BG104705A - Substituted 1,2,4-triazolo[3,4-a]pyridazine - Google Patents

Abstract

A substituted triazolopyridazine derivative, its use in cognition enhancement therapy, compositions conta9ining it and processes for its manufacture are disclosed. 5 claims

Description

Technical field

The invention relates to substituted triazolo-pyridazine derivatives, to their use in medicine, to compositions containing them, and to a method for their preparation.

We have now found that it is possible to obtain drugs that have a cognitive (cognitive) enhancing effect and that can be used at a lower risk of pro-convulsive effects than the previously described benzodiazepine receptor partial or total inverse agonists. Inverse agonists that are inverse agonists for the α5 receptor and which are relatively inactive with α1, α2 and α3 receptor binding sites are preferred.

BACKGROUND OF THE INVENTION

European Patents 0085840 and 0134946 describe related series of 1,2,4-triazolo [3,4-a] phthalazine derivatives, which are claimed to have antitrust activity. However, it has not been described, nor is it alleged in any of the two publications, that the compounds of the present invention or those of the cited descriptions have any cognition enhancing properties.

SUMMARY OF THE INVENTION

The invention relates to a compound which is:

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

Improvement in cognition can be demonstrated by testing the compound in the Morris Water Maze Experiment by McNamara and Skelton, Psychobiology, 21: 101 - 108. The functional efficacy of the various receptor subtypes can be calculated using those described in WO-A- 9625948 method.

Thus, the compound of the invention can be used in various disorders of the central nervous system. Such disorders include dilirium, dementia and amnestic or other cognitive impairments. Examples of delirium are delirium due to substance intoxication or abstinence, delirium due to multiple etiologies, and delirium NOS (not otherwise specified). Examples of dementia are: early onset Alzheimer's type dementia, which may be uncomplicated or may have delirium, hallucinations or depressed mood; dementia due to HIV disease; dementia due to the tram of the heart, dementia due to Parkinson's disease; dementia due to Huntington's disease, dementia due to Pick disease; dementia due to Creutzfeld-Jakob disease; lingering dementia or due to multiple etiologies and NOS dementia. Examples of amnestic disorders are amnestic disorders that are due to a specific medical condition or which are caused by substances or which are amnestic NOS disorders.

The invention also provides pharmaceutical compositions comprising the compound of the invention and a pharmaceutically acceptable carrier. Preferably, these compositions are in unit dosage form

forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories for oral, parenteral, intranasal, sublingual or sublingual administration inhalation or injection. For the preparation of solids such as tablets, the active ingredient is mixed with a pharmaceutical carrier, for example, conventional tabletting ingredients such as corn starch, lactose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or resins or surfactants such as sorbitan polyethylene acetate sorbitol pharmaceutical diluents, for example water, to form a solid pre-composition comprising a homogeneous mixture of the compound of the invention or a pharmaceutically acceptable salt thereof. When these pre-formulations are said to be homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules. The solid pre-formulation is then divided into separate unit dosage forms of the type described above containing from 0.1 to 500 mg of the active ingredient of the invention. The usual unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg of the active substance. The tablets or pills of the new composition may be coated or otherwise formulated to provide a prolonged dosage form. For example, the tablet or pill may include an inner or outer dosage component, the latter being in the form of a shell. The two components may be separated by an enteric layer that serves to resist digestion in the stomach and allow the internal component to pass intact into the duodenum or be released slowly. For such enteric layers or coatings different materials may be used including different polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms, in which the new compositions may be for oral administration or injection, include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cotton, sesame, coconut or peanut, as well as elixirs and similar pharmaceutical carriers . Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural resins such as tragacanth, acacia, alginate, dextran, sodium carboxy methyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The invention also relates to the use of a compound for the manufacture of a medicament for improving cognition, preferably in humans suffering from a dementia such as Alzheimer's disease.

To improve cognition, a suitable dose is about 0.01 to 250 mg / kg per day, preferably about 0.01 to 100 mg / kg per day, and in particular about 0.01 to 5 mg / kg per kg of body weight per day. The compound can be administered in regimen 1 to 4 times daily. However, in some cases quantities beyond these limits may be used.

It is preferred that the compound of the invention be ground using pestle and mortar or their industrial equivalents to particle sizes between 1 and 10 microns and preferably less than 5 microns before formulation. The compound may be micronised or sonicated by methods known in the art or reduced to nanosized particles, for example by methods described in U. S. A5145684.

• *

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

The reaction is usually carried out in a solvent such as dimethylformamide, most often at a temperature below 0 ° C with warming to about room temperature and usually in an inert gas such as nitrogen. The reaction mixture is usually allowed to stand for 4-12 hours. The desired product is usually purified from side compounds by conventional means such as preparative HPLC.

In some of the above synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on some of the interacting molecules. This can be achieved 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 can be removed at a convenient subsequent stage using methods known in the art.

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

Reagents:

- phosphate buffered saline (PBS);

- test buffer: 10 mM KH ₂ PO ₄ , pH 7.4 at room temperature;

'6 • ·

- [ ³ H] -flumazenil (18 nm for α1β3γ2 cells; 18 nm for α2β3γ2

cells; 10 nM for α3β3γ2 cells; 10 nm for α5β3γ2 cells) in assay buffer;

- flunitrazepam 100 μM in assay buffer;

- cells resuspended in test buffer (1 plate in up to 10 ml).

Cell collection

The upper fluid was removed from the cells. PBS (approximately 20 ml) was added. The cells were scraped and placed in a 50 ml centrifuge tube. This is repeated with another 10 ml of PBS to ensure that most of the cells are removed. Cells were pelleted by centrifugation for 20 min at 3000 rpm in a benchtop centrifuge and then frozen if desired. The pellets were resuspended in 10 ml plate buffer (25 cm x 25 cm).

The test

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

- 300 µl of test buffer;

- 50 μl of [ ³ H] -flumazenil (final concentration for α1β3γ2: 1.8 nM;

for α2β3γ2: 1.8 nm; for α3β3γ2: 1.0 nM; for α5β3γ2; 1.0 nm);

- 50 µl of buffer or vehicle solvent (eg 10% DMSO) if the compound is dissolved in 10% DMSO (total); test compound is flunitrazepam (to determine nonspecific binding), 10 μM final concentration;

- 100 µl of cell.

The assay samples were incubated for 1 h at 40 ° C, then filtered using either a Tomtec or Brandel cell collector on GF / B filters followed by 3 x 3 ml washes with ice-cold test buffer, the filters were dried and counted by liquid scintillation counting. Expected values for total

· · · · · · · ·

bindings are 3000 - 4000 dpm total or less than 200 dpm for non-specific binding if a liquid scintillation count is used or 1500 - 2000 dpm for a total count and less than 200 dpm for non-specific binding if counted with multilex solid scintillant. The binding parameters are determined by a nonlinear least squares regression analysis for which the Ki inhibition constant can be calculated for the test compound.

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

The compound of the example provided was tested by the above method and was found to have a Ki value to replace the [ ³ H] Ro 15-1788 of the α5 subunit of the human GABAα receptor at 100 nM or less.

The compound of the invention has been shown to improve cognition in the rat water maze test (Morris, Learning and Motivation, 1981, 12, 239ff). Further details of the methodology for demonstrating that the present compound improves cognition can be found in WO-A-9625948. This is demonstrated at a minimum effective dose of 0.3 mg / kg at which the compound of the invention has 40% receptor occupancy. It is also indicated at a dose of 3 mg / kg.

The compound of the invention can be prepared as described in the following examples. Details and conditions of the reaction as well as obvious modifications are within the skill of one of ordinary skill in the art.

Examples of carrying out the invention

Intermediate 1

6-chloro-3- (5-methylisoxazol-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 a boiling solution of hydrazine monohydrate (37.3 ml, 0.765 mol) in ethanol (500 ml) and the mixture was heated at reflux for 0.5 hours. The mixture was cooled to room temperature and the solid was filtered off and washed with ether. The precipitate was taken up in n-butanol and ammonia solution (mp 0.91) and heated to dissolve the solid. The organic layer was separated, evaporated in vacuo and the residue was distilled azeotropically with xylene (x 2) and dried in vacuo 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 (mp 1.42) / water (2: 3) (50 ml) was carefully brought to reflux with nitrogen and refluxed for 1 hour. The solution was cooled to room temperature and allowed to stand overnight. The resulting precipitate was filtered off, washed with cooled water (2x7 ml) and hexane and dried in vacuo 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 (5.21 g, 41.3 mmol), bis (2-oxo-3-oxazolidinyl) phosphine chloride (10.5 g, 41.2 mmol) and triethylamine (11.5 ml, 82.5 mmol) were added successively with stirring. suspension of 1-chloro-4-hydrazinophthalazine (8.00 g, 41.2 mmol) in dichloromethane (1 l) at 0 ° C under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 2 hours and at room temperature overnight. The solvent is evaporated in vacuo, the residue is triturated with water and the precipitate is filtered off, washed with hexane and dried in vacuo to

·· give ketohydrazine (11 g), MS (ES ⁺ ) m / e 304 [MH] ⁺ . A solution of ketohydrazine (11 g) and triethylamine hydrochloride (2.2 g, 20% w / w) in xylene (500 ml) was heated at 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 with water (x 2), dried over magnesium sulfate and evaporated in vacuo. Recrystallization (dichloromethane / hexane) gave 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] ⁺ .

Reference Example 1

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

Sodium hydride (244 mg of 60% dispersion in oil, 6.10 mmol) was added while stirring to a solution of 2-pyridylcarbinol (470 mg, 4.27 mmol) in dimethylformamide (60 ml) at room temperature under nitrogen and the mixture was stirred 0.25 o'clock. Intermediate 1 (1160 mg, 4.07 mmol) was then added and the mixture was stirred for 2 hours. The solvent was removed in vacuo and the residue dissolved in dichloromethane, washed with water (x 2), dried over magnesium sulfate and evaporated in vacuo. Flash chromatography on silica gel, eluting with 3% methanol / dichloromethane and then recrystallizing (dichloromethane / hexane) afforded the title compound (640 mg, 44%), mp 234-236 ° C; 1 H NMR (360 MHz, CDCI 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 = 7.8 Hz, Ar-H), 8.64 8.72 (2H, m, Ar-H); MS (ES ⁺ ) m / e 359 [MH] ⁺ .

Analysis found C 62.93; H, 3.56; N, 22.94;

calculated for C ₁₉ H ₁₄ N ₆ O ₂ 0.05 (CH ₂ Cl ₂ ) C 63.10; H, 3.92; N, 23.17%.

Reference Example 2 ·· ·· • · ·

6- (6-bromopyridin-2-yl) methyloxy-3- (5-methylisoxazol-3-yl) -

1,2,4-triazolo [3,4-a] phthalazine

The title compound was obtained from intermediate 1 and 2-bromopyridine-6-methanol (Tetrahedron Lett., 1996, 50, 2537) following the method of Reference Example 1. The product was isolated by the addition of water to the reaction mixture and the resulting precipitate. is filtered out. Flash chromatography over silica gel, eluting with ethyl acetate and recrystallization (ethyl acetate methanol) afforded the title phthalazine, m.p. 247.5 - 249 ° C. ¹ H

NMR (360 MHz, CDCl3) δ 2.61 (3H, d, J = 0.7 Hz, Me), 5.73 (2H, s, CH2, 6.82 (1H, d, J = 0.7 Hz, Ar-H), 7.48 (1H , d, J = 7.8 Hz, Ar-H), 7.63 (1H, t, J = 7.7 Hz, Ar-H), 7.76 (1H, d, J = 7.4 Hz, Ar-H), 7.84 (1H, t , J = 8.4 Hz, Ar-H), 7.98 (1H, t, J = 8.4 Hz, Ar-H), 8.31 (1H, d, J = 8.5 Hz, Ar-H), 8.70 (1H, d, Ar MS (ES ⁺ ) m / e 437 [MH] ⁺ Analysis: Found C 52.27; H 2.85; N 19.14;

calculated for C ₁₉ H ₁₃ N ₆ O ₂ Br. 0.1 (H ₂ O) C 51.98; H 3.03; N, 18.60%.

Intermediate 2

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

A solution of sodium hydroxide (0.67 g, 17 mmol) in water (7.5 ml) was added to a solution of intermediate 1 (1.0 g, 3.5 mmol) in dioxane (37.5 ml) with stirring and the mixture was refluxed for 4 hours. The solvent was evaporated in vacuo and the residue partitioned between water and diethyl ether. The aqueous layer was separated, washed with ether (x 1) and then acidified with 2 N hydrochloric acid to achieve pH 2. The solid precipitate was separated from the solution by filtration and the aqueous filtrate was extracted with dichloromethane (x 3). The combined extracts were dried over magnesium sulphate, evaporated in vacuo and collected with the residue to give the title compound (0.45 g, 48%); 1 H NMR (250 MHz, d ⁶ DMSO) δ 2.58 (3H, d, J = 0.7 Hz, Me), 7.07 (1H, d, J = 0.9 Hz, Ar-H), 7.94 (1H, m, Ar- H), 8.08 (1H, m, Ar-H), 8.24 (1H, d, J = 7.4)

9999 • · · · • · • 9

9999 9999

Hz, Ar-H), 8.54 (1H, d, J = 7.4 Hz, Ar-H), 13.32 (1H, br s, NH); MS (ES ⁺ ) m / e 268 [MH] ^< ^{+ &} gt ^; .

Reference Example 3

3- (5-methylisoxazol-3-yl) -6- (1H, -1,2,3-triazol-5-yl) methyloxy-

1,2,4-triazolo [3,4-a] phalazine

5-Formyl-1- [2- (trimethylsilyl) ethoxy] methyl-1,2,3-triazole n-butyllithium (6.8 ml of 1.6 M solution in hexanes, 10.9 mmol) was added dropwise over 0.08 hours with stirring. to a solution of 1- [2- (trimethyl-silyl) ethoxy] methyl-1,2,3-triazole (J. Heterocycl.

Chem., 1992, 29, 1203) (2.077 g, 10.42 mmol) in tetrahydrofuran (30 ml) at -78 ° C under nitrogen. The solution was allowed to warm to -60 ° C for 0.67 hours and again cooled to -78 ° C under nitrogen and dimethylformamide (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 over magnesium sulfate, 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%). ^1H

NMR (360 MHz, CDCl3) δ 0.01 (9H, s, Me ₃ Si), 0.92 - 0.99 (2H, m, CHg), 3.64 3.69 (2H, m, CHg), 6.05 (2H, m, CHg), 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 while stirring a short solution of the above triazole (1.704 g, 7.495 mmol) in methanol (8 ml) at 0 ° C under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 0.5 hours and at room temperature for 0.5 hours. Water was added and the mixture was partitioned between dichloromethane and saturated brine. The aqueous layer was separated and further extracted with dichloromethane (x 2). The combined organic layers were dried over magnesium sulfate and evaporated in vacuo.

• · · · • ·

The residue was chromatographed on silica gel, eluting with 70% ethyl acetate / hexane to give the title compound (1.34 g, 78%). 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 ^, 5.80 (2H, s, CHg), 7.68 (1H, S, αΓΗ).

c) 3- (5-methylisoxazol-3-yl) -6- {1- [2- (trimethylsilyl) ethoxy] methyl-

1.2.3-triazol-5-yl} methoxy-1,2,4-triazolo [3,4-a] phthalazine

The title compound was prepared from intermediate 1 and the above alcohol following the procedure described in Example 10, 1 H NMR (360 MHz, CDCl ₃ ) δ 0.00 (9H, s, Me ₃ Si), 0.88-0.93 (3H, m, Me), 2.63 (3H, s, Me), 3.61-3.66 (2H, m, CH ₂ ), 5.92 (2H, s, CH ₂ ), 5.97 (2H, s, CH ₂ ), 6.89 (1H. s, Ar-H), 7.86 (1H, m, Ar-H), 8.02 (1H, t, J = 7.7 Hz, Ar-H), 8.18 (1H, s, Ar-H), 8.23 (1H, d , J = 8.0 Hz, Ar-H), 8.76 (1H, d, J = 8.0 Hz, Ar-H); MS (ES ⁺ ) m / e 479 [MH] ⁺ .

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 above compound, ethanol (10 ml) and 2 N 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 solvents were evaporated in vacuo. The residue was azeotroped with ethanol (x 2) and chromatographed on silica gel eluting with 0-4% methanol / dichloromethane (gradient elution) to give the title compound. ¹ H NMR (360 MHz, CDCl 3) δ 2.65 (3H, s, Me), 5.73 (2H, s, CH ₂ ), 7.02 (1H, s, Ar-H), 7.87 (1H, t, J = 7.8 Hz , Ar-H), 7.99 - 8.03 (2H, m, 2 οτ ΑΓΗ), 8.24 (1H, d, J = 8.2 Hz, Ar-H), 8.72 (1H, d, J = 7.9 Hz, Ar-H) ; MS (ES ⁺ ) m / e 349 [MH] ⁺ .

Example 1

3- (5-methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-5yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine, 3- ( 5-Methylisoxazol3-yl) -6- (2-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-

• · • J ·· • ·· • · · · • · · • ·

a] phthalazine and 3- (5-methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine

Lithium hexamethyldisilazide (1.63 ml of 1 M solution in tetrahydrofuran, 1.63 mmol) was added dropwise while stirring to a solution of 3- (5-methylisoxazol-3-yl) -6- (1H, -1,2,3-triazole- 5yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine (241 mg, 0.626 mmol) prepared according to Reference Example 3 in dimethylformamide (50 ml) at -31 ° C under nitrogen atmosphere. The mixture was warmed to -23 ° C for 1.5 hours, methyl iodide (0.10 ml, 1.6 mmol) was added dropwise and the reaction 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 extracted again with dichloromethane (x 1). The combined organic extracts were washed with brine (x 1), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with 0-5% methanol / dichloromethane (gradient elution) and then preparative HPLC (YMC Sil column, 250 x 20 mm) eluting with 5% methanol / 1-chlorobutane to separate the triazoles isomers:

At least polar isomer (HPLC solvent system): 3- (5methylisoxazol-3-yl) -6- (2-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4 triazolo [3, 4-a] 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 = 8.0 Hz, Ar-H); MS (ES ⁺ ) m / e 363 [MH] ⁺ .

Intermediate polar isomer: 3- (5-methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine ¹ H NMR (400

MHz, CDCI ₃ ) δ 2.60 (3H, s, Me), 4.09 (3H, s, Me), 5.78 (2H, s, CHg), 6.90 (1H, d, J = 0.8 Hz, 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 ⁺ ) m / e 363 [MH] ⁺ .

The most polar isomer (HPLC solvent system): 3- (5methylisoxazol-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, CHg), 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 = 8.0 Hz, Ar-H); MS (ES ⁺ ) m / e 363 [MH] ⁺ .

Claims (5)

Claims 1. 3- (5-Methylisoxazol-3-yl) -6- (1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a] phthalene azine. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 3. 3- (5-methylisoxazol-3-yl) -6- (2-methyl-1,2,3-triazol-4yl) methyloxy-1,2,4-triazolo [3,4-a] phthalazine for use in the process for the treatment of humans and animals. Use of the compound of claim 1 for the manufacture of a medicament for improving cognition (cognition). A method for improving cognition in a patient suffering from reduced cognition, which comprises administering to the patient a cognition-enhancing amount of a compound according to claim 1.