to HIV disease; dementia due to head trauma; dementia due to Parkinson's disease; - dementia due to Huntington's disease; dementia due to Pick's disease; ⁇ dementia due to Creutzfeld-Jakob disease; dementia which is substance-induced persisting or due to multiple etiologies; and dementia NOS.
  • amnestic disorders are amnestic disorder due to a particular medical condition or which is substance-induced persisting or which is amnestic disorder NOS.
  • compositions comprising the compound of this invention and a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • a pharmaceutical carrier e.g.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the present invention further provides the use of the compound of the present invention in the manufacture of a medicament for the enhancement of cognition, preferably in a human suffering from a dementing illness such as Alzheimer's disease.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg per day, and especially about 0.01 to 5 mg/kg of body weight per day.
  • the compound may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used.
  • the compound of the present invention be ground, for example using a pestle and mortar or industrial equivalent thereto, to a particle size of between 1 and 10 ⁇ M, and preferably less than 5 ⁇ M, before formulation.
  • the compound may be micronised or sonicised by methods known in the art or nanonised, for example by methods disclosed in US-A-5145684.
  • the present invention also provides a process for the production of the compound of the present invention, which comprises reacting a methylating reagent, such as lithium hexamethyldisilazide with 3-(5-methylisoxazol-3-yl)-6- (lH-l,2,3-triazol-5-yl)methyloxy-l,2,4-triazolo[3,4-a]phthalazine.
  • a methylating reagent such as lithium hexamethyldisilazide
  • the reaction is generally carried out in a solvent such as DMF, generally at a temperature below 0°C with warming to about room temperature and generally under an inert gas such as nitrogen.
  • the reaction mixture is generally allowed to stand for 4-12 hours.
  • the desired product is generally pur
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compound in accordance with this invention potently inhibit the binding of [ 3 H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the ⁇ 5 subunit stably expressed in Ltk- cells.
  • PBS Phosphate buffered saline
  • Assay buffer 10 mM KH 2 P0 4 , 100 mM KC1, pH 7.4 at room temperature.
  • the cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed.
  • the cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in
  • Each tube contains: • 300 ⁇ l of assay buffer.
  • the compound in accordance with this invention potently inhibits the binding of [ 3 H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the ⁇ 5 subunit stably expressed in Ltk- cells.
  • the compound of the accompanying Example was tested in the above assay, and was found to possess a K_ value for displacement of [ 3 H]Ro 15-1788 from the ⁇ .5 subunit of the human GABAA receptor of 100 nM or less.
  • the compound of the present invention has been shown to enhance cognition in the rat water maze test (Morris, Learning and Motivation, 1981, 12, 239ff). Further details of methodology for demonstrating that the present compounds enhance cognition can be found in WO-A-9625948. This has been demonstrated at a minimum effective dose of 0.3mg/kg at which the compound of the present invention has 40% receptor occupancy. It has also been demonstrated at a dose of 3mg/kg.
  • 1,4-Dichlorophthalazine (20.0g, 0.100 mol) was added to a boiling solution of hydrazine monohydrate (37.3 ml, 0.765 mol) in ethanol (500 ml) and the mixture heated at reflux for 0.5 h. The mixture was cooled to room temperature and the solid collected by filtration and washed with ether. The material was taken with n-butanol and ammonia solution (sp. gr. 0.91) and heated until the solid dissolved.
  • 5-Methylisoxazole-3-carboxylic acid (5.24 g, 41.3 mmol), bis(2-oxo-3- oxazolidinyl)phosphinic chloride (10.5 g, 41.2 mmol) and triethylamine (11.5 ml, 82.5 mmol) were added successively to a stirred suspension of l-chloro-4- hydrazinophthalazine (8.00 g, 41.2 mmol) in dichloromethane (1 1) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 2h and at room temperature overnight.
  • Lithium hexamethyldisilazide (1.63ml of a 1M solution in THF, 1.63mmol) was added dropwise to a stirred solution of 3-(5-methylisoxazol-3-yl)- 6-(lH-l,2,3-triazol-5-yl)methyloxy-l,2,4-triazolo[3,4-a]phthalazine (241mg, 0.626mmol) prepared as in Reference Example 3 in DMF (50ml) at -31°C under nitrogen. The mixture was warmed to -23°C over 1.5h, methyl iodide (0.10ml, l. ⁇ mmol) added dropwise and the reaction mixture allowed to warm to room temperature overnight.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Dérivé de triazolopyridazine, utilisation dudit dérivé dans les thérapies d'amélioration cognitive, compositions contenant ledit dérivé et procédés de préparation dudit dérivé.
EP99905069A 1998-02-25 1999-02-17 1,2,4-TRIAZOLO 3,4-a]PYRIDAZINE SUBSTITUEE Withdrawn EP1070066A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GBGB9803992.8A GB9803992D0 (en) 1998-02-25 1998-02-25 Therapeutic agents
GB9803992 1998-02-25
PCT/GB1998/001307 WO1998050385A1 (fr) 1997-05-08 1998-05-06 Derives de 1,2,4-triazolo[3,4,-a]phtalazine substitues comme ligands de gaba alpha 5
GB9801307 1998-05-06
GBGB9824896.6A GB9824896D0 (en) 1998-11-12 1998-11-12 Therapeutic compound
GB9824896 1998-11-12
PCT/GB1999/000485 WO1999043677A1 (fr) 1998-02-25 1999-02-17 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE SUBSTITUEE

Publications (1)

Publication Number Publication Date
EP1070066A1 true EP1070066A1 (fr) 2001-01-24

Family

ID=27269184

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99905069A Withdrawn EP1070066A1 (fr) 1998-02-25 1999-02-17 1,2,4-TRIAZOLO 3,4-a]PYRIDAZINE SUBSTITUEE

Country Status (14)

Country Link
EP (1) EP1070066A1 (fr)
JP (1) JP2002504554A (fr)
CN (1) CN1291194A (fr)
AU (1) AU746719B2 (fr)
BG (1) BG104705A (fr)
CA (1) CA2317416A1 (fr)
EA (1) EA002824B1 (fr)
HR (1) HRP20000555A2 (fr)
HU (1) HUP0100647A3 (fr)
NZ (1) NZ505695A (fr)
PL (1) PL341975A1 (fr)
SK (1) SK12772000A3 (fr)
TR (1) TR200002469T2 (fr)
WO (1) WO1999043677A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9821179D0 (en) * 1998-09-30 1998-11-25 Merck Sharp & Dohme Therapeutic use

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH21834A (en) * 1982-01-18 1988-03-17 Lepetit Spa New 6-substituted-s-triazolo(3,4-a)phthalazine derivatives
US6465462B1 (en) * 1996-07-25 2002-10-15 Merck Sharp & Dohme Ltd. Substituted triazolo pyridazine derivatives as inverse agonists of the GABAAα5 receptor subtype
AU732455C (en) * 1997-05-08 2002-09-05 Merck Sharp & Dohme Limited Substituted 1,2,4-triazolo{3,4-a}phthalazine derivatives as gaba alpha 5 ligands

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9943677A1 *

Also Published As

Publication number Publication date
NZ505695A (en) 2002-03-01
AU2536899A (en) 1999-09-15
TR200002469T2 (tr) 2000-12-21
SK12772000A3 (sk) 2001-03-12
JP2002504554A (ja) 2002-02-12
EA002824B1 (ru) 2002-10-31
WO1999043677A1 (fr) 1999-09-02
HRP20000555A2 (en) 2001-08-31
CN1291194A (zh) 2001-04-11
HUP0100647A2 (hu) 2001-09-28
EA200000878A1 (ru) 2001-02-26
HUP0100647A3 (en) 2003-03-28
PL341975A1 (en) 2001-05-07
BG104705A (bg) 2001-04-30
AU746719B2 (en) 2002-05-02
CA2317416A1 (fr) 1999-09-02

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