SK12772000A3 - Substituted 1,2,4-triazolo[3,4-a]pyridazine - Google Patents

Abstract

A substituted triazolopyridazine derivative, its use in cognition enhancement therapy, compositions containing it and processes for its manufacture are disclosed.

Description

3- (5-Methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine, a pharmaceutical composition thereof and its use

Technical field

The invention relates to a substituted triazolo-pyridazine derivative, to its use in therapy, to pharmaceutical compositions containing it and to a process for its preparation.

BACKGROUND OF THE INVENTION

European patent applications 0085840 and 0134946 disclose related series of 1,2,4-triazolo [3,4-a] phthalazine derivatives which are said to have anti-anxiety activity. In neither of these publications, however, is there any finding or suggestion of the compounds of the present invention nor that the compounds described in these applications have cognition enhancing properties.

It has been found that it is possible to obtain drugs having cognition enhancing effects which can be used with a lower risk of seizure-inducing effects than previously described for partially or totally inverse benzodiazepine receptor agonists. Inverse agonists which are inverse agonists for the α5 receptor and are relatively inactive for α1, α2 and α3 receptor binding sites are preferred.

SUMMARY OF THE INVENTION

The present invention provides 3- (5-methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] ftalazí n.

Improvement in cognition can be demonstrated by testing the substance in Morris's aqueous labyrinth, as reported by McNamar and Skelton, Psychobiology, 21: 101-108. Functional efficacy at various receptor subtypes can be calculated using the methods described in WO-A-9625948.

The compound of the invention can be used in various disorders of the central nervous system. Such disorders include delirium, dementia and amnesia and other cognitive disorders. Examples of delirium are delirium due to chemical intoxication or withdrawal of addictive chemicals, delirium due to multiple etiologies, and NOS delirium (without further specification). Examples of dementia are: early-onset dementia of Alzheimer's type, which may be uncomplicated or with delirium, delusions or depressed mood; late-onset Alzheimer's type dementia that may be uncomplicated or with delirium, delusions or depressed mood; vascular dementia, which may be uncomplicated or with delirium, delusions or depressed mood; dementia due to HIV disease; dementia due to head injury; 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 having substance-induced duration or dementia due to multiple etiologies; and NOS dementia. Examples of amnesia disorders are an amnesia disorder due to particular medical conditions or amnesia having a substance-induced duration or an amnesia disorder NOS.

The invention also provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical 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-injection devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing a solid pharmaceutical composition such as a tablet, the main active ingredient is admixed with a pharmaceutical carrier, for example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, calcium hydrogen phosphate or gums or surfactants such as sorbitan monooleate, polyethylene glycol, and other pharmaceutical diluents,

For example, water to form a solid pre-formulation of a pharmaceutical composition comprising a homogeneous mixture of a compound of the invention, or a pharmaceutically acceptable salt thereof. By designating these pre-formulation pharmaceutical compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. The solid pre-formulation 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 pharmaceutical composition may be coated or otherwise coated to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope around the previous component. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach and to allow the inner component to pass intact into the duodenum or to be released in a delayed manner. Various materials may be used for such enteric layers or coatings, such materials including numerous 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 this invention for administration orally or by injection may be included include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. 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, polyvinylpyrrolidone or gelatin.

The present invention further provides the use of a compound of the invention for the manufacture of a medicament for improving cognition, preferably in a human suffering from a dementia disease such as Alzheimer's disease.

For improving cognition, a dosage level of 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 body weight per day, is suitable. The agent may be administered on a regimen of 1 to 4 times per day. However, in some cases a dose outside these limits may be used.

It is preferred that the substance of the invention is ground prior to preparation, for example by using a mortar with a piston or its industrial equivalent, to a particle size between 1 and 10 µm, and preferably less than 5 µm. The agent may be micronized or sonicated by methods known in the art or nanonized, for example, by the methods described in US-A-5145684.

The invention also provides a process for the preparation of a compound of the invention which comprises reacting a methylating agent such as lithium hexamethyldisilazide with 3- (5-methylisoxazol-3-yl) -6- (1H-1,2,3-triazole-5- yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazin.

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 to 12 hours. The desired product is generally purified from other reaction products by conventional separation techniques such as preparative HPLC.

During any of the above synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be accomplished by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protective groups may be removed at a suitable subsequent step using methods known in the art.

In accordance with the present invention, the compound strongly inhibits the binding of [ ³ H] -flumazenil to the benzodiazepine binding site of human GABA _and receptors containing α5 subunits stably expressed in Ltk cells.

-5Činidlá

Phosphate buffered saline (PBS).

Test buffer: 10 mmol / l KH ₂ PO ₄ , 100 mmol / l KCl, pH 7.4 at room temperature.

- [ ³ H] -Flumazenil (18 nmol / l for α1β3γ2 cells; 18 nmol / l for α2β3γ2 cells; 10 nmol / l for α3β3γ2 cells; 10 nmol / l for α5β3γ2 cells) in assay buffer.

- Flunitrazepam 100 μίτιοΙ / Ι in assay buffer.

Cells resuspended in assay buffer (1 block per 10 ml).

Collecting cells

The supernatant was removed from the cells. PBS (about 20 mL) was added. Cells were scraped and placed in a 50 ml centrifuge tube. The procedure was repeated with an additional 10 mL of PBS to ensure that most cells were removed. Cells were pelleted by centrifugation for 20 minutes at 3000 rpm. in a table centrifuge and then frozen as required. The pellets were resuspended in 10 ml buffer per block (25 cm x 25 cm) of cells.

An exam

It can be done in deep 96-well plates or tubes. Each tube contains:

- 300 μΙ test buffer.

- 50 μΙ [ ³ H] -flumazenil (final concentration for α1β3γ2: 1,8 nmol / l; for α2β3γ2: 1,8 nmol / l; for α3β3γ2: 1,0 nmol / l; for α5β3γ2: 1,0 nmol / l).

- 50 μΙ of buffer or solvent carrier (eg 10% DMSO) when the substance is dissolved in 10% DMSO (total); test substance or Flunitrazepam (to determine non-specific binding), 10 μπιοΙ / Ι final concentration.

-100 μΙ cells.

Assays were incubated for 1 hour at 40 ° C, then filtered using either Tomtec or Brandel cell collectors on GF / B filters, followed by washing with 3 x 3 ml with ice-cold assay buffer. Filters up

-Dried and measured using a liquid scintillator. Expected values for full binding are 3000-4000 min ^-1 (dpm) for total counts and less than 200 min ^-1 (dpm) for nonspecific binding using liquid scintillator measurements, or 1500-2000 min ^-1 (dpm) for total counts and less than 200 min ^-1 (dpm) for non-specific binding using a scattering solid scintillator measurement. Binding parameters are determined by non-linear least-squares regression analysis from which the inhibition constant K of the test substance can be calculated.

The compound of the invention strongly inhibits the binding of [ ³ H] -flumazenil to the benzodiazepine binding site of human GABAs _and receptors containing the α5 subunit stably expressed by Ltk cells.

The accompanying Example was tested in the above assay, and was found to have a K value for the replacement of [ ³ H] Ro 15-1788 from the α5 subunit of human GABA _and receptor of 100 nmol / L or less.

The compound of the invention has been shown to improve cognition in rats in an aqueous labyrinth assay (Morris, Learning and Motivation, 1981, 12, 239ff). Further details of a method of demonstrating that these agents improve cognition can be found in WO-A-9625948. This has been demonstrated at a minimum effective dose of 0.3 mg / kg at which the compound of the invention has 40% receptor occupancy. This was also demonstrated at a dose of 3 mg / kg.

The compound of the invention can be made as described in the following examples. Those skilled in the art are able to know the exact details of the reaction conditions and conventional modifications to the reaction procedure.

DETAILED DESCRIPTION OF THE INVENTION

Intermediate 1

6-Chloro-3- (5-methyl-isoxazol-3-yl) -1,2,4-triazolo [3,4-a] phthalazine

(a) 1-Chloro-4-hydrazinophthalazine

1,4-Dichlorophthalazine (20.0 g, 0.100 mol) was added to the boiling solution

-7-hydrazine monohydrate (37.3 mL, 0.765 mol) in ethanol (500 mL) and the mixture was heated under reflux for 0.5 h. The mixture was cooled to room temperature and the solid collected by filtration and washed with ether. This material was mixed with n-butanol and ammonia solution (specific gravity 0.91) and heated until the solid dissolved. The organic layer was separated, evaporated in vacuo and the residue azeotroped with xylene (x2) and dried under vacuum to give the title hydrazine (11.5 g, 59%), ¹ H NMR (250 MHz, d ₆ DMSO) δ 7.84 - 8.04 (3H, m, Ar-H), 8.20 (1H, m, Ar-H); MS (ES ⁺ ) m / e 194 [MH] +.

b) 5-Methylisoxazole-3-carboxylic acid

A mixture of acetonylacetone (10 g, 88 mmol) and nitric acid (specific gravity 1.42) / water (2: 3) (50 mL) was carefully transferred to reflux under a stream of nitrogen and boiled for 1 hour. The solution was cooled to room temperature and stood overnight. The resulting solid was collected by filtration, washed with cold water (2 x 7 mL) and hexane and dried under vacuum to give the title acid (4.4 g, 40%), ¹ H NMR (CDCl ₃ ) δ 2.50 (3H, d, J = 0.8 Hz, Me), 6.41 (1H, d, J = 0.8 Hz, Ar-H).

c) 6-Chloro-3- (5-methylisoxazol-3-yl) -1,2,4-triazolo [3,4-a] phthalazine

5-Methylisoxazole-3-carboxylic acid (5.24 g, 41.3 mmol), bis (2-oxo-3-oxazolidinyl) phosphoric acid chloride (10.5 g, 41.2 mmol) and triethylamine (11.5 g) mL, 82.5 mmol) was then added to a stirred suspension of 1-chloro-4-hydrazino-phthalazine (8.00 g, 41.2 mmol) in dichloromethane (1 L) at 0 ° C under nitrogen. The mixture was stirred at 0 ° C for 2 hours and at room temperature overnight. The solvent was evaporated in vacuo, the residue was triturated with water and the solid was filtered off, washed with hexane and dried under vacuum to give ketohydrazine (11 g), MS (ES *) m / e 304 [MH] +. A solution of ketohydrazine (11 g) and triethylamine hydrochloride (2.2 g, 20% by weight) in xylene (500 mL) was heated under reflux for 3 hours. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane, washed

-8vodou (x2), dried _(MgSO4) and evaporated in vacuo and the solid was recrystallized (dichloromethane / hexane) to give the title compound (6.8 g, 58%). ¹ H NMR ( 360 MHz, CDCl ₃ ) δ 2.59 (3H, s, Me), 6.90 (1H, s, Ar-H), 7.95 (1H, m, Ar-H), 8.07 (1H, m, Ar-H), 8.34 (1H, m, Ar-H), 8.78 (1H, s, Ar-H); MS (ES ⁺ ) m / e 286 [MH] +.

Comparative Example 1

3- (5-Methyl-isoxazol-3-yl) -6- (2-pyridyl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine

Sodium hydride (244 mg 60% dispersion in oil, 6.10 mmol) was added to a stirred solution of 2-pyridylcarbinol (470 mg, 4.27 mmol) in DMF (60 mL) at room temperature under nitrogen and the mixture was stirred for 0.25 hours. After this time, Intermediate 1 (1160 mg, 4.07 mmol) was added and the mixture was stirred for 2 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane, washed with water (x2), dried _(MgSO4) and evaporated in vacuo. Flash chromatography on silica gel eluting with 3% methanol / dichloromethane followed by recrystallization (dichloromethane / hexane) gave the title product (640 mg, 44%), mp = 234-236 ° C; ¹ H NMR (360 MHz, CDCl 3) δ 2.59 (3H, d, J = 0.8 Hz, Me), 5.77 (2H, s, CH 2), 6.82 (1H, d, J = 0) 8 Hz, Ar-H), 7.30 (1H, m, Ar-H), 7.74-7.85 (3H, m, Ar-H), 7.95 (1H, m, Ar-H) ), 8.33 (1H, d, J = 7.8Hz, Ar-H), 8.64-8.72 (2H, m, Ar-H); MS (ES ⁺ ) mlz 359 [MH] ⁺ ; Found: C, 62.93; H, 3.56; N, 22.94; ClBH ₁₄ N ₆ O ₂ 0.05 (CH ₂ Cl ₂ ) requires C, 63.10; H, 3.92; N, 23.17%.

Comparative Example 2

6- (6-Bromo-pyridin-2-yl) methyloxy-3- (5-methyl-isoxazol-3-yl) -1,2,4-triazolo [3,4-a] phthalazine

The title compound was prepared from Intermediate 1 and 2-bromopyridine-6-methanol (Tetrahedron Lett., 1996, 50, 2537) according to the procedure of Comparative Example 1. The product was isolated by adding water to the reaction mixture.

The resulting precipitate was filtered off. Flash chromatography on silica gel, eluting with ethyl acetate and recrystallization (ethyl acetate-methanol) gave the title phthalazine, mp = 247.5-249 ° C; ¹ H NMR (360 MHz, CDCl 3) δ 2.61 (3H, d, J = 0.7 Hz, Me), 5.73 (2H, s, CH 2), 6.82 (1H, d, J = 0) 7 Hz, Ar-H), 7.48 (1H, d, J = 7.8Hz, Ar-H), 7.63 (1H, t, J = 7.7Hz, Ar-H), 7 76 (1H, d, J = 7.4Hz, Ar-H), 7.84 (1H, t, J = 8.4Hz, Ar-H), 7.98 (1H, t, J = 8) 4 Hz, Ar-H), 8.31 (1H, d, J = 8.5Hz, ArH), 8.70 (1H, d, Ar-H); MS (ES ⁺ ) m / e 437, [MH] +; Found: C, 52.27; H, 2.85; N, 19.14; C19H ₁₃ N ₆ O ₂ Br.0,1 (H ₂ O) requires C, 51.98; H, 3.03; N, 18.60%.

Intermediate 2

6-Hydroxy-3- (5-methylisoxazol-3-yl) -1,2,4-triazolo [3,4-a] phthalazine

A solution of sodium hydroxide (0.67 g, 17 mmol) in water (7.5 mL) was added to a stirred solution of Intermediate 1 (1.0 g, 3.5 mmol) in dioxane (37.5 mL) and the mixture was heated under reflux for 4 hours. The solvent was evaporated in vacuo and the residue was partitioned between water and diethyl ether. The aqueous layer was separated, washed with ether (x 1) and then acidified with 2 mol / L hydrochloric acid until pH 2 was obtained. The solid that precipitated from the solution was filtered off and the aqueous filtrate was extracted with dichloromethane ( x 3). The combined extracts were dried (MgSO ₄ ) and evaporated in vacuo and combined with the precipitate to give the title product (0.45 g, 48%), ¹ H NMR (250 MHz, d ₆ -DMSO) δ 2.58 (3H, d, J = 0.7Hz, Me), 7.07 (1H, d, J = 0.9Hz, Ar-H), 7.94 (1H, m, Ar-H) 8.08 (1H, m, ArH), 8.24 (1H, d, J = 7.4Hz, Ar-H), 8.54 (1H, d, J = 7.4Hz, Ar-H) 13.32 (1H, broad s, NH); MS (ES ⁺ ) m / e 268 [MH] +

Comparative Example 3

3- (5-Methylisoxazol-3-yl) -6- (1H-1,2,3-triazol-5-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine

a) 5-Formyl-1- [2- (trimethylsilyl) ethoxy] methyl-1,2,3-triazole

-10n-Butyllithium (6.8 mL of a 1.6 M solution in hexanes, 10.9 mmol) was added dropwise over 0.08 hours to a stirred solution of 1- [2- (trimethylsilyl) ethoxy] methyl-1. 2,3-triazole (J. Heterocycl. Chem., 1992, 29, 1203) (2.077 g, 10.42 mmol) in THF (30 mL) at -78 ° C under nitrogen. The solution was allowed to warm to -60 ° C for 0.67 hours, then re-cooled to -78 ° C and DMF (0.9 mL, 11.6 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16.5 hours. Saturated ammonium chloride solution (50 mL) was added and the reaction mixture was extracted with diethyl ether (3 x 80 mL). The combined ether extracts were dried (MgSO ₄ ), evaporated in vacuo and the residue chromatographed on silica gel eluting with 30% ethyl acetate / hexane to give the title triazole (1.713 g, 72%), ¹ H NMR ( 360 MHz, CDCl ₃ ) δ 0.01 (9H, s, Me ₃ Si), 0.92-0.99 (2H, m, CH ₂ ), 3.64 - 3.69 (2H, m, CH ₂ 6.05 (2H, s, CH ₂ ), 8.31 (1H, s; Ar-H), 10.12 (1H, s, CHO).

b) 5-Hydroxymethyl-1- [2- (trimethylsilyl) ethoxy] methyl-1,2,3-triazole

Sodium borohydride (0.284 g, 7.51 mmol) was added to a stirred solution of the previous triazole (1.704 g, 7.495 mmol) in methanol (8 mL) at 0 ° C under nitrogen. The mixture was stirred at 0 ° C for 0.5 h and at room temperature for 0.5 h. Water was added and the mixture was partitioned between dichloromethane and saturated brine. The aqueous layer was separated and further extracted with dichloromethane (x2). The combined organic layers were dried ((MgSO ₄ ) and evaporated in vacuo and the residue chromatographed on silica gel eluting with 70% ethyl acetate / hexane to give the title product (1.34 g, 78%), ^m.p. 1 H NMR (360 MHz, CDCl ₃ ) δ 0.00 (9H, s, Me ₃ Si), 0.90 - 0.95 (2H, m, CH ₂ ), 3.58 - 3.63 (2H, m CH ₂ ), 4.84 (2H, s, CH ₂ ), 5.80 (2H, s, CH ₂ ), 7.68 (1H, s, Ar-H).

c) 3- (5-Methylisoxazol-3-yl) -6- {1- [2- (trimethylsilyl) ethoxy] methyl-1,2,3-triazol-5-yl} methyloxy-1,2,4-triazolo [3,4-a] phthalazine

The title compound was prepared from Intermediate 1 and the preceding alcohol according to the procedure described in Example 10, 360 MHz (360

-11 MHz, CDCl ₃ ) δ 0.00 (9H, s, Me ₃ Si), 0.88 - 0.93 (2H, m, CH ₂ ), 2.63 (3H, s, Me), 3, 61 3.66 (2H, m, _CH2), 5.92 (2H, s, _CH2), 5.97 (2H, s, _CH2), 6.89 (1H, s, Ar-H); 7.86 (1H, m, Ar-H); 8.02 (1H, t, J = 7.7Hz, Ar-H); 8.18 (1H, s, Ar-H); 8.23 (1H, m, Ar-H); 1H, d, J = 8.0Hz, Ar-H), 8.76 (1H, d, J = 8.0Hz, Ar-H); MS [ES < ^{+ &gt};] m / e 479 [MH] < ^{+ &gt};.

d) 3- (5-Methylisoxazol-3-yl) -6- (1H-1,2,3-triazol-5-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine

A mixture of the previous product, ethanol (10 mL) and 2M HCl (20 mL) was heated at 50 ° C for 15.25 hours. The solution was basified to pH 12 with saturated sodium carbonate solution and the solvent was evaporated in vacuo. The residue was azeotroped with ethanol (x2) and chromatographed on silica gel, eluting with 0-4% methanol / dichloromethane (gradient elution) to give the title product, ¹ H NMR (400 MHz, CDCl ₃ ) δ 2 65 (3H, s, Me), 5.73 (2H, s, _CH2), 7.02 (1H, s, Ar-H), 7.87 (1H, t, J = 7.8 Hz, Ar-H), 7.99-8.03 (2H, m, 2 of Ar-H), 8.24 (1H, d, J = 8.2Hz, Ar-H) 8.72 (1H, d) J = 7.9 Hz, Ar-H); MS (ES ⁺ ) mlz 349 [MH] ⁺ .

Example 1

3- (5-Methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-5-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine,

3- (5-methylisoxazol-3-yl) -6- (2-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine, and

3- (5-Methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine

Lithium hexamethyldisilazide (1.63 mL of a 1M solution in THF, 1.63 mmol) was added dropwise to a stirred solution of 3- (5-methylisoxazol-3-yl) -6- (1H-1,2,3-triazole-5). -yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine (241 mg, 0.626 mmol) prepared as Comparative Example 3 in DMF (50 mL) at -31 ° C under nitrogen. The mixture was warmed to -23 ° C for 1.5 h, methyl iodide (0.10 mL, 1.6 mmol) was added after

The reaction mixture was allowed to warm to room temperature overnight. Water was added and the solvent was evaporated in vacuo. The residue was partitioned between dichloromethane and water and the aqueous phase separated and re-extracted with dichloromethane (x1). The combined organic extracts were washed with brine (x1), dried (MgSO 4 and evaporated in vacuo. Chromatography of the residue on silica gel, eluting with 0-5% methanol / dichloromethane (gradient elution), followed by preparative HPLC (YMC Sil column) , 250 x 20 mm) eluting with 5% methanol / chlorobutane, separating the triazole isomers:

At least Polar Isomer (HPLC solvent system): 3- (5-methylisoxazol-3-yl) -6 (2-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3] 4-phthalazine ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.59 (3H, s, Me), 4.21 (3H, s, Me), 5.73 (2H, s, CH ₂ ), 6.89 (1H, s, Ar-H);

7.79 (1H, m, Ar-H), 7.94 (1H, m, Ar-H), 8.10 (1H, s, Ar-H), 8.22 (1H, d, J = 8.0) Hz, Ar-H), 8.67 (1H, d, J = 8.0Hz, Ar-H); MS (ES ⁺ ) mlz 363 [MH] ⁺ .

Medium polarity isomer: 3- (5-methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a ] phthalazine Ή NMR (400 MHz, CDCl ₃ ) δ 2.60 (3H, s, Me), 4.09 (3H, s, Me), 5.78 (2H, s, CH ₂ ), 6.90 ( 1H, d, J = 0.8Hz, Ar-H), 7.80 (1H, m, Ar-H), 7.94 (1H, m, Ar-H), 8.25 (1H, d, J = 8.0 Hz, Ar-H), 8.65 (1H, d, J = 8.0 Hz, Ar-H), 8.73 (1H, s, Ar-H); MS (ES ⁺ ) mlz 363 [MH] ⁺ .

Most polar isomer (HPLC solvent system): 3- (5-Methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-5-yl) methyloxy-1,2,4-triazolo [3,4] -a] phthalazine ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.56 (3H, s, Me), 4.19 (3H, s, Me), 5.76 (2H, s, CH ₂ ), 6 82 (1H, s, Ar-H);

7.80 (1H, m, Ar-H), 7.96 (1H, m, Ar-H), 8.04 (1H, s, Ar-H), 8.12 (1H, d, J = 8.8) Hz, Ar-H), 8.67 (1H, d, J = 8.0Hz, Ar-H); MS (ES ⁺ ) mlz 363 [MH] ⁺ .

Claims (5)

PATENT CLAIMS 3- (5-Methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine . 2. A pharmaceutical composition comprising 3- (5-methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4- triazolo [3,4-a] phthalazine according to claim 1 and a pharmaceutically acceptable carrier. 3- (5-Methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine for use in treating humans or animals. 3- (5-Methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine for use in improving cognition in a subject suffering from reduced cognition. Use of 3- (5-methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine according to of claim 1 for the manufacture of a medicament for improving cognition.