WO2003091248A1

WO2003091248A1 - Benzoxazinone derivative

Info

Publication number: WO2003091248A1
Application number: PCT/EP2003/004351
Authority: WO
Inventors: Antonio Vong
Original assignee: Glaxo Group Limited
Priority date: 2002-04-23
Filing date: 2003-04-22
Publication date: 2003-11-06
Also published as: GB0209244D0; AU2003224130A1

Abstract

The compound 6-(4-(1-(2-(5-(7-Fluoro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one and pharmaceutically acceptable salts thereof are disclosed. Methods of preparation and use in therapy, particularly for a CNS disorder such as depression and anxiety, are also disclosed.

Description

Benzoxazinone derivative

The present invention relates to a novel compound, processes for its preparation, pharmaceutical compositions containing the same and their use as medicaments. More particularly this invention relates to a novel benzoxazinone derivative and its use in the treatment of CNS and other disorders.

WO 97/45419 discloses a series of benzoxazinone compounds as dopamine D4 receptor antagonists which are claimed to be useful in the treatment of psychosis and schizophrenia. EP 0900 792 A1 discloses a series of piperazine and piperidine derivatives as 5-HT-j receptor agonists which are claimed to be useful for treating CNS disorders.

Artigas (Trends in Pharmacological Sciences, Vol. 14, 262, 1993) suggests that the co- administration of a 5-HT-iA receptor antagonist and a selective serotonin reuptake inhibitor (SSRI) may give rise to an improvement in anti-depressant efficacy.

Patent applications WO 00/40580 and WO 00/40581 both disclose a series of benzoxazine derivatives that are claimed to possess such a combined activity profile. WO02/34754 discloses a series of benzoxazinone compounds as being useful for treating certain CNS disorders such as depression. A novel compound has now been discovered which fall within the generic scope of WO02/34754, but is not specifically disclosed therein, and has been found to exhibit a surprisingly high affinity for 5-HT<|A receptors combined with >100-fold selectivity over 5-HT-| B and 5-HT-| D receptors. In addition this compound has a surprisingly good pharmacokinetic profile in preclinical species.

Thus the present invention therefore provides, in a first aspect, the following compound:

or a pharmaceutically acceptable salt thereof.

The compound may be described as 6-(4-(1-(2-(5-(7-Fluoro-2- methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one.

The compound of the present invention can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compound of the present invention should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. The compound of the present invention may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

The compound of the present invention may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.

The compound of the present invention may be prepared according to the processes disclosed in WO02/34754 or the process described herein. Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

The affinities of the compound of this invention for 5-HT-|A. 5-HT-|β and 5-HT-J D receptors can be determined by the radioligand binding assay as described in WO 99/07700. The intrinsic activity of the compounds of this invention can be determined according to the [35s]GTPγS functional assay which is also described in WO 99/07700. Using these assays, the compound of the present invention has been found to have antagonist affinity for the human recombinant 5-HT-| A receptor, displaying a pKi of 9.5

The efficacy of the compounds of this invention to inhibit the re-uptake of serotonin can be measured in [3HJ-5-HT uptake assays in LLCPK cells expressing human serotonin transporters. In brief, cells are harvested and plated onto 96-well plates (10,000 cells per well). 24hr later cells are washed 2x with HBSSH (Hanks'balanced salt solution + 20mM HEPES). 50ul of test compound or vehicle is added to each well and incubated for 10min. Subsequently, [3H]5-HT (final concentration 25nM) is added and the test mixture is incubated for a further 7min. The reaction is terminated by aspiration of test mixture and the cells are washed 6x with HBSSH. 50ul of scintillation cocktail (Microscint-20, Packard) is added onto the cells and the top and bottom of the plate is sealed. Plates are read, 30min later, in a Packard TopCount. A [3H]5-HT uptake assay using rat cortical synaptosomes may also be used as described in Thomas, D.R.; Nelson, D.R.; and Johnson, A.M. Psychopharmacology 93:193-200 (1987). The compound of the present invention has been found to have potency at the 5-HT uptake site with a plC50 of greater than or equal to 7.4 (PIC50 of 7.4 against the human 5-HT transporter and 8.1 against the rat native 5-HT transporter). The compound of the present invention and its pharmaceutically acceptable salts are of use in the treatment of certain CNS disorders such as depression, which term is used herein to include bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia for example of the Alzheimer's type, vascular dementia with depressed mood, schizoaffective disorder or the depressed type, and depressive disorders resulting from general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc. Other CNS disorders which may be treated or prevented include anxiety disorders, including generalised anxiety disorder and social anxiety disorder, schizophrenia, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, pain (particularly neuropathic pain), memory disorders, including dementia, amnesic disorders and age-associated memory impairment, disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine (phencyclidine-like compounds), opiates (e.g. cannabis, heroin, morphine), sedative ipnotic, amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) or a combination thereof, motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.

The compound of the present invention may also have utility in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome, Crohn's disease, ulcerative colitis, non-steroidal anti-inflammatory drug induced damage.

Thus the invention also provides a compound:

or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment of the above disorders. In particular the invention provides a compound as defined above or a pharmaceutically acceptable salt thereof for use as a therapeutic substance in the treatment of depression. It is to be understood that the term "treatment" as used herein includes amelioration of established symptoms as well as prophylaxis.

The compound of the present invention may be administered in combination with other active substances such as 5HT3 antagonists, NK-1 antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.

Suitable 5HT3 antagonists which may be used in combination of the compound of the inventions include for example ondansetron, granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with the compound of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.

Suitable SSRIs which may be used in combination with the compound of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compound of the invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.

The invention further provides a method of treatment of the above disorders, particularly a CNS disorder, particularly depression or anxiety, in mammals including humans, which comprises administering to the sufferer a therapeutically safe and effective amount of:

or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides for the use of a compound of as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders, particularly a CNS disorder, particularly depression or anxiety.

In order to use the compound of the present invention in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound of the first aspect and a pharmaceutically acceptable carrier or excipient.

In a further aspect, the present invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of the first aspect and a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);, fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate);, tabletting lubricants lubricants (e.g. magnesium stearate, talc or silica);, disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p- hydroxybenzoates or sorbic acid), and, if desired, conventional flavourings or colorants, buffer salts and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non- aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.

The compound of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

The compound of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For intranasal administration, the compound of the invention may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.

Thus compound of the present invention may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).

The compound of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

The following Descriptions and Examples illustrate the preparation of the compound of the invention.

7-Fluoro-5-hydroxy-2-methylquinoline hydrobromide (D1)

Crotonaldehyde (28 mL, 0.33 mol) was added dropwise to a refluxing solution of 3,5- difluoroaniline (10.8 g) in 5 N hydrochloric acid (450 mL) and reflux was continued for a further 0.5 h. Reaction mixture was cooled, diluted with water (200 mL) and washed with ether (200 mL). The aqueous layer was basified (pH 14) with 50% NaOH (aq) and extracted into MDC (3 x 200 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a dark oil which was purified by chromatography on silica gel (-100 g) with 50 - 100% ethyl acetate in hexane gradient elution to give 5,7-difluoro-2- methylquinoline as a brown solid (6.57 g, 44%). A mixture of 5,7-difluoro-2- methylquinoline (1.0 g, 5.6 mmol) and sodium methoxide (1.6 g, 30 mmol) in methanol (50 mL), was stirred at reflux for 18 h, cooled, and most of the methanol removed in vacuo. The residue was partitioned between ethyl acetate (100 mL), and water (100 mL). The organic phase was dried (Na2SO4) and evaporated in vacuo to give a brown oil which was purified by chromatography on silica gel (-60 g) with 20 - 30% ethyl acetate hexane gradient elution to give a yellow solid (0.57 g) which was suspended in 48% HBr (aq) (5 mL) and heated at reflux for 18 h. Reaction mixture was cooled and evaporated in vacuo to give the title compound as a brown solid (0.7g, 46%). Mass spectrum (API⁺): Found 178 (MH⁺). C-_joH_βFNO requires 177.

Description 2 2-(5-(7-Fluoro-2-methyl)quinolinyl)oxyethyl bromide (D2)

A mixture of 7-fluoro-5-hydroxy-2-methylquinoline (2.9g), 1 ,2-dibromoethane (31 g) and potassium carbonate (11.5g) in methyl ethyl ketone (70 mL) was allowed to stir at reflux for 18 h. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the title compound (3.8 g).

¹H NMR (CDCI₃) δ: 2.72 (3H, s), 3.78 (2H, t, J = 6 Hz), 4.45 (2H, t, J = 6 Hz), 6.58 (1H, m), 7.20-7.35 (2H, m), 8.44 (1 H, d, J = 9 Hz).

Description 3 2-Fluoro-4-methoxy-5-nitro-benzaldehyde (D3)

2-Fluoro-4-methoxy-benzaldehyde (25g) was dissolved in concentrated sulfuric acid (150mL) and cooled to -15°C. Concentrated nitric acid (10.3mL) in concentrated sulfuric acid (20mL) was added dropwise over 55mins. After an additional hour of stirring at below -10°C, the mixture was poured into crushed ice. the precipitate was collected by filtration and partitioned between dichloromethane (200mL) and saturated sodium hydrogen carbonate (150mL). The organic layer was dried (MgSO4) and evaporated in vacuo to give the title compound (29g) as a cream solid. ¹H NMR (CDCI3) δ: 4.06 (3H, s), 6.87 (1H, d, J = 12 Hz), 8.46 (1 H, d, J = 8 Hz), 10.20 (1H, s).

Description 4 (2-Fluoro-4-methoxy-5-nitro-phenyl)-methanol (D4)

Sodium borohydride (10.9g) was added portionwise to a stirring solution of 2-fluoro-4- methoxy-5-nitro-benzaldehyde (28.7g) in methanol (500mL) at 5°C. After 2 hours, the methanol was removed in vacuo. The residue was treated with cold water and extracted with dichloromethane. The combined organic layer was washed with brine, dried (MgSO4) and then evaporated in vacuo to give the title compound as a crude solid (30.7g). ¹H NMR (CDCI3) δ: 1.85 (1H, t, J = 2 Hz), 3.96 (3H, s), 4.74 (2H, d, J = 6 Hz), 6.80 (1 H, d, J = 12Hz), 8.09 (1H, d, J = 8Hz).

Description 5 1-Bromomethyl-2-fluoro-4-methoxy-5-nitro-benzene (D5)

Carbon tetrabromide (55.8g) in anhydrous diethyl ether (100mL) was added dropwise to a stirred solution of (2-fluoro-4-methoxy-5-nitro-phenyl)-methanol (30.7g) and triphenyl phosphine (44.1g) in anhydrous diethyl ether (900mL). The mixture was left to stir overnight before it was concentrated down to a sticky oil. Silica gel chromatography eluting with ethyl acetate in hexane (0-10%) gave the title compound as pale yellow solid (17.5g).

¹H NMR (CDCI3) δ: 3.98 (3H. s), 4.46 (2H, s), 6.82 (1 H, d, J = 12 Hz), 8.04 (1 H, d, J = 8 Hz).

Description 6 (2-Fluoro-4-methoxy-5-nitro-benzyl)-phosphonic acid diethyl ester (D6)

A mixture of 1-bromomethyl-2-fluoro-4-methoxy-5-nitro-benzene (9.8g) and triethyl phosphite (7.4g) was heated to 160°C for 2 hours followed by drying in vacuo to give the title compound as an amber solid (12.8g). ¹H NMR (CDCI₃) δ: 1.25-1.40 (6H, m), 3.14 (2H, d, J = 21 Hz), 3.95 (3H, s), 4.05-4.16 (4H, m), 6.81 (1 H, d, J = 12 Hz), 7.99 (1H, dd, J = 7, 3 Hz).

Description 7

4-(2-Fluoro-4-methoxy-5-nitro-benzylidene)-piperidine-1 -carboxylic acid ferf-butyl ester (D7)

Sodium hydride (60% oil suspension) (1.64g) was added to a stirred solution of (2-fluoro- 4-methoxy-5-nitro-benzyl)-phosphonic acid diethyl ester (11.95g) in anhydrous THF (80mL) at 0°C. The mixture was left to stir for 40min at room temperature. 4-Oxo- piperidine-1 -carboxylic acid terf-butyl ester (7.4g) in anhydrous THF (30mL) was added to the mixture at 0°C. Stirring was continued overnight at room temperature. Dimethylformamide (17mL) was then added. The mixture was allowed to stir until all the starting material is consumed and then concentrated down in vacuo. It was treated with saturated ammonium chloride and extracted with ether. The combined organic layer was washed with brine, dried (MgSO4) and then evaporated in vacuo to give the title compound as a solid (13.6g).

¹H NMR (CDCI3) δ: 1.48 (9H, s), 2.36 (4H, m), 3.43 (2H, m), 3.52 (2H, m), 3.96 (3H, s), 6.14 (1H, s), 6.79 (1H, d, J = 11 Hz), 7.81 (1 H, d, J = 7 Hz).

Description 8

4-(2-Fluoro-4-hydroxy-5-nitro-benzylidene)-piperidine-1 -carboxylic acid tert-butyl ester (D8)

A mixture of 4-(2-fluoro-4-methoxy-5-nitro-benzylidene)-piperidine-1 -carboxylic acid tert- butyl ester (13.6g) and lithium chloride (7.9g) in DMF (100mL) was stirred at 120°C for 12 hours. It was allowed to cool to room temperature and evaporated in vacuo. The residue was treated with saturated hydrogen carbonate and extracted with ethyl acetate. The combined organic layers was dried (MgSO4) and evaporated in vacuo to give crude oil. Silica gel chromatography eluting with ethyl acetate in petroleum ether (0-40%) gave the title compound as a yellow solid (8.1g).

¹ H NMR (CDCI3) δ: 1.48 (9H, s), 2.20-2.40 (4H, m), 3.42 (2H, m), 3.52 (2H, m), 6.14 (1 H, s), 6.85 (1 H, d, J = 12 Hz), 7.97 (1 H, d, J = 7 Hz), 10.70 (1 H, s).

Description 9

4-(5-Amino-2-fluoro-4-hydroxy-benzyl)-piperidine-1 -carboxylic acid terf-butyl ester

A solution of 4-(2-fluoro-4-hydroxy-5-nitro-benzylidene)-pipehdine-1-carboxylic acid tert-butyl ester (8.1) in ethanol (180mL) was stirred under atmospheric hydrogen in the presence of 10% palladium on charcoal for 18 hours. The catalyst was removed and the filtrate was evaporated in vacuo to give the title compound (7.5g). Mass spectrum (API^*): Found 323 ([M-H]^"). C-17H25FN2O3 requires 324.

Description 10 6-(4-(W-(ϊ-Butyloxycarbonyl)piperidinyl)methyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (D10)

Chloroacetyl chloride (3.1g) was added dropwise to a stirring mixture of 4-(5-amino-2- fluoro-4-hydroxy-benzyl)-piperidine-1 -carboxylic acid tert-butyl ester (7.5g) in 2-butanone (30mL) and sodium hydrogen carbonate (4.8g) in water (30mL) at 0°C. The mixture was stirred at room temperature for 2 hours and then at 80°C for 8 hours. It was partitioned between water and ethyl acetate. The organic layer was evaporated in vacuo. Silica gel chromatography of the resulting residue eluting with ethyl acetate in hexane (0-30%) gave the title compound as a solid (5.8g)

¹H NMR (CDCI3) δ: 1.10-1.20 (2H, m), 1.45 (9H, s), 1.50-1.75 (3H, m), 2.49 (2H, d, J = 7 Hz), 2.60-2.70 (2H, m), 4.00-4.12 (2H, m), 4.60 (2H, s), 6.52 (1 H, d, J = 8 Hz), 6.70 (1 H, d, J = 10, 2 Hz), 7.87 (1H, s).

Description 11

7-Fluoro-6-(4-(piperidinylmethyl)-4W-benzo[1 ,4]oxazin-3-one hydrochloride (D11 )

6-(4-(Λ/-(^-Butyloxycarbonyl)piperidinyl)methyl)-7-fluoro-4H-benzo[1 ,4]oxazin-3-one (0.6g), 1M hydrogen chloride in ether (18mL) and ethanol (10mL) was stirred at 45°C for 2.5hours. The mixture was evaporated in vacuo to gave the title compound as a solid (0.5g). Mass spectrum (API⁺): Found 265 (MH⁺). C-14H17FN2O2 requires 264

Preparation of

6-(4-(1-(2-(5-(7-Fluoro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-7-fluoro-4 y- benzo[1 ,4]oxazin-3-one

D11 (7-Fluoro-6-(4-(piperidinylmethyl)-4H-benzo[1 ,4]oxazin-3-one hydrochloride, 0.200g, 0.67mmol), 2-(5-(7-fluoro-2-methyl)quinolinyl)oxyethyl bromide (0.188 g, 0.67mmol), sodium iodide (0.099 g, 0.67mmol) and N,N diisopropylethylamine (0.81 mL, 4.7 mmol) in IPA (10mL) were heated at 80°C for 18 hours under a blanket of argon. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, washed with brine, dried (MgSO ) and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel eluting with dichloromethane to 5% methanol/dichloromethane to give the title compound as an oil (0.198 g, 64%).

¹H NMR (CDCI₃) δ: 1.32-1.39 (2H, m), 1.51-1.64 (3H,m), 2.12-2.17 (2H, m), 2.49 (2H, d, J = 6 Hz), 2.70 (3H, s), 2.93 (2H, t, J = 6 Hz), 3.01 (2H, d, J = 12 Hz), 4.24 (2H, t, J = 6 Hz), 4.58 (2H, s), 6.52 (1H, d, J = 7 Hz), 6.60 (1 H, dd, J = 11 Hz, 2 Hz), 6.68 (1 H, d, J = 10 Hz), 7.18 (1H, d, J = 9 Hz), 7.20-7.23 (1H, m), 8.28 (1 H,bs), 8.34 (1 H, d, 8 Hz). Mass spectrum (AP⁺): Found 468 (MH⁺). C₂₆H₂₇N₃O₃F₂ requires 467.

Claims

1. The compound:

or a pharmaceutically acceptable salt thereof.

2. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance.

3. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier or excipient.

4. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of a CNS disorder such as depression or anxiety.

5. A method of treatment of a CNS disorder, particularly depression or anxiety, in mammals including humans, which comprises administering to the sufferer a therapeutically safe and effective amount of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof.

6. Use of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a CNS disorder, particularly depression or anxiety.