PYRIDAZINONE COMPOUNDS AND THEIR USE AS DAAO INHIBITORS

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R.sup.1 and R.sup.2 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

##STR00001##

Claims

1-16. (canceled)

17. A compound that is 4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one or a pharmaceutically acceptable salt thereof, wherein the compound is in crystalline form.

18. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutically acceptable adjuvant, diluent or carrier.

19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition further comprises one or more therapeutic agents and/or serine.

20. A method of preparing a compound that is 4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one or a pharmaceutically acceptable salt thereof, wherein the compound is in crystalline form, the method comprising recrystallizing the compound from a mixture comprising one or more solvents.

21. The method of claim 20, wherein the compound is recrystallized from a mixture comprising two solvents.

22. The method of claim 20, wherein the compound is recrystallized from a mixture comprising heptane and ethyl acetate.

23. A compound that is obtained according to the method of claim 20.

24. A compound that is obtained according to the method of claim 22.

25. A pharmaceutical composition comprising the compound of claim 24 and a pharmaceutically acceptable adjuvant, diluent or carrier.

26. A method of treating a condition whose development or symptoms are linked to D-amino acid oxidase enzyme (DAAO) enzyme activity in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 17 to the patient.

27. A method of treating a disorder selected from schizophrenia, dementia, an anxiety disorder, a mood disorder, a major depressive disorder, a bipolar disorder, a sleep disorder, a disorder usually first diagnosed in infancy, childhood, or adolescence, pain, and a neurodegenerative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 17 to the patient.

28. A method of treating at least one symptom or condition associated with a disorder selected from schizophrenia, schizophreniform disorder, schizoaffective disorder, dementia, an anxiety disorder, a mood disorder, a sleep disorder, a disorder usually first diagnosed in infancy, childhood, or adolescence, pain, and a neurodegenerative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 17 to the patient.

29. A method of treating at least one symptom or condition associated with schizophrenia in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 17 to the patient.

30. The method of claim 29, wherein the at least one symptom is a positive symptom of schizophrenia.

31. The method of claim 29, wherein the at least one symptom is a negative symptom of schizophrenia.

32. A method according to claim 30, wherein in the positive symptom of schizophrenia is cognitive impairment associated with schizophrenia.

33. A method of treating conditions whose development or symptoms are linked to D-amino acid oxidase enzyme (DAAO) enzyme activity in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 24 to the patient.

34. A method of treating a disorder selected from schizophrenia, dementia, an anxiety disorder, a mood disorder, a major depressive disorder, a bipolar disorder, a sleep disorder, a disorder usually first diagnosed in infancy, childhood, or adolescence, pain, and a neurodegenerative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 24 to the patient.

35. A method of treating at least one symptom or condition associated with a disorder selected from schizophrenia, schizophreniform disorder, schizoaffective disorder, dementia, an anxiety disorder, a mood disorder, a sleep disorder, a disorder usually first diagnosed in infancy, childhood, or adolescence, pain, and a neurodegenerative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 24 to the patient.

36. A method of treating at least one symptom or condition associated with schizophrenia in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 24 to the patient.

37. The method of claim 36, wherein the at least one symptom is a positive symptom of schizophrenia.

38. The method of claim 36, wherein the at least one symptom is a negative symptom of schizophrenia.

39. A method according to claim 37, wherein in the positive symptom of schizophrenia is cognitive impairment associated with schizophrenia.

Description

2. EXAMPLES

[0547] ##STR00121##

Example 1: 4-Hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one

[0548] ##STR00122##

[0549] 3,4-bis(Benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2; 320 mg, 0.815 mmol) was dissolved in ethanol and palladium on carbon (87 mgs, 0.815 mmol) was added before the mixture was purged and subjected to hydrogen gas. The reaction was then filtered and evaporated and the residue was purified on silica using 0-10% methanol in dichloromethane to yield a red solid. This was triturated with ethanol to give the crude title compound as a white solid and the mother liquors were evaporated and dissolved in a minimum amount of dimethyl sulfoxide and purified by C.sub.18 reverse phase silica chromatography to yield 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (31 mg, 0.14 mmol, 17.6% yield).

[0550] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.80 (s, br, 1H), 10.7 (s, br, 1H), 7.15-7.30 (m, 6H), 2.85-2.95 (m, 2H) and 2.76-2.83 (s, 2H).

[0551] MS ES.sup.+: 217.

Example 2: 6-[2-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0552] ##STR00123##

[0553] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)ethynyl]pyridazine (Intermediate 3).

[0554] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.22-7.28 (m, 2H), 7.05-7.13 (m, 2H), 6.58 (s, 1H), 2.85-2.94 (m, 2H) and 2.73-2.79 (m, 2H)

[0555] MS ES.sup.+: 236.

Example 3: 4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}pyridazin-3(2H)-one

[0556] ##STR00124##

[0557] 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6; 460 mg, 0.997 mmol) was dissolved in ethanol and palladium on carbon was added before the mixture was purged and subjected to hydrogen gas. On completion of the reaction the solvent was removed in vacuo to yield a residue which was purified by reverse phase chromatography using 5-90% acetonitrile in acidic water (0.05% trifluoroacetic acid) to give, after recrystallisation from an ethanol-heptane mixture, 4-hydroxy-6-(2-(5-(trifluoromethyl)pyridin-2-yl)ethyl)pyridazin-3(2H)-one (136 mg, 0.48 mmol, 48% yield).

[0558] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.66 (br s, 1H), 10.72 (br s, 1H), 8.89 (s, 1H), 8.11 (s, 1H), 7.54 (s, 1H), 6.62 (s, 1H), 3.13-3.19 (m, 2H) and 2.90-2.98 (m, 2H)

[0559] MS ES.sup.+: 286.

##STR00125##

Example 4: 6-[(4-Chlorobenzyl)sulfanyl]-4-hydroxypyridazin-3(2H)-one

[0560] ##STR00126##

[0561] To a solution of 6-[(4-chlorobenzyl)sulfanyl]-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (Intermediate 8; 527 mg, 1.04 mmol) in methanol (5177 l) was added a solution of hydrogen chloride in dioxane (4.0 M, 5177 l, 20.71 mmol) and the reaction was allowed to stir at room temperature for 72 hours. The resulting mixture was concentrated in vacuo to afford a yellow solid which was recrystallised from ethanol to afford 6-[(4-chlorobenzyl)sulfanyl]-4-hydroxypyridazin-3(2H)-one as white crystals (153 mg, 56.9 mmol, 55%).

[0562] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.99 (s, br, 1H), 10.6 (s, br, 1H), 7.35-7.46 (m, 4H), 6.53 (s, 1H) and 4.24 (s, 2H).

[0563] MS ES.sup.+: 269.

Example 5: 4-Hydroxy-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one

[0564] ##STR00127##

[0565] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 9) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1). The resulting crude product was purified by preparative HPLC under acidic conditions to afford 4-hydroxy-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one as a cream solid (26% yield).

[0566] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.68 (br s, 1H), 10.80 (s, br, 1H), 8.64 (s, 1H), 7.92-7.98 (m, 1H), 7.80-7.88 (m, 1H), 6.61 (s, 1H), 2.98-3.08 (m, 2H) and 2.80-2.88 (m, 2H).

[0567] MS ES.sup.+: 286.

Example 6: 6-[2-(3-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0568] ##STR00128##

[0569] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-fluorophenyl)ethynyl]pyridazine (Intermediate 10) except that the reaction was carried out in methanol. The resulting crude product was recrystallised from a mixture of ethanol and heptane to afford 6-[2-(3-fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one as cream crystals (yield=63%).

[0570] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.67 (br s, 1H), 10.71 (br s, 1H), 7.25-7.38 (s, 1H), 6.95-7.15 (m, 3H), 6.61 (s, 1H), 2.88-2.95 (m, 2H) and 2.73-2.81 (m, 2H).

[0571] MS ES.sup.+: 235.

[0572] Example 7: 6-[2-(2-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

##STR00129##

[0573] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2-fluorophenyl)ethynyl]pyridazine (Intermediate 11).

[0574] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.69 (br s, 1H), 10.77 (br s, 1H), 7.21-7.35 (m, 2H), 7.08-7.21 (m, 2H), 6.60 (s, 1H), 2.85-2.95 (m, 2H) and 2.72-2.79 (m, 2H)

[0575] MS ES.sup.+: 235.

Example 8: 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0576] ##STR00130##

[0577] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3,5-difluorophenyl)ethynyl]pyridazine (Intermediate 12). The crude material was purified by reverse phase column chromatography (10 g C18) cartridge eluting with 0-100% methanol and water with acidic modifier to afford a pale orange oil solid. This was recrystallised from a mixture of ethanol and heptane to give a peach coloured solid (yield=29%).

[0578] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.69 (br s, 1H), 10.74 (br s, 1H), 6.95-7.05 (m, 3H), 6.60 (s, 1H), 2.88-2.95 (m, 2H) and 2.74-2.81 (m, 2H).

[0579] MS ES.sup.+: 253.

Example 9: 6-[2-(3,4-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0580] ##STR00131##

[0581] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3,4-difluorophenyl)ethynyl]pyridazine (Intermediate 13). The crude material was purified by reverse phase chromatography, eluting with 5-100% acetonitrile in water with a 0.05% formic acid modifier in the water.

[0582] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.6 (s, br, 1H), 10.8 (s, br, 1H), 7.24-7.38 (m, 2H), 7.02-7.09 (m, 1H), 6.64 (s, 1H), 2.84-2.92 (m, 2H) and 2.72-2.81 (m, 2H).

[0583] MS ES.sup.+: 253.

Example 10: 4-Hydroxy-6-{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one

[0584] ##STR00132##

[0585] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[3-(trifluoromethoxy)phenyl]ethynyl}pyridazine (Intermediate 14). The residue was purified by reverse phase column chromatography (30 g C18) cartridge eluting with 0-100% methanol in water with acidic modifier and the appropriate fractions combined and concentrated. The crude product was recrystallised from ethyl acetate/heptane to give a white solid (yield=23%).

[0586] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.67 (br s, 1H), 10.71 (br s, 1H), 7.35-7.45 (m, 1H), 7.15-7.30 (m, 3H), 6.51 (s, 1H), 2.92-2.98 (m, 2H) and 2.74-2.84 (m, 2H).

[0587] MS ES.sup.+: 301.

Example 11: 4-Hydroxy-6-{2-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one

[0588] ##STR00133##

[0589] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[3-(trifluoromethyl)phenyl]ethynyl}pyridazine (Intermediate 15) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (2:1). The crude material was purified by reverse phase chromatography, eluting with 5-80% acetonitrile/water with a 0.05% formic acid modifier in the water. The crude product was recrystallised from ethanol/heptane to give a white solid (yield=27%).

[0590] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.7 (s, br, 1H), 10.7 (s, br, 1H), 7.59 (s, 1H), 7.49-7.53 (m, 3H), 6.61 (s, 1H), 2.95-3.01 (m, 2H) and 2.77-2.81 (m, 2H).

[0591] MS ES.sup.+: 285.

Example 12: 4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one

[0592] ##STR00134##

[0593] To a solution of 3,4-bis(benzyloxy)-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 16, 1.5 g) in methanol (10 ml) was added 10% palladium on carbon (0.04 g) slowly under nitrogen and the reaction mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through a Celite (trade mark) diatomaceous earth bed under nitrogen atmosphere and washed with methanol before the filtrate was concentrated under vacuum to afford crude 3,4-bis (benzyloxy)-6-(2-(5-(trifluoromethyl) pyridin-3-yl) ethyl)pyridazine (0.4 g, 0.86 mmol). This was taken up in methanol (10 ml) at room temperature and 10% palladium on carbon (0.04 g) was added slowly under nitrogen atmosphere. The mixture was then stirred under hydrogen (200 psi) at room temperature overnight before being filtered through a bed of Celite diatomaceous earth under nitrogen and washed with methanol. The organic layer was concentrated in vacuo to afford the crude product (0.2 g) which was purified by the preparative HPLC to afford homogeneous 4-hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one (0.03 g, 81.6% yield).

[0594] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.72 (s, br, 1H), 10.81 (s, br, 1H), 8.80 (s, 1H), 8.75 (s, 1H), 8.10 (s, 1H), 6.63 (s, 1H), 3.00-3.34 (m, 2H) and 2.81-2.85 (m, 2H).

[0595] MS ES.sup.+: 286.

[0596] Example 13: 6-(2-Cyclohexylethyl)-4-hydroxypyridazin-3(2H)-one

##STR00135##

[0597] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclohexylethynyl)pyridazine (Intermediate 17) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1). The resulting crude product was purified by preparative HPLC under acidic conditions. The solid obtained was recrystallised from methyl tert-butyl ether and ethyl acetate to afford 6-(2-cyclohexylethyl)-4-hydroxypyridazin-3(2H)-one as a cream solid (11% yield).

[0598] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.62 (br s, 1H), 10.68 (br s, 1H), 6.52 (s, 1H), 2.39-2.48 (m, 2H), 1.56-1.76 (m, 5H), 1.38-1.49 (m, 2H), 1.05-1.27 (m, 4H), 0.80-0.97 (m, 2H)

[0599] MS ES.sup.+: 223.

Example 14: 6-(2-Cyclopropylethyl)-4-hydroxypyridazin-3(2H)-one

[0600] ##STR00136##

[0601] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclopropylethynyl)pyridazine (Intermediate 18) except that the reaction was carried out in ethanol. The resulting crude product was purified by preparative HPLC under acidic conditions to afford 6-(2-cyclopropylethyl)-4-hydroxypyridazin-3(2H)-one as a cream solid (14% yield).

[0602] .sup.1H NMR (400 MHz, MeOH-d.sub.6) 6.55 (s, 1H), 2.55-2.63 (m, 2H), 1.45-1.54 (m, 2H), 0.67-0.75 (m, 1H), 0.38-0.42 (m, 2H) and 0.04-0.06 (m, 2H)

[0603] MS ES.sup.+: 181.

Example 15: 6-(2-Cyclopentylethyl)-4-hydroxypyridazin-3(2H)-one

[0604] ##STR00137##

[0605] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclopentylethynyl)pyridazine (Intermediate 19) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1). The resulting crude product was purified by preparative HPLC under acidic conditions to afford 6-(2-cyclopentylethyl)-4-hydroxypyridazin-3(2H)-one after recrystallisation from ethanol and heptane as a white solid (51% yield).

[0606] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.63 (br s, 1H), 10.67 (br s, 1H), 6.54 (s, 1H), 2.41-2.48 (m, 2H), 1.67-1.79 (m, 3H), 1.41-1.63 (m, 6H), 1.00-1.15 (m, 2H).

[0607] MS ES.sup.+: 209.

Example 16: 4-Hydroxy-6-[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one

[0608] ##STR00138##

[0609] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-methoxycyclohex-1-en-1-yl)ethynyl]pyridazine (Intermediate 20) except that the reaction was carried out in methanol. The resulting crude product was purified by preparative HPLC under acidic conditions to afford 4-hydroxy-6-[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one (mixture of isomers) as a white solid (26% yield).

[0610] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.62 (s, 1H), 10.66 (br s, 1H), 6.52-6.55 (m, 1H), 3.21 and 3.18 (2 singlets, total 3H), 2.97-3.08 (m, 1H), 2.40-2.47 (m, 2H), 1.91-2.01 (m, 1H), 1.70-1.80 (m, 2H), 0.84-1.51 (m, 8H)

[0611] MS ES.sup.+: 253.

Example 17: 6-[2-(2,4-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0612] ##STR00139##

[0613] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2,4-difluorophenyl)ethynyl]pyridazine (Intermediate 21) except that the reaction was carried out in a mixture of ethanol and tetrahydrofuran (1:1). The crude material was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give a yellow solid. This was recrystallised from ethanol to give a white solid (yield=26%).

[0614] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 10.78 (br s, 1H), 7.24-7.40 (m, 1H), 7.09-7.26 (m, 1H), 6.93-7.07 (m, 1H), 6.58 (s, 1H), 2.82-2.97 (m, 2H), 2.63-2.80 (m, 2H).

[0615] MS ES.sup.+: 253.

Example 18: 6-{2-[3-(Difluoromethyl)phenyl]ethyl}-4-hydroxypyridazin-3(2H)-one

[0616] ##STR00140##

[0617] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-(difluoromethyl)phenyl)ethynyl]pyridazine (Intermediate 22) except that the reaction was carried out in a mixture of ethanol and tetrahydrofuran (1:1). The crude material was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give a pale orange solid (yield=32%).

[0618] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 10.77 (br s, 1H), 7.33-7.47 (m, 5H), 6.79-7.18 (m, 1H), 6.61 (s, 1H), 2.89-3.00 (m, 2H), 2.71-2.83 (m, 2H).

[0619] MS ES.sup.+: 267.

Example 19: 6-Benzyl-4-hydroxypyridazin-3(2H)-one

[0620] ##STR00141##

[0621] To a degassed solution of 6-benzyl-3,4-bis(benzyloxy)pyridazine (Intermediate 23: 0.16 g, 0.418 mmol) in methanol (4.18 ml) was added 10% palladium on carbon (0.045 g, 0.042 mmol). The mixture was degassed, evacuated and filled with hydrogen from a balloon. After 1 hour the reaction mixture was degassed and filtered through a pad of Celite diatomaceous earth, washing with methanol and concentrated to give a yellow oil. The crude oil was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give a cream solid (yield=77%).

[0622] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.72 (br s, 1H), 10.78 (br s, 1H), 7.15-7.40 (m, 5H), 6.46 (s, 1H), 3.79 (s, 2H).

[0623] MS ES.sup.+: 203.

Example 20: 6-[2-(3-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0624] ##STR00142##

[0625] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-chloromethyl)phenyl)ethynyl]pyridazine (Intermediate 24) except that the reaction was carried out in ethyl acetate. The crude material was purified by reverse phase chromatography (50 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give an orange solid. This was recrystallised from ethyl acetate to give a white solid (yield=32%).

[0626] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.67 (s, 1H), 10.72 (br s, 1H), 7.10-7.40 (m, 4H), 6.60 (s, 1H), 2.82-3.05 (m, 2H), 2.71-2.82 (m, 2H).

[0627] MS ES.sup.+: 251.

Example 21: 4-Hydroxy-6-(1-phenylcyclopropyl)pyridazin-3(H)-one

[0628] ##STR00143##

[0629] Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(1-phenylcyclopropyl)pyridazine (Intermediate 26) except that the reaction was carried out in ethyl acetate. The crude material was recrystallised from ethyl acetate to give a pink solid (yield=27%).

[0630] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 10.74 (br s, 1H), 7.13-7.39 (m, 5H), 6.32 (s, 1H), 1.27-1.39 (m, 2H), 1.10-1.24 (m, 2H).

[0631] MS ES.sup.+: 229.

[0632] Example 22: 4-[2-(5-Hydroxy-6-oxo-1,6-dihydropyridazin-3-yl)ethyl]benzonitrile

##STR00144##

[0633] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 4-{2-[5,6-bis(benzyloxy)pyridazin-3-yl]ethynyl}benzonitrile (Intermediate 27) except that the solvent mixture used for the hydrogenation was made up from tetrahydrofuran and methanol (1:1) and the final compound was recrystallised from tetrahydrofuran.

[0634] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.59 (br s, 1H), 10.66 (br s, 1H), 7.56-7.78 (m, 2H), 7.27-7.44 (m, 2H), 6.52 (s, 1H), 2.82-3.01 (m, 2H) and 2.56-2.82 (m, 2H).

[0635] MS ES.sup.+: 242.

Example 23: 6-[2-(3-Fluoro-4-methylphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0636] ##STR00145##

[0637] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3-fluoro-4-methylphenyl)ethynyl]pyridazine (Intermediate 28) except that the solvent mixture used for the hydrogenation was ethyl acetate and methanol (1:1) and the final product was recrystallised from ethyl acetate.

[0638] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.67 (s, 1H), 10.71 (br s, 1H), 7.09-7.24 (m, 1H), 6.85-7.07 (m, 2H), 6.59 (s, 1H), 2.80-2.93 (m, 2H), 2.68-2.77 (m, 2H) and 2.18 (s, 3H).

[0639] MS ES.sup.+: 249.

Example 24: 6-[2-(4-Fluoro-3-methylphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0640] ##STR00146##

[0641] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(4-fluoro-3-methylphenyl)ethynyl]pyridazine (Intermediate 29) except that the solvent mixture used for the hydrogenation was made up of ethyl acetate and methanol (1:1) and the final material was recrystallised from ethyl acetate.

[0642] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.67 (s, 1H), 10.70 (br s, 1H), 6.90-7.20 (m, 3H), 6.58 (s, 1H), 2.61-2.91 (m, 4H) and 2.20 (s, 3H).

[0643] MS ES.sup.+: 249.

Example 25: 6-[2-(3,4-Dimethoxyphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0644] ##STR00147##

[0645] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3,4-dimethoxyphenyl)ethynyl]pyridazine (Intermediate 30) except that the solvent mixture used for the hydrogenation was ethanol and tetrahydrofuran (1:1) and the final material was recrystallised from a mixture of ethyl acetate and heptane.

[0646] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.66 (br s, 1H), 10.69 (br s, 1H), 6.76-6.94 (m, 2H), 6.63-6.77 (m, 1H), 6.58 (s, 1H), 3.59-3.82 (m, 6H) and 2.60-2.91 (m, 4H).

[0647] MS ES.sup.+: 277.

Example 26: 4-Hydroxy-6-{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one

[0648] ##STR00148##

[0649] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((3(trifluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 39) except that the solvent used for the hydrogenation was ethanol and the final compound was recrystallised from a mixture of ethyl acetate and heptane.

[0650] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.67 (s, 1H), 10.71 (br s, 1H), 7.36-7.45 (m, 1H), 7.13-7.30 (m, 3H), 6.60 (s, 1H), 2.88-2.99 (m, 2H) and 2.73-2.82 (m, 2H).

[0651] MS ES.sup.+: 301.

Example 27: 6-[2-(4-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0652] ##STR00149##

[0653] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((4-chlorophenyl)ethynyl)pyridazine (Intermediate 34) except that the solvent used for the hydrogenation was tetrahydrofuran and the final compound was recrystallised from a mixture of ethyl acetate and heptane.

[0654] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.66 (s, 1H), 10.72 (br s, 1H), 7.14-7.44 (m, 4H), 6.58 (s, 1H), 2.83-2.92 (m, 2H) and 2.69-2.79 (m, 2H).

[0655] MS ES.sup.+: 251, 253.

Example 28: 6-[2-(2-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0656] ##STR00150##

[0657] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((2-chlorophenyl)ethynyl)pyridazine (Intermediate 35) except that the solvent used for the hydrogenation was ethyl acetate and the final material was recrystallised from a mixture of ethyl acetate and heptane

[0658] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.67 (s, 1H), 10.73 (br s, 1H), 7.14-7.46 (m, 4H), 6.58 (s, 1H), 2.91-3.05 (m, 2H) and 2.70-2.81 (m, 2H).

[0659] MS ES.sup.+: 251, 253.

Example 29: 4-Hydroxy-6-{2-[2-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one

[0660] ##STR00151##

[0661] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((2-trifluoromethylphenyl)ethynyl)pyridazine (Intermediate 40) except that the final product was recrystallised from a mixture of ethyl acetate and heptane.

[0662] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.66 (br s, 1H), 10.79 (br s, 1H), 7.35-7.74 (m, 4H), 6.56 (s, 1H), 2.97-3.11 (m, 2H) and 2.71-2.82 (m, 2H).

[0663] MS ES.sup.+: 285.

Example 30: 6-(4-(Difluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one

[0664] ##STR00152##

[0665] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((4-(difluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 36) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final material was recrystallised from 2-propanol and heptanes.

[0666] .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2) 7.17-7.24 (m, 2H), 7.00-7.11 (m, 2H), 6.55 (s, 1H), 6.31-6.74 (m, 1H), 2.91-3.00 (m, 2H) and 2.81-2.91 (m, 2H).

[0667] MS ES.sup.+ 283.

Example 31: 6-(4-(Trifluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one

[0668] ##STR00153##

[0669] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((4-(trifluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 37) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final compound was recrystallised from MTBE and heptane.

[0670] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.70 (s, 1H), 10.75 (br s, 1H), 7.21-7.41 (m, 4H), 6.61 (s, 1H) and 2.67-2.99 (m, 4H).

[0671] MS ES.sup.+ 301.

Example 32: 6-(3-(Difluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one

[0672] ##STR00154##

[0673] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((3-(difluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 38) except that the mixture of solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final compound was recrystallised from a mixture of ethanol and heptane.

[0674] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.65 (br s, 1H), 6.92-7.43 (m, 6H), 6.58 (s, 1H), 2.83-2.97 (m, 2H) and 2.70-2.84 (m, 2H).

[0675] MS ES.sup.+ 283.

Example 33: 6-[1-(4-Fluorophenyl)cyclopropyl]-4-hydroxypyrdazin-3(2H)-one

[0676] ##STR00155##

[0677] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[1-(4-fluorophenyl)cyclopropyl]pyridazine (Intermediate 42) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and MTBE.

[0678] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 10.77 (br s, 1H), 7.26-7.42 (m, 2H), 7.01-7.26 (m, 2H), 6.32 (s, 1H), 1.28-1.39 (m, 2H) and 1.09-1.22 (m, 2H).

[0679] MS ES.sup.+: 247.

Example 34: 6-[1-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one

[0680] ##STR00156##

[0681] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 41) except that the solvent mixture used for the hydrogenation consisted of ethyl acetate and tetrahydrofuran and the product was recrystallised from a mixture of heptane and MTBE.

[0682] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.75 (s, 1H), 10.74 (br s, 1H), 7.24-7.35 (m, 2H), 7.00-7.19 (m, 2H), 6.43 (s, 1H), 3.85-4.13 (m, 1H) and 1.38-1.55 (m, 3H).

[0683] MS ES.sup.+: 235.

Example 35: 4-Hydroxy-6-{1-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one

[0684] ##STR00157##

[0685] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(3-methylbut-1-ynyl)pyridazine (Intermediate 43) except that the solvent mixture used for the hydrogenation was made up of ethyl acetate and tetrahydrofuran and the product was recrystallised from heptane and MTBE.

[0686] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.79 (s, 1H), 10.80 (br. s., 1H), 7.47-7.66 (m, 4H), 6.51 (s, 1H), 4.02-4.25 (m, 1H), 1.41-1.60 (m, 3H)

[0687] MS ES.sup.+: 285

Example 36: 4-Hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one

[0688] ##STR00158##

[0689] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from (E)-3,4-bis(benzyloxy)-6-(4-(trifluoromethyl)styryl)pyridazine (Intermediate 44) except that the product was recrystallised from a mixture of heptane and ethyl acetate.

[0690] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.67 (s, 1H), 10.73 (br s, 1H), 7.58-7.68 (m, 2H), 7.40-7.49 (m, 2H), 6.61 (s, 1H), 2.92-3.03 (m, 2H) and 2.72-2.85 (m, 2H)

[0691] MS ES.sup.+: 285.

Example 37: 6-((Cyclopropylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one

[0692] ##STR00159##

[0693] A suspension of 5,6-bis(benzyloxy)-N-(cyclopropylmethyl)-N-methylpyridazin-3-amine (Intermediate 46; 2.44 mmol) and palladium on carbon (10% wt loading, dry basis; 0.259 g, 0.244 mmol) in ethyl acetate (10 ml) was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a diatomaceous earth cartridge commercially sold under the trade mark Celite, eluting with ethyl acetate, tetrahydrofuran and methanol. The filtrate was concentrated in vacuo to afford a brown solid, which was triturated from ethyl acetate to give the title compound as a pale brown solid (27.9 mg, 38%).

[0694] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.81-11.98 (m, 1H), 6.48 (s, 1H), 3.12 (d, 2H), 2.84 (s, 3H), 0.84-1.01 (m, 1H), 0.36-0.51 (m, 2H) and 0.09-0.26 (m, 2H).

[0695] MS ES.sup.+ 196.

Example 38: 6-((Cyclohexylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one

[0696] ##STR00160##

[0697] Prepared according to the procedure for 6-((cyclopropylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one (Example 37) using 5,6-bis(benzyloxy)-N-(cyclohexylmethyl)-N-methylpyridazin-3-amine (Intermediate 47) but purified by reverse phase C18 chromatography, eluting with 5-100% acetonitrile/water with a 0.1% ammonia modifier in both the water and acetonitrile to give the title compound as a pale cream solid (45 mg, 26%).

[0698] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 11.88 (br s, 1H), 6.44 (s, 1H), 2.98-3.13 (m, 2H), 2.82 (s, 3H), 1.52-1.74 (m, 6H), 1.04-1.26 (m, 3H) and 0.82-0.99 (m, 2H).

[0699] MS ES.sup.+ 238.

Example 39; 6-(3-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one

[0700] ##STR00161##

[0701] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-chlorophenyl)methyl]pyridazine (Intermediate 48) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from ethyl acetate.

[0702] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.75 (s, 1H), 10.83 (br s, 1H), 7.15-7.40 (m, 4H), 6.52 (s, 1H) and 3.81 (s, 2H).

[0703] MS ES.sup.+: 237 and 239.

Example 40: 6-(4-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one

[0704] ##STR00162##

[0705] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-chlorophenyl)methyl]pyridazine (Intermediate 49) except that the solvent used for the hydrogenation was ethyl acetate and tetrahydrofuran and the product was recrystallised from ethyl acetate.

[0706] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.74 (s, 1H), 10.81 (br s, 1H), 7.32-7.45 (m, 2H), 7.16-7.32 (m, 2H), 6.48 (s, 1H) and 3.79 (s, 2H).

[0707] MS ES.sup.+: 237 and 239.

[0708] Example 41: 6-(Cyclohexylmethyl)-4-hydroxypyridazin-3(2H)-one

##STR00163##

[0709] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclohexylmethyl)pyridazine (Intermediate SO) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of MTBE and heptanes.

[0710] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.64 (s, 1H), 10.64 (br s, 1H), 6.51 (s, 1H), 2.21-2.39 (m, 2H), 1.44-1.72 (m, 6H), 1.03-1.25 (m, 3H) and 0.75-1.05 (m, 2H).

[0711] MS ES.sup.+: 209.

Example 42; 6-(4-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one

[0712] ##STR00164##

[0713] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of MTBE and heptanes.

[0714] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.73 (s, 1H), 10.79 (br s, 1H), 7.22-7.33 (m, 2H), 6.96-7.18 (m, 2H), 6.47 (s, 1H) and 3.79 (s, 2H).

[0715] MS ES.sup.+: 221.

Example 43: 6-(2-Chloro-6-fluorobenzyl)-4-hydroxypyridazin-3(2H)-one

[0716] ##STR00165##

[0717] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2-chloro-6-fluorophenyl)methyl]pyridazine (Intermediate 52) except that the solvent used for the hydrogenation was tetrahydrofuran and the product was recrystallised from a mixture of MTBE and heptanes.

[0718] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.66 (s, 1H), 10.90 (br s, 1H), 7.31-7.48 (m, 2), 7.05-7.32 (m, 1H), 6.55 (s, 1) and 4.00 (s, 2H).

[0719] MS ES.sup.+: 255, 257.

Example 44: 6-(2-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one

[0720] ##STR00166##

[0721] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2-chlorophenyl)methyl]pyridazine (Intermediate 53) except that the solvent used for the hydrogenation was tetrahydrofuran and the product was recrystallised from a mixture of MTBE and heptanes.

[0722] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.72 (s, 1H), 10.80 (br s, 1H), 7.40-7.57 (m, 1H), 7.20-7.42 (m, 3H), 6.48 (s, 1H) and 3.95 (s, 2H).

[0723] MS ES.sup.+: 237, 239.

[0724] Example 45; 6-(3-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one

##STR00167##

[0725] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-fluorophenyl)methyl]pyridazine (Intermediate 54) except that the solvent used for the hydrogenation was ethanol and the product was recrystallised from a mixture of MTBE and heptanes.

[0726] .sup.1H NMR (400 MHz, DMSO-ds) 12.75 (s, 1H), 10.82 (br s, 1H), 7.25-7.44 (m, 1H), 6.99-7.14 (m, 3H), 6.41-6.58 (m, 1H) and 3.68-3.89 (m, 2H).

[0727] MS ES.sup.+: 221.

[0728] Example 46: 6-(2-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one

##STR00168##

[0729] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2-fluorophenyl)methyl]pyridazine (Intermediate 55) except that the product was recrystallised from a mixture of ethyl acetate and heptanes.

[0730] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.71 (br s, 1H), 10.85 (br s, 1H), 7.26-7.37 (m, 2H), 7.12-7.22 (m, 2H), 6.48 (s, 1H) and 3.85 (s, 2H).

[0731] MS ES.sup.+: 221.

Example 47: 6-(4-Methylbenzyl)-4-hydroxypyridazin-3(2H)-one

[0732] ##STR00169##

[0733] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-methylphenyl)methyl]pyridazine (Intermediate 56) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptanes.

[0734] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.70 (br s, 1H), 10.75 (br s, 1H), 7.12 (s, 4H), 6.42 (s, 1H), 3.64-3.82 (s, 2H) and 2.26 (s, 3H).

[0735] MS ES.sup.+: 217.

Example 48: 6-(3-Methylbenzyl)-4-hydroxypyridazin-3(2H)-one

[0736] ##STR00170##

[0737] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-methylphenyl)methyl]pyridazine (Intermediate 57) except that the solvent mixture used for the hydrogenation was made up from tetrahydrofuran and ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptane.

[0738] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.71 (br s, 1H), 10.78 (br s, 1H), 7.14-7.25 (m, 1H), 6.96-7.10 (m, 3H), 6.44 (s, 1H), 3.74 (s, 2H) and 2.17-2.35 (m, 3H).

[0739] MS ES.sup.+: 217.

Example 49: 4-Hydroxy-6-(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one

[0740] ##STR00171##

[0741] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(3-(trifluoromethyl)benzyl) pyridazine (Intermediate 58) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptanes.

[0742] 1H NMR (400 MHz, CD.sub.2Cl.sub.2) ppm 10.68 (br s, 1H), 7.40-7.70 (m, 4H), 6.56 (s, 1H) and 3.99 (s, 2H).

[0743] MS ES.sup.+ 271.

Example 50: 4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one

[0744] ##STR00172##

[0745] 3,4-bis(Benzyloxy)-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 31; 1.5 g, 3.25 mmol) was dissolved in methanol (10 mL) and 10% palladium on carbon (0.04 g) was added before the mixture was purged and subjected to hydrogen gas. The reaction mixture was stirred for 30 min at room temperature under a hydrogen atmosphere. The reaction mass was then filtered through a celite bed under nitrogen atmosphere and washed with methanol. The filtrate was concentrated in vacuo before the crude was re-dissolved in methanol (10 mL) and 10% palladium on carbon (0.04 g) was added before the mixture was purged and subjected to a pressure of hydrogen gas (200 psi), stirring at room temperature overnight. Upon completion the resulting mixture was filtered through celite under nitrogen and washed with methanol. The filtrate was concentrated under vacuum to afford the crude compound (0.2 g) which was then purified by the preparative HPLC to yield 4-hydroxy-6-(2-(5-(trifluoromethyl) pyridin-3-yl) ethyl) pyridazin-3(2H)-one (0.03 g, 82% yield).

[0746] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.72 (s, 1H), 10.82 (s, 1H), 8.75-8.80 (d, 2H), 8.10 (s, 1H), 6.63 (s, 1H), 3.30-3.04 (t, 2H) and 2.81-2.85 (t, 2H).

[0747] LC-MS ES.sup.+: 286.

Example 51: 4-Hydroxy-6-[2-(oxan-4-yl)ethyl]pyridazin-3(2H)-one

[0748] ##STR00173##

[0749] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3,6-dihydro-2H-pyran-4-yl)ethynyl]pyridazine (Intermediate 60) except that the pressure of hydrogen gas was 200 psi at room temperature overnight and the solvent used for the hydrogenation was methanol and the product was purified by column chromatography (silica gel, eluting with 0-5% methanol in dichloromethane to afford the title compound (0.1 g, 16% yield).

[0750] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.67 (s, 1H), 10.72 (s, 1H), 6.56 (s, 1H), 3.802-3.84 (q, 2H), 3.22-3.34 (q, 2H), 1.57-1.60 (d, 2H), 1.43-1.52 (m, 4H) and 1.19-1.24 (m, 3H).

[0751] LC-MS ES.sup.+: 225.

Example 52: 6-{[(4-Fluorophenyl)methyl](methyl)amino}-4-hydroxy-pyridazin-3(2H)-one

[0752] ##STR00174##

[0753] Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 5,6-bis(benzyloxy)-N-[(4-fluorophenyl)methyl]-N-methylpyridazin-3-amine (Intermediate 61) except that the solvent used for the hydrogenation was methanol and the product was purified by triturating in n-pentane (0.15 g, 52% yield)

[0754] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.07 (s, 1H), 10.6 (s, 1H), 7.2-7.34 (m, 2H), 7.12-7.18 (m, 2H), 4.49 (s, 2H) and 2.84 (s, 3H).

[0755] LC-MS ES.sup.+: 250.

Example 53: 6-[2-(2,6-Difluorophenyl)ethyl]-4-hydroxy-pyridazin-3(2H)one

[0756] ##STR00175##

[0757] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(2,6-difluorophenyl)ethynyl]pyridazine (Intermediate 33) except that the solvent mixture used for the hydrogenation was methanol and the final material was purified by preparative HPLC (0.035 g, 24.8% yield).

[0758] .sup.1H NMR (400 MHz, DMSO-d) 12.68 (s, 1H), 10.78 (s, 1H), 7.27-7.35 (m, 1H), 7.03-7.07 (m, 2H), 6.55 (s, 1H), 2.90-2.94 (t, 2H) and 2.69-2.73 (t, 2H).

[0759] LC-MS ES.sup.+: 253.

Example 54: 6-[2-(2-Chloro-6-fluorophenyl)ethyl]-4-hydroxy-pyridazin-3(2H)-one

[0760] ##STR00176##

[0761] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(2-chloro-6-fluorophenyl)ethynyl]pyridazine (Intermediate 32) except that the catalyst used for the hydrogenation was platinum oxide and the solvent was methanol and the final material was purified by preparative HPLC (0.035 g, 24.8% yield).

[0762] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.68 (s, 1H), 10.78 (s, 1H), 7.27-7.35 (m, 1H), 7.03-7.07 (m, 2H), 6.55 (s, 1H), 2.90-2.94 (t, 2H) and 2.69-2.73 (t, 2H).

[0763] LC-MS ES.sup.+: 253.

Example 55: 6-{[3,5-bis(Trifluoromethyl)phenyl]methyl}-4-hydroxypyridazin-3(2H)-one

[0764] ##STR00177##

[0765] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{[3,5-bis(trifluoromethyl)phenyl]-methyl}pyridazine (Intermediate 58a) except that the solvent used for the hydrogenation was tetrahydrofuran and the final compound was recrystallised from a mixture of ethyl acetate and heptanes (27% yield).

[0766] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.80 (br s, 1H), 10.95 (br s, 1H), 7.93-8.02 (m, 3H), 6.60 (s, 1H) and 4.05 (s, 2H).

[0767] MS ES.sup.+: 339.

Example 56: 6-(1-Phenylethyl)-4-hydroxypyridazin-3(2H)-one

[0768] ##STR00178##

[0769] Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25) except that upon completion of the reaction the resulting mixture was filtered through Celite washing with ethanol and then concentrated in vacuo to afford an orange solid. This was purified initially by eluting on a reverse phase C18 chromatography column (0-60% methanol in water with an acidic modifier) and upon combining and concentrating the appropriate fractions the crude product was recrystallised from a mixture of ethyl acetate and heptanes to afford a white solid and the final compound was recrystallised from a mixture of ethyl acetate and heptanes (32% yield).

[0770] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.90 (br s, 1H), 10.80 (br s, 1H), 7.13-7.35 (m, 6H), 3.99 (q, 1H) and 1.47 (d, 3H).

[0771] MS ES.sup.+: 217.

Example 57: 6-(Cyclopropylmethyl)-4-hydroxy-2,3-dihydropyridazin-3-one

[0772] ##STR00179##

[0773] Prepared in the same manner as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclopropylidenemethyl)pyridazine (Intermediate 65) except that methanol was used as the reaction solvent. The crude compound was purified by preparative HPLC to yield 6-(cyclopropylmethyl)-4-hydroxypyridazin-3(2H)-one (46% yield)

[0774] .sup.1H NMR (DMSO-d.sub.6): 12.69 (s, 1H), 10.75 (s, 1H), 6.63 (s, 1H), 2.09-2.34 (d, 2H), 0.89-0.99 (m, 1H), 0.43-0.49 (m, 2H) and 0.16-0.17 (m, 2H).

[0775] LC-MS ES.sup.+: 167.

Example 58: 4-Hydroxy-6-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-2,3-dihydropyridazin-3-one

[0776] ##STR00180##

[0777] Prepared in the same manner as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{1-[4-(trifluoromethyl)phenyl]-cyclopropyl}-pyridazine (Intermediate 68) in 20% yield.

[0778] .sup.1H NMR (DMSO-d.sub.6) 12.76 (s, 1H), 10.87 (br. s., 1H) 7.67 (m, 2H), 7.47 (m, 2H), 6.37 (s, 1H), 1.38-1.42 (m, 2H) and 1.23-1.28 (m, 2H).

[0779] MS: ES.sup.+: 297.

Example 59: 6-{2-[2-Chloro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one

[0780] ##STR00181##

[0781] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[2-chloro-4-(trifluoromethyl)phenyl]-ethynyl}pyridazine (Intermediate 69) in 11% yield.

[0782] .sup.1H NMR (DMSO-d.sub.6) 12.68 (s, 1H), 10.78 (br. s., 1H), 7.83 (s, 1H), 7.64-7.68 (m, 1H), 7.55-7.59 (m, 1H), 6.61 (s, 1H), 3.05-3.11 (m, 2H) and 2.80 (m, 2H).

[0783] MS: ES.sup.+: 319.

Example 60: 6-(2-(2-Fluoro-4-(trifluoromethyl)phenylethyl)-4-hydroxy-2,3-dihydropyridazin-3-one

[0784] ##STR00182##

[0785] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-ethynyl}pyridazine (Intermediate 70) except that THF was used as the solvent. The reaction was filtered through diatomaceous earth flushing with further tetrahydrofuran and concentrated in vacuo. The residue was purified by column chromatography (silica C18 cartridge; eluting with 0-65% acetonitrile in water with acid modifier). The appropriate fractions were combined and concentrated in vacuo to remove the acetonitrile before the aqueous portion was extracted with ethyl acetate (2), dried (MgSO.sub.4) and concentrated in vacuo. The resulting solid was recrystallised from a mixture of methyl tert-butyl ether and heptane to afford 6-{2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one as a cream solid (29% yield).

[0786] .sup.1H NMR (DMSO-d.sub.6) 12.67 (s, 1H), 10.76 (br. s., 1H), 7.60 (m, 1H), 7.48-7.57 (m, 2H), 6.61 (s, 1H), 2.95-3.04 (m, 2H) and 2.75-2.83 (m, 2H)

[0787] MS: ES.sup.+: 303.

Example 61: 6-{2-[3,5-bis(Trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one

[0788] ##STR00183##

[0789] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[3,5-bis(trifluoromethyl)phenyl]-ethenyl]pyridazine (Intermediate 71) in 49% yield.

[0790] .sup.1H NMR (DMSO-d.sub.6) 12.69 (s, 1H), 10.75 (br. s., 1H), 7.96 (s, 2H), 7.91 (s, 1H), 6.64 (s, 1H), 3.06-3.14 (m, 2H) and 2.84 (m, 2H)

[0791] MS: ES.sup.+: 353.

Example 62: 6-{2-[2,4-bis(Trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydro-pyridazin-3-one

[0792] ##STR00184##

[0793] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[2,4-bis(trifluoromethyl)phenyl]-ethenyl]pyridazine (Intermediate 72) in 31% yield.

[0794] .sup.1H NMR (DMSO-d.sub.6) 12.71 (s, 1H), 10.80 (br. s., 1H), 8.03 (m, 1H), 7.97 (s, 1H), 7.79 (m, 1H), 6.62 (s, 1H), 3.14 (m, 2H), 2.77-2.86 (m, 2H)

[0795] MS: ES.sup.+: 353.

Example 63: 6-{2-[3,4-bis(Trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one

[0796] ##STR00185##

[0797] To a solution of 3,4-bis(benzyloxy)-6-[(E)-2-[3,4-bis(trifluoromethyl)phenyl]-ethenyl]pyridazine (Intermediate 73, 227 mg, 0.428 mmol) in THF (4279 l) was added palladium on carbon (45.5 mg, 0.043 mmol) and the reaction vessel evacuated and purged with nitrogen (3). The reaction was stirred under a hydrogen atmosphere for 4 hours and the resulting mixture was filtered through a short pad of diatomaceous earth and concentrated in vacuo. The residue was purified by chromatography (C18 silica cartridge eluting with 0-50% acetonitrile in water with basic modifier). The appropriate fractions were combined and concentrated to remove the organics and the aqueous fractions were acidified with hydrochloric acid (2 N) and extracted with ethyl acetate (2), dried (MgSO.sub.4) and concentrated in vacuo to yield 6-{2-[3,4-bis(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one as a cream solid (39 mg, 26%)

[0798] .sup.1H NMR (DMSO-d.sub.6) 12.69 (s, 1H), 10.76 (br. s., 1H), 7.95 (m, 1H), 7.88-7.93 (m, 1H), 7.76 (m, 1H), 6.65 (s, 1H), 3.04-3.12 (m, 2H) and 2.83 (m, 2H).

[0799] MS: ES.sup.+: 353

Example 64:4-Hydroxy-6-(3-methyl-4-(trifluoromethyl)phenethyl)pyridazin-3(2H)-one

[0800] ##STR00186##

[0801] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)phenyl)-ethynyl)pyridazine (Intermediate 74) except THF was used as the solvent. The reaction mixture was filtered through a diatomaceous earth cartridge, eluting with further THF and methanol. The filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography (eluting with 5-100% aqueous acetonitrile with acid modifier). The desired fractions were combined and freeze dried to give a pale yellow solid, which was recrystallised from methyl tert-butyl ether to give a white solid. The filtrate was concentrated under reduced pressure, and the filtrate and crystals purified separately by preparative HPLC. The two batches were combined and recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 4-hydroxy-6-(3-methyl-4-(trifluoromethyl)-phenethyl)pyridazin-3(2H)-one as a white solid (31 mg, 4%).

[0802] .sup.1H NMR (CD.sub.3OD) 7.51 (d, 1H), 7.22 (s, 1H), 7.16 (d, 1H), 6.57 (s, 1H), 2.94-3.02 (m, 2H), 2.81-2.90 (m, 2H) and 2.44 (s, 3H).

[0803] MS ES.sup.+: 299

[0804] M. p.=174-175 C.

Example 65: 3,4-bis(Benzyloxy)-6-((3-chloro-4-(trifluoromethyl)phenyl)ethyl)-pyridazine

[0805] ##STR00187##

[0806] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[3-chloro-4-(trifluoromethyl)phenyl]-ethynyl}pyridazine (Intermediate 75) except that THF was used as the solvent. The crude product was purified by reverse phase chromatography (eluting with 5-100% acetonitrile in water with acid modifier) to give a pale yellow solid. The solid was recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 3,4-bis(benzyloxy)-6-((3-chloro-4-(trifluoromethyl)phenyl)ethyl)-pyridazine as a white solid (0.182 g, 17%).

[0807] .sup.1H NMR (CD.sub.3OD) 7.67 (d, 1H), 7.50 (s, 1H), 7.33 (d, 1H), 6.63 (s, 1H), 3.00-3.09 (m, 2H) and 2.85-2.93 (m, 2H).

[0808] MS ES.sup.+: 319.

[0809] M. p.=169-170 C.

Example 66: 4-Hydroxy-6-{2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl}-2,3-dihydropyridazin-3-one

[0810] ##STR00188##

[0811] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[2-methyl-4-(trifluoromethyl)phenyl]-ethenyl]pyridazine (Intermediate 76) except that THF was used as the solvent. The crude product was purified by reverse phase chromatography, eluting with 5-100% acetonitrile with acid modifier) and then recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 4-hydroxy-6-{2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl}-2,3-dihydropyridazin-3-one as a white powder (0.23 g, 36%).

[0812] .sup.1H NMR (CD.sub.2Cl.sub.2) , 7.42 (s, 1H), 7.39 (d, 1H), 7.25 (d, 1H), 6.60 (s, 1H), 2.96-3.08 (m, 2H), 2.77-2.90 (m, 2H), and 2.38 (s, 3H).

[0813] MS ES.sup.+: 299.

[0814] M. p.=170-172 C.

Example 67: 6-{2-[3,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one

[0815] ##STR00189##

[0816] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethenyl]-pyridazine (Intermediate 77) except that THF was used as the solvent. The crude product was purified by reverse phase chromatography (silica, eluting with 5-100% acetonitrile in water with acid modifier) to afford a white solid, which was recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 6-{2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one as a white solid (0.079 g, 10%).

[0817] .sup.1H NMR (CD.sub.3OD) 7.09 (d, 2H), 6.64 (s, 1H), 3.00-3.10 (m, 2H) and 2.82-2.96 (m, 2H).

[0818] MS ES.sup.+: 321.

[0819] M.p.=211-212 C.

Example 68: 6-{2-[3-Fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one

[0820] ##STR00190##

[0821] Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]pyridazine (Intermediate 79) in 60% yield. The solid was purified by reverse phase chromatography, eluting with 5-100% acetonitrile in water with acid modifier to yield 6-{2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one in 60% yield.

[0822] .sup.1H NMR (DMSO-d.sub.6) 12.68 (s, 1H), 10.76 (br. s., 1H), 7.68 (m, 1H), 7.42 (m, 1H), 7.27 (in, 1H), 6.61 (s, 1H), 2.93-3.04 (m, 2H) and 2.73-2.87 (m, 2H).

[0823] MS ES.sup.+: 303.

3. BIOLOGICAL EFFICACY OF COMPOUNDS OF THE INVENTION

In Vitro DAAO Enzyme Assay

[0824] The functional activity of compounds inhibiting the DAAO enzyme was determined by utilizing the co-product of the catalysis of D-Serine, H.sub.2O.sub.2 which can be quantitatively measured using the Amplex (trade mark) Red (Invitrogen) detection. Amplex Red reagent is a colorless substrate that reacts with hydrogen peroxide (H.sub.2O.sub.2) with a 1:1 stoichiometry in the presence of hydrogen peroxide to produce highly fluorescent resorufin (excitation/emission maxima=570/585 nm). The changes in fluorescence were monitored by a fluorescence plate reader, Envision (Perkin Elmer) and increases in DAAO activity were readily detected upon addition of D-Serine and suppression of this response observed with the application of test compounds.

[0825] Human DAAO enzyme was supplied by the Takeda Pharmaceutical Company (Osaka) and each batch was tested and used at concentrations giving comparable levels of activity. The K.sub.m of D-Serine was measured for each enzyme batch to maintain consistency; this K.sub.m was used in subsequent assays.

[0826] On the day of the assay compounds were serially diluted in DMSO before being diluted 1:20 with assay buffer (20 mM Tris ph 7.4). A 5 l portion of assay buffer was added to the wells of a 384 clear base black-walled plate (Corning), 5 l of diluted compound was then added via automated plate to plate transfer using the Bravo liquid handler (Agilent technologies) followed by 5 l of human DAAO enzyme and then 5 l D-Serine 50 mM was added to all but the negative control wells (final concentration of 10 mM). Finally 5 l Amplex red reagent (Invitrogen) was added to all wells as per manufacturer's protocol. The plate was incubated for 60 minutes in the dark at 25 C. and the fluorescence in each well was measured in the Envision plate reader.

[0827] The IC.sub.50 values for compounds were determined from ten point half log scale dose-response studies and represent the concentration of compound required to prevent 50% inhibition of DAAO activity in the presence of 10 mM D-Serine. Concentration response curves were generated using the average of duplicate wells for each data point and analyzed using non-linear regression and four parameter curve fit.

Results

[0828]

TABLE-US-00003 Example No. Mean IC.sub.50 (nM) Example No. Mean IC.sub.50 (nM) 1 10 2 10 3 21 4 3.7 5 30 6 9.7 7 13 8 11 9 10 10 22 11 16 12 23 13 31 14 41 15 16 16 52 17 13 18 14 19 12 20 8.4 21 21 22 13 23 14 24 6 25 45 26 22 27 13 28 20 29 45 30 18 31 20 32 16 33 23 34 26 35 41 36 19 37 220 38 20 39 13 40 12 41 99 42 15 43 26 44 22 45 18 46 15 47 26 48 12 49 23 50 23 51 30 52 130 53 19 54 14 55 760 56 32 57 380 58 61 59 19 60 15 61 57 62 29 63 15 64 13 65 13 66 12 67 10 68 19

[0829] These results indicate that compounds of the invention have potent inhibitory activity against the DAAO enzyme. The compounds tested above exhibit IC.sub.50 values significantly less than 5 M, with the most potent compounds showing activity at the DAAO enzyme with IC.sub.50 values <250 nM. Accordingly, the compounds of the invention are expected to have usefulness in the prevention or treatment of conditions, such as those discussed above, in which DAAO enzyme activity is implicated.

[0830] In addition, the compounds of the present invention possess variously advantageous pharmacological and/or toxicological profiles, when tested in a variety of standard tests for such parameters. For example, the compounds of the invention exhibit one or more potentially useful properties for in vivo use, when characterised by pharmacological and/or toxicological tests including: hERG interaction (which is an indication of potential cardiotoxicity, and measures the effects of the compounds on the human ether-a-go-go-related gene, using for example the PatchXpress 7000A platform); CypP.sub.450 interactions (which may be measured in accordance with the FDA draft guidelines for drug interaction studies (study design, data analysis and implications for dosing and labeling) (September 2006), see www.fda.gov); phototoxicity (for example using a protocol in accordance with assay details outlined in the OECD guidelines for testing of chemicals: 432 In Vitro 3T3 Neutral Red Uptake phototoxicity test, April 2004); determination of pharmacokinetic parameters (for example following in vivo dosing via multiple routes, with plasma concentrations of compounds being determined from venous blood samples using an LC-MS/MS protocol); and in vivo receptor occupancy (determined, for example, using protocols based on Medhurst et al., Journal of Pharmacology and Experimental Therapeutics, 2007, 321, 1032). These standard tests for the characterisation of drug molecules are well known to the skilled person.