ZA200503509B - Benzoxazocines and their use as monoamine-reuptake inhibitors - Google Patents

Description

BENZOXAZOCINES AND THEIR USE AS MONOAMINE-REUPTAKE INHIBITORS

This invention relates to novel benzoxazocine compeunds which inhibit monoamine reuptake and their therapeutic use.

Background of the Invention

Nefopam [(+)-3,4,5,6-tetrahydro-5-methyl-1-phenyi-1 H-2,5-benzoxazocine hydrochloride] is a centrally acting non-narcotic analgesic not structurally related to other analgesics. Nefopam has been shown to induce antinociception in animal models of pain and in humans (reviewed in Heel ef al., 1980). However, nefopam is not active in the mouse tail-flick test, or the hot plate test and the

Randall-Selitto pressure test in rats (Conway and Mitchell, 1977) suggesting that its analgesic mechanism is not opiate-like or anti-inflammatory in nature.

Nefopam's antinociception is not blocked by nalaxone further suggesting that its analgesic action is not through opiate receptors. Although the precise mechanism of antinociception is not known it is thought to involve inhibition of synaptosomal uptake of dopamine, norepinephrine and serotonin (VonVoigtlander et a/., 1983; Rosland and Hole, 1990; Mather et al., 2001).

Previous in vitro and in vivo studies with nefopam enantiomers have shown that (+)-nefopam has more potent analgesic and dopamine, norepinephrine and serotonin uptake inhibitory properties than (-)-nefopam with the order of potency given as (+)-nefopam > (:)-nefopam > (-)-nefopam (Fasmer et al., 1987; Rosland and Hole, 1990; Mather ef a/., 2001).

Summary of the invention

According to this invention, novel compounds are of general formula (1):

Rs Ry o

CX aN PF

N

\ €y) wherein

R; is H, C;-Cealkyl, optionally substituted with F or Cs-Ce cycloalkyl or Co

Cs alkenyl; either R; and Rs are the same or different and are H, a halogen, CN, CF3,

C4-Csalkyl or ORy, or R; and Rs form a five or six membered ring which may be carbocyclic, heterocyclic (containing 1-2 heteroatoms taken from O, N or S), aromatic (such as in naphthalene for example), heteroaromatic (containing 1-2 heteroatoms taken from O, such as in benzofuran for example, N as in guinaline, isoquinoline and quinazoline for example); and

W, X, Yor Z are each N, CH or CR,.

The case where W = X =Y = Z = CH is specifically excluded. When W is

NorRs X=Y=2=CH; when XisNorR, W=Y=2Z=CH;whenYisNorR,,

W=X=Z=CH;andwhenZisNorR, W=X=Y =CH.

Rs is halogen, CFs, CN, OR;, SO:N(Rs). (where each Rg is the same or different), CORs, CO;Rs, CON(Rs)2 (Where Re maybe the same or different),

NR,CORs, NR;SO;Rs, NR;CO2Rs, NR{CON(Rs), (where each Rg is the same or different), OC;-Cs alkyl optionally substituted with Rs, C1-Cs alkyl optionally substituted with Rs, C3-Cs cycloalkyl optionally substituted with Rs, C2-Ce alkenyl optionally substituted with Rs, C2-Cs alkynyl optionally substituted with Rs, and aryl optionally substituted with R,. Rs may also be a five or six membered aromatic heterocycle containing 1-4 heteroatoms selected from N (such as in pyrrole, pyridine, diazoles, diazines, triazoles, triazines or tetrazoles for example) and O (such as in furan, oxazoles, isoxazoles or oxadiazoles for example). Such rings can be linked either through carbon or nitrogen.

Rs is Cy-Csalkyl, C,-Cealkenyl, C,-Cs alkynyl, Cs-Cecycloalkyl, ary! or heteroaryl.

Re is H, Ci-Csalky), C,-Csalkeny!, C,-Cs alkynyl, Cs-Cscycloalkyl, aryl or heteroaryl.

Ry is aryl or heteroaryl. _

Salts, solvates and polymorphs of these compounds are also included . -

Compounds of the invention are useful as therapeutic agents. Further, in compounds of formula (1), those wherein R, is a halogen atom such as Br are useful as intermediates.

Description of Preferred Embodiments it will be appreciated that the 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, alone or in combination, the term "C;-Ce alkyl" refers to straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, pentyl, hexyl and the like.

The term "C,-Cs 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 would include for example, vinyi, 1-propenyl, 1- and 2- butenyl, 2- methyl-2-propeny! etc.

The term “C.-C; 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 would include for example, ethynyl, 1-propargyl, 1- and 2- butynyl etc.

The term “C,-Cs 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 “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 from the group N,

O, 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 or which at least one atom is selected from the group, O, N, or S and includes for example benzofused furanyl, thiophenyl, pyridyl, indolyl, pyridazinyl, piperazinyl, pyrimidinyl and the like.

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 sterecisomer 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 (e.g. HPLC).

The compounds according to the invention may be prepared by the following process. In the description and formulae below the groups Ry, Rz, Ra,

Rs Rs, Re, W, X, Y and Z are as defined above, except where otherwise indicated. It will be appreciated that functional groups, such as amino, hydroxyl or carboxy! 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, TW Greene, PGM

Wuts.

A process required for preparing compounds of general formula (1), where W, X, Y or Z are N or C-Br comprises acid (for instance p- toluenesulphonic acid) cyclisation of the diol of general formula (2) which can in turn be obtained by reduction of the ketone (3) with a suitable reducing agent.

Ra 7, Rs R,

PAN OH OH A © OH

NP J NF J

N N

\ o \, (2) (3)

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 sait enhancer) are 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 of general formula (3) can be prepared by condensation of a carboxylic acid of general formula (4) or an active derivative thereof, with an amine of formula (5). Active derivatives of acids of formula (4) include for example acid anhydrides or acid halides, such as acid chlorides.

Rs % 0

AN is

NF OH HN

0) \ (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 ata low temperature e.g. -30°C to ambient temperature, such as -20°C to 0°C, 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-methyimorpholine. Where an acid of formula (4) is used directly, the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as NN- 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 of formula (5).

Acids of general formula (4) are prepared by Friedel-Crafts acylation of an arene of general formula (6) with an anhydride of formula (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).

0]

IN of

J 0

NF Ra \ (7) (6)

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 tradition flash column chromatography. For example, where Y = C-

Br and W = X = Z = CH and R; and R; are H, 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 Xor Y are C-Br, by the route described above.

CC

Br COzH COLH (4a) (4b)

Compounds of general formula (1) where either W, X, Y or Z is CRs and

Rs is a halogen such as Br (1a) represent flexible intermediates that may be used for the preparation of other compounds of general formula (1). For instance, compounds of general formula (1) where either W, X, Y or Zis CRs and

R, is Br can be smoothly converted into the corresponding nitrile (1b; Ry = CN) either by reaction with cuprous cyanide in a dipclar aprotic solvent such as N-

methylpyrrolidinone (NMP) or under palladium-catalysed conditions (Scheme 1).

Scheme 1:

Ry : 2 Rj R2 Rs 0) o x — AN

A PZ

Ry | R, (1a) (1b)

The nitrile of general formula (1) where either W, X,Y or Zis CRs and Ry is CN (1b) can be readily converted, by hydrolysis, into the primary amide (1c, Ry = CONH,), esters and the corresponding carboxylic acid (1d, COzR;,) or into the corresponding tetrazole (1e) by treatment with a suitable azide donor such as sodium azide or trimethylsilylazide (Scheme 2).

Scheme 2:

Ry Rs : 'o)

X

Re Rs | Re Ra

HNOC N lc \, fo} fo)

IAN IAN

—

F FF

: 7 N R we N \ Rs \ 1b R4 1d R4

AN

BD

PF

TT \

N R

"N le

In addition, compounds of general formula (1) where either W, X, YorZis

CR: and R; is a halogen such as Br (1a) can be lithiated with n-, sec-, or tert- 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°C. Treatment with either a carbon (e.g. carbon dioxide, N,N-dimethyl formamide or paraformaldehyde),

sulphur (e.g. SO,Cl,, 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 Rs is COzR:;

CON(R;); (Where each R, is the same or different); CH.OR; (1f), SON(R:)2 (18, where each R; is the same or different); and NR;CORs NR;SO:zRs (1h);

NR;CO.Rs; NR;CON(R;,); (where each R, is the same or different). Examples are given in Scheme 3.

Scheme 3:

Ra Re o}

AN

Re Ra | Re Ra

MeOH,C \ et i Ra 0 o} x XX —

AF —_—— PF

J N R oss” N \ \ Rs \ la Ry lg Ry

N

»

AF

MeO,SHN N \

Ry 1h in addition, compounds of general formula (1) where either W, X, Yor Z is

CRs and R; is a halogen such as Br (1a) can undergo palladium-catalysed coupling reactions with carbon-based coupling partners. Thus, compounds of general formula (1) where either W, X, Y or Zis CR; and R, is a halogen such as

Br can be coupled to alkenes of a general type CH.=CHR; under Heck conditions, alkynes of a general type CH=CHR, under Scnogoshira conditions,

or metalloheterocycles e.g. where the metal is tin, under Stille coupling conditions. This gives access to compounds where either W, X, Y or Z can be

C.,-Cs alkenyl substituted with R4 (1i) C2-Ce alkynyl substituted with R,4 (1j) and where R; is a five membered aromatic heterocycle containing 1-4 heteroatoms taken from N (such as in pyrrole, diazoles, triazoles or tetrazoles for example) and O (such as in furan (1k), oxazoles or oxadiazoles for example). Such coupling reactions ensure that chains and rings are linked either through carbon.

Examples are in Scheme 4.

Scheme 4:

R, Rs : 0

AN

Rs R, | Ra R, = ) \ 7 li R,

Rd 0 0 » B®

FE —— 2 = —_— =

Br N N \ a \ la R; 1 R,

RS

NN R: Ry lo ®

PF

— N \ x 0 R 1k

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 of formula (11) wherein Rs is @ C1. alkyl group may be prepared by hydrogenation (using palladium on carbon in suitable solvent, such as an alcohol — e.g. ethanol) of a compound of formula (11) wherein

Rs is a Ca. alkenyl group (e.g. as in Scheme 5).

Scheme 5:

Ra

Ra Ro Rs ° 0)

XN . ——e

FZ

N F

N

\ li \ \ 1 11 R,

R

4 R4

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 among other things in the treatment of pain and emesis but also may 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 of 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.

Compunds of formula (1) may be administered orally, topically, buccally, ocularly, rectally, vaginally, parenterally, intra-nasaily, 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 gastointestinal 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 the US Patents 4,256,108;4,166,452; and 4,265,874 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 polyvinyl-

pyrrolidone, gum tragacanth and gum acacia, dispersing or wetting agents may be a naturally occuring 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-occuring 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 the purposes of this application, 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 gms 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 gms 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 heaith, 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.

Experimental 2-Benzoyl-4-bromobenzoic acid (2a) and 2-Benzoyl-5-bromobenzoic acid (2b) : C ®

SN AlCl; Benzene oO ————— Br o + 0

CL os or CC lo} lo} 1 2a 2b

A mixture of 4-bromophthalic anhydride (1) (8.6g, 37.9mmol) and aluminium chloride (10g, 75mmol, 2 equiv.) were heated under reflux for six hours under an atmosphere of nitrogen. The hot reaction mixture was poured into a solution of water: conc. hydrochloric acid (9:1, 200mL) and the aqueous layer extracted with dichloromethane (2 x 150mL). The organic extract was dried over magnesium sulphate, filtered and evaporated under reduced pressure to furnish the crude product as an off white solid. The solid was dissolved in ethanol (80mL) and water added until the solution remained turbid. The mixture was allowed to stand at room temperature for four hours; the precipitate formed was filtered, washed with hexane (2 x 10mL.) and dried under suction to furnish compound 2a. Yield 4.1g, 35%.

'H nmr (250MHz, CDCla); 7.94 (1H, d, J 8.0, CHa), 7.71 (3H, m, CHa), 7.68 (1H, t, J7.5, CHa), 7.51 (1H, d, J 1.5 CHa), 7.44 (2H, t,J7.5, CHa) 7.06.4 (1H, Bs, OH).

The mother liquors were concentrated under reduced pressure to half the volume and stirred at room temperature. The precipitate formed was filtered, washed with hexane (2 x 10mL) and dried under suction to provide 2b. Yield 4.89, 42% 'H nmr (250MHz, CDCl); 8.70-8.30 (1H, bs, OH), 8.20 (1H, d, J 1.5,

CHa.:), 7.80 (2H, dd, J8.0, 1.5, CHa), 7.71 (2H, m, CHa), 7.58 (1H, m, CHa), 7.44 (2H, m, CHar), 7.26 (1H, d, J 8.0 CHa).

N-(2-hydroxyethy!)-N-methyl- 2-benzoyl-4-bromobenzamide (3a) ® Ee ~A ae _~o i. DCM, cat. DMF, (COC gr.__ I nocwm uw “~~ ii. DCM, Ra So 2a 3a

A solution of 2M oxaly! chloride (3.69mL, 7.38mmof, 1.1 equiv.) in dichloromethane was added dropwise to a suspension of compound 2a in dichloromethane (12mL) and catalytic N,N-dimethylformamide (2 drops) at room temperature under a nitrogen atmosphere. Gas evolution was rapid and as the reaction proceeded the solid dissolved in the dichloromethane. After 2.5 hours the solvent was removed under reduced pressure and the resulting solid co- evaporated with dichloromethane (2 x 20mL) to remove traces of excess oxalyl chloride. The crude acid chloride was dissolved in dichloromethane (15mL) and added dropwise to a solution of N-methylaminoethanol (§93uL, 7.38mmol, 1.1 equiv.) and triethylamine, (1.03mL, 7.38mmol, 1.1 equiv) in dichloromethane (15mL) cooled to 0°C in an ice bath. The resulting solution was stirred at room temperature for 3 hours, quenched with saturated aqueous sodium dicarbonate (20mL) and separated. The aqueous layer was extracted with dichloromethane (30mL.) and the combined organic fractions washed with brine (20mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the crude product purified by column chromatography, eluting with ethyl acetate : hexane (4:1), followed by ethyl acetate (100%) as product eluted.

Compound 3a was furnished as a semi solid. Yield 2.23g, 92%. The product exists are a mixture of rotomers in a 3:2 ratio. "MH nmr (250MHz, CDCls); 7.85 (2H, m, CHa), 7.75-7.62 (3H, m, CHa), 7.34 (0.6H, J 8.0, CH,,), 7.33 (0.4H, J 8.0, CH.,), 3.83 (1.2H, t, J 4.5, CH.OH), 3.76 (0.8H, t, J4.5, CH,OH), 3.59 (2H, t, J4.5, NCH.), 3.08 (0.4H, s, NCH) 2.99 (0.6H, s, NCH), 2.45 (1H, bs, OH).

N-(2-hydroxyethyl)-N-methyl- 2-benzoy!-5-bromobenzamide (3b) ® J oo = o I DCM, cat. DMF, (COC), ° ar oH ii. DCM, Se, . Oe, o lo) 2b 3b

A solution of oxalyl chloride (6.5mL, 74.3mmol, 1.1 equiv.) in dichloromethane (150mL) was added dropwise to a suspension of compound 2a (20.89, 67.5mmol, ratio of 3:1 of 2a:2b respectively) in dichloromethane (50mL) and catalytic N,N-dimethylformamide (4 drops) at room temperature under a nitrogen atmosphere. Gas evolution was rapid and as the reaction preceeded the solid dissolved in the dichloromethane. After 2.5 hours the solvent was removed under reduced pressure and the resulting solid co-evaporated with dichloromethane (2 x 50mL) to remove traces of excess oxalyl chloride. The crude acid chloride was dissolved in dichloromethane (100mL) and added dropwise to a solution of N-methylaminoethanol (mL, 74.3mmol, 1.1 equiv.) and triethylamine, (10.4mL, 74.3mmol, 1.1 equiv) in dichloromethane (150mL) cooled to 0°C in an ice bath. The resulting solution was stirred at room temperature for 3 hours, quenched with saturated brine (100ml) and separated. The aqueous layer was extracted with dichloromethane (2 x 50mL) and the combined organic fractions washed with brine (100ml), dried over magnesium sulfate and filtered.

The solvent was removed under reduced pressure and the crude product purified by column chromatography, eluting with ethyl acetate ; hexane (4:1) to elute compound 3b. Yield 6.2g, 25%. Eluting with ethyl acetate (100%) furnished compound 3a as a semi solid. Yield 14.6g, 60%. The product exists are a mixture of rotomers in a 3:2 ratio. "H nmr (250MHz, CDCls); 7.78 (1.8H, m, CHa), 7.60 (2.7H, m, CH.,), 7.49 (2.5H, CH.,), 7.45 (0.4H, d, J 8.5, CH), 7.37 (0.6H, d, J 8.5, CHa), 3.86 (1.2H, m, CH,OH), 3.76 (0.8H, m, CH,OH), 3.61 (2H, m, NCH), 3.08 (0.4H, s, NCHa), 3.00 (0.6H, s, NCH).

N-(2-hydroxyethyl)-N-methyi- 4-bromo-2-(1-hydroxy-1-phenyl)methyl benzylamine (4a)

C) i. THF, BH3.SMe, @

Br 0 O%cRT Br (Amen SG: 0 : OH 3a 4a

Amide 3a (13.8g, 38mmol) was dissolved in tetrahydrofuran (75mL) and cooled to 0°C in an ice bath. A 2M solution of borane dimethylsulfide complex (84mL, 188mmol, 4.4 equiv.) was added dropwise and the resulting solution stirred at room temperature for 17 hours. The reaction was carefully quenched with 6M hydrochloric acid solution (84mL) and the resulting solution heated under reflux for 1 hour. Tetrahydrofuran was removed under reduced pressure and remaining solution diluted with water (70mL) and extracted with diethyl ether (2 x 100mL). The aqueous layer was basified with 3.75M sodium hydroxide solution and extracted with ethyl acetate (2 x 200mL). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to furnish the desired product 4a as a colourless glass.

Yield 10.29, 77%. 'H nmr (250MHz, CDCls); 7.88-7.27 (7H, m, CHa.,), 7.08 (1H, d, J 8.0,

CH.r), 5.83 (1H, s, CHOH), 3.70-3.65 (2H, m, OCH), 3.41 (1H, d, J 12.5,

ArCH,HuN), 3.29 (1H, d, J 12.5, ArCH,HuN), 2.58-2.55 (2H, m, NCH), 2.21 (3H, s, NCHa).

N-(2-hydroxyethyl)-N-methyl- 5-bromo-2-(1-hydroxy-1-phenyl)methyl benzylamine (4b) @ i. THF, BH3.SMe; C

O°C-RT 0 ————————————

Br C NC ~on @® No o Br ~"0H 3b 4b

Amide 3b (7.4g, 20.4mmol) was dissolved in tetrahydrofuran (40mL) and cooled to 0°C in an ice bath. A 2M solution of borane dimethylsulfide complex (45mL, 90mmol, 4.4 equiv.) was added dropwise and the resulting solution stirred at room temperature for 17 hours. The reaction was carefully quenched with 8M hydrochloric acid solution (45mL) and the resulting solution heated under reflux for 1 hour. Tetrahydrofuran was removed under reduced pressure and the remaining solution was diluted with water (45mL) and extracted with diethyl ether (3 x 50mL). The aqueous layer was basified with 3.75M sodium hydroxide solution and extracted with ethyl acetate (2 x 100mL). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to furnish the desired product 4b as a colourless glass. Yield 6.5g, 91%. 'H nmr (250MHz, CDCly); 7.41-7.27 (TH, m, CHa), 7.06 (1H, d, J 8.0,

CHa), 5.86 (1H, s, CHOH), 3.72-3.66 (2H, m, OCH,), 3.44 (1H, d, J 12.5,

ArCH.HuN), 3.32 (1H, d, J 12.5, ArCH,H:N), 2.59 (2H, m, NCH), 2.23 (3H, s,

NCH). 9-Bromo-5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine (5a) ® I. p-TSA, 105°C (¢ °

ROG+N el

OH N_ 4a 5a

Diol 4a (14.6g, 41.6mmol) was dissolved in toluene (115ml) and para- : toluenesulfonic acid monohydrate (11.9g, 62.4mmol, 1.5equiv.) added. The toluene was removed under reduced pressure and the resulting oil heated at 105°C for 4 hours. On cooling the oil was suspended in water (100mL) and basified with 3.75M sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (2 x 200mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to furnish the product 5a as pale brown oil.

Yield 9.25g, 67%. 'H nmr (250MHz, CDCl); 7.38-7.25 (5H, m, CHar), 7.11 (2H, t, J 8.0, CHa), 5.72 (1H, s, CHO), 4.82 (1H, d, J 13.0, ArCH.Hy), 4.19 (1H, dt, J 3.0, 8.0,

OCH,Hs), 3.82 (1H, ddd, J 3.0, 6.0, 13.0, OCH.H.), 3.62 (1H, d, J 13.0,

ArCH,Hy), 2.81(1H, m NCH.Hy), 2.61 (1H, ddd, J 3.0, 8.0, 13.0, NCH,H.), 2.43 (3H, s, CHa). 8-Bromo-5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine (5b)

NS | mS

Ne i. p-TSA, 105°C ~

LCC Ih

Br ~"oH Br NN 4b 5b

Diol 4b (6.5g, 18.6mmol) was dissolved in toluene (50mL) and para- toluenesulfonic acid monohydrate (5.3g, 27.8mmol, 1.5equiv.) added. The toluene was removed under reduced pressure and the resulting oil heated at 105°C for 4 hours. On cooling the oil was dissolved in 3.75M sodium hydroxide solution and extracted with ethyl acetate (2 x 80mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to furnish the crude product. The crude product was purified by dry flash chromatography eluting with ethyl acetate (100%, followed by ethyl acetate:methanol (5%)). Fractions containing product were combined and evaporated under reduced pressure to furnish 5b as pale brown oil. Yield 3.6g, 58%. 'H nmr (250MHz, CDCl,); 7.37-7.22 (7H, m, CHa), 6.86 (1H, d, J 8.0,

CHa), 5.74 (1H, s, CHO), 4.79 (1H, d, J 13.0, ArCH.H,), 4.16 (1H, dt, J 3.0, 8.0,

Claims (19)

1. A compound of the general formula (1): - Re R2 o 9@ AN N \ (1) wherein : Rs is H, C1-Cealkyl optionally substituted with F, C3-Cg cycloalkyl or C2-Cs alkenyl; either R; and Rj are the same or different and are H, halogen, CN, CF, C1-Csalkyl or OR; or R; and R; form a five or six membered ring which may be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from O, Nand S), aromatic or heteroaromatic (containing 1-2 heteroatoms selected from O and N), one of W, X, Y and Z is N or CR, and the others are each CH;

R. is a halogen atom, CF3, CN, OR7, SO2N(Rs)2, CORg, CO2Rs, CON(Rs):, NR,CORs, NR;SO;Rs, NR;CO;Rs, NR{CON(Rg)., OC:-Cs alkyl optionally substituted with Rs, C4-Cg alkyl optionally substituted with Rs, Ca-Ce cycloalkyl optionally substituted with Rs, C2-Cs alkeny! optionally substituted with Rs, C>-Cs alkynyl! optionally substituted with Rs, aryl optionally substituted with Ry, or a five or six membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, linked either through carbon or nitrogen; : : Rs is Cy-Cgalkyl, C,-Cealkenyl, C2-Cs alkynyl, Ci-Cecycloalkyl, aryl or heteroaryl; :

each Rs (which may be the same or different ) is H, Ci-Cealkyl, Ca- Cealkenyl, C,-Cs alkynyl, Cs-Cecycloalkyl, aryl or heteroaryl; and Ry is aryl or heteroaryl; or a pharmaceutically acceptable salt thereof. .

2. A compound of claim 1, which is exemplified herein.

3. A pharmaceutical composition for use in therapy, comprising a compound of claim 1 or claim 2, and a pharmaceutically acceptable diluent or carrier.

4, Use of a compound of claim 1 or claim 2, for the manufacture of a human or veterinary medicament for the treatment or prevention of a condition associated with monoamine re-uptake.

5. Use according to claim 4, wherein the condition is selected from depression, post-traumatic stress disorders, attention-deficit disorders, obsessive compulsive disorders, pre-menstrual syndrome, substance abuse, micturition disorders and sexual dysfunction. :

6. Use according to claim 4, where the condition is acute, chronic or neuropathic pain (including, but not limited to, pain associated with cancer, surgery, arthritis, dental surgery, painful neuropathies, trauma, musculo-skeletal injury or disease, visceral diseases), dysmennorhoea or migraine headache.

7. Use according to claim 6, wherein the subject is also treated with an opiate. :

8. Use according to claim 6, wherein the subject is also treated with an analgesia inducer selected from acetaminophen, a non-steroidal anti- inflammatory drug, a narcotic analgesic, a local anesthetic, an NMDA antagonist, a neuroleptic agent, an anti-convulsant, an anti-spasmodic, an anti-depressant or a muscle relaxant.

9. Use according to claim 4, wherein the condition is emesis.

10. Use according to claim ©, wherein the emesis is acute, delayed, post- operative, last-phase, or anticipatory emesis.

11. Use according to claim 9, wherein the emesis is induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorder, motion, post- operative sickness, surgery, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain, migraine or opioid analgesics.

. v 16-12-2004 ] ‘ GB0305708 65

12. A compound of claim 1, wherein R, is CN, OR,, SO,N (Re) 2+ COR,, CO;R;, CON(R;),, NR,CORs, NR,SO:Rs. NR,CON (Rg) ;, 0Cy-Ce alkyl substituted with Ry, C,-Cs alkyl substituted with Ry, C,-Cs cycloalkyl optionally substituted with R, C,-Ce alkenyl optionally substituted with R,, GC,-C¢ alkynyl optionally substituted with R,, aryl optionally substituted with R,, or a five or six-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, linked either through carbon or nitrogen.

13. A compound of claim 12, wherein R, is CN, CON (Rg) 2,» optionally substituted cycloalkyl or aryl, or a five or six-membered aromatic heterocycle.

14. A compound of any of claims 1, 12 and 13, wherein R, is halogen, CN, CF,, C,-Ce alkyl or OR,.

15. A compound of any of claims 1, 12 and 13, wherein R, and R, form a ring.

16. A compound of claim 14, wherein R, is OR,.

17. A compound of claim 2, selected from N- (2-hydroxyethyl) -N-methyl -4-bromo-2- (1-hydroxy-1- phenyl) methyl benzylamine (4a) N- (2-hydroxyethyl) -N-methyl-5-bromo-2- (1-hydroxy-1- phenyl)methyl benzylamine (4b) 9-bromo-5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H- benz [f]-2,5-oxazocine (5a) 8-bromo-5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H- benz (f)-2,5-oxazocine (5b) 9-bromo-5-methyl-1- (4-methoxy) phenyl-1,3,4,6- tetrahydro-5H-benz [f] -2, 5-oxazocine (17a) 8-bromo-5-methyl-1- (4-methoxy)phenyl-1,3,4,6- tetrahydro-5H-benz [f] -2,5-oxazocine (17b) 9-bromo-5-methyl-1- (3 -methoxy)phenyl-1,3,4,6- tetrahydro-5H-benz [f]-2,5-0oxazocine (21a) 8-bromo-5-methyl-1-(3-methoxy)phenyl-1,3,4,6- tetrahydro-SH-benz[f] -2,5-0oxazocine {21b) 9-methoxy-5-methyl-1- (3-methoxy)phenyl-1,3,4,6- tetrahydro-5H-benz [f]-2,5-0oxazocine (24a) AMENDED SHEET

J Vow 16-12-2004 . GB0305708 8-methoxy-5-methyl-1- (3-methoxy) phenyl-1,3,4,6- tetrahydro-5H-benz [f) -2,5-oxazocine (24b) 9-methoxy-5-methyl-1- (4-methoxy)phenyl-1,3,4,6- tetrahydro-5H-benz [£] -2, 5-oxazocine (31a) and g8-methoxy-5-methyl-1- (3-methoxy)phenyl-1,3,4,6- tetrahydro-5H-benz [£] -2, 5-oxazocine (31b) .

18. A compound of claim 2, selected from 9-cyano-5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H- benz [£] -2, 5-oxazocine (6a) 8-cyano-5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H- benz [f] -2, 5-oxazocine (6b) 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz [£]-2,5- oxazocine (7a) S-methyl-1-phenyl-1,3, 4, 6-tetrahydro-5H-benz [£] -2,5- oxazocine-8-carboxamide (7b) N- (1,1, 1-trimethylmethoxycarbonyl) -5-methyl-1-phenyl- 1,3,4,6-tetrahydro-5H-benz [f] -2, 5-oxazocine-9-methylamine (8a) N- (1,1, 1-trimethylmethoxycarbonyl) -5-methyl-1-phenyl- 1,3,4,6-tetrahydro-5H-benz [f] -2, 5-oxazocine-8-methylamine (8b) 5-methyl-1,9-diphenyl-1,3, 4, 6-tetrahydro-5H-benz [£] - 2,5-oxazocine (9a) 5-methyl-1,8-diphenyl-1,3, 4, 6-tetrahydro-5H-benz[£] - 2,5-oxazocine (9b) 9-(3,5-dimethylisoxazol-4-yl)-5-methyl-1-phenyl- 1,3,4,6-tetrahydro-5H-benz [f] -2, 5-0xazocine (10a) 8- (3,5-dimethylisoxazol-4-yl) -5-methyl-1-phenyl- 1,3,4,6-tetrahydro-5H-benz [£] -2, 5-oxazocine {(10b) 2- (5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz [f] - 2,5-oxazocine-9-ethenyl) carboxamide (11a) 2- (5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz (f] - 2,5-oxazocine-8-ethenyl) carboxamide (11b) 2- (5-methyl-1-phenyl-1,3,4,6-tetrahydro-SH-benz[f]- 2,5-oxazocine-9-ethyl) carboxamide (12a) 2- (5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz[£f] - 2,5-oxazocine-8-ethyl) carboxamide (12b) AMENDED SHEET

I 16-12-2004 “es GB0305708 S-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz [£]-2,5" oxazocine-9-methylamine (13a) 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz [£]-2, 5 oxazocine-8-methylamine (13b) 9-cyano-5-methyl-1- (3-methoxy) phenyl-1,3,4,6- tetrahydro-5H-benz [£] -2,5-oxazocine (22a) 8-cyano-5-methyl-1- (3-methoxy) phenyl-1,3,4.,6- tetrahydro-SH-benz [£] -2, 5-0xazocine (22b) 9-cyclopropyl-5-methyl-1-phenyl-1,3,4, 6-tetrahydxo-5SH- benz [£] -2,5-oxazocine (26a) . 8-cyclopropyl -5-methyl-1-phenyl-1,3,4, 6-tetrahydro-SH- benz [f] -2,5-0xazocine (26Db) N- (acetyl) -5-methyl-1-phenyl-1,3,4, 6-tetrahydro-5H- benz [f] -2,5-oxazocine-9-methylamine (27a) N- (acetyl) -5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H- benz [f] -2,5-oxazocine-8-methylamine (27b) 9-cyclopropyl-5-methyl-1- (3-methoxy)phenyl-1,3,4,6- tetrahydro-5H-benz [£] -2,5-0xazocine (29a) 8-cyclopropyl-5-methyl-1- (3-methoxy)phenyl-1,3,4,6- tetrahydro-5H-benz [£] -2,5-oxazocine {29b) 9-cyclopropyl-5-methyl-1- (4-methoxy)phenyl-1,3,4,6- tetrahydro-SH-benz [£] -2, 5-oxazocine (30a) 8-cyclopropyl-5-methyl-1- (4-methoxy)phenyl-1,3.4,6- tetrahydro-5H-benz [£]-2, 5-oxazocine (30b) and 9-cyano-5-methyl-1- (4-methoxy)phenyl-1,3,4,6- tetrahydro-5H-benz [£] -2, 5-oxazocine (32a).

19. Use according to any of claims 4 to 11, wherein the compound is selected from 9-Methoxy-5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H- - benz [f] -2,5-oxazocine (23a) and 8-Methoxy-5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H- benz [f] -2,5-oxazocine (23D). AMENDED SHEET