WO2004099198A1 - Benzoxazinone derivatives having affinity for 5- ht receptors, their preparation and use - Google Patents

Abstract

Benzoxazinone derivatives, their preparation and use Compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed: (I) wherein R1 is hydrogen or C1-6alkyl; R2 is fluoro or chloro; R3 is hydrogen, fluoro or chloro; and X is nitrogen or CH. Methods of preparation and uses thereof in treatment of CNS disorders, such as depression or anxiety, are also disclosed.

Description

BENZOXAZINONE DERIVATIVES HAVING AFFINITY FOR 5-HT RECEPTORS , THEIR PREPARATION A ND USE

The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing the same and their use as medicaments. More 5 particularly this invention relates to novel benzoxazinone derivatives and their utility in the treatment and/ of CNS and other disorders.

Artigas (Trends in Pharmacological Sciences, Vol. 14, 262, 1993) suggests that the co- administration of a 5-HT-jA receptor antagonist and a selective serotonin reuptake 0 inhibitor (SSRI) may give rise to an improvement in anti-depressant efficacy. WO02/34754 discloses a series of benzoxazinone compounds as being useful for treating certain CNS disorders such as depression.

A novel class of compounds has now been discovered which fall within the generic scope 5 of WO02/34754, but are not specifically disclosed therein, and have been found to exhibit surprisingly enhanced SSRI activity and excellent pharmacokinetics.

Thus, the present invention provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof: 0

(i) wherein

R1 is hydrogen or C-j.βalkyl; R2 is fluoro or chloro; 5 R3 is hydrogen, fluoro or chloro; and X is nitrogen or CH.

The term "C-i.galkyl", whether alone or part of another group, refers to alkyl groups having from one to six carbon atoms, in all isomeric forms, including methyl, ethyl, propyl, 0 isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.

Preferably R1 is hydrogen, methyl or ethyl.

5 Preferably R2 is fluoro. Preferred compounds of this invention are:

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

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

5-Fluoro-6-{1-[2-(2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1 ,4]oxazin-3-one

6-{1-[2-(7-Chloro- 2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-5-fluoro-4H- benzo[1 ,4]oxazin-3-one 5-Fluoro-6-{1 -[2-(7-fluoro-2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1 ,4]oxazin-3-one

5-Fluoro-6-{1-[2-(2-methyl-quinazolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1 ,4]oxazin-3-one

5-Fluoro-4-methyl-6-{1-[2-(2-methyl-quinazolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4/- - benzo[1 ,4]oxazin-3-one and pharmaceutically acceptable salts thereof.

The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) 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. Certain of the compounds of formula (I) 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 compounds of formula (I) 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 compounds of the present invenion may be prepared in an analogous manner to the processes disclosed in WO02/34754. Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

The affinities of the compounds of this invention for 5-HT-|A, 5-HT-| B ^and 5-HT-| D receptors can be determined by the following assay. CHO cells expressing 5-HT-IA receptors (4 x 10? cells/ml) are homogenised in Tris buffer and stored in 1ml aliquots. CHO cells expressing 5-HT-| β receptors (4 x 10? cells/ml) are homogenised in Tris buffer and stored in 1.5 m! aliquots. CHO cells expressing 5-HT-| Q receptors (1 x l O^/ml) are homogenised in Tris buffer and stored in 1 ml aliquots. 0.4 ml of a cell suspension is incubated with [³H]-5-HT (4nM) for 5-HT_{1 B 1 D} receptors and [³H]WAY100635 (1 nM) for 5-HT-j A receptors in Tris Mg HCI buffer (pH 7.7) and test drug, at 37°C for 45 minutes. Each test drug is tested at 10 concentrations (0.01 mM to 0.3 nM final concentration), with non-specific binding defined using 0.01 mM 5-HT. The total assay volume is 0.5 ml. Incubation is stopped by rapid filtration using a Packard Filtermate and radioactivity measured by Topcount scintillation counting. pKi values are calculated from the IC50 generated by an iterative least squares curve fitting programme.

All the Example compounds shown below were tested according to the radioligand binding assay described above and were found to have pKi values > 7.5 at 5-HT-JA receptors, with many showing a considerably higher affinity (having pKi values in the range 7.5 - 8.8). Certain compounds of this invention also demonstrate comparable affinity for 5-HT-j Q and 5-HT-j rj receptors.

The intrinsic activity of the compounds of this invention can be determined according to the following assay. HEK293 cell membranes stably expressing human 5-HT-_j A receptors and CHO cell membranes stably expressing human 5-HT-j Q receptors are homogenised in HEPES/EDTA buffer and stored in 1 ml aliquots, and [³5s]GTPγS binding studies are carried out essentially as described by Lazareno et al., (Life Sci., 1993, 52, 449) with some minor modifications. Membranes from 10^ cells are pre-incubated at 30°C for 30 minutes in 20 mM HEPES buffer (pH 7.4) in the presence of MgCl2 (3 mM), NaCI (100 mM), GDP (10 μM) and ascorbate (0.2 mM), with or without test compounds. The reaction is started by the addition of 50 μl of [³⁵S]GTPγS (100 pM, assay concentration) followed by a further 30 minutes incubation at 30°C. Non-specific binding is determined using nonradiolabelled GTPγS (20 μM) added prior to the membranes. The reaction is terminated by rapid filtration through Whatman GF/B grade filters followed by 5 x 1 ml washes with ice cold HEPES (20 mM) /MgCl2 (3 mM) buffer. Radioactivity is measured using liquid scintillation spectrometry. This procedure is hereafter referred to as the [³⁵S]GTPγS functional assay.

It has been found, using the [35s]GTPγS functional assay, that certain compounds of formula (I) appear to be antagonists at 5-HT-j type receptors whilst others appear to be partial agonists.

The efficacy of the compounds of this invention to inhibit the re-uptake of serotonin can be measured in a 5-HT uptake assay by measurement of uptake of [³H]-5-HT into LLCPK cells expressing human or rat 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.

Some of the Example compounds tested according to this uptake assay were found to have potency at the uptake site of PIC50 of > 6.0. Some showed a considerably higher potency (PIC50 > 6.5-7.8).

Certain compounds of formula (I) demonstrate both affinity for the 5-HT-_j A receptor (or affinity for 5-HT-_| A. 5-HT-J B and 5-HT-j rj receptors) and potency at the 5-HT uptake site in the higher ranges indicated above.

Compounds of the present invention are of use in the treatment of certain CNS disorders, particularly serotonin-related 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), 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 ***e, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine (phencyclidine-like compounds), opiates (e.g. cannabis, heroin, morphine), 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. Compounds of formula (I) 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 of formula (I) 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 of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a CNS disorder, particularly depression or anxiety.

It is to be understood that the term "treatment" as used herein includes amelioration of established symptoms as well as prophylaxis.

Compounds of the 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 compounds of the inventions include for example ondansetron, granisetron, metoclopramide.

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

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

Suitable SNRIs which may be used in combination with the compounds 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, in particular depression or anxiety, in mammals including humans, which comprises administering to the sufferer a therapeutically safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides for the use of a compound of formula (I) 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, in particular depression or anxiety.

In order to use the compounds of formula (I) in therapy, they 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 formula (I) or a pharmaceutically acceptable salt thereof, 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 formula (I) or a pharmaceutically acceptable salt thereof 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 compounds 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 compounds 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 compounds 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 compounds 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 compounds of formula (I) 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 compounds 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 compounds of the invention.

Description 1

5-Chloro-2-f luoro-4-methoxy-benzaldehyde (D1 )

Sulfuryl chloride (16 mL) was added dropwise to a stirring solution of 2-fluoro-4-methoxy- benzaldehyde (25g, 0.16 mol) and pyridine (0.37 mL) in dichloromethane (20 mL) at ambient temperature. This was allowed to stir for 16 hours and then partitioned between saturated sodium hydrogen carbonate (150 mL) and dichloromethane (250 mL). The organic layer was washed with 10% w/v sodium sulfite solution, dried (Na₂SO ) and evaporated in vacuo to give a crude solid. Recrystallisation from ethyl acetate gave the title compound (14g, 74%) as a cream solid.

¹ H NMR (CDCI3) δ: 3.98 (3H, s), 6.72 (1H, d, J = 12 Hz), 7.89 (1 H, d, J = 7 Hz), 10.20

(1 H, s).

Description 2 5-Chloro-2-fluoro-4-methoxy-3-nitro-benzaldehyde (D2)

5-Chloro-2-fluoro-4-methoxy-benzaldehyde (7.8g, 41mmol) was added to stirred concentrated sulfuric acid (60mL) at -15°C. Nitric acid (70% w/w) (4g) was added dropwise. After 40 mins. of stirring, the mixture was poured into ice cold sodium hydrogen carbonate solution. Extraction with dichloromethane (2x150mL) and evaporation of the combined organic layer in vacuo gave the title compound as a crude oil (8.8g). ¹ H NMR (CDCI3) δ: 4.12 (3H, s), 8.05 (1H, d, J = 7 Hz), 10.23 (1H, s).

Description 3 (5-Chloro-2-fluoro-4-methoxy-3-nitro-phenyl)-methanol (D3)

Sodium borohydride (3.8g) was added to a stirring solution of crude 5-chloro-2-fluoro-4- methoxy-3-nitro-benzaldehyde (8.8g) in methanol (200mL) at 5°C. After 2 hours, the methanol was removed in vacuo. The residue was treated with cold water (150mL) and extracted with dichloromethane (2x150mL). The combined organic layer was evaporated in vacuo to give a crude oil. Silica gel chromatography eluting with ethyl acetate in petroleum ether (10-20%) gave the title compound as an oil (4.6g, 49%). H NMR (CDCI3) δ: 1.90 (1 H, t, J = 2 Hz), 4.02 (3H, s), 4.78 (2H, d, J = 6 Hz), 7.68 (1H, d, J = 6 Hz).

Description 4

1 -Bromomethyl-5-chloro-2-fluoro-4-methoxy-3-nitro-benzene (D4)

Carbon tetrabromide (7g, 21 mmol) and triphenyl phosphine (5.5g, 21mmol) were added to a stirred solution of (5-chloro-2-fluoro-4-methoxy-3-nitro-phenyl)-methanol (4.6g, 19.5mmol) in anhydrous diethyl ether (300mL). After 2 hours, the mixture was filtered and the filtrate was evaporated in vacuo. Silica gel chromatography of the crude residue eluting with diethyl ether in petroleum ether (5-20%) gave the title compound (4g, 69%). ¹ H NMR (CDCI3) δ: 4.03 (3H, s), 4.43 (2H, s), 7.58 (1 H, d, J = 8 Hz).

Description 5

(5-Chloro-2-fluoro-4-methoxy-3-nitro-benzyl)-phosphonic acid diethyl ester (D5)

A mixture of 1-bromomethyl-5-chloro-2-fluoro-4-methoxy-3-nitro-benzene (4g, 13mmol) and triethyl phosphite (2.25g) was heated to 160°C for 4 hours to give the title compound as an amber oil (4.7g, 100%). H NMR (CDCI3) δ: 1.22-1.36 (6H, m), 3.09 (2H, d, J = 21 Hz), 4.01 (3H, s), 4.02-4.16 (4H, m), 6.56 (1 H, dd, J = 7, 3 Hz).

Description 6

4-(5-Chloro-2-fluoro-4-methoxy-3-nitro-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (D6)

Sodium hydride (60%) (0.54g) was added to a stirred solution of (5-chloro-2-fluoro-4- methoxy-3-nitro-benzyl)-phosphonic acid diethyl ester (4.7g, 11.3mmol) in anhydrous THF (50mL) at 0°C. The mixture was left to stir for 30min. 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5g, 12.4mιmol) in anhydrous THF (10mL) was added to the mixture. Stirring was continued for 4 days at room temperature. The mixture was poured into saturated ammonium chloride (250mL) and extracted with ethyl acetate (2x150mL). The combined organic layer was evaporated in vacuo to give a crude oil. Silica gel chromatography eluting with ethyl acetate in petroleum ether (5-10%) gave the title compound as an oil (4g, 88%).

1 H NMR (CDCI₃) δ: 1.48 (9H, s), 2.30 (2H, m), 2.52 (2H, m), 3.43 (2H, m), 3.52 (2H, m), 4.01 (3H, s), 6.12 (1 H, s), 7.32 (1 H, d, J = 7 Hz).

Description 7

4-(5-Chloro-2-fluoro-4-hydroxy-3-nitro-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (D7)

A mixture of 4-(5-chloro-2-fluoro-4-methoxy-3-nitro-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (3.4g, 8.2mmol) and lithium chloride (1.7g) in DMF was stirred at 140°C for 4 hours. It was allowed to cool to room temperature and evaporated in vacuo. The residue was treated with water (50mL) and extracted with diethyl ether (2x100mL). The combined organic layers was washed with water (50mL) and dried (Na₂SO ). Evaporation of solvent gave a crude residue. Silica gel chromatography eluting with ethyl acetate in petroleum ether (20-30%) gave the title compound as an oil (2.1g, 62%). H NMR (CDCI3) δ: 1.45 (9H, s), 2.20-2.40 (4H, m), 3.37 (2H, m), 3.46 (2H, m), 6.05 (1 H, s), 7.21 (1 H, d, J = 7 Hz).

Description 8

4-(3-Amino-2-fluoro-4-hydroxy-benzyl)-piperidine-1-carboxylic acid tert-butyl ester

(D8)

A solution of 4-(5-chloro-2-fluoro-4-hydroxy-3-nitro-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (2g, 4.9mmol) in methanol (150mL) was stirred under atmospheric hydrogen in the presence of 10% palladium on charcoal (0.5g) for 18 hours. The catalyst was removed and the filtrate was evaporated in vacuo to give the title compound as an oil (1.8g, 90%).

Mass spectrum (API^"): Found 323 ([M-H]^"). C-17H25FN2O3 requires 324.

¹ H NMR (CDCI3) δ: 1.00-1.18 (2H, m), 1.44 (9H, s), 1.47-1.67 (3H, m), 2.35 (2H, m), 2.61

(2H, m), 4.00 (2H, m), 6.72 (2H, br s), 8.02 (1 H, s).

Description 9

6-(4-( V-(f-Butyloxycarbonyl)piperidinyl)methyl)-5-fluoro-4H-benzo[1,4]oxazin-3-one

(D9)

Chloroacetyl chloride (0.72g) was added dropwise to a stirring mixture of 4-(3-amino-2- fluoro-4-hydroxy-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (1.8g) in 2-butanone (10mL) and sodium hydrogen carbonate (1.34g) in water (10mL) at 0°C. The mixture was stirred at 0°C for 2 hours and then at 80°C for 4 hours. It was partitioned between water (50mL) and ethyl acetate (100mL). The organic layer was evaporated in vacuo. Silica gel chromatography of the resulting residue eluting with ethyl acetate in petroleum ether (20- 30%) gave the title compound as an oil (1.3g, 67%).

¹ H NMR (CDCI3) δ: 1.10-1.20 (2H, m), 1.45 (9H, s), 1.55-1.75 (3H, m), 2.53 (2H, d, J = 7 Hz), 2.55-2.70 (2H, m), 4.00-4.15 (2H, m), 4.62 (2H, s), 6.71 (2H, m), 7.73 (1 H, s).

Description 10

5-Fluoro-6-piperidin-4-ylmethyl-4H-benzo[1,4]oxazin-3-one hydrochloride (D10)

6-(4-(Λ/-(^-Butyloxycarbonyl)piperidinyl)methyl)-5-fluoro-4H-benzo[1 ,4]oxazin-3-one

(0.200g, 0.55mmol) was dissolved in ethanol (3 mL) and 1 M hydrochloride solution in diethyl ether (5 mL) was added. The mixture was heated at 45°C for 2.5 hours. The solvents were removed under reduced pressure, the solid triturated with diethyl ether and dried to give the title compound as a cream coloured solid (0.163g, 99%). Mass spectrum (ES⁺): Found 265 (MH⁺). C₁ Hi7N₂O₂F requires 264. ¹H NMR (MeOD) δ: 1.42-1.49 (2H, m), 1.87-1.91 (3H, m), 2.62 (2H, dd, J = 7 Hz, 1 Hz), 2.94 (2H, dt, J = 13 Hz, 2 Hz), 3.35-3.38 (2H, m), 4.57 (2H, s), 6.73 (1 H, dd, J = 8 Hz, 1 Hz), 6.82 (1 H, t, J = 8 Hz).

Description 11

6-(4-(W-(f^:-Butyloxycarbonyl)piperidinyl)methyl)-5-fluoro-4-methyl-4H- benzo[1,4]oxazin-3-one (D11)

A solution of 6-(4-(A/-(f-Butyloxycarbonyl)piperidinyl)methyl)-5-fluoro-4H-benzo[1 ,4]oxazin- 3-one (0.21 g) in anhydrous DMF (0.5mL), was added dropwise to a stirred suspension of sodium hydride (60%) (0.028g) in anhydrous DMF (2mL) at 0°C. Stirring was continued for a further 20 mins. before iodomethane (0.1g) in anhydrous DMF (1mL) was added. The mixture was allowed to stir at room temperature for 4 hours. It was quenched with saturated ammonium chloride (10mL) and extracted with diethyl ether (40mL). The organic layer was dried (Na₂SO₄) and evaporated in vacuo to give a crude oil. Silica gel chromatography eluting with ethyl acetate in hexane (10-20%) gave the title compound as a solid (0.21g).

¹ H NMR (CDCI₃) δ: 1.10-1.20 (2H, m), 1.45 (9H, s), 1.57-1.70 (3H, m), 2.55 (2H, m), 2.65 (2H, m), 3.48 (3H, d, J = 6 Hz), 4.00-4.15 (2H, m), 4.53 (2H, s), 6.70-6.80 (2H, m).

Description 12

5-Fluoro-4-methyl-6-piperidin-4-ylmethyl-4r -benzo[1,4]oxazin-3-one hydrochloride (D12)

The title compound was prepared in a similar manner to description D10. Mass spectrum (ES⁺): Found 279 (MH⁺). C15H-J9N2O2F requires 278. ¹H NMR (MeOD) δ: 1.42-1.52 (2H, m), 1.87-1.94 (3H, m), 2.65 (2H, dd, J = 7 Hz, 2 Hz), 2.91-2.98 (2H, m), 3.37 (2H, d, J = 13 Hz), 3.45 (3H, d, J = 6 Hz), 4.54 (2H, s), 6.82 (1 H, dd, J = 8 Hz, 1 Hz), 6.94 (1 H, t, J = 8 Hz).

Description 13

6-(4-(Λ/-(f-Butyloxycarbonyl)piperidinyl)methyl)-5-fluoro-4-ethyl-4H- benzo[1,4]oxazin-3-one (D13)

The title compound was prepared in a similar manner to Description 11.

¹ H NMR (CDCI₃) δ: 1.10-1.20 (2H, m), 1.28 (3H, t, J = 7 Hz), 1.45 (9H, s), 1.57-1.65 (3H, m), 2.55 (2H, m), 2.65 (2H, m), 4.00-4.15 (4H, m), 4.50 (2H, s), 6.70-6.80 (2H, m).

Description 14

5-Fluoro-2-methyl-3,4-dihydro-quinazoline (D14)

2-Aminomethyl-3-fluoro-phenylamine (50.0 g, 357 mmol), was dissolved in ethanol (300 mL) and triethylorthoacetate (72 mL, 393 mmol) added. The mixture was heated at 80°C for 16 hours under argon. The solvent was removed under reduced pressure and the residue triturated with diethyl ether to give the title product as a pale yellow coloured solid.

(39.5 g). The mother liquors were concentrated under reduced pressure and triturated with diethyl ether/petroleum spirit (1 :1) to give a second batch of the title compound as a pale yellow coloured solid (7.7 g). Combined yield 81%.

Mass spectrum (AP⁺): Found 165 (MH⁺). C9H9N2F requires 164.

¹H NMR (CDCI3) δ: 2.02 (3H, s), 4.67 (2H, s), 6.64-6.69 (2H, m), 7.04-7.09 (1 H, m).

Description 15 5-Fluoro-2-methyl-quinazoline (D 5)

5-Fluoro-2-methyl-3,4-dihydro-quinazoline (20.0 g, 122 mmol) was dissolved in chloroform

(450 mL) and manganese (IV) oxide (94.8 g, 1091 mmol) added. The mixture was allowed to stir at room temperature for 88 hours. The mixture was filtered through a plug of celite and the solvent removed under reduced pressure to give the title compound as a yellow coloured solid (19.6 g, 99%).

Mass spectrum (AP⁺): Found 163 (MH⁺). C9H7N2F requires 162. H NMR (CDCI3) δ: 2.92 (3H, s), 7.20-7.26 (1 H, m), 7.75-7.85 (2H, m), 9.60 (1 H, s).

Description 16 2-(2-Methyl-quinazolin-5-yloxy)-ethanol (D16)

Sodium hydride (60% in mineral oil, 14.5 g, 363 mmol) was added portionwise to a solution of ethylene glycol (22.5 g, 363 mmol) in DMF (330 mL) under argon. The mixture was stirred at room temperature for 30 minutes. A solution of 5-fluoro-2-methyl- quinazoline (19.6 g, 121 mmol) was added and the mixture stirred at 80°C under argon for 16 hours. Water (a few drops) was added to the cooled mixture and the solvents removed under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with ethyl acetate in DCM to give the title compound as a yellow coloured solid (2.5 g, 10%). Mass spectrum (AP⁺): Found 205 (MH⁺). C-j -j H12N2O2 requires 204.

¹H NMR (CDCI3) δ: 2.71 (1 H, bs), 2.88 (3H, s), 4.14 (2H, t, J = 4 Hz), 4.32 (2H, t, J = 4 Hz), 6.88 (1H, d, J = 8 Hz), 7.50 (1 H, d, J = 9 Hz), 7.74 (1H, t, J = 8 Hz), 9.64 (1H, s).

Description 17 Methanesulfonic acid 2-(2-methyI-quinazolin-5-yloxy)-ethyl ester (D17)

2-(2-Methyl-quinazolin-5-yloxy)-ethanol (0.330 g, 1.62 mmol) was dissolved in anhydrous dichloromethane (10 mL) and triethylamine (0.34 mL, 2.43 mmol) under argon. Methanesulfonyl chloride (0.14 mL, 1.78 mmol) was added dropwise and the mixture allowed to stir at room temperature for 1 hour. The mixture was diluted with further dichloromethane (10 mL) and partitioned with saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The title compound was obtained as a pale yellow coloured solid (0.452 g, 99%). Mass spectrum (ES⁺): Found 283 (MH⁺). C-12H-J4N2O4S requires 282. ¹H NMR (CDCI3) δ: 2.90 (3H, s), 3.10 (3H, s), 4.46-4.48 (2H, m), 4.71-4.73 (2H, m), 6.86 (1 H, d, J = 8 Hz), 7.55 (1 H, d, J = 9 Hz), 7.74-7.78 (1 H, m), 9.69 (1 H, s).

Example 1

5-Fluoro-4-methyl-6-(4-(1-(2-(5-(2-methyl)-quinolinyloxy)-ethyl)piperidinyl)-methyl)- 4H-benzo[1,4]oxazin-3-one (E1)

A solution of 6-(4-(AV-(f-butyloxycarbonyl)piperidinyl)methyl)-5-fluoro-4-methyl-4H- benzo[1 ,4]oxazin-3-one (0.21 g) in dichloromethane (5mL), methanol (1mL) and 1 M hydrogen chloride in diethyl ether (1 mL) was stirred under reflux for 2h. The volatiles were removed in vacuo. The resulting solid residue was combined with 5-(2-bromo-ethoxy)-2- methyl-quinoline (0.16g), sodium iodide (0.2g), diisopropylethylamine (0.4g) and propan- 2-ol (10mL). This mixture was stirred at 80°C for 48h. The propan-2-ol was evaporated off in vacuo and the residue partitioned between saturated sodium hydrogen carbonate and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine and dried (Na₂SO₄). The solution was evaporated in vacuo and the resulting residue was purified by silica gel chromatography, eluting with ethyl acetate in hexane (50-100%) to give the title compound as a solid (0.2g). Mass spectrum (API⁺): Found 464 (MH⁺). C27H30FN3O3 requires 463. 1 H NMR (CDCI3) δ: 1.35-1.50 (2H, m), 1.50-1.63 (1 H, m), 1.63-1.75 (2H, m), 2.21 (2H, m), 2.55 (2H, dd, J = 7, 2 Hz), 2.73 (3H, s), 2.98 (2H, m), 3.10 (2H, m), 3.47 (3H, d, J = 6 Hz), 4.31 (2H, t, J = 6 Hz), 4.52 (2H, s), 6.70-6.82 (3H, m), 7.24 (1 H, d, J = 8 Hz), 7.50- 7.63 (2H, m), 8.42 (1 H, d, J = 8 Hz).

Example 2 5-Fluoro-4-ethyl-6-(4-(1 -(2-(5-(2-methyl)-quinolinyloxy)-ethyl)piperidinyl)-methyl)-4H- benzo[1,4]oxazin-3-one (E2)

The title compound was prepared in a similar manner to Example 1. Mass spectrum (API⁺): Found 478 (MH⁺). C28H32 N3O3 requires 477. ¹ H NMR (CDCI3) δ: 1.28 (3H, t, J = 7 Hz), 1.30-1.46 (2H, m), 1.50-1.63 (1 H, m), 1.63-1.75 (2H, m), 2.22 (2H, m), 2.56 (2H, dd, J = 7, 2 Hz), 2.73 (3H, s), 2.95 (2H, t, J = 6 Hz), 3.00- 3.10 (2H, m), 4.00-4.10 (2H, m), 4.29 (2H, t, J = 6 Hz), 4.49 (2H, s), 6.72-6.82 (3H, m), 7.24 (1 H, d, J = 8 Hz), 7.50-7.63 (2H, m), 8.42 (1 H, d, J = 8 Hz).

Example 3

5-Fluoro-6-{1-[2-(2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4r/- benzo[1,4]oxazin-3-one (E3)

A mixture of 5-fluoro-6-piperidin-4-ylmethyl-4H-benzo[1 ,4]oxazin-3-one hydrochloride (0.100 g, 0.33 mmol), 5-(2-bromo-ethoxy)-2-methyl-quinoline (0.093 g, 0.57 mmol) and sodium iodide (0.093 g, 0.35 mmol) in IPA (4 mL) and N.N'-diisopropylethylamine (0.29 mL) was heated at 85°C for 18 hours under a stream of argon. The solvents were removed 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 over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel eluting with 4% methanol in dichloromethane to give the title compound as a cream coloured foam (0.055 g, 37%)

Mass spectrum (ES⁺): Found 450 (MH⁺). C26H28 3O3F requires 449. ¹H NMR (CDCI3) δ: 1.33-1.42 (2H, m), 1.54-1.66 (3H, m), 2.16 (2H, dt, J = 12 Hz, 2 Hz), 2.53 (2H, d, J = 6 Hz), 2.71 (3H, s), 2.95 (2H, t, J = 6 Hz), 3.08 (2H, d, J = 12 Hz), 4.29 (2H, t, J = 6 Hz), 4.57 (2H, s), 6.65-6.71 (2H, m), 6.78 (1 H, dd, J = 7 Hz, 1 Hz), 7.21 (1 H, d, J = 9 Hz), 7.52-7.60 (2H, m), 8.40 (1 H, d, J = 9 Hz), 8.53 (1 H, bs).

Example 4

6-{1-[2-(7-Chloro- 2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-5-fluoro-

4H-benzo[1,4]oxazin-3-one (E4)

The title compound was prepared in a similar manner to Example 3.

Mass spectrum (ES⁺): Found 484/486 (MH⁺). C26H27N3O3FCI requires 483/485. ¹H NMR (CDCI3) δ: 1.31-1.38 (2H, m), 1.52-1.65 (3H, m), 2.13 (2H, dt, J = 12 Hz, 2Hz), 2.52-2.54 (2H, m), 2.70 (3H, s), 2.92 (2H, t, J = 6 Hz), 3.02 (2H, d, J = 12 Hz), 4.24 (2H, t, J = 6 Hz), 4.59 (2H, s), 6.67-6.73 (2H, m), 6.76 (1 H, d, 2 Hz), 7.20 (1 H, d, J = 9 Hz), 7.59 (1 H, m), 7.99 (1 H, bs), 8.33 (1 H, d, J = 9 Hz).

Example 5

5-Fluoro-6-{1-[2-(7-fluoro-2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1,4]oxazin-3-one (E5)

The title compound was prepared in a similar manner to Example 3. Mass spectrum (ES⁺): Found 468 (MH⁺). C26H27N3O3F2 requires 467. ¹H NMR (CDCI3) δ: 1.29-1.39 (2H, m), 1.52-1.66 (3H, m), 2.14 (2H, t, J = 12 Hz), 2.53 (2H, d, J = 7 Hz), 2.70 (3H, s), 2.92 (2H, t, J = 6 Hz), 3.03 (2H, d, J = 11 Hz), 4.24 (2H, t, J = 6 Hz), 4.59 (2H, s), 6.58 (1 H, d, J = 11 Hz), 6.67-6.73 (2H, m), 7.17 (1 H, d, J = 9 Hz), 7.21 (1 H, d, J = 10 Hz), 7.97 (1 H, bs), 8.34 (1 H, d, J = 9 Hz).

Example 6

5-Fluoro-6-{1-[2-(2-methyl-quinazolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1 ,4]oxazin-3-one (E6)

The title compound was prepared in a similar manner to Example 3.

Mass spectrum (ES⁺): Found 451 (MH⁺). C25H27N4O3F requires 450. ¹H NMR (CDCI3) δ: 1.29-1.38 (2H, m), 1.53-1.66 (3H, m), 2.17 (2H, m), 2.53 (2H, d, J = 6 Hz), 2.87 (3H, s), 2.95 (2H, t, J = 6 Hz), 3.04 (2H, d, J = 12 Hz), 4.30 (2H, t, J = 6 Hz), 4.60 (2H, s), 6.67-6.72 (2H, m), 6.84 (1H, d, J = 8 Hz), 7.48 (1 H, d, J = 8 Hz), 7.73 (1 H, t, J = 8 Hz), 8.23 (1 H, bs), 9.62 (1 H, s).

Example 7

5-Fluoro-4-methyl-6-{1-[2-(2-methyl-quinazolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}- 4H-benzo[1,4]oxazin-3-one (E7)

The title compound was prepared in a similar manner to Example 3.

Mass spectrum (ES⁺): Found 465 (MH⁺). C26H29N4O3F requires 464.

¹H NMR (CDCI3) δ: 1.34-1.41 (2H, m), 1.53-1.57 (1 H, m), 1.66 (2H, d, J = 13 Hz), 2.18

(2H, t, J = 10 Hz), 2.55 (2H, dd, J = 7 Hz, 2 Hz), 2.88 (3H, s), 2.95 (2H, t, J = 6 Hz), 3.04

(2H, d, J = 12 Hz), 3.47 (3H, d, J = 6 Hz), 4.31 (2H, t, J = 6 Hz), 4.52 (2H, s), 6.72-6.79

(2H, m), 6.84 (1 H, d, J = 8 Hz), 7.26 (1 H, s), 7.48 (1 H, d, J = 8 Hz), 7.74 (1 H, t, J = 8 Hz),

9.63 (1 H, s).

Claims

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(i) wherein

R1 is hydrogen or C-j.galkyl;

R2 is fluoro or chloro;

R3 is hydrogen, fluoro or chloro; and

X is nitrogen or CH.

2. A compound as claimed in claim 1 , wherein R1 is hydrogen, methyl or ethyl.

3. A compound as claimed in claim 1 or claim 2, wherein R2 is fluoro.

4. A compound as claimed in claim 1 , which is:

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

5-Fluoro-4-ethyl-6-(4-(1-(2-(5-(2-methyl)-quinolinyloxy)-ethyl)piperidinyl)-methyl)-4 7- benzo[1 ,4]oxazin-3-one; 5-Fluoro-6-{1-[2-(2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1 ,4]oxazin-3-one;

6-{1-[2-(7-Chloro- 2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-5-fluoro-4H- benzo[1 ,4]oxazin-3-one;

5-Fluoro-6-{1-[2-(7-fluoro-2-methyl-quinolin-5-yloxy)-ethyl]-pipehdin-4-ylmethyl}-4H- benzo[1 ,4]oxazin-3-one;

5-Fluoro-6-{1-[2-(2-methyl-quinazolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1 ,4]oxazin-3-one; or

5-Fluoro-4-methyl-6-{1-[2-(2-methyl-quinazolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H- benzo[1 ,4]oxazin-3-one; or a pharmaceutically acceptable salt thereof.

5. A compound as claimed in any of claims 1-4, for use as a therapeutic substance.

6. A compound as claimed in any of claims 1-4, for use in the treatment of a CNS disorder.

7. A compound as claimed in any of claims 1-4, for use in the treatment of depression or anxiety.

8. A method of treatment of a CNS disorder in mammals including humans, which comprises administering to the sufferer a therapeutically safe and effective amount of a compound as claimed in any of claims 1-4.

9. A method as claimed in claim 8, wherein the CNS disorder is depression or anxiety.

10. Use of a compound as claimed in any of claims 1-4 in the manufacture of a medicament for use in the treatment of a CNS disorder.

11. The use as claimed in claim 10, wherein the CNS disorder is depression or anxiety.

12. A pharmaceutical composition, which comprises a compound as defined in any of claims 1-4 and a pharmaceutically acceptable carrier or excipient.