WO1999043677A1 - SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE - Google Patents
SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE Download PDFInfo
- Publication number
- WO1999043677A1 WO1999043677A1 PCT/GB1999/000485 GB9900485W WO9943677A1 WO 1999043677 A1 WO1999043677 A1 WO 1999043677A1 GB 9900485 W GB9900485 W GB 9900485W WO 9943677 A1 WO9943677 A1 WO 9943677A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- triazolo
- methyloxy
- methylisoxazol
- cognition
- Prior art date
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.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (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)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000533432A JP2002504554A (ja) | 1998-02-25 | 1999-02-17 | 置換1,2,4−トリアゾロ[3,4−a]ピリダジン |
IL13711799A IL137117A0 (en) | 1998-02-25 | 1999-02-17 | Substituted 1,2,4-triazolo [3,4-a] pyridazine |
HU0100647A HUP0100647A3 (en) | 1998-02-25 | 1999-02-17 | Substituted 1,2,4-triazolo[3,4-a]pyridazine and its pharmaceutical use |
NZ505695A NZ505695A (en) | 1998-02-25 | 1999-02-17 | 3-(5-Methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine and pharmaceuticals thereof and its use for the enhancement of cognition |
CA002317416A CA2317416A1 (en) | 1998-02-25 | 1999-02-17 | Substituted 1,2,4-triazolo[3,4-a]pyridazine |
US09/600,988 US6448249B1 (en) | 1998-02-25 | 1999-02-17 | Substituted 1,2,4-triazolo[3,4-A]phthalazine derivatives as GABAα5 ligands |
SK1277-2000A SK12772000A3 (sk) | 1998-02-25 | 1999-02-17 | 3-(5-metylizoxazol-3-yl)-6-(1-metyl-1,2,3-triazol-4-yl)metyloxy- -1,2,4-triazolo[3,4-a]ftalazín, farmaceutický prostriedok s jeho obsahom a jeho požitie |
PL99341975A PL341975A1 (en) | 1998-02-25 | 1999-02-17 | Substituted 1,2,4-triazole[3,4-a]phtalazine |
EA200000878A EA002824B1 (ru) | 1998-02-25 | 1999-02-17 | ЗАМЕЩЕННЫЙ 1,2,4-ТРИАЗОЛО[3,4-а]ПИРИДАЗИН |
BR9908155-5A BR9908155A (pt) | 1998-02-25 | 1999-02-17 | Composto, composição farmacêutica, uso do composto, e, processo para intensificar cognição em um sujeito sofrendo de cognição diminuìda |
EEP200000514A EE200000514A (et) | 1998-02-25 | 1999-02-17 | Asendatud triasolopüridasiini derivaat, seda sisaldav farmatseutiline kompositsioon ning selle kasutamine kognitsioonivõimet suurendava ravimi valmistamiseks |
KR1020007009325A KR20010041234A (ko) | 1998-02-25 | 1999-02-17 | 치환된 1,2,4-트리아졸로[3,4-a]피리다진 |
AU25368/99A AU746719B2 (en) | 1998-02-25 | 1999-02-17 | Substituted 1,2,4-triazolo(3,4-a)pyridazine |
EP99905069A EP1070066A1 (en) | 1998-02-25 | 1999-02-17 | SUBSTITUTED 1,2,4-TRIAZOLO 3,4-a]PYRIDAZINE |
IS5575A IS5575A (is) | 1998-01-15 | 2000-07-25 | Setið 1,2,4-tríasóló[3,4-a]pýridasín |
BG104705A BG104705A (bg) | 1998-02-25 | 2000-08-22 | Заместен 1,2,4-триазоло/3,4-а/пиридазин |
NO20004242A NO20004242L (no) | 1998-02-25 | 2000-08-24 | Substituert 1,2,4-triazolo[3,4-a]pyridazin |
HR20000555A HRP20000555A2 (en) | 1998-02-25 | 2000-08-25 | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9803992.8A GB9803992D0 (en) | 1998-02-25 | 1998-02-25 | Therapeutic agents |
GBPCT/GB98/01307 | 1998-05-06 | ||
PCT/GB1998/001307 WO1998050385A1 (en) | 1997-05-08 | 1998-05-06 | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
GBGB9824896.6A GB9824896D0 (en) | 1998-11-12 | 1998-11-12 | Therapeutic compound |
GB9803992.8 | 1998-11-12 | ||
GB9824896.6 | 1998-11-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999043677A1 true WO1999043677A1 (en) | 1999-09-02 |
Family
ID=27269184
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/000485 WO1999043677A1 (en) | 1998-01-15 | 1999-02-17 | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PYRIDAZINE |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP1070066A1 (ru) |
JP (1) | JP2002504554A (ru) |
CN (1) | CN1291194A (ru) |
AU (1) | AU746719B2 (ru) |
BG (1) | BG104705A (ru) |
CA (1) | CA2317416A1 (ru) |
EA (1) | EA002824B1 (ru) |
HR (1) | HRP20000555A2 (ru) |
HU (1) | HUP0100647A3 (ru) |
NZ (1) | NZ505695A (ru) |
PL (1) | PL341975A1 (ru) |
SK (1) | SK12772000A3 (ru) |
TR (1) | TR200002469T2 (ru) |
WO (1) | WO1999043677A1 (ru) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2342043A (en) * | 1998-09-30 | 2000-04-05 | Merck Sharp & Dohme | The use of triazolo-pyridazine derivatives in the treatment of hearing loss and tinnitus |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0085840A1 (en) * | 1982-01-18 | 1983-08-17 | Gruppo Lepetit S.P.A. | New 6-substituted-s-triazolo(3,4-a)phthalazine derivatives |
WO1998004560A1 (en) * | 1996-07-25 | 1998-02-05 | Merck Sharp & Dohme Limited | SUBSTITUTED TRIAZOLO PYRIDAZINE DERIVATIVES AS INVERSE AGONISTS OF THE GABAAα5 RECEPTOR SUBTYPE |
WO1998050385A1 (en) * | 1997-05-08 | 1998-11-12 | Merck Sharp & Dohme Limited | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
-
1999
- 1999-02-17 PL PL99341975A patent/PL341975A1/xx not_active Application Discontinuation
- 1999-02-17 WO PCT/GB1999/000485 patent/WO1999043677A1/en not_active Application Discontinuation
- 1999-02-17 EA EA200000878A patent/EA002824B1/ru not_active IP Right Cessation
- 1999-02-17 CN CN99803190A patent/CN1291194A/zh active Pending
- 1999-02-17 CA CA002317416A patent/CA2317416A1/en not_active Abandoned
- 1999-02-17 AU AU25368/99A patent/AU746719B2/en not_active Ceased
- 1999-02-17 HU HU0100647A patent/HUP0100647A3/hu unknown
- 1999-02-17 NZ NZ505695A patent/NZ505695A/en unknown
- 1999-02-17 TR TR2000/02469T patent/TR200002469T2/xx unknown
- 1999-02-17 EP EP99905069A patent/EP1070066A1/en not_active Withdrawn
- 1999-02-17 SK SK1277-2000A patent/SK12772000A3/sk unknown
- 1999-02-17 JP JP2000533432A patent/JP2002504554A/ja not_active Withdrawn
-
2000
- 2000-08-22 BG BG104705A patent/BG104705A/bg unknown
- 2000-08-25 HR HR20000555A patent/HRP20000555A2/hr not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0085840A1 (en) * | 1982-01-18 | 1983-08-17 | Gruppo Lepetit S.P.A. | New 6-substituted-s-triazolo(3,4-a)phthalazine derivatives |
WO1998004560A1 (en) * | 1996-07-25 | 1998-02-05 | Merck Sharp & Dohme Limited | SUBSTITUTED TRIAZOLO PYRIDAZINE DERIVATIVES AS INVERSE AGONISTS OF THE GABAAα5 RECEPTOR SUBTYPE |
WO1998050385A1 (en) * | 1997-05-08 | 1998-11-12 | Merck Sharp & Dohme Limited | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
Non-Patent Citations (1)
Title |
---|
TARZIA G ET AL: "BENZODIAZEPINE RECEPTOR LIGANDS. SYNTHESIS AND PRELIMINARY PHARMACOLOGICAL EVALUATION OF SOME 3-ARYL-6-THIOALKYL-, 3-ARYL-6 -ALKYLSULPHINYL-, 3-ARYL-6-ALKYLSULPHONYL-, AND 3-ARYL-6-ALKOXY-1,2,4-TRIAZOLO 3,4-APHTHALAZINES", FARMACO, EDIZIONE SCIENTIFICA, vol. 43, no. 2, 1 February 1988 (1988-02-01), pages 189 - 201, XP002041885 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2342043A (en) * | 1998-09-30 | 2000-04-05 | Merck Sharp & Dohme | The use of triazolo-pyridazine derivatives in the treatment of hearing loss and tinnitus |
Also Published As
Publication number | Publication date |
---|---|
SK12772000A3 (sk) | 2001-03-12 |
HUP0100647A2 (hu) | 2001-09-28 |
EP1070066A1 (en) | 2001-01-24 |
CA2317416A1 (en) | 1999-09-02 |
PL341975A1 (en) | 2001-05-07 |
HRP20000555A2 (en) | 2001-08-31 |
CN1291194A (zh) | 2001-04-11 |
NZ505695A (en) | 2002-03-01 |
BG104705A (bg) | 2001-04-30 |
TR200002469T2 (tr) | 2000-12-21 |
EA200000878A1 (ru) | 2001-02-26 |
HUP0100647A3 (en) | 2003-03-28 |
AU2536899A (en) | 1999-09-15 |
JP2002504554A (ja) | 2002-02-12 |
EA002824B1 (ru) | 2002-10-31 |
AU746719B2 (en) | 2002-05-02 |
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