GB2413326A - Nefopam analogues - Google Patents

Abstract

Benzothiazocines or benzazocines of formula (1): <EMI ID=1.1 HE=50 WI=45 LX=840 LY=620 TI=CF> <PC>wherein R1 is hydrogen, C1-6alkyl, optionally substituted with F, C3-6 cycloalkyl or C2-C4alkenyl; R2 and R3 are hydrogen, halogen, CN, CF3, C1-6alkyl or OR1, or R2 and R3 together may from a five or six-membered ring; A is CH2, S, S(O) or S(O)2; one of W, X, Y and Z are CH, CR4 or N while the others are CH; R4 is halogen, CN, CF3, OR7, SO2N(R6)2, COR6, CO2R6, CON(R6)2, NR1COR5, NR1SO2R5, NR1CO2R5, NR1CON(R6)2, or OC1-C6 alkyl, C1-6alkyl, C3-6 cycloalkyl, C2-4alkenyl, C2-6 alkynyl or aryl each optionally substituted with unsubstituted C4; R4 is a five or six membered aromatic heterocycle; R5 is C1-6alkyl, C3-6 cycloalkyl, C2-4alkenyl, C2-6 alkynyl, aryl or heteroaryl; R6 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-4alkenyl, C2-6 alkynyl, aryl or heteroaryl; R7 is aryl or heteroaryl; or a pharmaceutically acceptable salt thereof may be useful in the treatment of monoamine re-uptake related conditions. In particular these compounds may be useful as analgesic agents and for the treatment of emesis, depression, post traumatic stress disorders, attention deficit disorders, obsessive compulsive disorders and sexual dysfunction.

Description

NOVEL BENZOXAZOCINES

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 such as depression, post traumatic stress disorders, attention deficit disorders, obsessive compulsive disorders, pre-menstrual syndrome, substance abuse, micturition disorders and sexual dysfunction. The present invention also relates to stereoisomers, pro-drugs and pharmaceutical formulations of these compounds.

Nefopam [5-methyl-1-phenyl -3,4,5,6-tetrahydro-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 et a/., 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 naloxone 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 a/., 2001). Previous in vitro and in viva 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 a/., 1987; Rosland and Hole, 1990; Mather et a/., 2001). In opposition to the study of Mather et a/. (2001) who conclude that there is currently no compelling rationale to justify administering or monitoring individual enantiomers [of nefopam] , we have shown significant advantages of using the single enantiomers of nefopam for the treatment of pain and emesis.

Nefopam has also been shown to be opiate sparing when given with morphine in trials of patient controlled analgesia (Mimoz et a/., 2001) suggesting that nefopam may be additive or may work synergistically with the opiate in its analgesic effect. Co- formulation of nefopam with an opiate or other compound with analgesic activity could enhance the analgesic properties of both analgesics giving a more effective combined antinociceptive agent.

Conventional release preparations of nefopam have been commercially available for many years for use in moderate to severe pain yet the short elimination half-life of nefopam (four hours) means that it is difficult to maintain analgesic efficacy over the normal dosing period (three times daily). Dose escalation of nefopam brings about an increase in the frequency of adverse drug reactions associated with the analgesic and adverse effects on pulse and blood pressure have been observed following parenteral delivery of therapeutic doses of nefopam (Heel et a/., 1980). It is felt that controlled release formulations of nefopam will extend its analgesic efficacy and reduce the occurrence of the side-effects associated with the plasma peak concentrations of the immediate release product. Indeed, the chronotropic and ionotropic effects on the heart are not present when nefopam is administered orally (Bhatt et a/., 1981) suggesting that refinement of nefopam's plasma profile could minimize adverse drug reactions. Despite nefopam's long-standing use, controlled release preparations for oral administration containing nefopam as active ingredient have not even previously been described in the literature.

According to a first aspect of this invention, novel compounds are of general formula (1), stereoisomers, pharmaceutically acceptable salts, solvates and polymorphs thereof: R gR2 X,W: A: (1) Wherein: A may be CH2, S. S(O)n; where n is an integer 0-2 R. may be H. C,-C6 alkyl, optionally substituted with F or C3-C6 cycloalkyl or C2-C4 alkenyl either R2 and R3 may be the same or different and may be H. a halogen, ON, CF3, C,-C6 alkyl or OR,, or R2 and R3 may 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 naphthalene for example), heteroaromatic (containing 1-2 heteroatoms taken from O. such as benzofuran for example, N as in quinoline, isoquinoline and quinazoline

for example); and.

W. X, Y or Z are each N. CH or CR4.

The case where W = X = Y = Z = CH is specifically excluded. When W is N or CR4,X=Y=Z=CH;whenXisNorCR4,W=Y=Z=CH;whenYisNorCR4,W=X =*Z=CH; end when Zis N orR4,W=X=Y=CH.

R4 is halogen, CF3, CN; OR7; SO2N(R6)2 (where each R6 is the same or different); COR6; CO2R6; CON(R6)2 (where R6 maybe the same or different); NR,COR5; NR,SO2R5 NR,CO2R5; NR,CON(R6)2 (where each R6 is the same or different), OC,-C6 alkyl substituted with R4, C,-C6 alkyl optionally substituted with R4, C3-C6 cycloalkyl optionally substituted with R4, C2C6 alkenyl optionally substituted with R4, C2-C6 alkynyl optionally substituted with R4 and aryl optionally substituted with R4 R4 may also be a five or six membered aromatic heterocycle containing 1-4 heteroatoms taken 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.

R5 can be C,-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, aryl and heteroaryl.

R6 can be H. C,-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, aryl and heteroaryl.

R7 is aryl or heteroaryl.

In compounds of formula (1), those wherein R4 is a halogen atom such as Br are useful as intermediates.

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'C6alkyl" refers to straight or branched chain alkyl moiety having from one to six carbon atoms, including S for example, methyl, ethyl, propyl, isopropyl, butyl, teff-butyl, pentyl, hexyl and the like.

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 would include for example, vinyl, 1- propenyl, 1- and 2- butenyl, 2methyl-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 would include 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 "aryi" 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 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).

The compounds according to the invention may be prepared by the following process. In the description and formulae below the groups R', R2, R3, R4, R5, R6, R7, 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 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.

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

RR2 RR2 (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 would be lithium aluminium hydride, although reagents based on borane (i.e. borane.tetrahydrofuran complex) or modified sodium borohydride reduction (i.e. with a nickel or cobalt salt enhancer) are equally effective.

Equally, reduction of the ketone in (3), for example with sodium borohydride, followed by acid cyclisation, for example with ptoluenesulphonic 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.

O

(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 eg. a substituted amide such as dimethylformamide, or a halogenated hydrocarbon such as dichloromethane at a 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 methylmorpholine. 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 N,N'-dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as 1hydroxybenzotriazole. Altematively, 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 bichloride). R3

(7) tie) (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 R2 and R3 are H. Friedel-Crafts acylation under aluminium bichloride 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 are C-Br, by the route described above.

To Or., ::OH (4a) (4b) Compounds of general formula (1) where either W. X, Y or Z is CR4 and R4 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 Z is CR4 and R4 is Br can be smoothly converted into the corresponding nitrile (1b; R4 = ON) either by reaction with cuprous cyanide in a dipolar aprotic solvent such as N-methylpyrrolidinone (NMP) or under palladium-catalysed conditions (Scheme 1).

Scheme 1 3N N Nh (1a) (1b) The nitrile of general formula (1) where either W. X, Y or Z is CR4 and R4 is ON (1b) can be readily converted, by hydrolysis, into the primary amide (1c, R4 = CONH2), esters and the corresponding carboxylic acid (1d, CO2R') or into the corresponding tetrazole (1e) by treatment with a suitable azide donor such as sodium azide or trimethylsilylazide (Scheme 2).

Scheme 2 R2 R3 NOW N R2 R3 (1b) \ R2 R3 (1d) (1e) In addition compounds of general formula (1) where either W. X, Y or Z is CR4 and R4is a halogen such as Br (1a) can be lithiated with n-, see-, or teff-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. S02C12, followed by amidation, such as with ammonia) or nitrogen (diphenylphosphoryl aside, followed by reduction, such as with REDAL) provides access, by subsequent derivatisation to derivatives where R4is CO2R6; CON(R6)2 (where R6 maybe the same or different); CH20R6 (10, S02N(R6)2 (1g, where R6 maybe the same or different); and NR'COR5; NR'S02R5 (1h); NR'CO2R5; NR,CON(R6)2 (where R' maybe the same or different).(examples in Scheme 3) Scheme 3 R3 R2 MeOCHN R3 R2 NHlSO2) MeO2SHN N\R1 (1 h) In addition, compounds of general formula (1) where either W. X, Y or Z is CR4 and R4 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 Z is CR4 and R4 is a halogen such as Br can be coupled to alkenes of a general type CH2=CHR4 under Heck conditions, alkynes of a general type CH=CHR4 under Sonogoshira conditions or to 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 C2-C6 alkenyl substituted with R4 (1 i) C2-C6 alkynyl substituted with R4 (1j) and where R4 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 (1 k), 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 N) ) (1a) RR2R1 (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 R4 is a C'-6 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 (1i) wherein R4 is a C26 alkenyl group (e.g. Scheme 5).

Scheme 5 RR2 RR2 [A: A: R4 R4 (1 i) (1 l) 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 to 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.

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 nontoxic 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-butane dial. 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 application, topical application shall include 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 aboveindicated 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 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 Experimental Synthesis of 2-benzoyl-4-bromo-benzoic acid and 2-benzoyl-5-bromo-benzoic acid Bromophthalic anhydride (40.09, 0.176mol) was suspended in benzene (82.5 9, 1.06 mol) at RT under a nitrogen atmosphere. AIC13 (47 9, 0.35 mol) was added portionwise, the colour becoming more orange with each addition. After approximately 3/4 of the AIC13 had been added, further additions produced violent reactions and thus the additions were slowed. The reaction mixture was then heated at reflux temperature for 5.5hours before quenching into HCI/H2O (1:9 mix, 1L). A white precipitate formed immediately. The aqueous phase was extracted into ethyl acetate (2L), dried (MgSO4), filtered and concentrated in vacua to give an off- white solid. Trituration with ethyl acetate, followed by a recrystallisation from EtOH/H2O gave the target keto-acid as a mixture of 2 regio-siomers (19.29, 33%) in 2 batches.

dH(MeOD; 250MHz) 7.41-7.57 (5H, m, ArO, 7.67-7.70 (2H, m, ArO, 7.79 (1H, dd, J8.3, 2.0,ArO,7.97(1H,d,J8.3,ArO.

Synthesis of [5-bromo-2-(thiazolidine-3-carbonyl)-phenyll-phenylmethanone A mixture of 2-benzoyl-4-bromo-benzoic acid and 2-benzoyl-5-bromo-benzoic acid, (17 9, 0.06 mol), was suspended in dichloromethane (125 ml) at RT under a nitrogen atmosphere. DMF (2 drops) and then oxalyl chloride (5.83 ml, 0.067 mol) were added dropwise and the resulting mixture was stirred at RT for 5 hours, at which point gas evolution had ceased. The mixturewas concentrated in vacuo to provide the crude acid chloride. This material was dissolved in dichloromethane (150 ml) and added to a cooled (ice bath) solution of thiazolidine (4.8 ml, 0.061 mol) and triethylamine (8.50 ml, 0.061 mol) in dichloromethane (150 ml). The reaction mixture was stirred overnight at RT. The reaction was quenched by the addition of sat. aq. sodium bicarbonate (300 mL) and extracted into dichloromethane (2 x 250 ml). The organic extracts were dried (MgSO4), filtered and concentrated in vacua to provide the crude amide as a mixture of regioisomers. Upon standing, the mixture began to crystalline. The crystals were isolated and found to be the desired amide (12.816 9, 56%).

OH (CDC13; 250MHz) 3.02 (2H, t, .3, two of thiazolidine En, 3.65-3.80 (2H, m, two of thiazolidine O. 4.38-4.54 (2H, m, two of thiazolidine O. 7.36 (1H, d, J8.O, ArO, 7.46 7.52 (2H, m, ArO, 7.58-7.78 (5H, m, ArO.

(5-bromo-2-1{(2-mercapto-ethyl)-methylamino}-methyll-phenyl)phenylmethanol [5-bromo-2-(thiazolidine-3-carbonyl)-phenyl]-phenylmethanone (12.0 9, 31. 7 mmol) was dissolved in dry THF (120 ml) at RT under a nitrogen atmosphere. BH3SMe2 (2.0 M in THF, 63 ml, 0.127 mol) was added dropwise and the resulting solution stirred at RT overnight. The reaction was quenched by the careful addition of 6M HCI (74 ml) and the mixture was then heated at reflux temperature for 1 hour. The reaction mixture was then concentrated to remove the THF before partitioning between MTBE and H2O. The aqueous phase was basified with 2M NaOH and extracted into ethyl acetate. The organic extracts were dried (MgS04), filtered and concentrated in vacua to provide the crude thiol. Purification was achieved by repeated silica gel column chromatography.

OH (CDC13; 250MHz) 2.17 (3H, s, CH3), 2.62-2.79 (4H, m, CH2CH2), 3.29 (2H, d, J4.O, ArCH2NR2), 5.80 (1 H. s, CHOH), 7.06 (1 H. d, J8.5, ArO, 7.23-7. 41 (7H, m ArO.

Note. Over time, it became apparent (test with Ellman's reagent) that the thiol was oxidised to the corresponding disulfde (shown below).

Reduction of disulfide e Broth Ho//Br Br:OH 4\/ S-S JO -SH Disulfide (2.703 9, 3.7 mmol) was dissolved in dichloromethane (25 ml) at RT under nitrogen. Dithiothreitol (DTT) (628 mg, 4.07 mmol) was added and the resulting solution was stirred at RT overnight, during which time a precipitate formed. The mixture was diluted with dichlormethane and washed with water. The organic phase was separated and dried (MgS04), filtered then concentrated in vacuo to provide (5-bromo-2 [{(2-mercapto-ethyl)-methylamino}-methyl]-phenyl)-phenylmethanol (tested with Ellman's reagent) (2.4g, 89%) which was used immediately in the next step.

[4-bromo-2-(phenylpropylsulfanylmethyl)-benzyl]-methylamine

Q

Br: Br, - (5-bromo-2-[{(2-mercapto-ethyl)-methylaminomethyl]-phenyl)phenylmethanol (2.40 9, 6.56 mmol) was heated to reflux temperature under Dean-Stark conditions in toluene (25 ml) with pTSA (1.87 9, 9.84 mmol) under a nitrogen atmosphere, for 4 hours. The mixture was allowed to cool before diluting with ethyl acetate and washing with sat. aq.

sodium bicarbonate solution. The organic extracts were dried (MgS04), filtered and concentrated in vacua to provide the target compound as an impure oil. Purification by silica gel column chromatography [EtOAc] gave the product (584 mg, 26%).

AH (CDC13; 250MHz) 2.28 (1H, aft, J15.9, 6.4, one of CH2CH2), 2.44 (3H, s, CH3), 2.55 (1H, aft, J15.9, 4.6, one of CH2CH2), 3.00 (2H, t, J4.6, two of CH2CH2), 3.51 (1H, d, J14.3, one of ArCH2NR2), 4.08 (1 H. d, J14.3, one of ArCH2NR2), 6.46 (1 H. s, CHSH), 7.05-7.09 (2H, m, ArO, 7.25-7.40 (4H, ArO, 7.46-7.49 (2H, m, ArO.

{4-bromo-2lphenyl-(propane-1 -sulfinyl)-methyl]-benzyl}-methylamine [4-bromo-2-(phenylpropylsulfanylmethyl)-benzyl]-methylamine (339 mg, 0.97 mmol) was dissolved in methanol (4 ml) and cooled in an ice bath. NalO4 (229 mg, 1.07 mmol) in water (3 ml) was added dropwise and the resulting mixture was stirred for 20 minutes in the ice bath and for 5 hours at RT. The reaction mixture was filtered and the filter cake washed with methanol. The filtrate was concentrated in vacua to remove the solvent and as the mixture concentrated, a precipitate formed. Ethyl acetate was added to extract the crude product from the aqueous phase; the organic extracts were dried (MgSO4), filtered and concentrated in vacuo to provide the crude material. Purification by gravity silica gel column chromatography [EtOAc] gave the product (35 mg, 10%) as a cream solid.

OH (COCK; 250MHz) 2.35 and 2.44 (2 x 3H, 2 x s, CH3 two diastereoisomers), 2.46-2.52 (2H, m, one of CH,CH2 for each diastereoisomer), 2.54-2.81 (2H, m, one of CH2CH, for each diastereoisomer), 2.82-2.99 (4H, m, two of ArCH'NCH,CH' for each diastereoisomer), 3.59-3.76 (2H, m, one of ArCH2NCH2CH2 for each diastereoisomer), 4.09-4.19 (2H, m, one of ArCH2NCH2CH' for each diastereoisomer), 6.35 and 6.38 (2 x 1H, 1 x s, CHS), 7.15 (2H, dd, J7.9, 2.1, one ArH for each diastereoisomer), 7.24-7.27 (2H, m, one ArH for each diastereoisomer), 7.36-7.47, (8H, m, four of ArH for each diastereoisomer), 7.55 (2H, ted, n.3, one of ArH for each diastereoisomer), 7.68 (2H, ted, J6.7, one of ArH for each diastereoisomer); m/z (ES+) 364 and 366 (MH+ for Br79 and Brat).

Claims (11)

1. Claims 1. A compound of general formula (1) ;: (1) wherein: R. is H. C'-C6

   alkyl, optionally substituted with F or C3-C6 cycloalkyl or C2-C4 alkenyl; either R2 and R3 are the same or different and are each H. halogen, ON, CF3, C, C6 alkyl or OR,, or R2 and R3 may form a five or six membered ring which may be carbocyclic, heterocyclic (containing 1-2 heteroatoms taken from 0, N and S), aromatic or heteroaromatic (containing 1-2 heteroatoms taken from O and N); and one of W. X, Y and Z is N. CH or CR4 and the others are CH; R4 is halogen; CF3; ON; OR7; S02N(R6)2 (where each R6 is the same or different); COR6; CO2R6; CON(R6)2 (where R6 is the same or different); NR,COR5; NR,SO2R5; NR,CO2R5; NR,CON(R6)2 (where each R6 is the same or different), OC'-C6 alkyl substituted with unsubstituted R4, C'-C6 alkyl optionally substituted with unsubstituted R4, C3-C6 cycloalkyl optionally substituted with unsubstituted R4, C2-C6 alkenyl optionally substituted with unsubstituted R4, C2-C6 alkynyl optionally substituted with unsubstituted R4 and aryl optionally substituted with unsubstituted R4, or R4 is a five or six membered aromatic heterocycle containing 1-4 heteroatoms taken from N and O; R5is C,-C6alkyl, C2- C6alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, aryl and heteroaryl; R6 can be H. C,-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, aryl and heteroaryl; and R7is aryl or heteroaryl; or a pharmaceutically acceptable salt thereof.
2. 2. A compound of claim 1, in the form of a single (+) or (-) enantiomer.
3. 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. 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. 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. 6. Use according to claim 4, where the condition is acute, chronic or neuropathic pain, dysmennorhoea or migraine headache.
7. 7. Use according to claim 6, wherein the subject is also treated with an opiate.
8. 8. Use according to claim 6, wherein the subject is also treated with an analgesia inducer selected from acetaminophen, a non-steroidal antiinflammatory 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. 9. Use according to claim 4, wherein the condition is emesis.
10. 10. Use according to claim 9, wherein the emesis is acute, delayed, postoperative, last-phase, and anticipatory emesis.
11. 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 analgesic.