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Title:
BENZOXAZOCINES AND THEIR THERAPEUTIC USE AS MONOAMINE REUPTAKE INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2005/103019
Kind Code:
A1
Abstract:
Compounds having therapeutic utility are of general formula (1) wherein R, is H, C 1-C6 alkyl optionally substituted with F or C3-C6 cycloalkyl or C2-C4 alkenyl; A is O, CH2 or S(O)n where n is 0-2; one of W, X, Y and Z is N, CH or CR3 and the others are CH; R2 is C5-C6 heteroaryl, C5-C10 cycloalkyl or cycloalkenyl optionally containing one or more heteroatoms selected from O, N and S(O)n where n is 0-2, and optionally substituted with R3; or a phenyl group optionally substituted in one or more positions with one or more substituents independently selected from halogen, CN, CF3, C1-C6 alkyl and OR1, or the phenyl group is fused to a five or six membered ring which may be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from O, N and S), aromatic or heteroaromatic (containing 1-2 heteroatoms selected from O and N); R3 is selected from halogen; CF3; CN; OR5; SO2N(R5)2; COR5; CO2R5; CON(R5)2; NR1,COR4; NR1SO2R4; NR1CO2R4; NR1,CON(R5)2; OC1-C6 alkyl substituted with R3; C1-C6 alkyl optionally substituted with unsubstituted R3; C3-C6 cycloalkyl optionally substituted with unsubstituted R3; C2-Cs alkenyl optionally substituted with unsubstituted R3; C2-Cs alkynyl optionally substituted with unsubstituted R3; aryl optionally substituted with unsubstituted R3; and five or six membered aromatic heterocycles containing 1-4 heteroatoms selected from N and O; R4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl and heteroaryl; and R5 is H, C1-C6 alkyl; C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl and is the same as or different to another R5; or a pharmaceutically acceptable salt thereof.

Inventors:
Baxter, Andrew Douglas (Sosei R&D Ltd, Chesterford Research Park Little Chesterfor, Saffron Walden Essex CB10 1XL, GB)
Walmsley, Andrea (Sosei R&D Ltd, Chesterford Research Park Little Chesterfor, Saffron Walden Essex CB10 1XL, GB)
Lasterra, Elena (Sosei R&D Ltd, Chesterford Research Park Little Chesterfor, Saffron Walden Essex CB10 1XL, GB)
Application Number:
PCT/GB2005/001519
Publication Date:
November 03, 2005
Filing Date:
April 21, 2005
Export Citation:
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Assignee:
SOSEI R&D LTD. (Chesterford Research Park, Little Chesterford Saffron Walden, Essex CB10 1XL, GB)
Baxter, Andrew Douglas (Sosei R&D Ltd, Chesterford Research Park Little Chesterfor, Saffron Walden Essex CB10 1XL, GB)
Walmsley, Andrea (Sosei R&D Ltd, Chesterford Research Park Little Chesterfor, Saffron Walden Essex CB10 1XL, GB)
Lasterra, Elena (Sosei R&D Ltd, Chesterford Research Park Little Chesterfor, Saffron Walden Essex CB10 1XL, GB)
International Classes:
C07D267/22; C07D273/00; C07D413/04; (IPC1-7): C07D267/22; C07D413/04; A61K31/395
Domestic Patent References:
WO2001032625A12001-05-10
WO2004056788A12004-07-08
Foreign References:
GB1148717A1969-04-16
US3978085A1976-08-31
Other References:
ROSLAND J H ET AL: "The effect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations", JOURNAL OF PHARMACY AND PHARMACOLOGY, LONDON, GB, vol. 42, no. 6, June 1990 (1990-06-01), pages 437 - 438, XP008029309, ISSN: 0022-3573
PATENT ABSTRACTS OF JAPAN vol. 008, no. 098 (C - 221) 9 May 1984 (1984-05-09)
PATENT ABSTRACTS OF JAPAN vol. 008, no. 098 (C - 221) 9 May 1984 (1984-05-09)
Attorney, Agent or Firm:
GILL JENNINGS & EVERY LLP (Broadgate House, 7 Eldon Street, London EC2M 7LH, GB)
Download PDF:
Description:
BENZOXAZOCINES AND THEIR THERAPEUTIC USE AS MONOAMINE REUPTAKE INHIBITORS

Field of the Invention This invention relates to novel benzoxazocine compounds which inhibit monoamine reuptake. In particular, compounds of the present invention exhibit activity as analgesic agents and also as anti-emetics but also may find utility in a range of other therapeutic indications. Background of the Invention Nefopam, i.e. 5-methyl-1-phenyl-3,4,5,6-tetrahydro-1 H-2,5-benzoxazocine hydrochloride, is a centrally acting non-narcotic analgesic. WO03/092689 discloses that the single enantiomers of nefopam are useful for the treatment of pain and emesis. WO2004/056788 discloses derivatives of nefopam. Its publication date is later than the priority dates now claimed. Summary of the Invention Novel compounds according to this invention are of general formula (1):

wherein R1 is H, CrC6 alkyl optionally substituted with F or C3-C6 cycloalkyl or C2-C4 alkenyl; A is O, CH2 or S(O)n where n is 0-2; one of W, X, Y and Z is N, CH or CR3 and the others are CH; R2 is C5-C6 heteroaryl, C5-C10 cycloalkyl or cycloalkenyl optionally containing one or more heteroatoms selected from O, N and S(O)n where n is 0-2, and optionally substituted with R3; or a phenyl group optionally substituted in one or more positions with one or more substituents independently selected from halogen, CN, CF3, CrC6 alkyl and OR1, or the phenyl group is fused to a five or six membered ring which may be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from O, N and S), aromatic or heteroaromatic (containing 1-2 heteroatoms selected from O and N); R3 is selected from halogen; CF3; CN; OR5; SO2N(Rs)2; COR5; CO2R5; CON(R5)2; NR1COR4; NRiSO2R4; NR1CO2R4; NR1CON(Rs)2; OC1-C6 alkyl substituted with R3; C1-C6 alkyl optionally substituted with unsubstituted R3; C3-C6 cycloalkyl optionally substituted with unsubstituted R3; C2-C6 alkenyl optionally substituted with unsubstituted R3; C2-C6 alkynyl optionally substituted with unsubstituted R3; aryl optionally substituted with unsubstituted R3; and five or six membered aromatic heterocycles containing 1-4 heteroatoms selected from N and O; R4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl and heteroaryl; and R5 is H, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl and is the same as or different to another R5; or a pharmaceutically acceptable salt thereof. Compounds disclosed in WO2004/056788 may be excluded, e.g. those of the general formula:

wherein R1 is H, C1-C6 alkyl, optionally substituted with F or C3-C6 cycloalkyl or C2-C6 alkenyl; either R2 and R3 are the same or different and are H, a halogen, CN, CF3, CrC6 alkyl or OR1, or R2 and R3 form a five or six membered ring which may be carbocyclic, heterocyclic (containing 1-2 heteroatoms taken from O, N or S)1 aromatic or heteroaromatic (containing 1-2 heteroatoms taken from O and N) ; one of W, X, Y and Z is N, or CR4 and the others are each CH; R4 is a halogen atom, CF3, CN, OR7, SO2N(Re)2, COR6, CO2R6, CON(R6)2, NR1COR5, NR1SO2R5, NR1CO2R5, NR1CON(Re)2, OC1-C6 alkyl optionally substituted with R4, C1-C6 alkyl optionally substituted with R4, C3-C6 cycloalkyl optionally substituted with R4, C2-C6 alkenyl optionally substituted with R4, C2O6 alkynyl optionally substituted with R4, aryl optionally substituted with R4, or a five or six membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, linked either through carbon or nitrogen; R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl; each R6 (which may be the same or different) is H1 C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl; and R7 is aryl or heteroaryl; or a pharmaceutically acceptable salt thereof. Compounds of the invention have utility as therapeutic agents. Compositions containing them and their therapeutic uses are further aspects of the invention. Further, compounds of formula (1) wherein R3 is a halogen atom such as Br are useful as intermediates. Description of Preferred Embodiments It will be appreciated that compounds according to the invention contain an asymmetrically substituted carbon atom. The presence of this asymmetric centre in a compound of formula (1) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic and non-racemic mixtures thereof. As used in this specification, the term "C1-C6 alkyl" refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, fe/f-butyl, pentyl, hexyl and the like. The term "C5-C6 heteroaryl" refers to an aryl system of five or six atoms, of which at least one atom is selected from O, N and S. This term includes, for example, pyridine, tetrahydropyran etc. The term "C2-C6 alkenyl" refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term includes, for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl etc. The term "C2-C6 alkynyl" refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one triple bond. This term includes, for example, ethynyl, 1-propargyl, 1- and 2-butynyl etc. The term "C3-C6 cycloalkyl" refers to a saturated alicyclic moiety having from three to six carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "C5-Ci0 cycloalkenyl" refers to an unsaturated alicyclic moiety having from five to ten carbon atoms and at least one double bond and includes, for example, phenyl and the like. The term "aryl" means an optionally substituted phenyl or naphthyl group. The term "carbocyclic" refers to a saturated alicyclic moiety having five or six carbon atoms and includes, for example, benzofused cyclopentyl and cyclohexyl and the like. The term "heterocyclic" refers to a saturated heterocyclic moiety having from five or six atoms but containing one or more heteroatom selected from N, O and S, and includes, for example, benzofused pyrrolidinyl, tetrahydrofuranyl, piperidinyl, dioxalane and the like. The term "heteroaromatic" refers to aromatic ring systems of five or six atoms of which at least one atom is selected from O, N and S, and includes, for example, pyrrolyl, pyridinyl, diazolyl, diazinyl, triazolyl, triazinyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl or oxadiazolyl as well as benzofused furanyl, thiophenyl, pyridyl, indolyl, pyridazinyl, piperazinyl, pyrimidinyl and the like, e.g. benzofuranyl, quinolinyl, isoquinolinyl or quinazolinyl. Such rings can be linked either through carbon or nitrogen. The term "halogen" means fluorine, chlorine, bromine or iodine. Compounds of the general formula (1) may be prepared by any suitable method known in the art and/or by the processes described below. It will be appreciated that where a particular stereoisomer of formula (1) is required, the synthetic processes described herein may be used with the appropriate homochiral starting material and/or isomers maybe resolved from mixtures using conventional separation techniques (eg. HPLC). In the description and formulae below, variables such as R1, R2, R3, R4, R5, A, W1 X, Y and Z are as defined above, except where otherwise indicated. It will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see "Protective Groups in Organic Synthesis", Wiley Interscience, T W Greene, PGM Wuts. A process for preparing compounds of general formula (1), where W, X, Y or Z is N or C-Br and A is O or S(O)n, comprises cyclisation with acid (for instance with p- toluenesulphonic acid) of a diol (2) which can in turn be obtained by reduction of ketone (3) with a suitable reducing agent.

(2) O) Reduction of a keto amide of general formula (3) can be carried out with reagents well known to those familiar in the art of synthetic organic chemistry. An example of a highly reactive reducing agent is lithium aluminium hydride, although reagents based on borane (e.g. borane.tetrahydrofuran complex) or modified sodium borohydride reduction (e.g. with a nickel or cobalt salt enhancer) may be equally effective. Equally, reduction of the ketone in (3), for example with sodium borohydride, followed by acid cyclisation, for example with p-toluenesulphonic acid, then ultimate reduction of the amide group, for example with borane, also leads to compounds of general formula (1). Ketones (3) can be prepared by condensation of a carboxylic acid (4) or an active derivative thereof, with an amine (5). Active derivatives of acids of formula (4) include, for example, acid anhydrides or acid halides, such as acid chlorides.

(4) (5) The coupling reaction may be performed using standard conditions for amidation reactions of this type. Thus, the reaction may be achieved in a solvent, for example an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, an amide, e.g. a substituted amide such as dimethylformamide, or a halogenated hydrocarbon such as dichloromethane at low temperature, e.g. -3O0C to ambient temperature, such as -2O0C to 00C, optionally in the presence of as base, e.g. an organic base such as an amine, e.g. triethylamine or a cyclic amine such as N- methylmorpholine. Where an acid (4) is used directly, the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as N1N1- dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as 1- hydroxybenzotriazole. Alternatively, the acid may be reacted with a chloroformate, for example ethyl chloroformate, prior to reaction with the amine (5). Acids (4) may be prepared by Friedel-Crafts acylation of R2 with an anhydride (7). This reaction is carried out in an inert solvent (such as dichloromethane) in the presence of a Lewis acid catalyst (such as aluminium trichloride).

(7)

It is well recognised by those skilled in the art that such reactions may provide mixtures of products and in turn that these mixtures can often be separated by flash column chromatography. For example, where Y = C-Br, W = X = Z = CH and R2 is phenyl, Friedel-Crafts acylation under aluminium trichloride catalysis provides two isomeric bromides (4a) and (4b). These can be readily separated by column chromatography and independently progressed to compounds of general formula (1), wherein X or Y is C-Br, by the route described above.

Compounds of general formula (1) where one of W1 X1 Y and Z is C-hal such as C-Br represent flexible intermediates that may be used for the preparation of other compounds of general formula (1). For instance, such compounds can be smoothly converted into the corresponding nitrile (R3 = CN) either by reaction with cuprous cyanide in a dipolar aprotic solvent such as /V-methylpyrrolidinone (NMP) or under palladium-catalysed conditions. The nitrile can be readily converted, by hydrolysis, into the primary amides (R3= CONH2), esters and the corresponding carboxylic acids (CO2Rs) or into the corresponding tetrazoles, by treatment with a suitable azide donor such as sodium azide or trimethylsilylazide. In addition, compounds of general formula (1) where one of W, X, Y and Z is C- hal such as C-Br can be lithiated with n-, sec- or te/f-butyllithium in an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, at very low temperature, e.g. -78 0C. Treatment with either a carbon (e.g. carbon dioxide, N1N- dimethylformamide or paraformaldehyde), sulphur (e.g. SO2CI2, followed by amidation, such as with ammonia) or nitrogen (diphenylphosphoryl azide, followed by reduction, such as with REDAL) provides access, by subsequent derivatisation, to derivatives where R3 is CO2R5, CON(R5), CH2OR5, SO2N(R4)2, NR1COR4, NR1CO2R5 or NR1CON(Rs)2. In addition, compounds of general formula (1) where one or W, X, Y and Z is C- hal such as C-Br can undergo palladium-catalysed coupling reactions with carbon-based coupling partners. Thus, such compounds can be coupled to alkenes of the general type CH2=CHR3 under Heck conditions, to alkynes of the general type CH=CHR3 under Sonogoshira conditions, or to metalloheterocycles, e.g. where the metal is tin, under Stille coupling conditions. This gives access to compounds where R3 is optionally substituted C2-C6 alkenyl or C2-C6 alkynyl, or a five-membered aromatic heterocycle containing 1-4 heteroatoms selected from N (such as in pyrrole, diazoles, triazoles or tetrazoles) and O (such as in furan, oxazoles or oxadiazoles). Such coupling reactions ensure that chains and rings are linked through carbon. In addition to the examples described above, additional compounds of formula (1) may be prepared by interconversion of other compounds of formula (1). Thus, for example, a compound wherein R3 is alkyl may be prepared by hydrogenation (using palladium on carbon in a suitable solvent, such as an alcohol, e.g. ethanol) of a corresponding compound wherein R3 is alkenyl. Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances. The compounds according to the invention exhibit in vitro inhibiting activities with respect to monoamine (i.e. noradrenaline, serotonin and dopamine) reuptake. The activity and selectivity of the compounds may be determined by use of an appropriate monoamine reuptake assay. This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat or fur industries or as pets) suffering from disorders or diseases which can be attributed to monoamine reuptake as previously described, and more specifically, a method of treatment involving the administration of the monoamine reuptake inhibitor of formula (1) as the active constituents. Accordingly, the compounds of formula (1) can be used in the treatment of pain and emesis. Pain and related conditions that can be treated include syndromes characterised by chronic pain and fatigue, fibromyalgia, chronic fatigue syndrome, complex regional pain syndrome, irritable bowel syndrome, myofacial pain and atypical chest pain. The compounds may also find utility in a range of other therapeutic indications such as depression, post-traumatic stress disorders, attention-deficit disorders, obsessive-compulsive disorders, pre-menstrual syndrome, substance abuse and sexual dysfunction; a method of management (by which is meant treatment or prophylaxis) of disease or conditions mediated by monoamine reuptake in mammals, in particular in humans, which method comprises administering to the mammal an effective, amount of a compound of formula (1) above, or a pharmaceutically acceptable salt thereof; and a compound of formula (1) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by monoamine reuptake; and the use of a compound of formula (1) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by monoamine reuptake. The disease or conditions referred to above include pain, emesis, depression, post-traumatic stress disorders, attention-deficit disorders, obsessive-compulsive disorders, pre-menstrual syndrome, substance abuse and sexual dysfunction. Compounds of formula (1) may be administered orally, topically, buccally, ocularly, rectally, vaginally, parenterally, intra-nasally, sublingually or by inhalation spray, e.g. in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats etc, the compounds of the invention are effective in the treatment of humans. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The composition may be in immediate or controlled release form. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyeryl distearate may be employed. They may also be coated by the techniques described in US4256108, US4166452 and US4265874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters dervied from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occuring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example gycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of formula (1) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc containing the compounds of Formula (1) are employed. For purposes of this specification, topical application includes mouth washes and gargles. Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 2.5 mg to about 7 g per patient per day). For example, emesis may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. The following Examples illustrate the invention. They include compounds which are in the following Table.

All 1H NMR recorded on a Bruker AC250. All chemical shifts (δ) have been rounded to 2 decimal places, and coupling constants (J) are measured in Hz and to the nearest 0.1 decimal place. Example 1 5-BenzyI-1 -phenyl-1 ,3,4,6-tetrahydro-5H-benz[fI-2,5-oxazocine To a stirring solution of desmethylnefopam (96 mg, 0.41 mmol) in DMF (3 ml) were added sodium hydride (15 mg, 0.49 mmol) and then benzyl bromide (0.7 ml, 0.61 mmol). The resulting blue solution was heated at 65°C for 2 hours. The reaction was quenched by the addition of water and the organics were extracted into dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to provide the crude material. Purification by silica gel column chromatography (1-»2%MeOH / DCM) furnished the target product (45 mg, 34%) as a brown oil. δH (CDCI3; 250MHz) 2.74-2.80 (1 H, m, one of CH2), 2.96-3.00 (1 H, m, one of CH2), 3.88- 4.07 (4H, m, four of CH2), 4.27-4.36 (1 H, m, one of CH2), 4.92 (1 H, d, J12.7, one of ArCjH2NR2), 5.82 (1 H, s, CHOR), 7.05-7.07 (1H, m, aromatic H), 7.26-7.42 (11 H1 aromatic H), 7.56-7.60 (2H, m, aromatic H) Example 2 5-AIIyM -phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine Sodium hydride (24 mg, 1.01 mmol) was added to a solution of desmethylnefopam (200 mg, 0.84 mmol) at RT. The resulting mixture was stirred for 2 hours before allyl bromide (0.12 ml, 1.33 mmol) was added dropwise. The blue solution was heated at 65°C for a further two hours, then quenched with water. The aqueous mixture was extracted with dichloromethane and the combined extracts dried (MgSO4), filtered and concentrated in vacuo to provide the target product (66 mg, 28%). δH (CDCI3; 250MHz) 2.90-3.13 (2H, m, two of CH2), 3.64 (2H, d, J6.1 , two of CIH2), 4.01 (1 H, bd, J13.6, one of CH2), 4.26 (1H, d, J12.1, one Of ArCH2NR2), 4.38-4.49 (1 H, m, one of CIH2), 5.01 (1 H, d, J12.1, one Of ArC]H2NR2), 5.42-5.49 (2H, m, two terminal alkenic H), 5.77 (1 H, s, CHOR), 6.27-6.37 (1 H, m, alkenic H), 7.11-7.39 (8H, aromatic H), 7.51 (1 H, bs, aromatic H). Example 3 S-Cyclopropyl-i-phenyl-ijS.^e-tetrahydro-δH-benztfl^.S-oxaz ocine Sodium cyanoborohydride (106 mg, 1.69 mmol) was added to a stirring suspension of desmethylnefopam (100 mg, 0.42 mmol), acetic acid (0.24 ml, 4.22 mmol), (i-ethoxycyclopropyloxyjtrimethylsilane (0.51 ml_, 2.53 mmol) and 4A molecular sieves in methanol (1.5 ml). The resulting brown solution was heated at reflux temperature overnight. The reaction mixture was quenched by the addition of sodium bicarbonate solution and extracted into dichloromethane. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (DCM→2%MeOH/DCM) to provide the target product (84 mg, 68%). δH (CDCI3; 250MHz) 0.56 (4H1 bs, cyclopropyl CH2CJH2), 1.90-1.94 (1 H1 m, cyclpropyl CM), 2.88 (1 H, ddd, J14.3, 6.1 , 2.7, one of CH2CH2), 3.00 (1 H, ddd, J14.3, 7.3, 2.1, one of CH2CH2), 3.87 (1H, ddd, J12.5, 6.1 , 2.1 , one of CJH2CH2), 3.96 (1 H, d, J12.8, one of ArChI2NR2), 4.15 (1 H, ddd, J12.5, 7.3, 2.7, one of CM2CM2), 4.86 (1 H, d, one of ArCMsNR2), 5.84 (1H, s, CMOR), 6.99-7.00 (1H, m, aromatic M), 7.18-7.30 (8H, aromatic M)- Example 4 5-Propyl-1 -phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine 5-AIIyM -phenyl-1,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine (66 mg, 0.24 mmol) was dissolved in THF (4 ml) and 10% Pd/C (2 micro-spatulas) added. The reaction vessel was shaken under a hydrogen atmosphere for 3 hours. After this time, the mixture was filtered and the filtrate concentrated in vacuo. Purifcation of the crude mixture by silica gel column chromatography (DCM-»5%MeOH/DCM) furnished the target product as a pale yellow oil (42 mg, 62%). δH (CDCI3; 250MHz)1.03 (3H, t, /7.3, CH3), 1.99-2.10 (2H, m, two of propyl CM2CM2), 2.96-3.22 (4H, m, two of propyl CM2CM2 and two of ring CM2CM2), 4.02-4.10 (1 H, m, ArCM2NR2), 4.37-4.51 (2H, m, two of CM2CM2) 5.03-5.31 (1H, bs, one of ArCM2NR2), 5.77 (1 H, CMOR), 7.15-7.18 (3H, m, aromatic H), 7.27-7.40 (5H, m, aromatic M), 7.63 (1 H, bs, aromatic M)- Example 5 δ-Methylcyclopropyl-i-phenyl-I.S^.β-tetrahydro-δH-benztfl ^jS-oxazocine Desmethylnefopam (110 mg, 0.43 mmol) was dissolved in anhydrous DMF (2 ml) under a nitrogen atmosphere and sodium hydride (as a 60% suspension in mineral oil, 21 mg, 0.52 mmol) was added. The resulting mixture was heated to 8O0C. (Bromomethyl)cyclopropane (0.06 ml, 0.65 mmol) was added and the reaction mixture kept between 80 and 900C. Once the starting material was shown to have been consumed by TLC, the reaction was quenched by the addition of water and brine. The aqueous mixture was extracted three times with ethyl acetate, and the combined organics were washed with brine, before being dried (MgSO4), filtered and concentrated in vacuo to give a red/pink oil. Purification by silica gel column chromatography (DCM->1.5%MeOH/DCM) furnished the target product as a red oil (35 mg, 26%). δH(CDCI3; 250MHz) 0.08-0.20 (2H, m, two of cyclopropyl CH2CM2), 0.57-0.63 (2H, m, two of cyclopropyl CM2CM2), 0.99-1.04 (1 H, m, cyclopropyl CH), 2.41 (1 H, dd, J12.5, 7.0, one of CH2), 2.70 (1H, dd, J12.5, 5.8, one of CH2), 2.83-3.00 (2H, m , two of CjH2CIH2), 3.90 (1H1 ddd, J12.5, 5.8, 2.4, one of CH2CH2), 3.95 (1H1 d, J12.5, one of ArCH2NR2), 4.22 (1H, ddd, J12.5, 7.6, 3.2, one of CH2CH2), 4.77 (1H, d, J12.5, one of ArCH2NR2), 5.83 (1 H, s, CHOR), 7.01 (1H, d, J7.0, aromatic H), 7.16-7.33 (8H, m, aromatic H). Example 6 5-lsopropyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz[fl-2,5-oxa2o cine Desmethylnefopam (116 mg, 0.45 mmol) was dissolved in acetone (3ml) over 4A molecular sieves (spatula tip). A drop of acetic acid was added and the resulting mixture was stirred at RT for one hour. After this time, sodium cyanoborohydrde (114 mg, 1.82 mmol) was added and the mixture was stirred overnight at RT, after which time, TLC showed that starting material had been consumed. The reaction mixture was filtered and the collected solids washed with ethyl acetate. The filtrate was concentrated in vacuo to remove the acetone, providing a pale yellow residue. This was re-dissolved in dichloromethane and washed with a sat. aq. solution of sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel column chromatography (DCM-»1%MeOH/DCM) furnished the desired compound (34 mg, 30%). δH (CDCI3; 250MHz) 1.13 (3H, d, J6.7, one CH3 Of N(CHa)2), 1-25 (3H, d, J6.4, one CH3 of N(CH3)2), 1.73 (1H, dd, J4.6, 1.5, CIH), 2.77-3.11 (2H, m, two Of CH2CiH2), 3.71 (1H1 d, J12.8, one Of ArCH2NR2), 3.87 (1 H, ddd, J12.2, 8.9, 1.8, one of CH2CH2), 4.11 (1H, ddd, J12.2, 5.0, 2.3, one of CH2CH2), 4.34 (1 H, d, J12.8, one of ArCH2NR2), 5.90 (1H, s, CHOR), 7.02 (1H, d, J7.3, aromatic H), 7.16-7.30 (8H, aromatic JH). Example 7 β^-PyridyO-S-methyl-i-tS-methoxyJphenyl-ijS.^β-tetrahydro- SH-benztfJ^^- oxazocine 8-Bromo-5-methyl-1-(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine, i.e. compound 21b in WO2004/056788 (117 mg, 0.32 mmol), pyridine-4- boronic acid (52 mg, 0.42 mmol), Pd(PPh3)4 (10 mol%) and KOH (2M solution in water, 0.48 ml) were suspended in DME (2 ml). The mixture was degassed and then purged with nitrogen before heating at reflux temperature under a nitrogen atmosphere for 17 hours. The mixture was allowed to cool to RT and diluted with ethyl acetate (20 ml) and washed with water (20 ml). The aqueous phase was extracted into ethyl acetate (2 x 20 ml) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel column chromatography (EtOAc-»10% MeOH/EtOAc) furnished the target compound as a pale yellow oil (25 mg, 22%). δH(CDCI3; 250MHz) 2.50 (3H1 s, NCH3), 2.60 (1H1 ddd, J14.2, 5.8, 2.6, one of CId2CH2), 2.86 (1H, ddd, J14.2, 8.3, 2.1, one of CH2CfH2), 3.75 (1 H, d, J12.8, one of ArCIH2NR2), 3.78 (3H, s, OCH3), 3.88 (1 H, ddd, J12.5, 5.8, 2.1 , one of CjH2CH2), 4.22 (1H1 ddd, J12.5, 8.3, 2.6, one of CIH2CIH2), 4.87 (1H, d, J12.8, one Of ArCIH2NR2), 5.81 (1H, s, CHOR), 6.79-6.91 (4H, m, aromatic H), 7.14 (1 H, d, J7.6, aromatic H), 7.22-7.28 (1H, m, aromatic H), 7.44-7.62 (4H, m, aromatic H), 8.65 (1 H, d, J5.8, aromatic H). 5-Pyrimidineboronic acid "BuLi (3.02 ml, 2M solution in hexane, 7.55 mmol) was added dropwise to a stirring solution of 5-bromopyrimidine (1 g, 6.29 mmol) and triisopropylborate (1.46 ml, 7.55 mmol) in anhydrous toluene (16 ml) and anhydrous THF (4 ml) at -700C under a nitrogen atmosphere. The reaction mixture was stirred at -70°C for 30 mins and then removed from the cold bath. When the internal temp, reached -200C, the reaction was quenched by the dropwise addition of 2M HCI (10 ml). The mixture was allowed to warm to RT and then separated. The aqueous phase was taken to pH 5.5 with 2M KOH and extracted into THF (3 x 25 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide a colourless solid. The solid was slurried in acetonitrile (2 ml), collected by filtration and dried on the sinter to give the target boronic acid as a brilliant white solid (340 mg, 44%). δH(MeOD; 250MHz) 8.98 (2H, s), 9.14 (1H, s). Example 8 S-JS-PyrimidineJ-δ-methyl-I^S-methoxyJphenyl-i^.^e-tetrahyd ro-SH-benzCfl^S- oxazocine 8-Bromo-5-methyl-1-(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine, i.e. compound 21b in WO2004/056788 (118 mg, 0.3 mmol), CsF (148 mg, 0.98 mmol), 5-pyrimidine boronic acid (52 mg, 0.42 mmol) and Pd(PPh3)4 (10 mol%) were suspended in DME (2 ml) and water (100 μL). The mixture was degassed and purged with nitrogen then heated to reflux temperature for 17 hours. The reaction mixture was allowed to cool to RT before diluting with ethyl acetate (20 ml) and washing with water (20 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were dried (MgSO4), filtered and evaporated to dryness to provide crude material. Purification by silica gel column chromatography (EtOAc→10% MeOH/EtOAc) furnished the target product as a pale yellow/brown solid (36 mg, 30%). δH (CDCI3; 250MHz) 2.53 (3H, s, NCIH3), 2.68 (1 H, ddd, J14.2, 5.8, 2.6, one of CH2CjH2), 2.88 (1 H, ddd, J14.2, 8.2, 2.2, one of CjH2CjH2), 3.79 (1 H, d, J12.8, one of ArCjH2NR2), 3.79 (3H, s, OCIH3), 3.89 (1 H, ddd, J12.8, 5.8, 2.2, one of CH2CIH2), 4.24 (1 H, ddd, J12.8, 8.2, 2.6, one of CJd2CH2), 4.89 (1 H, d, J12.8, one Of ArCH2NR2), 5.82 (1H, s, CHOR)1 6.79-6.91 (3H, m, aromatic H), 7.17-7.29 (2H, m, aromatic H), 7.40-7.43 (2H, m, aromatic H), 8.95 (s, 2H, pyrimidine H), 9.20 (1H, s, pyrimidine H). Example 9 5-Methyl-1 -(3-methoxy)phenyl-1 ,3,4,6-tetrahydiO-5H-benz[fl-2,5-oxazocine 8-Bromo-5-methyl-1-(3-methoxy)phenyl-1,3,4,6-tetrahydro-5H-b enz[f]-2,5- oxazocine, i.e. compound 21 b in WO2004/056788 (206 mg, 0.57mmol), was suspended in toluene (3 ml) and degassed under vacuum, then purged with nitrogen. Palladium tetrakis (33 mg) was added to the mixture, which was then subjected to the degassing/nitrogen purge sequence again. A degassed solution of sodium carbonate (2M, 12 ml) and boronic ester (117 mg, 0.57 mmol) were added and the whole mixture was then degassed, purged with nitrogen and heated to 80°C overnight. The reaction mixture was allowed to cool, diluted with water (10 ml) and the resulting mixture extracted into ethyl acetate (3 x 50 ml). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel column chromatography [EtOAc] was carried out twice to give a mixture of products. Mass spec analysis suggested the debrominated species had been formed, m/z (ES+) 284 (MH+). δH (CDCI3; 250MHz) 2.51 (3H, s, /V-CH3), 2.68 (1H1 ddd, J14.2, 5.2, 2.9, one of CH2CH2), 2.88 (1H, ddd, J14.2, 9.0, 2.6, one of CH2CH2), 3.78 (3H, s, OCH3), 3.81 (1 H1 d, J12.8, one of ArCH2NR2), 3.88 (1 H, ddd, J12.8, 5.2, 2.6, one of CH2CH2), 4.23 (1H, ddd, J12.8, 9.0, 2.9, one of CH2CH2), 4.86 (1H1 -Cl1 J12.8, one Of ArCH2NR2), 5.76 (1H, s, CHOR), 6.78-6.86 (3H, m, aromatic JH), 7.03-7.05 (1 H1 m, aromatic H), 7.20- 7.27 (4H, m, aromatic HJ. Example 10 5-Methyl-1-(3-methoxy)phenyMA4,6-tetrahydro-5H-benz[f]-2,5-o xazocine-8- carboxamide 8-Cyano-5-methyl-1-(3-methoxy)phenyl-1 l3l4,6-tetrahydro-5H-benz[f]-2,5- oxazocine, i.e. compound 21b in WO2004/056788 (73 mg, 0.24 mmol), was heated to reflux temperature in fBuOH (3 ml_) with KOH (20 mg, 0.36 mmol) for 90 mins. At the end of this time, the reaction mixture was allowed to cool to RT. The mixture was then washed with brine (20 ml) and extracted into dichloromethane (3 x 20 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to provide the crude amide as a yellow solid. The solid was slurried in ethyl acetate, collected by suction filtration, washed with heptane and dried on the sinter to provide amide (24 mg, 31%). δ (MeOD; 250MHz) 2.44 (3H, s, NCH3), 2.51-2.60 (1H, m (poorly resolved ddd), one of CH2CH2), 2.72-2.81 (1 H, m (poorly resolved ddd), one of CH2CH2), 3.75 (4H, s, OCH3 and one of ArCH2), 3.84-3.90 (1 H, m (poorly resolved ddd), one of CjH2CH2), 4.17-4.27 (1H, m (poorly resolved ddd), one of CH2CH2), 5.01 (1H, d, J12.5, one of ArCH2), 5.83 (1H, s, CHOR), 6.80-6.83 (3H, m, aromatic H), 7.14-7.21 (2H, m, aromatic JH), 7.70-7.76 (2H1 m, aromatic H). MS (ESP) 325 ([M-HD; (ESI+) 349 ([M+Na]+) 2-Benzoyl-4-fluorobenzoic acid and 2-Benzoyl-5-fluorobenzoic acid 3-Fluorophthalic anhydride (5 g, 33 mmol) was suspended in benzene (17.7 ml) at RT under nitrogen. Aluminium chloride (8.8 g, 66 mmol) was added in portions, turning the mixture orange in colour. The reaction was heated at reflux temperature for 4 hours before cooling to RT. The yellow slurry was added carefully to 10%HCI (100 ml), producing a white precipitate. The aqueous mixture was extracted into ethyl acetate (3 x 100 ml_) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide a mixture of the keto-acids 2-benzoyl-4-fluorobenzoic acid and 2-benzoyl-5-fluorobenzoic acid as colourless crystals (8 g, quantitative yield). δH (MeOD; 250MHz) 7.17-7.25 (3H, m, ArH), 7.31-7.42 (2H, m, ArH), 7.48 (2H, d, J8.Q, ArH), 7.69 (1 H, d, J8.0, ArH). 2-Benzoyl-6-fluoro-Λ/-(2-hydroxyethyI)-/V-methylbenzamide and 2-Benzoyl-3-fluoro- Λ/-(2-hydroxyethyl)-Λ/-methylbenzamide A crude mixture of 2-benzoyl-6-fluorobenzoic acid and 2-benzoyl-3-fluorobenzoic acid (7 g, 28 mmol) was suspended in dichloromethane (70 ml) at RT. A few drops of DMF, followed by oxalyl chloride (3 ml, 34 mmol) were added dropwise and the resulting mixture was stirred until gas evolution had ceased, and the suspended solid had dissolved. The mixture was concentrated in vacuo and co-evaporated with dichloromethane (2 x 40 ml_) to provide the crude acid chloride. (2-methylamino)- ethanol (2.24 ml, 28 mmol) and triethylamine (3.9 ml, 28 mmol) were dissolved in dichloromethane (50 ml) and cooled in an ice bath. The acid chloride was dissolved in dichloromethane (50 ml) and added dropwise to the cooled solution of amine. The mixture was allowed to warm to RT and stirred for 4.5 hours, after which point the reaction was quenched by the addition of sat. aq ammonium chloride solution (200 ml). The organics were extracted into dichloromethane (3 x 100 ml), and the combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved by gravity silica gel column chromatography (50% EtOAc/heptane to 100% EtOAc) with pre-absorption of the crude amide onto silica. 2-Benzoyl-6-fluoro-/V-(2-hydroxyethyl)-Λ/-methylbenzamide (490 mg) was obtained as a 3:4 mixture of two rotamers: δH (CDCI3; 250MHz) 3.04 (3H1 s, CH3, major rotamer), 3.10 (3H, s, CH3, minor rotamer), 3.33-3.40 (2H, two of CH2CjH2, major rotamer), 3.52-3.64 (2H, two of C]H2CH2, minor rotamer), 3.78-3.96 (4H, two of CH2CH2 for major and minor rotamer), 7.22-7.27 (4H, m, ArH both rotamers), 7.28-7.42 (6H, m, ArH both rotamers), 7.55-7.61 (2H, ArH both rotamers), 7.75-7.83 (4H, m, ArH both rotamers). 2-Benzoyl-3-fluoro-Λ/-(2-hydroxyethyl)-Λ/-methylbenzamide (2.74 g) was obtained as two rotamers: δH (CDCI3; 250MHz) 3.03 (3H, s, CH3, one rotamer), 3.05 (3H, s, CH3, one rotamer), 3.55-3.59 (4H, m, two of CH2CH2 for each rotamer), 3.75-3.79 (4H, m, two of CH2CH2 for each rotamer), 7.16-7.27 (4H, m, ArH both rotamers), 7.44-7.63 (4H, m, ArH both rotamers), 7.84 (2H, d, J7.9, ArH both rotamers). 2-{[3-Fluoro-2-(hydroxyphenyl-methyl)-benzyl]-methylamino}-e thanol 2-Benzoyl-3-fluoro-N-(2-hydroxyethyl)-N-methylbenzamide (2.58 g, 8.57 mmol) was dissolved in anhydrous THF (25ml) at RT under a nitrogen atmosphere. Borane- dimethylsulfide complex (2.0M in THF, 18.8 ml, 37.7 mmol) was added dropwise and the resulting mixture was stirred at RT overnight. The reaction was carefully quenched by the addition of HCI (10%, 36ml). The mixture was then heated to reflux temperature for approx. 1 hour before cooling to ambient temperature. The THF was removed in vacuo and the remaining solution was partitioned between MTBE (40 ml) and water (60 ml). The aqueous phase was separated, basified with 2M NaOH(aq) and extracted into ethyl acetate (4 x 50 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give 2-{[3-fluoro-2-(hydroxyphenyl-methyl)-benzyl]- methylamino}-ethanol as a viscous oil which later crystallised. δH (CDCI3; 250MHz) 2.17 (3H, s, CH3), 2.35-2.42 (1 H, m, one of CH2CH2), 2.52-2.62 (1 H, m, one of CIH2CH2), 2.88 (1 H, d, J12.5, one of ArCH2NR2), 3.42 (1 H, d, J12.5, one of ArCH2NR2), 3.62-3.65 (2H, m, two of CH2CH2), 6.38 (1H, s, CHOH), 6.96 (1 H, d, J7.3, ArH), 7.10-7.37 (7H, m, ArH). Example 11 10-Fluoro-5-methyl-1 -phenyl-1.S^.β-tetrahydro-δH-benzIfl-ajS-oxazocine Crude 2-{[3-fluoro-2-(hydroxyphenylmethyI)benzyl]methylamino}ethan ol (234 mg, 0.81 mmol) was heated to reflux temperature with pTSA (231 mg, 1.21 mmol) in toluene (4 ml). The reaction was kept open to allow the toluene/water to evaporate. After approx. 1.5 hours, a gummy residue remained in the reaction flask. It was allowed to cool to RT at which point, sat. aq sodium bicarbonate solution and ethyl acetate were added to solubilise the residue. The aqueous phase was repeatedly extracted with ethyl acetate, and the combined extracts were dried (MgSO4), filtered and evaporated to dryness to provide the crude cyclised product. Purification by gravity silica gel column chromatography [EtOAc] furnished the target compound, (90 g, 25%). δH (CDCI3; 250MHz) 2.47 (3H, S, CjH3), 2.59 (1H1 ddd, J13.9, 5.6, 3.3, one of CH2CH2), 2.78 (1H1 ddd, J13.9, 8.5, 2.6, one of CjH2CH2), 3.58 (1H, d, J12.4, one of ArCiH2NR2), 3.83 (1 H, ddd, J12.3, 5.6, 2.6, one of CjH2CjH2), 4.30 (1 H, ddd, J12.3, 8.5, 3.3, one of CjH2CjH2), 5.09 (1 H, d, J12.4, one of ArCIH2NR2), 5.94 (1 H1 d, J1.9, CjHOR), 6.89-6.96 (1 H, m, ArH)1 7.04 (1 H, d, J7.6, ArH)1 7.19-7.32 (6H, m, ArH) 2-{[2-Fluoro-6-(hydroxylphenylmethyl)benzyl]methylamino}etha nol 2-Benzoyl-6-fluoro-N-(2-hydroxyethyl)-N-methylbenzamide (440 mg, 1.46 mmol) was dissolved in dry THF (4 ml) under nitrogen. Borane-dimethylsulfide (2.0M solution in THF, 3.2 ml, 6.43 mmol) was added dropwise and the resulting mixture was stirred overnight at RT. The reaction was quenched by the addition of 2M HCI (6ml) and heated at reflux temperature for 1 hour. The acidic mixture was then cooled and partitioned between MTBE (30 ml) and water (30 ml). The aqueous phase was separated and extracted with ethyl acetate (4 x 30 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude amine. Purification by gravity silica gel column chromatography [EtOAc] furnished 2-{[2-fluoro-6- (hydroxylphenylmethyl)benzyl]methylamino}ethanol (19 mg, 5%). δH (250MHz; CDCI3) 2.72 (3H, s, NCH3), 2.54-2.73 (2H, m, two of CjH2CjH2), 3.36 (1H, dd, J12.8, 2.1 , one of ArCjH2NR2), 3.63-3.72 (3H, two of CjH2CjH2 and one of ArCjH2NR2), 5.91 (1H1 s, CjHOH), 6.97-7.07 (2H, m, aromatic H)1 7.22-7.40 (6H, m, aromatic H). Example 12 y-Fluoro-S-methyl-i-phenyl-I.S.^β-tetrahydro-SH-benztfl^.δ -oxazocine Crude 2-{[2-fluoro-6-(hydroxyphenyl-methyl)benzyl]methylamino}etha nol (20 mg, 0.069 mmol) was dissolved in toluene and pTSA (20 mg, 0.1 mmol) added. The mixture was heated to 120°C in an open vessel to allow evaporation of the solvent. After 30 mins, a gummy residue remained in the reaction vessel. The vessel was allowed to cool and the residue dissolved in ethyl acetate (5 ml) and sat. aq. sodium bicarbonate solution (10 ml). The aqueous phase was washed with ethyl acetate and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo to provide the product as a crude light brown oil (10 mg, 53%). δH (CDCI3, 250MHz) 2.50 (3H1 s, NCH3), 2.68 (1H, ddd, J13.9, 6.3, 2.8, one of CH2C]H2), 2.84 (1H, ddd, J13.9, 7.8, 2.1, one of CJj2CH2), 3.90 (1 H, ddd, J 12.5, 6.3, 2.1, one of C]H2CH2), 4.05 (1H, d, J13.4, one of ArCIH2), 4.21 (1H, ddd, J12.5, 7.8, 2.8, one of CIH2CH2), 4.71 (1 H, dd, J13.4, 3.4, one of ArCH2), 5.81 (1H, s, CHOR), 6.82 (1H, d, J7.6, aromatic H), 7.37 (1H, t, J8.5, aromatic H), 7.10-7.23 (2H, m, aromatic H), 7.25-7.35 (3H, m, aromatic H), 7.37-7.45 (1 H, m, aromatic H). Purity measured at 50%. TBS-protected 3-bromophenol To a solution of 3-bromophenol (100 g, 0.6 mol) in dichloromethane (600 ml) was added imidazole (100 g, 1.46 mol) at 00C. After 10 min, TBDMS-CI (96 g, 0.64 mol) was added, and the mixture was stirred at RT overnight. The mixture was then diluted with MTBE (1 L) and filtered. The filtrate was washed with sat. ammonium chloride (4 x 200 ml), sat. bicarb. (200 ml) and brine (200 ml), before being dried (MgSO4), filtered and concentrated in vacuo to give the product as a yellow oil (156.6 g) that was used without further purification. δH (CDCI3; 250MHz) 7.10-6.77 (4H, m, aromatics), 0.99 (9H, s, C(CH3)3), 0.21 (6H, s, 2 x CH3). 4-Bromo-2-(3-tbutyldimethylsilyloxy-benzoyl)-benzoic acid and 5-Bromo-2-(3- 'butyldimethylsilyloxy-benzoylj-benzoic acid A solution of TBS-protected 3-bromophenol (156.6 g, 0.54 mol) in anhydrous THF (160 ml) was added dropwise to a stirring suspension of magnesium turnings (13 g, 0.54 mol) in dry THF (240 ml). The Grignard formation initiated following the addition of 1 ml of solution. The resulting mixture was left stirring until the reflux had stopped, and then this was added in a single portion to a stirred solution of 4-bromophthalic anhydride (122.4 g, 0.54 mol) in anhydrous THF (240 ml). The reaction mixture was heated at reflux temperature overnight. After cooling to RT, the reaction was quenched by the addition of sat. aq. solution of ammonium chloride (250 ml) and the organics were extracted into ethyl acetate (3 x 250 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude acid as a brown oil (226.6 g). The crude material was carried through to the next step without further purification. δH (CDCI3; 250MHz) 8.07-6.75 (7H, m, aromatics), 0.99-0.94 (9H, m, C(CH3)3), 0.20-0.13 (6H, m, 2 x CH3). 5-Bromo-Λ/-(2-hydroxyethyI)-Λ/-methyI-2-(3-tbutyIdimethyls iIyloxy-benzoyl)- benzamide To a solution of a mixture of 4-bromo-2-(3-tbutyldimethyIsilyloxy-benzoyl)-ben2oic acid and δ-bromo^-β-'butyldimethylsilyloxy-benzoyO-benzoic acid (226.6 g, 0.52 mol) in anhydrous dichloromethane (900 ml), under an atmosphere of nitrogen, was added anhydrous Λ/,Λ/-dimethylformamide (1 ml) followed by the slow addition of oxalyl chloride (50.8 ml, 0.57 mol), and the reaction stirred at RT overnight. The dichloromethane was then removed in vacuo. Dichloromethane (2 x 500 ml) was added to the crude oil and evaporated in vacuo. The crude acid chloride was dissolved in dichloromethane (900 ml), cooled to O0C (ice bath) and triethylamine (81 ml, 0.57 mol) added dropwise. N- methylethanolamine (42.8 g, 0.57 mol) was then added dropwise and the mixture left to warm to RT overnight under an atmosphere of nitrogen. The mixture was then quenched with brine (800 ml) and the layers separated. The aqueous layer was then separated and washed with dichloromethane (800 ml), and the combined organics were dried (MgSO4), filtered and concentrated in vacuo to yield the mixture of regioisomers (255.5 g) as a dark brown oil. 100 g of the above brown oil was purified by silica gel column chromatography (3:1 EtOAc: Heptane). This afforded 14 g of 5-bromo-Λ/-(2-hydroxyethyI)-Λ/-methyl-2-(3- 'butyldimethylsilyloxy-benzoylj-benzamide. δH (CDCI3; 250MHz) 7.59-7.25 (7H, m, aromatics), 3.91-3.57 (4H, m, CH2-CH2), 3.11 and 2.99 (3H, 2 x s, NCH3), 0.98 (9H, s, C(CHg)3), 0.21 (6H, s, 2 x CH3). 5-Bromo-Λf-(2-hydroxyethyl)-yV-methyl-2-(3-tosyloxy-benzoyl )-benzamide TBAF (10.1 ml, 1M solution in THF, 10.14 mmol) was added to a stirred solution of 5-bromo-Λ/-(2-hydroxyethyl)-Λ/-methyl-2-(3-tbutyldimethyls ilyloxy-benzoyl)-benzamide (5g, 10.14 mmol) in THF (60 ml) at RT. A solution of tosyl chloride (1.9 g, 10.14 mmol) in THF (60 ml) was then added dropwise and the mixture heated to reflux temperature for 3 h. A further IOmmol of triethylamine followed by 7 mmol of TsCI were added over a further hour to drive the reaction to completion. After cooling to RT the mixture was diluted with ethyl acetate (100 ml), washed with water (2 x 100 ml), dried (MgSO4), filtered and concentrated in vacuo to give 7 g of an orange oil. Purification by silica gel column chromatography [2:1 EtOAc: Heptane] afforded the title compound (3.14 g, 58%) as a pale yellow oil. δH (CDCI3; 250MHz) 7.74-7.20 (11 H, m, aromatics), 3.86-3.53 (4H, m, CH2CH2), 3.07 and 2.97 (3H, 2 x s, NCH3), 2.47 (3H, s, Ar-CH3). 2-({5-Bromo-2-[hydroxyl-(3-tosyloxy-phenyl)-methyl]-benzyl}- methyIamino)- ethanol Borane dimethylsulfide complex (2.0M in THF1 12.94 ml, 25.88 mmol) was added dropwise to a solution of 5-bromo-Λ/-(2-hydroxyethyl)-Λ/-methyl-2-(3-tosyloxy-benzoy l)- benzamide (3.14 g, 5.88 mmol) in anhydrous THF (20 ml) at O0C. The reaction mixture was left to stir at RT overnight. The crude mixture was then quenched carefully by addition of an aqueous 6M HCI solution (20 ml) and then heated to reflux temperature for 2h. After cooling to RT, the THF was removed in vacuo. Water (10 ml) was added and the mixture was then basified to pH 10 by addition of an aqueous solution of sodium hydroxide solution (50 %), and then extracted with ethyl acetate (2 x 20 ml_). The combined organic layers were then dried (MgSO4), filtered and concentrated in vacuo to give a white oil/solid (3.17 g). Purification by silica gel column chromatography [5: 1,EtOAc: Heptane] afforded the title compound (0.74g, 24%) as a colourless oil. δH (CDCI3; 250MHz) 7.67-6.83 (11H1 m, aromatics), 5.72 (1H, s, CHOH), 3.73-3.67 (2H, m, CH2), 3.39-3.27 (2H1 m, CH2), 2.63-2.53 (2H, m, CH2), 2.44 (3H, s, Ar-CH3), 2.22 (3H1 s, NCH3). Example 13 8-Bromo-5-methyl-1-(3-tosyloxy)phenyl-1,3,4,6-tetrahydro-5H- ben2[fI-2,5- oxazocine 2-({5-Bromo-2-[hydroxyl-(3-tosyloxyphenyl)methyllbenzyl}meth ylamino)ethanol (0.74 g, 1.43 mmol) was heated to reflux temperature under Dean-Stark conditions with pTSA (0.41 g, 2.14 mmol) in toluene (20 ml) for 2 h. The reaction mixture was allowed to cool and then diluted with ethyl acetate (10 ml). The mixture was washed with sat. aq. sodium bicarbonate solution (2 x 10 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide 0.65 g of product that was used without further purification. δH (CDCI3; 250MHz) 7.67-6.72 (11 H, m, aromatics), 5.67 (1 H, s, CH-O), 4.55 (1H, d, J 13, AΓCHAHBN), 4.11 (1 H, ddd, J 13, 8 and 2.5, CHAHBCH2), 3.83 (1H, ddd, J 13, 8 and 2.5, CHAH8CH2), 3.60 (1H, d, J 13, AΓCHAHBN), 2.79-2.59 (2H, m, CH2CH2), 2.48 and 2.46 (6H, 2 x s, 2 x CH3). Example 14 8-Bromo-5-methyl-1-(3-hydroxy)phenyI-1,3,456-tetrahydro-5H-b enz[f|-2,5-oxa2ocine Potassium hydroxide (0.30 g, 5.33 mmol) was added to a stirred solution of 8- bromo-5-methyl-1-(3-tosyloxy)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2,5-oxazocine (0.65 g, 1.3 mmol) in MeOH (5 ml) and DMF (5 ml) and the mixture heated at 60 0C for 3h. After cooling to RT1 the crude mixture was poured into water (10 ml) and the mixture extracted with dichloromethane (2 x 10 ml). The aqueous layer was then acidified to pH 9 and extracted with dichloromethane (2 x 10 ml). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give 0.42 g of a yellow oil. Purification by silica gel column chromatography (5% MeOH/DCM) afforded the title compound (0.20 g, 44%) as a white solid. δH (CDCI3; 250MHz) 7.34-6.67 (7H, m, aromatics), 5.60 (1H, s, CH-O), 5.17 (1 H, d, J 13, AΓCHAHBN), 4.20 (1 H, ddd, J 13, 8 and 2.5, CIHAHBCH2), 3.80 (1 H, ddd, J 13, 8 and 2.5, CHAHBCH2), 3.53 (1H, d, J 13, AΓCHAJHBN), 2.75-2.56 (2H, m, CH2CH2), 2.36 (3H, S, NCH3). Example 15 δ-Cyano-δ-methyl-i-CS-hydroxyJphenyl-I.S^^-tetrahydro-SH-b enztfl^jS-oxazocine 8-Bromo-5-methyl-1-(3-hydroxy)phenyl-1,3,4,6-tetrahydro-5H-b enz[f]-2,5- oxazocine (100 mg, 0.29 mmol), Zn (1 mg, 0.02 mmol), Zn(OAc)2 (7 mg, 0.034 mmol), Zn(CN)2 (25 mg, 0.22 mmol), Pd2(dba)3 (37 mg, 0.04 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene (18 mg, 0.034 mmol) were heated to 140°C in DMF (3 ml) and H2O (30 μl) for 4h. The black reaction mixture was allowed to cool to RT and diluted with water (20 ml). The resulting brown precipitate was collected by filtration and washed with water then brine. The filtrate was extracted with ethyl acetate (2 x 60 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product as a brown oil. Purification by gravity silica gel column chromatography [dichloromethane] furnished the desired product (25 mg, 29%) as a yellow oil. δH(CDCI3; 250MHz) 7.45-6.70 (7H, m, aromatics), 5.65 (1H, s, CHO), 5.03 (1 H, d, J 13, AΓCHAHB-N), 4.26-4.18 (1H, m, C(HAHBCH2), 3.81-3.75 (1H, m, CHAHBCH2), 3.61 (1H, d, J 13, AΓCHAHB-N), 2.70-2.53 (2H, m, CH2CH2), 2.41 (3H, s, NCH3). Example 16 δ-Cyclopropyl-δ-methyl-i-tS-hydroxyJphenyl-i^j^β-tetrahyc lro-SH-benzffl^jS- oxazocine 8-Bromo-5-methyl-1-(3-hydroxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine (100 mg, 0.29 mmol), cyclopropylboronic acid (33 mg,0.36 mmol), K3PO4 (217 mg, 1.01 mmol), Pd(OAc)2 (4 mg, 0.015 mmol) and P(cyclohexane)3 (9 mg, 0.029 mmol) were heated to 100°C in toluene (2.5 ml_) and H2O (125 μl) for 4 hours. After cooling to RT, water (2.5 ml) was added and the mixture extracted with ethyl acetate (2 x 5 ml), washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by gravity silica gel column chromatography [dichloromethane] furnished the desired product (40 mg, 44%) as a colourless oil. δH(CDCI3; 250MHz) 7.27-6.69 (7H, m, aromatics), 5.61(1 H, s, CHO), 5.04 (1H, d, J 13, AΓCJHAHB-N) 4.23-4.15 (1 H1 m, CHAHBCH2), 3.83-3.78 (1H1 m, CHAHBCH2), 3.66 (1 H1 d, J 13, AΓCHAHB-N), 2.78-2.58 (2H1 m, CH2CH2), 2.41 (3H, s, NCH3), 1.84-1.78 (1 H, m, CIHCH2), 0.95-0.90 (2H, m, CH2CH2), 0.64-0.62 (2H, m, CH2CH2). Example 17 δ-Bromo-δ-methyl-i^a-allyloxyJphenyMjS^.e-tetrahydro-SH-be nztfl-a.S-oxazocine 8-Bromo-5-methyl-1-(3-hydroxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine (50 mg, 0.14 mmol), allyl alcohol (33 mg, 0.57 mmol), Pd(OAc)2 (1 mg, 0.0035 mmol), triphenylphosphine (2 mg, 0.0075 mmol), Ti(O1Pr)4 (10 mg, 0.035 mmol), molecular sieves (4 A, 28 mg) were heated at 50°C in benzene (1 ml) overnight. After cooling to RT, the black reaction mixture poured into water (5 ml), extracted with MTBE (2 x 5 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product as a brown oil. Purification by gravity silica gel column chromatography [dichloromethane] furnished the desired product (16 mg, 30%) as a pale yellow oil. δH(CDCI3; 250MHz) 7.38-7.19 (3H, m, aromatics), 6.90-6.80 (4H, m, aromatics), 6.09- 5.96 (1H, m, CH=CH2), 5.71 (1H, s, CHO), 5.42-5.25 (2H, m, CH=CH2), 4.76 (1 H, d, J 13, AΓCHAHB-N), 4.51 (2H, d, J 5, OCH2), 4.21-4.12 (1 H, m, CHAHBCH2), 3.88-3.80 (1H, m, CHAHBCH2), 3.63 (1H, d, J 13, AΓCHAHB-N), 2.87-2.77 (1H, m, CH2CHAHB), 2.69-2.60 (1 H, m, CH2CHAH8) 2.47 (3H1 S1 NCH3). Example 18 δ-Cyano-δ-methyl-i-tS-allyloxyJphenyl-I.S^jβ-tetrahydro-S H-benztfl^.S-oxazocine 8-Cyano-5-methyl-1-(3-hydroxy)phenyl-1,3,4,6-tetrahydro-5H-b enz[f]-2,5- oxazocine (50 mg, 0.17 mmol), allyl alcohol (49 mg, 0.68 mmol), Pd(OAc)2 (1 mg, 0.0035 mmol), triphenylphosphine (2 mg, 0.0075 mmol), Ti(O1Pr)4 (20 mg, 0.07 mmol), molecular sieves (4 A, 40 mg) were heated at 50°C in benzene (2 ml) overnight. After cooling to RT, the black reaction mixture poured into water (5 ml) and extracted with MTBE (2 x 5 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product as a brown oil. Purification by gravity silica gel column chromatography [dichloromethane] furnished the desired product (4 mg, 7%) as a pale yellow oil. δH(CDCI3; 250MHz) 7.65-6.81 (7H, m, aromatics), 6.08-5.97 (1 H, m, CH=CH2), 5.74 (1H, s, CHO), 5.42-5.25 (2H, m, CH=CH2), 4.98 (1 H, d, J 13, AΓCHAHB-N), 4.51 (2H, <J, J 5, OCH2), 4.31-4.23 (1H, m, CHAHBCH2), 3.90-3.82 (1H, m, CHAHBCH2), 3.74 (1H, d, J 13, AΓCHAHB-N), 2.81-2.70 (2H, m, CH2CH2), 2.51 (3H, s, NCH3). Example 19 δ-Cyclopropyl-δ-methyl-i-JS-allyloxyJphenyl-i^j^e-tetrahyd ro-SH-benztq-a^- oxazocine δ-Cyclopropyl-δ-methyl-HS-hydroxyJphenyl-I.SAe-tetrahydro- SH-benzff]^^ oxazocine (90 mg, 0.29 mmol), allyi alcohol (0.1 ml, 1.16 mmol), Pd(OAc)2 (1 mg, 0.0035 mmol), triphenylphosphine (3 mg, 0.011 mmol), Ti(O1Pr)4 (0.03 mL, 0.07 mmol), molecular sieves (4 A1 64 mg) were heated at 500C in benzene (3 ml) overnight. After cooling to RT1 the black reaction mixture was poured into water (5 ml), extracted with MTBE (2 x 5 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product as a brown oil. Purification by gravity silica gel column chromatography [dichloromethane] furnished the desired product (3 mg, 3%) as a pale yellow oil. δH(CDCI3; 250MHz) 7.24-6.76 (7H, m, aromatics), 6.04-5.97 (1 H, m, CH=CH2), 5.41 (1H, s, CHO), 5.41-5.24 (2H, m, CH=CJH2), 4.70 (1 H, d, J 13, AΓCHAHB-N), 4.49 (2H, d, J 5, OCH2), 4.19-4.11 (1H, m, CHAHBCH2), 3.88-3.82 (1 H, m, CHAHBCH2), 3.71 (1 H, d, J 13, AΓCHAHB-N), 2.92-2.82 (1H, m, CH2CHAHB), 2.69-2.66 (1H1 m, CH2CHAHB), 2.49 (3H, s, NCH3), 1.89-1.83 (1H, m, CHCH2), 0.98-0.90 (2H, m, CHCH2), 0.71-0.65 (2H1 m, CHCH2). The following Examples were prepared in a similar manner. The substituted 'bromophenyl' starting materials, used for the Grignard formation, were either sourced commercially or generated synthetically via known organic chemistry, e.g. as in the following example where a nitro group was converted to a bromo via the intermediate amine. 2-Methoxy-6-aminotoluene 2-methyl-3-nitroanisole (20 g, 0.12 mol) was suspended in methanol (200 ml) at RT under nitrogen. Pd/C (5%, 2 g) was added and the system was shaken under an atmosphere of hydrogen overnight, until TLC indicated one product. The reaction mixture was filtered through celite, and the celite washed with methanol (3 x 100 ml) and the filtrate concentrated in vacuo. This afforded 18 g of a red oil that was used without further purification. δH (CDCI3; 250MHz) 7.01 (1H1 1, J 8, aromatics), 6.38 (2H, d, J 8, aromatics), 3.83 (3H, s, OCH3), 2.08 (3H, s, CIH3). 2-Methoxy-4-bromotoluene Crude 2-methoxy-6-amino-toluene (max. 120 mmol) was suspended in HBr (48%, 48 ml) and water (120 ml) and cooled to O0C in an ice bath. Sodium nitrite (9.2 g) in water (24 ml) was added dropwise to the cold mixture, which turned yellow then brown. After 10 min, excess nitrite was destroyed by addition of urea (0.08 g) and the mixture was rapidly filtered into cold (O0C) acetone (480 ml) to give a bright yellow solution. CuBr (99.999%, 18.89, 131 mmol) was then added portionwise and the resulting mixture stirred at O0C for 3h. Gas evolution was observed. The mixture was allowed to warm to ambient temperature, and then concentrated in vacuo. Dichloromethane was then added and the mixture washed with sat. aq. sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to give the product (23.1 g, 96%) as a red oil. δH (CDCI3; 250MHz) 7.18-6.77 (3H, m, aromatics), 3.83 (3H, s, OCH3), 2.32 (3H, s, CH3). 5-Bromo-2-(3-methoxy-2-methylbenzoyl)-benzoic acid and 4-Bromo-2-(3-methoxy- 2-methylbenzoyl)-benzoic acid 2-methoxy-4-bromo-toluene (23.1 g, 115 mmol) in dry THF (35 ml) was added dropwise to a stirred suspension of magnesium turnings (2.77 g, 115 mmol) and a crystal of iodine in dry THF (40 ml) under a nitrogen atmosphere. Upon addition, the reaction mixture reached reflux. After cooling to RT, this Grignard solution was added dropwise to a stirred solution of 4-bromophthalic anhydride (26.1 g, 115 mmol) in dry THF (45 ml) and the resulting mixture heated to reflux temperature overnight. After cooling, the reaction was quenched with sat. aq. ammonium chloride solution, and extracted with ethyl acetate. The organics were dried (MgSO4), filtered and concentrated in vacuo to give the crude mixture of keto-acids (34 g) as a brown solid. This material was carried straight on to the subsequent step. 5-Bromo-/V-(2-hydroxyethyl)-/V-methyl-2-(3-methoxy-2-methyI- benzoyI)-benzamide A crude mixture of 5-bromo-2-(3-methoxy-2-methylbenzoyl)-benzoic acid and A- bromo-2-(3-methoxy-2-methylbenzoyl)-benzoic acid (34 g, 98.5 mmol) was dissolved in dichloromethane (200 ml) at RT. DMF (1 ml) followed by oxalyl chloride (9.67 ml, 13.98 g, 108.35 mmol) were added dropwise and the reaction stirred at RT overnight. The reaction mixture was then concentrated in vacuo and co-evaporated with dichloromethane (2 x 200 ml) to provide the crude acid chloride. This was dissolved in dichloromethane (200 ml), cooled to 00C, and triethylamine (15.35 ml, 11.22 g, 108.35 mmol) was added dropwise, followed by Λ/-methy!ethanolamine and the mixture left to warm to RT overnight. The reaction was then quenched with brine and extracted with dichloromethane. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude amide as a mixture of regioisomers. The 5- bromo-Λ/-(2-hydroxyethyl)-Λ/-methy!-2-(3-methoxy-2-methyl- benzoyl)-benzamide (10 g, 25 %) was separated by silica gel column chromatography [4:1 EtOAc/heptane]. δH (CDCI3; 250MHz) 7.55-6.91 (6H1 m, aromatics), 3.98-3.69 (7H, m, OCH3 and CH2CH2), 3.15 and 2.99 (3H, 2 x s, NCH3), 2.20 and 2.17 (3H, 2 x s, CH3). 2-({5-Bromo-2-[hydroxyl-(3-methoxy-2-methylphenyl)methyl]ben zyl}methylamino)- ethanol Borane-dimethyl sulphide complex (2.0 M1 55 ml, 0.11 mol) was added dropwise to a stirring solution of 5-bromo-/V-(2-hydroxyethyl)-Λ/-methyl-2-(3-methoxy-2-methyl - benzoyl)-benzamide (10 g, 0.025 mol) in anhydrous THF (80 ml) at RT under nitrogen, and allowed to stir overnight. The reaction was quenched by the careful addition of 6M HCI (80 ml), and the resulting mixture was heated to reflux temperature for 2 hours. After cooling to RT1 the THF was removed in vacuo and the mixture partitioned between water (40 ml) and MTBE (80 ml). The aqueous phase was separated, basified with aq. 2M NaOH1 and extracted into ethyl acetate (3 x 90 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the desired amine as a viscous oil, which slowly crystallised (6.2 g, 63 %). The material was used in the next step without further purification. δH (CDCI3; 250MHz) 7.41-7.25 (4H1 m, aromatics), 6.89 (1 H, d, J 8, aromatics), 6.61 (1H1 d, J 8, aromatics), 6.10 (1H, s, CHOH), 4.33 (1H1 d, J 13, CJHAHBN), 3.84 (3H, s, OCH3), 3.84-3.62 (2H, m, CH2), 3.26 (1H, d, J 13, CHAHBN), 2.77-2.73 (2H1 m, CH2), 2.33 (3H1 s, NCH3), 1.83 (3H1 S1 CH3). Example 20 8-Bromo-5-methyl-1 -(2-methyl-3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine 2-({5-bromo-2-[hydroxyl-(3-methoxy-2-methylphenyl)-methyl]-b enzyl}- methylamino)-ethanol (5 g, 12.6 mmol) was heated to reflux temperature in toluene (250 ml) with pTSA (3.65 g, 18.95 mmol) under Dean-Stark conditions for 4 hours. The reaction mixture was allowed to cool to RT, diluted with ethyl acetate (200 ml) and washed with a sat. aq. solution of sodium bicarbonate (300 ml). The aqueous layer was extracted with ethyl acetate (3 x 200 ml) and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography [DCM] gave the target product as a pale straw coloured oil (2.8 g, 59 %). δH (CDCI3; 250MHz) 7.42-6.70 (6H1 m, aromatics), 5.97 (1 H, s, CHO), 4.69 (1 H, d, J 13, CHAHBN), 4.14-4.05 (1H, m, CHAH13), 3.89-3.73 (5H1 m, CHAHB, OCH3, and CHAHBN)1 2.92-2.82 (1H, m, CIHAHB)1 2.69-2.59 (1H, m, CHAJHB), 2.45 (3H1 S1 CH3N)1 2.15 (3H, s, CH3). Example 21 8-Cyano-5-methyl-1-(2-methyl-3-methoxy)phenyl-1,3,4,6-tetrah ydro-5H-ben2[f|-2,5- oxazocine 8-Bromo-5-methyl-1-(2-methyl-3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[fl- 2,5-oxazocine (250 mg, 0.66 mmol), Zn (4 mg, 0.04 mmol), Zn(OAc)2 (14 mg, 0.07 mmol), Zn(CN)2 (50 mg, 0.44 mmol), 1,1'-bis(diphenylphosphino)ferrocene (36 mg, 0.07 mmol) and Pd2(dba)3 (74 mg, 0.08 mmol) were heated to 140 0C in degassed DMF (3 ml) and H2O (30μl) overnight. The mixture was allowed to cool to RT and water (10 ml) was added, producing a brown precipitate. The precipitate was collected by filtration and washed with water and brine. The filtrate was then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide 100 mg of the crude product. Purification by gravity silica gel column chromatography [DCM] furnished the target product as a yellow oil (70 mg, 33 %). δH (CDCI3; 250MHz) 7.60 (1H, d, J 1.5, aromatics), 7.48 (1H, dd, J 1.5 and 8, aromatics), 7.12-7.01 (2H1 m, aromatics), 6.82 (1 H, d, J 8, aromatics), 6.46 (1H, d, J 8, aromatics), 5.97 (1H, s, CHO), 5.02 (1H, d, J 13, CHAHBN), 4.30-4.24 (1H1 m, CHAHBCH2), 3.96-3.80 (2H, m, CHAHBN and CHAHBCH2), 3.82 (3H, s, OCH3), 2.96-2.85 (1H, m, CH2CIHAHB), 2.76-2.65 (1H1 m, CH2CHAJHB), 2.53 (3H, s, NCH3), 2.20 (3H1 S1 CH3). Example 22 8-Cyclopropyl-5-methyl-1-(2-methyl-3-methoxy)phenyl-1,3,4,6- tetrahydro-5H- benz[f]-2,5-oxazocine 8-Bromo-5-methyl-1-(2-methyl-3-methoxy)phenyl-1,3l4,6-tetrah ydro-5H-benz[f]- 2,5-oxazocine (295 mg, 0.71 mmol), cyclopropylboronic acid (89 mg, 0.96 mmol), P(cyclohexane)3 (24 mg, 0.08 mmol), K3PO4 (586 mg, 2.73 mmol) and Pd(OAc)2 (10.4 mg, 0.04 mmol) were heated at 100 0C in toluene (7 ml) and water (336 μl) overnight. The reaction mixture was allowed to cool and then diluted with ethyl acetate (30 ml). The organic mixture was washed with water (30 ml) and the aqueous phase extracted into ethyl acetate (3 x 20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide 0.29 g of the crude product. Purification by silica gel gravity column chromatography [DCM] furnished the target product (100 mg, 38%) as a yellow oil/solid. δH (CDCI3; 250MHz) 7.11 (1 H, t, J 8, aromatics), 6.97 (1H1 d, J 1.5, aromatics), 6.88-6.71 (4H1 m, aromatics), 5.98 (1H, s, CHO), 4.63 (1H, d, J 13, CHAHBN), 4.18-4.06 (1H, m, CHAHBCH2), 3.89-3.82 (5H, m, CHAHBN, CHAHBCH2 and OCH3), 2.98-2.88 (1H1 m, CH2CIHAHB), 2.72-2.64 (1H1 m, CH2CHAJHB), 2.50 (3H, s, NCH3), 2.16 (3H1 s, CH3), 1.91- 1.84 (1 H, m, CHCH2), 0.99-0.91 (2H1 m, CH2CH2), 0.73-0.66 (2H, m, CH2CH2). Example 23 δ-Bromo-δ-methyl-i-tS-methoxy^-methylJphenyl-I.S^.β-tetra hydro-δH-benzEfl^.δ- oxazocine 2-({5-bromo-2-[hydroxyl-(3-methoxy-4-methylphenyl)-methyl]-b enzyl}- methylamino)-ethanol (879 mg, 2.23 mmol) was heated to reflux temperature in toluene (9ml) with pTSA (635 mg, 3.34 mmol) under Dean-Stark conditions for 3 hours. The reaction mixture was allowed to cool to RT1 diluted with ethyl acetate (50 ml) and washed with a saturated solution of sodium bicarbonate (60 ml). The aqueous layer was extracted into ethyl acetate (3 x 50 ml) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by gravity silica gel column chromatography [EtOAc] gave the target product as a pale straw coloured oil (23 g, 28%). A second impure batch of product was obtained from the column. δH (CDCI3; 250MHz) 2.18 (3H, s, CH3), 2.48 (3H, s, NCH3), 2.66 (1H1 ddd, J14.2, 5.6, 2.7, one of CH2CH2), 2.84 (1H, ddd, J14.2, 8.2, 2.1, one of CH2CH2), 3.67 (1H, d, J12.8, one of ArCH2NR2), 3.80 (3H, s, OCH3), 3.86 (1H, ddd, J12.7, 5.6, 2.1 , one of CH2CH2), 4.18 (1H, ddd, J12.8, 8.2, 2.7, one of CH2CH2), 4.80 (1H, d, J12.8, one of ArCH2NR2), 5.71 (1H, s, CHOR), 6.68 (1 H, dd, J7.6, 1.2, one of ArH), 6.76 (1 H, bs, one of Ar]H)1 6.89 (1H1 d, J 8.2, ArH), 7.06 (1H1 d, J7.6, one of ArH)1 7.32 (1H1 dd, J8.2, 1.8, one of ArJH), 7.39 (1H, d, J1.8, one Of ArJH). Example 24 δ-Cyano-δ-methyl-I^S-methoxy^-methylJphenyl-I.S^.β-tetrah ydro-SH-benzEfl^S- oxazocine 8-Bromo-5-methyl-1-(3-methoxy-4-methyl)phenyl-1,3,4l6-tetrah ydro-5H-benz[f]- 2,5-oxazocine (154 mg, 0.41 mmol), Zn (2 mg, 0.03 mmol), Zn(OAc)2 (10 mg, 0.05 mmol), Zn(CN)2 (29 mg, 0.25 mmol), 1,1'-bis(diphenylphosphino)ferrocene (30 mg, 0.05 mmol) and Pd2(dba)3 (55 mg, 0.06 mmol) were heated to 1400C in DMF (3 ml) and H2O (30 μl) overnight. The mixture was allowed to cool to RT and water (30 ml) was added, producing a brown precipitate. The precipitate was collected by filtration and washed with water and ethyl acetate. The filtrate was then washed with brine (2 x 40 ml) and the combined aqueous phases were extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel gravity column chromatography [EtOAc] furnished the target product as a brown oil (75 mg, 57%). δH (CDCI3; 250MHz) 2.17 (3H, S1 CjH3), 2.46 (3H1 S, NCH3), 2.65 (1H, ddd, J14.3, 5.1 , 3.0, one of CH2CH2), 2.78 (1H, ddd, J14.3, 8.6, 2.5, one of CH2CH2), 3.71 (1H, d, J13.0, one Of ArCH2NR2), 3.79 (3H, s, OCH3), 3.84 (1 H, ddd, J12.8, 5.1 , 2.5, one of CH2CH2), 4.26 (1H, ddd, J12.8, 8.6, 3.0, one of CH2CIi), 4.99 (1H, d, J13.0, one Of ArCH2NR2), 5.73 (1 H1 CHOR), 6.63 (1 H, d, J1.5, ArIH), 6.72 (1H, s, ArH), 7.06 (1 H, d, J7.6, ArH), 7.14 (1 H, d, J8.2, ArH)1 7.47 (1H, dd, J8.2, 1.8, ArH), 7.53 (1 H, d, J1.5, ArJH). Example 25 5-Methyl-1-(3-methoxy-4-methyl)phenyl-1,3,4,6-tetrahydro-5H- benz[f]-2,5- oxazocine-8-carboxamide 8-Cyano-5-methyl-1-(3-methoxy-4-methyl)phenyl-1 ,3,4,6-tetrahydro-5H-benz[fJ- 2,5-oxazocine (1.1 g, 3.56 mmol) was heated to reflux temperature in fBuOH (24 ml) with potassium hydroxide (0.29 mg, 5.34 mmol) for 2 h. At the end of this time, the reaction mixture was allowed to cool to RT. The mixture was then washed with brine (50 ml) and extracted into dichloromethane (3 x 50 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude amide as a light brown solid. Purification by silica gel column chromatography [1% MeOH in DCM to 12% MeOH in DCM] afforded the title compound (385 mg, 32%). δ (CDCI3; 250MHz) 2.16 (3H, s, CH3), 2.47 (3H, s, NCH3), 2.52-2.62 (1H, m (poorly resolved ddd), one of CH2CH2), 2.75-2.88 (1H, m (poorly resolved ddd), one of CH2CH2), 3.77 (4H, s, OCH3 and one of ArCH2), 3.81-3.92 (1 H, m (poorly resolved ddd), one of CH2CIH2), 4.15-4.28 (1H, m (poorly resolved ddd), one of CH2CH2), 4.89 (1H, d, J12.8, one of ArCH2), 5.77 (1 H, s, CHOR), 6.76-6.75 (3H, m, aromatic H), 7.03-7.12 (2H, m, aromatic JH), 7.59-7.68 (2H, m, aromatic H). Example 26 δ-Cyclopropyl-S-methyl-i-tS-methoxy^-methylJphenyl-I.S^jβ- tetrahydro-δH- benz[f]-2,5-oxazocine 8-Bromo-5-methyl-1-(3-methoxy-4-methyl)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]- 2,5-oxazocine (154 mg, 0.41 mmol), cyclopropylboronic acid (46 mg, 0.53 mmol), P(cyclohexane)3 (11 mg, 0.041 mmol), K3PO4 (304 mg, 1.43 mmol) and Pd(OAc)2 (5 mg, 0.02 mmol) were heated at 100°C in toluene (3 ml) and water (150 μl) for 3 hours 15 mins. The reaction mixture was allowed to cool and then diluted with ethyl acetate (30ml). The organic mixture was washed with water (30 ml) and the aqueous phase extracted into ethyl acetate (3 x 20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel gravity column chromatography [EtOAc] furnished the target product and recovered starting material. δH (CDCI3; 250MHz) 0.64-0.71 (2H1 m, two of cyclopropyl CH2CH2), 0.89-0.97 (2H, m, two of cyclopropyl CH2CjH2), 1.80-1.89 (1 H, m, cyclopropyl CJd), 2.16 (3H, s, CH3), 2.48 (3H, s, NCH3), 2.63 (1H, ddd, J14.2, 5.6, 2.6, one of CH2CH2), 2.85 (1 H, ddd, J14.2, 8.4, 2.3, one of CH2CH2), 3.70 (1H, d, J12.7, one of ArClH2NR2), 3.78 (3H, s, OCH3), 3.84 (1 H, ddd, J12.5, 5.6, 2.3, one of CH2C]H2), 4.17 (1 H, ddd, v/12.5, 8.4, 2.6, one of CH2CH2), 4.70 (1H, d, J12.7, one Of ArCIH2NR2), 5.73 (1 H, s, CHOR), 6.69 (1H, dd, J7.6, 1.2, one of ArH), 6.79 (1H, s, ArH), 6.86 (2H, d, J1.2, ArH), 6.94 (1 H, s, ArH), 7.03 (1H, d, J7.6, ArH). Example 27 θ-Bromo-S-methyl-i-tS^-methylenedioxyJphenyl-I.S^.β-tetrah ydro-SH-benzH^.δ- oxazocine 2-{[2-(Benzo-[1,3]-dioxol-yl-hydroxymethyl)-4-bromobenzyl]-m ethylamino}- ethanol (148 mg, 0.38 mmol) was heated to reflux temperature with pTSA (107 mg, 0.56 mmol) in toluene (3 ml) under Dean-stark conditions for 3 hours. The mixture was then cooled, diluted with ethyl acetate and washed with sat. aq. sodium bicarbonate solution. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel gravity column chromatography [3%MeOH/EtOAc to 10%MeOH/EtOAc] furnished product (89 mg, 62%). δH(CDCI3; 250MHz) 2.43 (3H, s, CH3), 2.60 (1 H, ddd, J14.2, 5.3, 2.9, one of CH2CH2), 2.78 (1H, ddd, J14.2, 8.7, 2.4, one of CH2CH2), 3.61 (1H, d, J12.7, one Of ArCIH2N), 3.81 (1 H, ddd, J12.5, 5.3, 2.4, one of CH2CH2), 4.20 (1 H, ddd, J12.5, 8.7, 2.9, one of CH2C]H2), 4.84 (1H, d, J12.7, one of ArCH2N), 5.61 (1H, s, CHOR), 5.93 (2H, s, ROCH2OR), 6.71-6.75 (3H, m, ArH), 7.07-7.14 (2H, m, ArHD, 7.36 (1H, dd, J8.0, 4.0, ArH). Example 28 9-Cyano-5-methyl-1 -(3,4-methylenedioxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine A solution of 9-bromo-5-methyl-1-(3,4-methylenedioxy)phenyl-1,3,4,6-tetrah ydro- 5H-benz[f]-2,5-oxazocine (89 mg, 0.23 mmol), Zn (1 mg, 0.012 mmol), Zn(CN)2 (16 mg, 0.138 mmol), Zn(OAc)2 (2 mg, 0.011 mmol), 1 ,1'-bis(diphenylphosphino)ferrocene (18 mg, 0.05 mmol) and Pd2(dba)3 (11 mg, 0.06 mmol) in DMF (2 ml) and H2O (20 μl) was degassed under vacuum for 15 minutes and then heated at 140°C overnight. The mixture was then allowed to cool and water added. The organics were extracted into ethyl acetate and then washed with brine to remove the DMF. The combined organic washings were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel column chromatography [EtOAc] furnished product (21 mg, 27%). δH (CDCI3; 250MHz) 2.45 (3H, s, NCjH3), 2.63 (1 H, ddd, J14.3, 5.2, 2.8, one of CH2CH2), 2.76 (1H, ddd, J14.3, 8.4, 2.4, one of CjH2CH2), 3.70 (1 H, d, J12.8, one of ArCjH2NR2), 3.81 (1 H, ddd, J12.6, 5.2, 2.4, one of CjH2Cu2), 4.20 (1 H, ddd, J12.6, 8.4, 2.8, one of CjH2CjH2), 4.90 (1H, d, J12.8, one of ArCIH2NR2), 5.69 (1H, s, CHOR), 5.94 (2H, s, ROC]H2OR), 6.69-6.78 (3H, m, ArH)1 7.27-7.33 (2H, m, ArH), 7.51 (1 H, dd, J7.9, 1.5, ArjH). Example 29 g-Cyclopropyl-δ-methyl-i-fS^-methylenedioxyJphenyl-ijS^jβ- tetrahydro-SH- benz[f]-2,5-oxazocine A mixture of 9-bromo-5-methyl-1-(3,4-methylenedioxy)phenyl-1,3,4,6-tetrah ydro- 5H-benz[f]-2,5-oxazocine (280 mg, 0.75 mmol), cyclopropylboronic acid (84 mg, 0.97 mmol), K3PO4 (555 mg, 2.61 mmol), Pd(OAc)2 (8.4 mg, 0.04 mmol) and P(cyclohexane)3 (21 mg, 0.075 mmol) in toluene (5 ml) and H2O (250 μl) was heated at 1000C for 3 hours, during which time it turned black. After cooling, water (12 ml) was added and the organics were extracted into ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification (repeated) by silica gel column chromatography [EtOAc] furnished product (56 mg, 22%). δH (CDCL3; 250MHz) 0.58-0.63 (2H, m, two of cyclopropyl CjH2CjH2), 0.86-0.94 (2H, m, two of cyclopropyl ClH2CjH2), 1.75-1.84 (1H, m, cyclopropyl CH), 2.44 (3H, s, CjH3), 2.55- 2.63 (1H, m, one of CjH2CjH2), 2.75-2.84 (1 H, m, one of CjH2CjH2), 3.62 (1H1 d, J12.5, one Of ArCH2NR2), 3.81 (1 H, ddd, J12.5, 5.6, 2.4, one Of CjH2CjH2), 4.14-4.22 (1 H, m, one of CIH2CIH2), 4.79 (1H, d, J12.5, one of ArCjH2NR2), 6.63 (1H, s, CHOR), 5.91 (2H, s, ROCjH2OR), 6.74 and 6.75 (4H, 2 x s, ArjH), 6.87 (1H, dd, J7.6, 1.9, ArHJ1 7.10 (1 H, d, J7.9). Example 30 8-Bromo-5-methyl-1-(3,4-methylenedioxy)phenyl-1,3,4,6-tetrah ydro-5H-benz[fI-2,5- oxazocine 2-{[2-(Benzo-[1 ,3]-dioxol-5-yl-hydroxymethyl)-5-bromobenzyl]-methylamino}- ethanol (715 mg, 1.82 mmol) and pTSA (519 mg, 2.73 mmol) were heated to reflux temperature in toluene (8 ml) under Dean-Stark conditions for 2 hours. Once cooled to RT, the reaction mixture was diluted with ethyl acetate and washed with sat. aq. sodium bicarbonate solution. The organic phases were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel column chromatography [100% EtOAc to 5%MeOH/EtOAc] yielded 214 mg, (31%). δH (CDCI3; 250MHz) 2.45 (3H, s, CH3), 2.61 (1 H, ddd, J14.1, 5.8, 2.8, one of CH2CH2), 2.79 (1 H, ddd, JUA, 8.2, 2.2, one of CH2CH2), 3.58 (1 H, d, J12.8, one of ArCH2NR2), 3.81 (1 H1 ddd, J12.5, 5.8, 2.2, one of CH2CJH2), 4.78 (1 H, ddd, J12.5, 8.2, 2.8, one of CH2CH2), 4.80 (1H, d, J12.8, one of ArC]H2NR2), 5.64 (1H, s, CHOR), 5.91 (2H, s, ROCH2OR), 6.70-6.77 (3H, m, ArH), 6.87 (1 H, d, J8.3, ArIH), 7.29-7.37 (2H, m, Ar]H). Example 31 δ-Cyano-S-methyl-i-ta^-methylenedioxyJphenyl-I.S.^β-tetrah ydro-SH-benztfl^.S- oxazocine 8-Bromo-5-methyl-1-(3,4-methylenedioxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[fJ- 2,5-oxazocine (99 mg, 0.26 mmol), Zn (1 mg, 0.015 mmol), Zn(OAc)2 (6 mg, 0.033 mmol), Zn(CN)2 (18 mg, 0.156 mmol), 1,1'-bis(diphenylphosphino)ferrocene (18 mg, 0.054 mmol) and Pd2(dba)3 (33 mg, 0.036 mmol) were degassed and then heated at 1400C overnight. The reaction mixture was cooled and water added. The organics were extracted three times with ethyl acetate.and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to provide the crude target as a black oil. Purification by silica gel column chromatography [EtOAc] furnished product 21 mg, (25%). δH (CDCI3; 250MHz) 2.46 (3H, s, CH3), 2.63 (1H, ddd, J14.3, 5.4, 3.1, one of CH2CH2), 2.75 (1H, ddd, J14.3, 8.3, 2.6, one of CH2CH2), 3.64 (1 H, d, J12.8, one of ArCH2NR2), 3.81 (1H, ddd, J12.7, 5.4, 2.6, one of CH2CH2), 4.24 (1H, ddd, J12.7, 8.3, 3.1, one of CH2CH2), 4.97 (1 H, d, J12.8, one of ArCH2NR2), 5.68 (1H, CHOR), 5.93 (2H, s, ROCH2OR), 6.69-6.78 (3H, m, ArH), 7.12 (1H, d, J7.9, ArH), 7.45- 7.52 (2H, m, ArH). Example 32 8-Cyclopropyl-5-methyl-1 -(3,4-methylenedioxy)phenyl-1 ,3,4,6-tetrahydro-5H- benz[f]-2,5-oxazocine 8-Bromo-5-methyl-1-(3,4-methylenedioxy)phenyl-1,3,4,6-tetrah ydro-5H-benz[f]- 2,5-oxazocine (90 mg, 0.24 mmol), cyclopropylboronic acid (26.8 mg, 0.312 mmol), K3PO4 (178 mg, 0.84 mmol), Pd(OAc)2 (3 mg, 0.012 mmol) and P(cyclohexane)3 (7 mg, 0.024 mmol) were heated to 1000C in toluene (2 ml) and water (100 μl) for 3 hours. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification was by silica gel column chromatography [100 %EtOAc to 5%MeOH/EtOAc] furnished 8-cyclopropyl-(3,4-methylenedioxy)-nefopam 49 mg,(61%). δH (CDCI3; 250MHz) 0.67-0.72 (2H, m, two of cyclopropyl CH2ClH2), 0.91-0.99 (2H, m, two of cyclopropyl CjH2CH2), 2.48 (3H, s, CH3), 2.61 (1 H1 ddd, J14.2, 5.7, 2.6, one of CH2CH2), 2.83 (1H1 ddd, J14.2, 8.4, 2.5, one of CH2CH2), 3.64 (1H, d, J12.8, one of ArCH2NR2), 3.83 (1H, ddd, J12.5, 5.7, 2.5, one of CH2CH2), 4.42 (1H1 ddd, J12.5, 8.4, 2.6, one of CH2CH2), 4.74 (1 H, d, J12.8, one of ArCH2NR2), 5.67 (1H, s, CHOH), 5.91 (2H, s, ROCH2OR), 6.75 (3H, s, ArH), 6.88-6.9 (3H, m, ArH) Example 33 8-Bromo-5-methyl-1-(3-ethoxy)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2,5-oxazocine 2-({5-Bromo-2-[hydroxyl-(3-ethoxy-phenyl)-methyl]-ben2yl}-me thylamino)-ethanol (1.06 g, 2.69 mmol) was heated to reflux temperature under Dean-Stark conditions with pTSA (0.78 g, 4.03 mmol) in toluene (40 ml) for 2.5 h. The reaction mixture was allowed to cool and then diluted with ethyl acetate (20 ml). The mixture was washed with sat. aq sodium bicarbonate solution (2 x 20 ml) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide 0.94 g of crude product. Purification by silica gel gravity column chromatography [EtOAc] gave the product (0.60 g, 59%) as a colourless oil. δH (CDCI3; 250MHz) 7.37-6.87 (7H, m, aromatics), 5.71 (1 H, s, CH-O), 4.77 (1H, d, J 13, ArCHAH8N), 4.14 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 4.00 (2H, q, J 7, CH2CH3), 3.84 (1H1 ddd, J 13, 8 and 2.5, CHAHBCH2), 3.62 (1H1 d, J 13, AΓCHAHBN), 2.85-2.79 (1H, m, CHAHBCH2), 2.68-2.60 (1H, m, CJHAHBCH2), 2.46 (3H, s, NCH3), 1.39 (3H, t, J 7, CH2CH3). Example 34 δ-Cyano-δ-methyl-i-fS-ethoxyJphenyl-I.Sj^e-tetrahydro-δH- benzCfl^jS-oxazocine 8-Bromo-5-methyl-1-(3-ethoxy)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2,5- oxazocine (250 mg, 0.65 mmol), Zn (3 mg, 0.05 mmol), Zn(OAc)2 (15 mg, 0.077 mmol), Zn(CN)2 (46 mg, 0.4 mmol), Pd2(dba)3 (93 mg, 0.1 mmol) and 1,1'- bis(diphenylphosphino)ferrocene (43 mg, 0.077 mmol) were heated to 1400C in DMF (5 ml) and H2O (100 μl) for 4h. The black reaction mixture was allowed to cool to RT and diluted with water. The resulting brown precipitate was collected by filtration and washed with water then brine. The filtrate was extracted with ethyl acetate (2 x 60ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product as a brown oil. Purification by silica gel gravity column chromatography [DCM] gave clean product (56 mg, 27%). δH(CDCI3; 250MHz) 7.50-6.78 (7H, m, aromatics), 5.72 (1H1 s, CIHO)1 4.96 (1H, d, J 13, AΓCHAHB-N), 4.39-4.19 (1 H, m, CHAHBCH2), 3.98 (2H, q, J 7, CH2CH3), 3.85-3.79 (1H, m, CHAHBCH2), 3.67 (1H, d, J 13, AΓCHAMB-N), 2.82-2.58 (2H, m, CH2CH2), 2.43 (3H, s, NCH3), 1.38 (3H, t, J 7, CH2CH3). Example 35 δ-Cyclopropyl-δ-methyl-i-tS-ethoxyJphenyl-I.S.^β-tetrahyd ro-δH-benzIfl-a.δ- oxazocine 8-Bromo-5-methyl-1-(3-ethoxy)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2,5- oxazocine (100 mg, 0.26 mmol), cyclopropylboronic acid (29 mg,0.33 mmol), K3PO4 (193 mg, 0.91 mmol), Pd(OAc)2 (3 mg, 0.013 mmol) and P(cyclohexane)3 (8 mg, 0.026 mmol) were heated to 100°C in toluene (2 ml) and H2O (100 μl) for 4 hours. After cooling to RT, water (2 ml) was added and the mixture extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel gravity column chromatography [DCM] furnished clean product (20 mg, 23%) as a colourless oil. δH(CDCI3; 250MHz) 7.26-6.76 (7H1 m, aromatics), 5.71 (1H, s, CHO), 4.75 (1H1 d, J 12.5, AΓCHAHB-N) 4.22-4.12 (1 H, m, CHAHBCH2), 3.99 (2H1 q, J 7, CH2CH3), 3.88-3.79 (1H1 m, CHAHBCH2), 3.81 (1 H1 d, J 12.5, AΓCHAHB-N), 2.90-2.61 (2H, m, CH2CH2), 2.50 (3H, s, NCH3), 1.89-1.82 (1 H, m, CHCH2), 1.39 (3H, t, J 7, CH2CH3), 0.96-0.92 (2H, m, CiH2CH2), 0.70-0.67 (2H, m, CH2CH2). Example 36 9-Bromo-5-methyl-1-(3-ethoxy)phenyl-1,3,4,6-tetrahydro-5H-be nz[fj-2,5-oxazocine 2-({4-Bromo-2-[hydroxyl-(3-ethoxy-phenyl)-methyl]-benzyl}-me thylamino)-ethanol (1.20 g, 3.04 mmol) was heated to reflux temperature under Dean-Stark conditions with pTSA (0.88 g, 4.57 mmol) in toluene (50 ml) for 4 h. The reaction mixture was allowed to cool and then diluted with ethyl acetate (25 ml). The mixture was washed with sat. aq sodium bicarbonate solution (2 x 25 ml), and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide 1.4 g of crude product. Purification by silica gel gravity column chromatography [EtOAc] gave product (0.59 g, 51%) as a colourless oil. δH (CDCI3; 250MHz) 7.37-6.76 (7H1 m, aromatics), 5.67 (1H1 s, CH-O), 4.79 (1H1 d, J 13, AΓCHAHBN), 4.16 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 4.01 (2H, q, J 7, CH2CH3), 3.81 (1H, ddd, J 13, 8 and 2.5, CHAHBCH2), 3.63 (1 H, d, J 13, AΓCHAMBN), 2.84-2.78 (1H, m, CHAHBCH2), 2.66-2.63 (1H1 m, CHAHBCH2), 2.44 (3H, s, NCH3), 1.40 (3H, t, J 7, CH2CJHa). • Example 37 θ-Cyano-δ-methyl-i-fS-ethoxyJphenyl-i^^.β-tetrahydro-SH-b enzIfl^.S-oxazocine 9-Bromo-5-methyl-1 -(3-ethoxy)phenyl-1.SAe-tetrahydro-δH-benzffi^.S- oxazocine (150 mg, 0.39 mmol), Zn (2 mg, 0.03 mmol), Zn(OAc)2 (9 mg, 0.046 mmol), Zn(CN)2 (28 mg, 0.24 mmol), Pd2(dba)3 (56 mg, 0.06 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene (25 mg, 0.046 mmol) were heated to 140°C in DMF (3 ml) and H2O (30 μl) overnight. The black reaction mixture was allowed to cool to RT and diluted with water. The resulting brown precipitate was collected by filtration and washed with water then brine. The filtrate was extracted with ethyl acetate (2 x 80 ml), and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel gravity column chromatography [DCM] gave clean product (12 mg, 10%). δH(CDCI3; 250MHz) 7.53-6.80 (7H, m, aromatics), 5.75 (1 H, s, CHO), 4.87 (1H, d, J 13, AΓCHAHBN), 4.29-4.14 (1 H, m, CHAHBCH2), 4.01 (2H, q, J 7, CH2CH3), 3.88-3.78 (1 H, m, CHAHBCH2), 3.73 (1H, d, J 13, ArCHAH6N), 2.82-2.71 (1H, m, CHAHB-CH2), 2.68-2.59 (1 H, m, CHAHBCH2), 2.46 (3H, s, N-CH3), 1.39 (3H, t, J 7, CH2CH3). Example 38 θ-Cyclopropyl-δ-methyl-i -(3-ethoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine 9-Bromo-5-methyl-1-(3-ethoxy)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2,5- oxazocine (140 mg, 0.36 mmol), cyclopropylboronic acid (41 mg,0.45 mmol), K3PO4 (269 mg, 1.26 mmol), Pd(OAc)2 (5 mg, 0.02 mmol) and P(cyclohexane)3 (11 mg, 0.04 mmol) were heated to 100°C in toluene (3 ml) and H2O (150 μl) for 4 hours. After cooling to RT, water (2 ml) was added and the mixture extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel gravity column chromatography [DCM] gave product (61 mg, 50%) as a colourless oil. δH(CDCI3; 250MHz) 7.25-6.76 (7H, m, aromatics), 5.69 (1H, s, CHO), 4.79 (1H, d, J 13, AΓCHAHBN), 4.23-4.16 (1 H, m, CHAHBCH2), 4.01 (2H, q, J 7, CIH2CH3), 3.89-3.81 (1 H, m, CHAHBCH2), 3.70 (1H, d, J 13, AΓCHAMBN), 2.88-2.78 (1H, m, CHAHB-CH2), 2.68-2.60 (1H, m, CHAHBCH2), 2.48 (3H, s, N-CH3), 1.83-1.72 (1H, m, CHCH2), 1.39 (3H, t, J 7, CH2CH3), 0.92-0.88 (2H, m, CjH2CH2), 0.62-0.58 (2H, m, CH2CH2). Example 39 8-Bromo-5-methyl-1-(3-trifluoromethoxy)phenyl-1,3,4,6-tetrah ydro-5H-benz[f]-2,5- oxazocine 2-({5-bromo-2-[hydroxyl-(3-trifluoromethoxy-phenyl)-methyl]- benzyl}- methylamino)-ethanol (635 mg, 1.47 mmol) was heated to reflux under Dean-Stark conditions with pTSA (420 mg, 2.21 mmol) in toluene (6 ml) for 2 hours. The reaction mixture was allowed to cool to RT and then diluted with ethyl acetate (30 ml). The mixture was washed with sat. aq. sodium bicarbonate solution (50 ml) and was extracted into ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude cyclised product. Purification by silica gel gravity column chromatography [EtOAc] furnished the target product (116 mg, 19%). δH (CDCI3; 250MHz) 2.47 (3H, s, CH3), 2.67 (1 H, ddd, J14.3, 6.1, 2.5, one of CH2CH2), 2.84 (1H, ddd, J14.3, 7.8, 2.2, one of CH2CH2), 3.67 (1H, d, J12.8, one of ArCH2NR2), 3.86 (1 H, ddd, J12.8, 6.1, 2.2, one of CH2CH2), 4.13 (1 H, ddd, J12.8, 7.8, 2.5, one of CH2CH2), 4.61 (1 H, d, J12.8, one Of ArCjH2NR2), 5.79 (1 H, s, CHOR), 6.85 (1 H, d, J8.2, ArH), 7.11-7.19 (3H, m, ArJH), 7.31-7.36 (3H, m, ArJH). Example 40 δ-Cyano-S-methyl-i-CS-trifluoromethoxyJphenyl-I.Sj^β-tetra hydro-δH-benztfl^.S- oxazocine 8-Bromo-5-methyl-1-(3-trifluoromethoxy)phenyl-1,3,4,6-tetrah ydro-5H-benz[f]-2,5- oxazocine (116 mg, 0.28 mmol), Zn (1 mg, 0.02mmol), Zn(OAc)2 (7 mg, 0.038 mmol), Zn(CN)2 (20 mg, 0.17 mmol), Pd2(dba)3 (40 mg, 0.04 mmol) and 1,1'-bis- (diphenylphosphine)ferrocene (20 mg, 0.036 mmol) were heated to 14O0C in DMF (3 ml) and H2O (30 μl) overnight. The black reaction mixture was allowed to cool and diluted with water. The resulting brown precipitate was collected by filtration and washed with ethyl acetate. The filtrate was washed with brine (2 x 60 ml) and the combined aqueous phases were then washed with ethyl acetate (2 x 80 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to provide the crude product. Purification by silica gel gravity column chromatography [1:1 ethyl acetate/heptane) furnished the desired product (9 mg, 9%). δH(CDCI3; 250MHz) 2.50 (3H,s, CJH3), 2.61-2.87 (2H, m, two of CJH2CJH2), 3.76 (1 H, d, J13.1 , one Of ArCJH2NR2), 3.87 (1H, ddd, J12.7, 5.4, 2.5, one of CIH2CH2), 4.25 (1 H, ddd, J12.7, 8,4, 3.1, one of CJH2CJH2), 4.86 (1H, d, J13.1, one of ArCJH2NR2), 5.82 (1 H, s, CHOR), 7.11-7.16 (4H, m, ArJH), 7.33-7.39 (1H, m, ArHJ, 7.52 (1 H, dd, J7.9, 1.8, ArJH), 7.57 (1H1 bs, ArH). Example 41 δ-Cyclopropyl-S-methyl-i^a-trifluoromethoxyJphenyl-i^j^β-t etrahydro-SH-benztfl- 2,5-oxazocine 8-Bromo-5-methyl-1-(3-trifluoromethoxy)phenyl-1,3,4,6-tetrah ydro-5H-benz[f]-2l5- oxazocine (160 mg, 0.39 mnnol), cyclopropylboronic acid (43 mg,0.5 mmol), K3PO4 (288 mg, 1.36 mmol), Pd(OAc)2 (4 mg, 0.019 mmol) and P(cyclohexane)3 (11 mg, 0.039 mmol) were heated to 100°C in toluene (2 ml) and H2O (100 μl) for 4 hours. The reaction mixture, now black in colour, was allowed to cool to RT. Water (50 ml) was added and the mixture extracted into ethyl acetate (3 x 80 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude cyclopropyl analogue. Purification by silca gel column chromatography [1:1 EtOAc/heptane, then 100% EtOAc] furnished 8-cyclopropyl-(m-trifluoromethoxy)- nefopam. δH (CDCI3; 250MHz) 0.67-0.74 (2H, m, two of cyclopropyl CH2CIH2), 0.89-1.00 (2H1 m, two of cyclopropyl CH2C]H2), 1.82-1.93 (1H, m, cyclopropyl CH), 2.51 (3H, s, CH3), 2.68 (1H, ddd, J14.2, 5.7, 2.5, one of CH2CH2), 2.89 (1 H, ddd, J14.2, 8.2, 2.0, one of CH2CH2), 3.74 (1 H, d, J12.8, one Of ArCH2NR2), 3.87 (1 H, ddd, J12.7, 5.7, 2.0, one of CH2CH2), 4.13 (1 H, ddd, J12.7, 8.2, 2.5, one of CH2CH2), 4.58 (1H, d, J12.5, one of ArCH2NR2), 5.81 (1 H, s, CHOR), 6.84-6.97 (3H, m, Arid), 7.09-7.20 (3H, m, ArH), 7.29- 7.37 (1 H1 m, ArH). Example 42 9-Bromo-5-methyl-1-(3-trifluoromethoxy)phenyl-1,3,4,6-tetrah ydro-5H-benz[fj-2,5- oxazocine Crude 2-({4-bromo-2-[hydroxyl-(3-trifluoromethoxy-phenyl)-methyl]- benzyl}- methylamino)-ethanol (1.159 g, 2.69 mmol) was heated to reflux with pTSA (768 mg, 4.04 mmol) in xylene (12ml) with Dean-Stark for 4 hours, 45 mins. The reaction mixture was allowed to cool and then washed with a saturated solution of sodium bicarbonate (100 ml). The organics were extracted into ethyl acetate (2 x 100 ml) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo to provide the crude product as a 2:1 mixture with starting material. Purification by silica gel column chromatography provided the target product (189 mg, 17%). δH (CDCI3; 250MHz) 2.44 (3H1 s, CH3), 2.64 (1H1 ddd, J15.0, 5.0, 2.5, one of CH2CH2), 2.81 (1 H, ddd, J15.0, 7.5, 2.5, one of CjH2CH2), 3.67 (1 H, d, J12.5, one of ArCH2NR2), 3.84 (1 H, ddd, J12.5, 5.0, 2.5, one of CH2CIH2), 4.14 (1 H, ddd, J12.5, 5.0, 2.5, one of CId2CH2), 4.65 (1H, d, J12.5, one Of ArCH2NR2), 5.75 (1H, s, CHOR)1 7.09-7.19 (5H, m, ArH)1 7.34 (1H, d, J8.0, one of ArH), 7.40 (1H, dd, J8.0, 1.9, one of ArIH). Example 43 θ-Cyclopropyl-δ-methyl-i-ta-trifluoromethoxyJphenyl-I.S^.e -tetrahydro-SH-benzCf]- 2,5-oxazocine θ-Bromo-δ-methyl-i-CS-trifluoromethoxyJphenyl-I.S^.e-tetra hydro-δH-benztfi^.S- oxazocine (95 mg, 0.28 mmol), K3PO4 (205 mg, 0.97 mmol), cyclopropylboronic acid (31 mg, 0.36 mmol), P(cyclohexane)3 (8 mg, 0.028 mmol) and Pd(OAc)2 (3 mg, 0.014 mmol) were heated at 1000C in toluene (2ml) and water (100 μl). The reaction mixture turned black in colour after about 20 mins. At the end of 3 hours, the mixture was allowed to cool to RT, and water (30 ml) was added. The organics were extracted into ethyl acetate (2 x 30 ml) and the combined extracts dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel gravity column chromatography [EtOAc] furnished product. δH (CDCI3; 250MHz) 0.58-0.63 (2H, m, two of cyclopropyl CH2CH2), 0.90-0.94 (2H, m, two of CH2CH2), 1.73-1.79 (1H, m, cyclopropyl CH), 2.45 (3H, s, CH3), 2.68 (1 H, ddd, J15.0, 5.0, 2.5, one of CH2CH2), 2.87 (1 H, ddd, J15.0, 7.5, 2.5, one of C]H2CH2), 3.75 (1H, d, J12.5, one Of ArCH2NR2), 3.88 (1 H, ddd, J 12.5, 5.0, 2.5, one of CH2CH2), 4.19 (1 H, ddd, J 12.5, 7.5, 2.5, one of CjH2CiH2), 4.67 (1 H, J12.5, one of ArCH2NR2), 5.75 (1 H, s, CHOR), 6.72 (1H, d, J2.5, one of ArIH), 6.93 (1H, dd, J7.5, 2.5, ArH), 7.10-7.19 (4H, m, ArH), 7.29-7.38 (1H1 ArJH) Example 44 9-Bromo-5-methyl-1-(2-methyl)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2,5-oxazocine 2-[(4-bromo-2-(hydroxyl-o-tolylmethyl)-benzyl)-methylamino]- ethanol (790 mg, 2.18 mmol) was dissolved in toluene (8 ml) at RT. pTSA (623 mg, 3.27 mmol) was added and the resulting mixture was heated to reflux temperature under Dean-Stark conditions for 1.5 hours. Once cooled to RT, the mixture was diluted with ethyl acetate and washed with sat. aq. solution of sodium bicarbonate. The organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude material as an oil. Purification by silica gel gravity column chromatography [20%EtOAc /heptane to 30%EtOAc] furnished the product (357 mg, 55% corrected yield) δH (CDCI3; 250MHz) 2.31 (3H, s, ArCH3), 2.44 (3H, s, NCH3), 2.63 (1 H, ddd, J14.4, 5.3, 2.4, one of CH2CH2), 2.86 (1 H, ddd, JUA, 8.9, 2.1 , one of CH2CIH2), 3.76 (1H, d, J.13.0, one Of ArCH2NR2), 3.85 (1 H, ddd, J12.7, 5.3, 2.1 , one of CH2CH2), 4.12 (1 H, ddd, J12.7, 8.9, 2.4, one of CIH2CH2), 4.68 (1H, d, J13.0, one Of ArCH2NR2), 5.95 (1 H, s, CHOR), 7.02-7.22 (6H, m, Ar]H)1 7.38 (1 H, dd, J8.2, 2.1, ArH). Example 45 9-Cyano-5-methyl-1-(2-methyl)phenyl-1,3,4,6-tetrahyclro-5H-b en2[q-2,5-oxazocine 9-Bromo-5-methyl-1-(2-methyl)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2l5- oxazocine (156 mg, 0.45 mmol), Zn dust (2 mg, 0.03 mmol), Zn(CN)2 (32 mg, 0.27 mmol), Zn(OAc)2 (10 mg, 0.054 mmol), 1,1'-bis(diphenylphosphino)ferrocene (30 mg, 0.054 mmol) and Pd2(dba)3 (55 mg, 0.06 mmol) were heated to 14O0C in DMF (3 ml) and water (30 μl) under a nitrogen atmosphere over-night. After cooling, water was added and the resulting black/brown precipitate was collected by suction filtration and washed well with ethyl acetate. The filtrate was washed with brine and extracted into ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude material as a very dark brown oil. Purification by silica gel gravity column chromatography [ EtOAc] furnished the product (79 mg, 60%). δH (CDCI3; 250MHz) 2.28 (3H, s, ArCH3), 2.45 (3H, s, ArCH3), 2.65 (1 H, ddd, J14.4, 5.5, 2.4, one of CH2CIH2), 2.85 (3H, ddd, J14.4, 8.9, 2.1 , one of CH2CH2), 3.82-3.90 (2H, m, one of CjH2CH2 and one of ArCH2NR2), 4.07-4.17 (1 H, m, one of CH2CH2), 4.74 (1H, d, J12.8, one Of ArCH2NR2), 6.02 (1 H, s, CHOR), 7.05 (1H, d, J6.7, ArH), 7.14-7.27 (4H, m, ArH), 7.34 (1 H, d, J7.9, ArH), 7.54 (1H, dd, J7.9, 1.7, ArH). Example 46 9-Cyclopropyl-5-methyl-1-(2-methyl)phenyl-1,3,4,6-tetrahydro -5H-benz[f|-2,5- oxazocine 9-Bromo-5-methyl-1-(2-methyl)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2,5- oxazocine (188 mg, 0.55 mmol) was dissolved in toluene (4 ml) and water (200 μl) at RT. Cyclopropylboronic acid (61 mg, 0.71 mmol), K3PO4 (409 mg, 1.93 mmol), Pd(OAc)2 (6 mg, 0.03 mmol) and P(cyclohexane)3 (15.4 mg, 0.055 mmol) were added. The mixture was heated to 100°C for a total of 3 hours, during which time the reaction mixture became black. After cooling to RT1 the mixture was diluted with water and extracted into ethyl acetate. The organic phases were dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel gravity column chromatography [EtOAc] furnished the product (129 g, 81%). δH (CDCI3; 250MHz) 0.54-0.60 (2H, m, two of cyclopropyl CH2CH2), 0.86-0.89 (2H, m, two of cyclopropyl CH2CH2), 1.69-1.80 (1H, m, cyclpropyl CIH)1 2.34 (3H1 s, ArCH3), 2.45 (3H1 s, ArCH3), 2.62 (1H1 ddd, J14.3, 5.5, 2.4, one Of CH2CjH2), 2.87 (1 H1 ddd, J14.3, 8.5, 2.1, one of CIH2CjH2), 3.75 (1 H, d, J13.0, one of ArCjH2NR2), 3.85 (1 H, ddd, J12.7, 5.5, 2.1, one of CjH2CjH2), 4.11 (1H1 ddd, J12.7, 8.5, 2.4, one of CH2CJH2), 4.64 (1H1 d, J13.0, one Of ArCH2NR2), 5.96 (1H1 s, CHOR), 6.62 (1 H, d, J1.8, Ar]H)1 6.89 (1H, dd, J7.9, 1.8, ArH), 7.05-7.20 (5H, ArH). Example 47 8-Bromo-5-methyl-1 -(2-methyl)phenyl-1 ,3,4,6-tetrahydro-5H-benz[fl-2,5-oxazocine 2[(5-bromo-2-(hydroxyl-o-tolylmethyl)-benzyl)methylamino]-et hanol (777 mg, 2.16 mmol) was dissolved in toluene (8 ml) at RT. pTSA (616 mg, 3.24 mmol) was added, and the resulting mixture heated at reflux temperature under Dean-Stark conditions for 4 hours. The reaction was allowed to cool to RT and then diluted with ethyl acetate, and washed with sat. aq. sodium bicarbonate solution. The organic washings were dried (MgSO4), filtered and concentrated in vacuo to provide the impure product. Purification by silca gel gravity column chromatography [1:1 EtOAc /heptane to 100% EtOAc] gave the desired product (504 mg, 64%). δH (CDCI3; 250MHz) 2.29 (3H, S, ArCH3), 2.46 (3H, s, NCH3), 2.66 (1 H, ddd, J14.4, 5.6, 2.4, one of CH2CH2), 2.89 (1H, ddd, J14.4, 8.5, 2.1, one of CH2CH2), 3.77 (1H, d, J13.1 , one Of ArCH2NR2), 3.86 (1H, ddd, J12.7, 5.6, 2.1, one of CH2CH2), 4.09 (1 H, ddd, J12.7, 8.5, 2.4, one of CH2CH2), 4.64 (1H, d, J13.1 , one Of ArCH2NR2), 5.97 (1H, s, CHOR), 6.74 (1H1 d, J8.2, ArH), 7.07-7.20 (4H, m, ArH), 7.29 (1 H1 dd, J8.6, 2.1, ArH), 7.41 (1 H, d, J2.1, ArH). Example 48 8-Cyano-5-methy 1-1 -(2-methyl)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine 8-Brorno-5-methyl-1-(2-methyl)phenyl-1,3,4,6-tetrahydro-5H-b enz[f]-2,5- oxazocine (207 mg, 0.60 mmol), Zn (2 mg,0.03 mmol), Zn(OAc)2 (13 mg, 0.071 mmol), Zn(CN)2 (42 mg, 0.36 mmol), 1,1'-bis(diphenylphosphino)ferrocene (40 mg, 0.072 mmol) and Pd2(dba)3 (75 mg, 0.082 mmol) were heated to 1400C in DMF (5 ml) and H2O (50 μl) overnight. The black reaction mixture was cooled and water added, producing a brown precipitate. The precipitate was washed with ethyl acetate and the filtrate washed with brine to remove the DMF. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide the crude product. Purification by silica gel gravity column chromatography [EtOAc] furnished the desired product (39 g, 22%). δH (CDCI3; 250MHz) 2.33 (3H, s, ArCH3), 2.46 (3H, s, NCH3), 2.64 (1H, ddd, J14.9, 5.1 , 2.6, one of CH2CH2), 2.77 (1 H, ddd, J14.9, 8.9, 2.4, one of CH2CH2), 3.78 (1 H, d, J13.1, one Of ArCH2NR2), 3.86 (1H, ddd, J12.7, 5.1, 2.4, one Of CH2C]H2), 4.18 (1 H, ddd, J12.7, 8.9, 2.6, one of CH2CH2), 4.89 (1 H, d, J13.1, one Of ArCH2NR2), 5.99 (1 H, s, CHOR), 6.91-6.98 (2H, m, ArH), 7.12-7.22 (3H, ArH), 7.46 (1H, dd, J7.9, 1.8, Ar]H), 7.55 (1 H, d, J1.5, ArH). Example 49 8-Cyclopropyl-5-methyl-1-(2-methyl)phenyl-1,3,4,6-tetrahydro -5H-benz[fj-2J5- oxazocine 8-Bromo-5-methyl-1-(2-methyl)phenyl-1,3,4,6-tetrahydro-5H-be nz[f]-2,5- oxazocine (205 mg, 0.60 mmol) was dissolved in toluene (4 ml) and H2O (200 μl) at RT. Cyclopropylboronic acid (67 mg, 0.77 mmol), K3PO4 (446 mg, 2.1 mmol), Pd (OAc)2 (7 mg, 0.03 mmol) and P(cyclohexane)3 (17 mg, 0.06 mmol) were added and the resulting mixture heated at 100°C for 3 hours. The mixture was then allowed to cool to RT before partitioning the mixture between water and ethyl acetate. The organic phases were dried (MgSO4), filtered and concentrated in vacuo to yield the crude product. Purification by silica gel gravity column chromatography [EtOAc] provided the desired target (117 g,

δH(CDCI3; 250MHz) 0.67-0.74 (2H, m, two of CH2CjH2), 0.92-1.0 (2H, m, two of CIH2CIH2), 1.83-1.93 (1H1 m, cyclopropyl CH), 2.28 (3H, s, ArCH3), 2.48 (3H, s, NCH3), 2.66 (1 H, ddd, J14.4, 5.6, 2.3, one of CH2CH2), 2.95 (1 H, ddd, J14.4, 8.5, 2.1, one of CH2CH2), 3.81 (1 H, d, J12.8, one of ArCH2), 3.87 (1H1 ddd, J12.8, 5.6, 2.1, one of CH2CH2), 4.08 (1 H, ddd, J12.8, 8.5, 2.3, one of CH2CH2), 4.56 (1 H, d, J12.8, one of ArCH2NR2), 5.98 (1H, s, CHOR), 6.73 (1 H, d, J7.9, ArH), 6.85 (1H, dd, J7.9, 1.8, ArH)1 6.97 (1 H1 d, J1.8, ArH), 7.14-7.18 (4H, m, ArJH). Example 50 9-Bromo-5-methyl-1-(3-pyridyl)-1,3,4,6-tetrahydro-5H-benz[f| -2,5-oxazocine 2-{[4-Bromo-2-(hydroxypyridin-3-yl-methyl)-benzyl]-methylami no}-ethanol (100 mg, 0.29 mmol) was dissolved in xylene (2 ml_) at RT. pTSA (434 mg, 2.28 mmol) was added, and the resulting mixture was heated at 12O0C in an open vessel until all solvent and water had evaporated. The reaction vessel was removed from the heat and allowed to cool. Ethyl acetate (20 ml) and a sat. aq. solution of sodium bicarbonate (20 ml) were added to partition the gummy mixture. The organic phase was separated, and the aqueous phase was extracted into ethyl acetate (2 x 20 ml). Combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give the cyclised product as a pale brown oil. Purification by silica gel column chromatography with a stepped gradient, [100%EtOAc to 3%/5%/10% MeOH/EtOAc)], furnished product (23 mg, 24%). δH(CDCI3l 250MHz) 2.46 (3H, s, NCH3), 2.66 (1 H, ddd, J14.4, 5.5, 2.8, one of CH2CH2), 2.83 (1 H, ddd, J14.4, 8.2, 2.1 , one of CjH2C]H2), 3.67 (1 H, d, J13.1, one Of ArCjH2NR2), 3.86 (1 H, ddd, J12.7, 5.5, 2.1 , one of CIH2CjH2), 4.19 (1H, ddd, JI 2.7, 8.2, 2.8, one of CjH2CjH2), 4.73 (1 H, d, J13.1 , one Of ArCJH2NR2), 5.77 (1 H1 s, CHOR), 7.11-7.14 (2H, m, aromatic H), 7.24-7.29 (1 H, m, aromatic H), 7.39 (1 H, dd, J7.9, 1.8, aromatic H)1 7.56 (1H, d, J7.9, aromatic H), 8.53-8.57 (2H, m, aromatic H). Example 51 8-Bromo-5-methyl-1-(3-pyridyl)-153,4,6-tetrahydro-5H-benz[f| -2,5-oxazocine 2-{[5-Bromo-2-(hydroxypyridin-3-yl-methyl)-benzyl]-methylami no}-ethanol (84 mg, 0.24 mmol) was dissolved in xylene (2 ml). pTSA (364 mg, 1.9 mmol) was added and the mixture was heated to reflux temperature in an open vessel to allow evaporation of the solvent and water. When the mixture had concentrated down to a dark gum, the vessel was removed from the heat and allowed to cool. The residue was partitioned between ethyl acetate (20 ml) and sat. aq. sodium bicarbonate solution (20 ml). The aqueous phase was extracted further with ethyl acetate (2 x 20 ml), and the combined organic extracts dried (magnesium sulphate), filtered and evaporated to dryness to give crude product. Purification was by silica gel column chromatography [Ethyl acetate] to provide the target compound as an oil/solid. δH (CDCI3; 250MHz) 2.46 (3H, s, CH3), 2.58 (1H, ddd, J14.3, 6.1 , 2.6, one of CH2CH2), 2.83 (1H, ddd, J14.3, 7.9, 2.1 , one of CH2CH1), 3.63 (1H, d, J13.1, one of ArCH2NR7). 3.86 (1 H, ddd, J12.6, 6.1 , 2.1 , one of CH2CH2), 4.16 (1 H, ddd, J12.6, 7.9, 2.6, one of CH2CH2), 4.68 (1 H, d, J13.1, one Of ArCH2NR2), 5.80 (1 H, s, CHOR), 6.84 (1 H, d, J8.3, aromatic H)1 7.21-7.27 (2H, m, aromatic H), 7.32-7.40 (2H, m, aromatic HJ, 7.55 (1H, dd, J7.8, 1.6, aromatic H), 8.52 (1 H, dd, J4.6, 1.6, aromatic H), 8.54 (1 H,d , J8.6, aromatic Jd). Example 52 δ-Cyano-δ-methyl-i-fS-pyridylJ-I.S^jβ-tetrahydro-SH-benzf fl-Zjδ-oxazocine 8-Bromo-5-methyl-1-(3-pyridyl)-1,3,4,6-tetrahydro-5H-benz[f] -2,5-oxazocine (50 mg, 0.15 mmol), Zn (1 mg, 0.01 mmol), Zn(OAc)2 (4 mg, 0.02 mmol), Zn(CN)2 (13 mg, 0.11 mmol), Pd2 (dba)3 (18 mg 0.02 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (9 mg 0.02 mmol) were heated to 140 0C in DMF (2 ml) and H2O (20 μl) overnight. The black reaction mixture was allowed to cool and diluted with water (20 ml). The resulting brown precipitate was collected by filtration and washed with water then brine. The filtrate was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were dried (magnesium sulphate), filtered and concentrated in vacuo to provide the crude product as a brown oil. Purification was by silica gel column chromatography [dichloromethane] to furnish the desired product (10 mg, 24%) as a yellow oil. δH (CDCI3; 250MHz) 2.47 (3H, s, CH2), 2.58-2.84 (2H, m, CH2CH2), 3.68 (1H1 d, J13.1, one of ArCH2NR2), 3.82-3.90 (1 H, m, one of CH2CH2), 4.19-4.29 (1H1 m, one of CH2CH2), 4.88 (1H, d, J13.1, one Of ArCH2NR2), 5.84 (1 H, s, CHOR), 7.11 (1H1 d, J8.3, aromatic H)1 7.22-7.30 (2H1 m, aromatic H), 7.49-7.55 (3H, m, aromatic H), 8.52 (1H, dd, J4.6, 1.6 aromatic H), 8.55 (1H, d, J8.6, aromatic H). Biological Assay The assay was carried out according to the method described by Perovic et a/ (1995), Arzneim-Forsch. Drug Res., 45: 1145. Assay for Inhibition of Noradrenaline Reuptake Activity Synaptosomes (100 μg) are incubated for 20 min at 37°C with 0.1 μCi [3H]norepinephrine in the absence (control) or presence of the test compound or the reference compound in a buffer containing 118 mM NaCI, 5 mM KCI, 2.5 mM MgSO4, 1.2 mM NaH2PO4, 25 mM NaHCO3, 11 mM glucose, 10 μM EGTA and 50 μM ascorbic acid (pH 7.4). Basal control activity is determined by incubating the same mixture for 20 min at 00C in the presence of 10 μM protriptyline to block the uptake. Following incubation, the samples are filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) and rinsed twice with ice-cold incubation buffer using a 96-sample cell harvester (Unifilter, Packard) to eliminate free [3H]norepinephrine. The filters are dried and the retained radioactivity is measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control uptake of [3H]norepinephrine. The standard inhibitory reference compound is protriptyline, which is tested in each experiment at several concentrations to obtain an inhibition curve from which its IC50 value is calculated. Assay for Inhibition of Serotonin Reuptake Activity Synaptosomes (100 μg) are incubated for 15 min at 37°C with 0.1 μCi [3H]serotonin in the absence (control) or presence of the test compound or the reference compound in a buffer containing 118 mM NaCI, 5 mM KCI, 2.5 mM MgSO4, 1.2 mM NaH2PO4, 25 mM NaHCO3, 11 mM glucose, 10 μM EGTA and 50 μM ascorbic acid (pH 7.4). Basal control activity is determined by incubating the same mixture for 15 min at 40C in the presence of 10 μM imipramine to block the uptake. Following incubation, the samples are filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) and rinsed twice with ice-cold incubation buffer using a 96-sample cell harvester (Unifilter, Packard) to eliminate free [3H]serotonin. The filters are dried and the retained radioactivity is measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control uptake of [3H]serotonin. The standard inhibitory reference compound is imipramine, which is tested in each experiment at several concentrations to obtain an inhibition curve from which its IC50 value is calculated.