3-BENZYLAMINO-2-PHENYLPIPERIDINES AS NEUROKININ ANTAGONISTS

Abstract: The invention relates to piperidine derivatives of formula (I), wherein R<1> is a C2-4alkoxy group, R<2> is (a); R<3> is a hydrogen or halogen atom; R<4> and R<5> may each independently represent a hydrogen or halogen atom, or a C1-4alkyl, C1-4alkoxy or trifluoromethyl group; and pharmaceutically acceptable derivatives thereof, to processes for their preparation, and their use in the treatment of conditions mediated by tachykinins.

Description: 3-Beπzyl am1 no-2-phenylp1per1d1 nes as neurokl nl n antagoni sts The present invention relates to pipendine derivatives, to processes for their preparation, pharmaceutical compositions containing them and their medical use. In particular the invention relates to novel compounds which are potent and specific antagonists of tachykinins, including substance P and other neurokinins. 3-Aminopipehdine derivatives described as having substance P antagonist activity are disclosed in, for example, WO-A-9300331 , WO-A-9301170, WO-A-9413663 and WO-A-95/08549. The present invention provides compounds of formula (I) wherein R 1 is a C 2^ »alkoxy group; R 2 is CF 3 N ~\ N N - N R 3 is a hydrogen or halogen atom; R 4 and R 5 may each independently represent a hydrogen or halogen atom, or a or trifluorometh l group; and pharmaceutically acceptable derivatives thereof. By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt or solvate of a compound of formula (I) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof. It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds of formula (I). It will be appreciated by those skilled in the art that the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position. Preferred pharmaceutically acceptable derivatives of the compounds of formula (I) are pharmaceutically acceptable salts and solvates thereo Suitable pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic or inorganic acids for example, hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates acetates, citrates, succinates, tartrates, fumarates and maleates Dihydrochloπde salts are particularly suitable. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining the compounds of formula (I) and their pharmaceutically acceptable acid addition salts. The solvates may, for example, be hydrates. References hereinafter to a compound according to the invention includes both compounds of formula (I) and their pharmaceutically acceptable derivatives. It will be appreciated by those skilled in the art that the compounds of formula (I) contain at least two chiral centres (shown as * in formula (I)) and thus exist in the form of two pairs of optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures. For example the compounds of formula (I) may be either cis isomers, as represented by figures (a) and (b), or trans isomers, as represented by figures (c) and (d), or mixtures thereof. All of the isomers of the compounds of formula (I) represented by the figures (a) to (d) and mixtures thereof including racemic mixtures are included within the scope of the invention. W=NHCH, The compounds of formula (I) are preferably in the form of their cis isomers (i.e. as represented by figures (a) and (b)). The 2S, 3S isomers (i.e. as represented by figure (b)) are particularly preferred. Referring to the general formula (I), a C 2 -«alkoxy group may be a straight chain or branched chain alkoxy group, for example, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy or 2-methylprop-2-oxy. A C^alkyl group may be a straight chain or branched chain alkyl group and may be, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-1 -yl or 2-methylprop-2-yl. Referring to the general formula (I), a halogen atom may be a fluorine, chlorine, bromine or iodine atom, such as a fluorine, chlorine or bromine atom. R 3 is preferably a hydrogen atom. R 4 and R 5 are preferably hydrogen or halogen, e.g. fluorine, atoms, e.g. R 4 may represent a halogen, e.g. a fluorine, atom and R 5 may represent a hydrogen atom More preferably R 4 and R 5 are both hydrogen atoms. A preferred class of compounds of formula (I) are those wherein R 1 is an ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy or 2-methylprop-2-oxy group, R 3 is a hydrogen atom and R 4 and R 5 are hydrogen or halogen, e g fluorine, atoms, more preferably R 4 and R 5 are both hydrogen atoms. Specific compounds according to the invention include (2-(2-Propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpιperιdιn- 3-yl)amιne (2-(1-Propoxy)-5-(5-trifluoromethyltetrazol-1 -yl)benzyl)-([2S,3S]-2-phenylpιperιdιn- 3-yl)amιne (2-(1-Butoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpιperidιn- 3-yl)amιne (2-(2-Butoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidιn- 3-yl)amine (2-(2-Methyl-1-propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2- phenylpiperidin-3-yl)amine (2-(2-Ethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-(4-fluorophenyl)- piperidin-3-yl)amine and pharmaceutically acceptable derivatives, e.g. salts, especially the dihydrochloride salts, and solvates thereof. A further specific compound according to the invention includes: (2-(2-Methyl-2-propoxy)^5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2- phenylpiperidin-3-yl)amine and pharmaceutically acceptable derivatives thereof. A preferred compound according to the invention is: (2-Ethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3- yl)amine and pharmaceutically acceptable derivatives, e.g. salts, especially the dihydrochloride salt, and solvates thereof. The compounds of the invention are antagonists of tachykinins, including substance P and other neurokinins both in vitro and in vivo and are thus of use in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins. The compounds of the invention possess NKi- receptor binding affinity as determined in vitro by their ability to displace [3H] - substance P (SP) from recombinant human NK, receptors expressed in Chinese Hamster Ovary (CHO) cell membranes. CHO membranes (3-5μg protein per tube) were prepared and incubated with [3H]-SP (0.6 - 0.8nM) at 20°C for 40mιn Non-specific binding was defined as that remaining in the presence of 1 μM (+) CP99.994 The compounds of the invention have been shown to have anti-emetic activity as indicated by for example their ability to inhibit radiation-induced emesis in the ferret. In this model of emesis the onset of retching and vomiting occurs approximately 20 minutes after whole body irradiation (2 Grey ≡ 200 Rads) The test compound is administered (e.g. i.p, p.o., i.v., s.c) immediately after irradiation and its effect on emesis determined by comparison with appropriate controls. Anti-emetic activity may also be demonstrated using other emetogens such as cisplatin and ipecacuanha. Alternatively, the test compounds may be administered before irradiation or before treatment with an emetogen, for example 1.5, 3 or 6 hours before irradiation. Compounds of the invention have been shown to inhibit radiation-induced emesis at a dose of 0.1 to 3mg/kg s.c. in the above test. The compounds of the invention are potent and specific NK ! antagonists Furthermore, they exhibit good oral bioavailability and have an advantageous duration of action. Compounds of the invention are useful as analgesics in particular they are useful in the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain, various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia, cancer pain; pain of visceral origin; gastrointestinal pain, nerve entrapment pain, sport's injury pain; dysmennorrhoea; menstrual pain, meningitis, arachnoiditis musculoskeletal pain; low back pain e g spinal stenosis, prolapsed disc, sciatica angina, ankylosing spondyolitis; gout, burns, scar pain, itch, and thalamic pain such as post stroke thalamic pain. Compounds of the invention are also useful as aπtiiπflammatory agents in particular they are useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis, in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease, non-steroidal anti-inflammatory drug induced damage and inflammatory and secretory effects of bacterial infection, e g due to Closthdium difficile: inflammatory diseases of the skin such as herpes and eczema, inflammatory diseases of the bladder such as cystitis and urge (i.e. urinary) incontinence; and eye and dental inflammation, e.g. gingivitis and periodontitis. Compounds of the invention are also useful in the treatment of allergic disorders in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis. Compounds of the invention may also be useful in the treatment of CNS disorders in particular psychoses such as schizophrenia, mania or dementia, cognitive disorders e.g. Alzheimer's disease; anxiety, AIDS related dementia, diabetic neuropathy; multiple sclerosis; depression, Parkinson's disease, and dependency on drugs or substances of abuse; and also the compounds of the invention may act as myorelaxants and antispasmodics Compounds of the invention are also useful in the treatment of emesis, l e nausea, retching and vomiting Emesis includes acute emesis, delayed or late emesis and anticipatory emesis The compounds of the invention, are useful in the treatment of emesis however induced For example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e g cyclophosphamide, carmustme, lomustme and chlorambucil, cytotoxic antibiotics, e.g dactinomycin, doxorubicin, mitomycm-C and bleomycin, anti-metabolites, e g cytarabine, methotrexate and 5- fluorouracil, vinca alkaloids, e g etoposide, vinblastme and vincπstme, and others such as cisplatin, dacarbazme, procarbazine and hydroxyurea, and combinations thereof, radiation sickness radiation therapy, e g irradiation of the thorax or abdomen, such as in the treatment of cancer, carcinoid syndrome, poisons, toxins such as toxins caused by metabolic disorders or by infection, e g gastritis, or released during bacterial or viral gastrointestinal infection, pregnancy, vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease, post-operative sickness dialysis-induced emesis, prostaglandin-induced emesis, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain, e g myocardial infarction or peritonitis, migraine, increased intercranial pressure, decreased intercranial pressure (e g altitude sickness), opioid analgesics, such as morphine gastro-oesophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia, organ failure, such as in terminal illness, AIDS and AIDS-related conditions, and treatments thereof, and cyclic vomiting syndrome Compounds of the invention are also useful in the treatment of gastrointestinal disorders such as irritable bowel syndrome; skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as sclerodenma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; disorders caused by a spiral urease-positive gram-negative bacterium such as Helicobacter pylori; and cough. Compounds of the invention are also useful as cosmetic treatments, for example in the formulation of cosmetic compositions for sensitive skin. The invention therefore provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in therapy, in particular in human medicine There is also provided as a further aspect of the invention the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for use in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof. It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms. Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation. Accordingly, the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Thus compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), transdermal, depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e g pregelatinised maize starch, polyvinylpyrro done or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystallme cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica). disintegrants (e.g. potato starch or sodium starch glycollate), or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e g sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e g lecithin or acacia), non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e g methyl or propyl-p- hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts flavouring, colouring and sweetening agents as appropriate Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner. The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e g eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents suspending agents, thickening agents, or colouring agents Drops may be formulated with an aqueous or non aqueous base also comprising one or more dispersing agents, stabilising agents, solubi sing agents or suspending agents They may also contain a preservative For transdermal administration the compounds according to the invention may be formulated as creams, gels, ointments or lotions or as a transdermal patch Such compositions may for example be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilising, dispersing, suspending, and/or colouring agents The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g containing conventional suppository bases such as cocoa butter or other glyceπdes The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. For intranasal administration, the compounds of the invention may be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. The compositions may contain from 0.1% upwards, e.g 0.1 - 99% of the active material, depending on the method of administration. A proposed dose of the compounds of the invention is 0.05 mg/kg to about 400 mg/kg bodyweight per day e.g 0.05mg/kg to 5mg/kg per day It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected The compounds of formula (I) may, if desired, be administered with one or more therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art For example, the compounds of formula (I) may be administered in combination with a systematic anti-inflammatory corticosteroid such as methyl prednisolone or dexamethasone, MMP or TNF convertase inhibitors, CD23 or CD4 antibodies or a 5HT 3 antagonist such as ondansetron, granisetron or metoclopramide. The compounds of formula (I) may also be administered in combination with sympathomimetics, such as ephedrine, pseudoephedπne and oxymetazoline, or the compounds may be administered with analgesics, such as non-steroidal antiinflammatory drugs (NSAIDs), opioids e.g. opiate agonists, lipoxygenase inhibitors, cyclooxygenase inhibitors, NMDA antagonists, e.g glycine antagonists, inhibitors of nitric oxide or its synthesis, sodium channel blockers or local anaesthetics. Compounds which are specific antagonists at NIK, receptors, such as the compounds of formula (I), may be administered in combination with compounds which are specific antagonists at NK 2 receptors. Compounds of formula (I), and salts and solvates thereof, may be prepared by the general methods outlined hereinafter. In the following description, the groups R 1 - R 2 , R 3 , R 4 and R 5 are as previously defined for compounds of formula (I) unless otherwise stated. According to a first general process (A), a compound of formula (I) may be prepared by reacting a compound of formula (II): with a compound of formula (III) to form the intermediate imine, which may be isolated if required, followed by reduction of the imine using a suitable metal reducing agent such as a metal hydride, for example a borane hydride, alane hydride or a metal hydride complex like lithium aluminum hydride or sodium borohydride, or an organo-metallic complex such as borane- methyl sulphide, 9-borabicyclononane (9-BBN), triethylsilane, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. Alternatively, catalytic hydrogenation may be used, for example using a platinum catalyst in a suitable solvent e.g. ethanol. The condensation reaction conveniently takes place in a suitable solvent such as an alcohol (e.g. methanol), an aromatic hydrocarbon (e.g. benzene, toluene or xylene) or a chlorinated hydrocarbon (e.g. dichloromethane or dichloroethane) at a temperature ranging from ambient to the reflux temperature of the reaction mixture. The reaction preferably takes place in the presence of a catalytic amount of a suitable acidic condensing agent such as p-toluenesulphonic acid or acetic acid and/or a dehydrating agent such as molecular sieves, or the reaction may take place under Dean-Stark conditions. The reduction step conveniently takes place in a suitable solvent such as acetonitrile, dimethylformamide, benzene, chlorinated hydrocarbons such as dichloromethane or dichloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2- dimethoxyethane and alcohols such as ethanol at a temperature ranging from 0°C to the reflux temperature of the reaction mixture Process (A) may also take place in one step without isolation of the intermediate imine if the condensation reaction takes place in the presence of sodium cyanoborohydride or sodium triacetoxyborohydπde Further reduction is therefore unnecessary in this case. Compounds of formula (II) may be prepared according to conventional procedures, for example as described in WO-A-9508549 which is incorporated herein by reference. Compounds of formula (III) may be prepared by reacting compounds of formula (IV) with an appropriate alkylating agent, such as a C 2 - 4 alkyl bromide or iodide in the presence of a base such as potassium carbonate. Compounds of formula (IV) may be prepared by reacting compounds of formula (V) with hexamethylenetetramine in the presence of trifluoroacetic acid at elevated temperature. Compounds of formula (V) may be prepared by reacting the appropriate p- hydroxyaniline, or a protected derivative thereof, with compounds of formula (VI) CF 3 - C(OR ) 3 (VI) (where R 7 is methyl or ethyl), for example tπethylorthoacetate, in acetic acid followed by reaction with sodium azide at elevated temperature and deprotection if necessary. Compounds of formula (III) may be prepared by oxidising compounds of formula (VII) with a suitable oxidising agent such as manganese dioxide in a suitable solvent such as an ether, e.g. tetrahydrofuran, at elevated temperature. Compounds of formula (VII), may be prepared by reducing compounds of formula (VIII) with a suitable reducing agent such as a metal hydride complex such as lithium borohydride in a suitable solvent such as an ether, e.g tetrahydrofuran, or an alcohol, e.g. ethanol, or a mixture thereof. Compounds of formula (VIII) may be prepared from the corresponding 2-alkoxy-5- amino benzoic acid methyl ester by reacting with compounds of formula (VI) as defined above, e.g. t ethyl orthoformate, and sodium azide in glacial acetic acid and dimethylform- amide at elevated temperature. Suitable 2-alkoxy-5-amino benzoic acid methyl esters are either known or may be prepared according to methods known for the preparation of known compounds e.g. the method described by Bergman et al in Can.J.Chem. (1973), 51, 162-70. According to a further general process (B), compounds of formula (I) may be prepared by reduction of compounds of formula (IX) with a suitable reducing agent, such as a metal hydride, for example a borane hydride, in a suitable solvent such as an ether, e.g. tetrahydrofuran, at ambient temperature. Compounds of formula (IX) may be prepared by reacting compounds of formula (III) with compounds of formula (X) R' under conditions as described above for process (A) Compounds of formula (X) are either known or may be prepared according to methods known for the preparation of known compounds, for example according to the method described in European Patent Application No. EP-A-0436334, incorporated herein by reference. According to a further general process (C) compounds of formula (I) may be prepared by reacting a compound of formula (XI) or an amino-protected derivative thereof, with L-C 2 - 4 alkyl where L represents a suitable leaving group such as iodine, bromine, chlorine, OS0 2 R c , where R c represents methyl, paratoluoyl or trifluoromethyl, in the presence of a base, such as potassium carbonate, and a suitable solvent, such as dimethylformamide, at a temperature between 0 and 100°C, e.g. at room temperature, followed by deprotection where necessary. Compounds of formula (XI) may be prepared by reacting compounds of formula (XII) where R β is C^alkyl, e.g. methyl, with borane-methyl sulphide complex in a suitable solvent, such as dichloromethane, at elevated temperature. Compounds of formula (XII) may be prepared according to similar methods described herein for the preparation of compounds of formula (I) and those methods described in WO-A-9508549. Suitable protecting groups for the hydroxyl function include benzyl groups which may be introduced and removed according to conventional procedures. For example deprotection may be effected by catalytic hydrogenatioπ. Aldehyde functions may be protected as acetals which may be introduced and removed according to conventional procedures. For example, deprotection may be effected by acid hydrolysis. Amino functions may be protected by, for example, a t-butyl carbamate (BOC) group or a benzyl group which may be introduced and removed according to conventional procedures. For example, deprotection of BOC groups may be effected by acid hydrolysis. Compounds of formulae (III), (IX) and (XII) are novel and therefore form a further feature of the invention. Where it is desired to isolate a compound of formula (I) as a salt, for example a pharmaceutically acceptable salt, this may be achieved by reacting the compound of formula (I) in the form of the free base with an appropriate amount of suitable acid and in a suitable solvent such as an alcohol (e g ethanol or methanol), an ester (e.g ethyl acetate) or an ether (e.g diethyl ether or tetrahydrofuran) Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods. The compounds of formula (I) may readily be isolated in association with solvent molecules by crystallisation from or evaporation of an appropriate solvent to give the corresponding solvates. When a specific enantiomer of a compound of general formula (I) is required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Thus, in one example an appropriate optically active acid may be used to form salts with the enantiomeric mixture of a compound of general formula (I). The resulting mixture of isomeric salts may be separated for example by fractional crystallisation, into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base. Alternatively, enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates using any of the general processes described herein. A particularly suitable route for the preparation of optically active intermediates of formula (II) from the enantiomeric mixture thereof is by fractional crystallisation using (2R, 3R)-bis-(4-methyl-benzoyloxy)-succinic acid. Thus, the cis (S,S) form of intermediate (II) may be obtained from an enantiomeric mixture thereof (e g the racemic mixture) by fractional crystallisation with (2R, 3R)-bιs-(4-methyl- benzoyloxy)-succinic acid in a suitable solvent, such as an aqueous alcohol, e g aqueous ethanol, isolating the resulting salt and converting it into the corresponding optically active free base by conventional procedures for example using aqueous ammonia. Alternative methods for preparing and resolving 2-phenyl-3-aminopiperidine are described in WO-A-9427966, incorporated herein by reference. Specific enantiomers of a compound of formula (I) may also be obtained by chromatography of the corresponding enantiomeric mixture on a chiral column, for example by chiral preparative h.p.l.c. Specific diasterβoisomers of a compound of general formula (I) may be obtained by conventional methods for example, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or by conversion of a mixture of isomers of a compound of general formula (I) into appropriate diastereoisomeric derivatives e.g. salts which can then be separated by conventional means e.g. by chromatography or by fractional crystallisation Alternatively, the diastereosiomers may be separable without the need for further derivatization. Standard resolving methods are described for example in ' Stereochemistry of Carbon Compounds' by E.L. Eiiel (McGraw Hill, 1962) and 'Tables of Resolving Agents' by S.H.Wilen. The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product The invention is further illustrated by the following Intermediates and Examples which are not intended as a limitation of the invention All temperatures are in °C Flash column chromatography (FCC) was carried out on silica (Merck 9385) The following abbreviations are used: ether-diethyl ether Intermediate 1 N-(4-Benzyloxy-phenv0-2.2.2-trifluoro-acetamide A mixture of 4-benzyloxyaniline hydrochloride (0.19mol) in dichloromethane (750ml) at 0° under nitrogen was treated dropwise with trifluoroacetic anhydride (27.6ml) then t ethylamine (60ml). After 24h the mixture was poured into t-butyl methyl ether (1.51) and was washed with 2N hydrochloric acid (11). The organic phase was dried (M gS0 4 ) and evaporated in vacuo to give the title compound as a white solid (52.3g). T.l.c. (cyclohexane/ethylacetate (9:1 )) Rf 0.36. Intermediate 2 ( 4-Benzyloxy-phenvn-(1-chloro-2.2.2-trifluoro-ethylideneVamine A mixture of resin-supported triphenylphosphine (3mmol thphenylphosphine/g resin; 58.6g) and N-(4-benzyloxy-phenyl)-2,2,2-trifluoro-acetamide (20.8g) in carbon tetrachloride (800ml) was heated to reflux under nitrogen for 18h. The mixture was allowed to cool then filtered, washing the resin with dichloromethane (11) and ether (11). The organics were concentrated in vacuo to give the title compound as a yellow solid (20.7g). T.l.c. (Cyclohexane/ethyl acetate (9:1 )) Rf 0.81 Intermediate 3 1 - ( 4-Benzyloxy-phenyl V5-trifluoromethyl-1 H-tetrazole (4-Benzyloxy-phenyl)-(1 -chloro-2,2,2-trifluoro-ethylidene)-amine (66mmol) was added to a stirred flask of glacial acetic acid (250ml) at 70° under nitrogen. After 4 min sodium azide (210mmol) was added and heating was continued for 3h. After cooling the mixture was filtered, the filtrate poured into water (750ml) then extracted with dichloromethane (500ml x3). The combined organic extracts were dried (Na 2 S0 4 ) and evaporated in vacuo. Purification by FCC using hexane-ethyl acetate (19:1 ) gave the title compound as a white solid (14.5g). T.l.c. (Cyclohexane/ethyl acetate (19:1 ) Rf 0.22 Intermediate 4 4-(5-Trifluoromethyl-tetrazol-1-yl)-phenol A solution of 1-(4-benzyloxy-phenyl)-5-trifluoromethyl-1 H-tetrazole (45.3mmol) in ethanol (100ml) and tetrahydrofuran (100ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium-carbon catalyst (6g). After 2h, the mixture was filtered and the filtrate was evaporated to give the title compound (10.4g) as a cream solid. T.l.c. (Dichlormethane/ethanol/ammonia(200:8:1 )) Rf 0.3. Intermediate 5 2-Hvdroxy-5-(5-trifluoromethyl-tetrazol-1-ylι-benzaldehvde A solution of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol (45mmol) in trifluoroacetic acid (200ml) and hexamethylenetetramine (186.9mmol) was heated at 100°, under nitrogen for 16h. The reaction mixture was quenched with 2N sulphuric acid (250ml) and extracted with ether (3x250ml)). The combined organics were dried (Na 2 S0 4 ) and evaporated to give a dark yellow oil. Purification by FCC (hexane/ether (2:1 )) afforded the title compound (8.8g) as a pale yellow solid. T.l.c. (hexane/ether (2:1 )) Rf 0.36 Intermediate 6 2-Methoxy-5-(5-trifluoromethyl-tetrazol-1-vh-benzaldehvde A mixture of 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde (1.56mmol), potassium carbonate (7.8mmol) and methyl iodide (7.8mmol), in acetone (25ml) was stirred for 18h at 23° under nitrogen. Water (150ml) was added and the mixture extracted with diethyl ether (3x50ml) The combined organic extracts were washed with saturated brine, dried (Na 2 S0 4 ) and evaporated to give the title compound as a yellow solid (0 48g) T.l.c. (ether/hexane (2:1 )) Rf 0.38. Intermediate 7 r2-Methoxy-5-(5-tπfluoromethyl-tetrazol-1-yl)-benzyll-(r2S.3S1-2-phenyl-piperιdιn- 3-yl)-amine dihydrochloride A mixture of [2S]-phenyl-pipehdin-[3S]-ylamιne (1 14mmol), 2-methoxy-5-(5- trifluoromethyl-tetrazol-1 -yl)-benzaldehyde (1.2mmol), sodium triacetoxyborohydπde (2.37mmol) and acetic acid (3 drops) in dichloromethane (25ml) was stirred at 23° under nitrogen for 64h. 2N sodium carbonate solution (50ml) was added and the mixture extracted with dichloromethane (3x25ml) The combined extracts were washed with saturated brine (50ml), dried (MgS0 4 ) and evaporated. Purification by FCC with dichloromethane/ethanol/ammonia (400:10:1 → 100:10:1 ) gave a colourless viscous oil. This was dissolved in methanol (10ml) and treated with 2N ethereal hydrogen chloride (~10ml). Evaporation in vacuo and trituration with i-propyl acetate gave the title compound as a white solid (210mg) T.l.c . (Dichloromethane/ethanol/ammonia (200.10.1 )) Rf 0.39 Optical Rotation (c 3mg/ml. water) +50.35°. Intermediate 8 r2-Hvdroxy-5-f5-trifluoromethyl-tetra2θl-1-vh-benzvn-(r2S.3S1-2-phenylPiperidin-3- vhamine A suspension of [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2- phβnylpiperidin-3yl)amine dihydrochloride (1.01g, 2mmol) in chloroform (20ml) was stirred at room temperature and treated with triethylamine, (0.58ml, 406mg, 4mmol) to give a clear solution. This was then treated slowly with a solution of boron tribromide: dimethylsulfide complex (20ml of 1M solution in dichloromethane; 20mmol) and the reaction mixture was refluxed under nitrogen for 3 days. Further reagent (10ml, 10mmol) was then added and after a further 3 days the mixture was cooled in an ice-bath, stirred and treated with methanol (40ml). The mixture was evaporated to dryness. This treatment was repeated twice further. The resulting oil was partitioned between ethyl acetate (100ml) and saturated aqueous sodium bicarbonate (100ml) The aqueous phase was extracted with further ethyl acetate (50ml) after pH adjustment (to pH ca 8) Combined extracts were washed with brine (100ml) dried (MgS0 4 ) and evaporated to a brown foam, which was chromatographed on silica (Merck 9385) elutmg with 2% then 5% methanol in dichloromethane. The required fractions were combined and evaporated to give the title compound as a light brown foam (672mg), mass spectrum (thermospray +ve) m/e 419 (MH * ). Intermediate 9 3-ftert-Butoxycarbonyl-f2-hvdroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl1- aminoH2S.3S1-2-phenylpipehdine-1-carboxylic acid tert-butyl ester A solution of [2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2- phenylpiperidιne-3-yl)amine (418mg, 1mmol) in dichloromethane (5ml) was treated with di-t-butyldicarbonate (240mg, 1.1mmol) and the solution was stirred for 19h at room temperature. Further reagent was then added (240mg) and after a further day the solution was evaporated to dryness. The resulting gum was chromatographed on silica (Merck 9385; 70g) eluting with 3:1 then 1 :1 cyclohexane:ethyl acetate. The required fractions were combined and evaporated to provide the title compound as a light brown foam (487mg), v(CHBr 3 ) 1663 and 1690cm "1 (carbamate C=0). Intermediate 10 3-ftert-Butoxycarbonyl-r2-ethoxy-5-(5-trifluoromethyl-tetrazol-1-vh-benzvn-amino>- r2S.3S1-2-phenylpiperidine-1-carboxylic acid tert-butyl ester A solution of 3-{tert-butoxycarbonyl-{2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)- Denzyl]-aminoH2S,3S]-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (300mg, 0.48mmol) in dimethylformamide (1ml) containing a suspension of finely ground potassium carbonate (83mg, O.δmmol) was stirred at room temperature and treated with ethyl iodide (47mg, 0.3mmol). After 2h further reagent was added (47mg) and after 4h the reaction mixture was evaporated to dryness. The residue was partitioned between ethyl acetate (50ml) and saturated aqueous sodium bicarbonate (50ml). The organic phase was washed with brine (2x50ml), dried (MgS0 ) and evaporated to a yellow gum. This was chromatographed on silica (Merck 9385; 30g) eluting with 3:1 cyclohexane:ethyl acetate. The required fractions were combined and evaporated to provide the title compound as a white foam (222mg), mass spectrum (thermospray +ve) m/e 647 (MH + ). Similarly prepared - Intermediate 11 3-ftert-Butoxycarbonyl-r2- ( 1-propoxy ) -5-f5-trifluoromethyl-tetrazol-1-yl)-benzvπ- aminoH2S.3S1-2-phenylpipehdine-1-carboxylιc acid tert-butyl ester From 3-{tert-butoxycarbonyl-[2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]- amino}-[2S,3S]-2-phenylpipe dine-1-carboxylic acid tert-butyl ester (400mg) amd 1 -iodopropane (111mg, 0.66mmol) to give the title compound as a white foam (167mg), mass spectrum (thermospray +ve) m/e 661 (MH * ). Intermediate 12 3 tert-Butoxycarbonyl-r2- ( 1 -butoxy V5-f5-thfluoromethyl-tetrazol-1-vπ-benzvn- aminoHr2S.3S1-2-phenylpiperidine-1-carboxylic acid tert-butyl ester From 3-{tert-butoxycarbonyl-[2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]- aminoH2S,3S]-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (402mg, 0.65mmol) and 1 -bromobutane (212mg, 1.56mmol) to give the title compound as a white foam (352mg), mass spectrum (thermospray +ve) m e 675 (MH + ). Intermediate 13 3 tert-Butoxycarbonyl-f2-(2-methyl-1-propoxy-5-(5-trifluoromethyl-tetrazol-1-vπ- benzvn-aminoH2S.3Sl-2-phenylpiperidine-1-carboxylic acid tert-butyl ester. From 3-{tert-butoxycarbonyl-[2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]- amino}-[2S,3S]-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (400mg, 0.65mmol) and 1-iodo-2-methylpropane (710mg, 3.9mmol) at 40-50°C to give the title compound as a pale yellow foam (190mg), mass spectrum (thermospray +ve) m e 675 (MH + ). Intermediate 14 f2-f2-Butoxy)-5- ( 5-trifluoromethyl-tetrazol-1-vni-benzaldehvde A solution of [2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde (250mg, 0.97mmol) in dimethylformamide (10ml) was stirred at room temperature and treated with potassium carbonate (134mg, 0.97mmol) and 2-iodobutane (267mg 1.45mmol). After ca 18h further 2-iodobutane was added (267mg, 1.45mmol) and the mixture was heated at 50°C for 3 days. It was then partitioned between ethyl acetate (50ml) and 2M-hydrochloric acid (25ml). The organic phase was washed with 2M-hydrochloric acid (2x25ml) and saturated brine (3x25ml), dried (MgS0 4 ) and evaporated to a yellow oil. This was purified by chromatography on silica (Merck 9385; 20g) eluting with 3:1 cyclohexane:ethyl acetate. The required fractions were combined and evaporated to give the title compound as a white foam (240mg), v (KBr powder) 1688cm- 1 (C=0 aldehyde). Intermediate 15 [2SH4-Fluoro-ohenvπ-piperidin-f3S1-yl-amine .2R.3R1-bis(4-methyl-benzoyloxy)- succinate (2R,3R)-bis-(4-methyl-benzoyloxy)-succinic acid (2.0g) was added portionwise over 5 min. to a stirred solution of racemic 2-(4-fluoro-phenyl)-piperidin-3-ylamine (1.0g) in ethanol and water at 60° . The solution was then allowed to stir for 0.5h at a temperature between 60-70°. The solution was allowed to cool overnight at ambient temperature. The solid material was collected and dried in vacuo at 70° (803.5mg). δ (CD3OD) includes 1.5-2.2 (m, 5H), 2.4 (s, 6H), 2.85-3.05 (m, 1 H), 3.5-3.6 (m, 1 H), 4.27 (d, 1 H, J = 2Hz), 5.86 (s, 2H), 7.0 (t, 2H, J = 8.7Hz), 7.3 (d, 4H, J = 8.5Hz), 7.45 (dd, 2H, J = 8.7 and 5Hz). Chiral HPLC on a CHIRALCEL- OD-H column eluting with hexane containing 2% isopropyl alcohol showed only one enantiomer (f/-> = 35.83 mins). T.l.c. (cyclohexane/ethylacetate (9:1 )) Rf 0.36 Example 1 r2-Ethoxy-5-f5-trifluoromethyl-tetrazol-1-yl -benzvn- ( r2S.3S1-2-phenylpiperidine-3- vhamine dihydrochloride A solution of 3-{tert-butoxycarbonyl-[2-ethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)- benzyl]-amino}-([2S,3S]-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (291 mg, 0.45mmol) in 4M-hydrogen chloride in dioxan (3ml) was kept at room temperature for 3.25h and then evaporated. The residue was triturated with ethanol to give the title compound as a white solid which was dried at 40°C under vacuum (110mg). Found C, 50.66; H, 5.23; N, 15.94, C 22 H 25 F 3 N 6 0 2HCI (519 4) requires C, 50.87; H, 5.24; N, 16.18%. Mass spectrum (thermospray +ve) m/e 447 (MH + ). Similarly prepared:- Example 2 f2-(1-Propoxy)-5-(5-trifluoromethyl-tetrazol-1-vn-benzvn-(f2S.3S1-2- phenylpipeπdin-3-yl)amine dihydrochloride From 3-{tert-Butoxycarbonyl-[2-(1-propoxy)-5-(5-tπfluoromethyl-tetrazol-1 -yl)- benzyl]-amιno}-[2S,3S]-2-phenylpiperidιne-1-carboxylιc acid tert-butyl ester (268mg, 0 4mmol) using 4M-hydrogen chloride in dioxan (2ml) to give the title compound as a white solid (93mg). Found C, 51.04, H, 5.52, N, 15 24, C 23 H 27 F 3 N 6 0.2HCI 0.4H 2 O (540 64) requires C, 51 10, H, 5 56, N, 15 54% Mass spectrum (thermospray +ve) m/e 461 (MH + ) Example 3 f2-f1-Butoxy)-5-f5-trifluoromethyl-tetrazol-1-yl)-benzvn-ιr2S.3Sl-2-phenylpiperιdιn- 3-vhamιne dihydrochloride From 3- tert-butoxycarbonyl-[2-(1 -butoxy )-5-(5-trifluoromethyl-tetrazol-1 -yl)- benzyl]-amino}-[2S,3S]-2-phenylpipeπdine-1-carboxylic acid tert-butyl ester (345mg, 0.51 mmol) using 4M-hydrogen chloride in dioxan (5ml) at 40°C to give the title compound as a white crystals from ethanol (218mg). Found C, 51.78; H, 5.62; N, 15.13; C 24 H 29 F3N 6 O.2HCI.0.5H 2 O (556.46), requires C.51.80; H, 5.80; N, 15.10%. Mass spectrum (thermospray + ve) m e 475 (MH + ). Example 4 r2-f2-Methyl-1-propoxy ) -5-f5-trifluoromethyl-tetrazol-1-vn-benzyl1-rr2S.3S1-2- phenylpiperidin-3-vOamine dihydrochloride From 3-{tert-Butoxycarbonyl-[2-(2-methyl-l-propoxy)-5-(5-trifluoromethyl-tetrazol-1- yl)-benzyl]-amino}-[2S,3S]-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (184 mg, 0.27 mmol) and 4M-hydrogen chlo de in dioxan (10ml) at 44°C to give the title compound as a white solid (156 mg), mass spectrum (thermospray + ve) m/e 475 (MH + ). Rp 0.5 (100: 8:1 dichloromethane: ethanol: ammonia). Example 5 r2-(2-Propoxy)-5-(5-trifluoromethyl-tetrazol-1 -yl)-benzvn-fr2S.3Sl-2- Dhenylpjperidin-3-yl amine dihydrochloride A solution of [2-hydroxy-5-(5-trifluoromethyl-tetrazol-1 -yl)-benzyl]-([2S,3S]-2- phenylpiperidine-3-yl)amine (672mg, 1.6mmol) in dimethylformamide (5ml) containing a suspension of potassium carbonate, (225mg, 1.6mmol) was stirred at room temperature for 10 minutes and then treated with 2-ιodopropane (80μl. 136mg, O.βmol). Further alkylating agent was added after 18h (80μl) and after 3 days (80μl). After an additional day the reaction mixture was evaporated to dryness. The residue was partitioned between ethyl acetate (100ml) and saturated aqueous sodium bicarbonate (100ml). The organic phase was washed with further bicarbonate (100ml) and brine (2 x 100ml), dried (MgS0 4 ) and evaporated to a brown oil which was chromatographed on silica (Merck 7734, 150g) eluting with 5% then finally 10% methanol in dichloromethane. The required fractions were combined and evaporated to provide a yellow foam (292mg). This (282mg) was dissolved in hot ethanol (6ml) and the solution was treated with concentrated hydrochloric acid (120μl). The crystals were filtered off, washed with ethanol and dried to give the title compound as a white crystalline solid (294mg) δ (D 2 0) 1.22 (3H, d, J=6Hz), 1.27 (3H, d, J=6Hz), 2.0-2.36 (3H, m), 2.46 (1 H, m), 3.31 (1 H, m), 3.6-3.78 (1 H, m), 3.86 (1 H, d, 4Hz), 4.18 (2H, Abq, J=14Hz), 4.59 (1 H, sept, J=6Hz), 4.89 (1 H, d, 3Hz), 7.14 (1 H, d, J=9Hz), 7.21 (1 H, d, J=9Hz), 7.38-7.56 (5H, m), 7.65 (1 H, dd, J=3, 9Hz). Found: C, 51.47; H, 5.52, N, 15.52, F, 10.7; C∞HferFsNβO (460.5) 2HCI (533.43) requires C, 51.79, H, 5.48; N, 15.75; F, 10.68%. Example 6 r2-f2-Butoxy)-5-(5-thfluoromethyl-tetrazol-1-vn-benzyl1- ( r2S.3S1-2-phenylpiperidin- 3-vOamine dihydrochloride A solution of [2-(2-butoxy-5-(5-trifluoromethyl-tetrazol-1-yl)]-benzaldehyde (100mg, 0.32mmol) and ([2S,3S]-2-phenylpipehdin-3-yl)amine (56mg, 0.32mmol) in glacial acetic acid (4ml) and dichloromethane (4ml) was stirred at room temperature and treated with sodium triacetoxyborohydride (108mg, 0.51 mmol) in acetic acid (2ml) After 24h the solvent was evaporated and the residue was partitioned between ethyl acetate (25ml) and 2M-sodium carbonate (25ml). The aqueous phase was extracted with further ethyl acetate (2x25ml). Combined organic phases were dried (Na 2 S0 4 ) and evaporated to an oil. This was dissolved in hot ethanol (1 ml) and the solution was treated with concentrated hydrochloric acid (0.7mmol) to give the title compound as a cream solid (140mg), mass spectrum (thermospray +ve) m/e 475 (MH*). R F 0.37 (100:8:1 dichloromethane: ethanol: ammonia). Example 7 f2-f2-Ethoxy-5-f5-trifluoromethyltetrazol-1-vnbenzylwr2S.3S1-2-(4-fluorophenyl - piperιdin-3-yl)amine dihydrochloride A suspension of [2S]-(4-Fluoro-phenyl)-pipehdιn-[3S]-yl-amιne[2R,3R]-bιs(4- methyl-benzoyloxy)-succinate(157mg, 0.27 mmol) in dichloromethane (anhydrous. 3ml) was stirred at room temperature and treated with triethylamine (78μl, 55mg, 0.54mmol) to give a solution. This was treated with [2-(2-ethoxy-5-(5- trifluoromethyl-tetrazol-1-yl)]-benzaldehyde (77mg, 0.27 mmol), acetic acid (glacial; 15μl, 16mg, 0.26mmol) and sodium triacetoxyborohydride (86mg, 0.40mmol). After 2.5h the solution was evaporated to dryness. The residue was partitioned between ethyl acetate (50ml) and saturated aqueous sodium bicarbonate (50ml). The organic phase was washed with water (50ml) and brine (2x50ml), dried (MgS0 4 ) and evaporated to a yellow oil, (118mg, 94%). Mass spectrum showed MH * 465. The entire sample was dissolved in boiling ethanol (c 3ml) and the solution was treated with concentrated hydrochloric acid (42 μl, O.δmmol). The white crystals were filtered off and dried at 40°C under vacuum, (68mg, 47%). Microanalysis Found: C, 49.02; H, 4.82; N, 15.47; C22H 2 4F4Nβ0.2HCI requires C, 49.17; H, 4.88; N, 15.64%. Pharmacy Examples Example A STERILE FORMULATION The components are dissolved in a portion of the water for injection and the solution made up to final volume to provide 0.25mg/ml of the compound of the invention. The solution may be packaged for injection, for example by filling and sealing in ampoules, vials or syringes. The ampoules, vials or syringes may be aseptically filled and/or terminally sterilised by, for example, autoclaving at 121 β C. TABLETS FOR ORAL ADMINISTRATION Tablets may be prepared by the normal methods such as direct compression or wet granulation. The tablets may be film coated with suitable film forming materials, such as Opadry White, type YS-1-7027, using standard techniques. Alternatively the tablets may be sugar coated. Example B Direct Compression Tablet mg/Tablet Compound of the invention 0.6mg Magnesium Stearate 0.75mg Avicel PH102 qs 150.00mg The compound of the invention is passed through a 30 mesh sieve and blended with Avicel PH102 and magnesium stearate. The resultant mix is compressed into tablets using a suitable tablet machine fitted with 9/32" diameter punches Example C WET GRANULATION A formulation as described in Example B may be used The compound of the invention (dihydrochloride) is dissolved in a suitable volume of granulating solution (purified water or 10% PVP K29/32 in water). After drying, the granules are screened, for example through 20 mesh screen, and blended with magnesium stearate. The granules are then compressed into tablets as described in Example B. Example D SUPPOSITORY Compound of the invention 10.0mg Witepsol W32, hard fat qs 2000.0mg Blend micronized drug in a portion of the melted Witepsol W32 at approximately 36°C for approximately 15 minutes in a high speed mixer. Incorporate the homogenized slurry into the remaining portion of the melted Witepsol W32 and blend at approximately 36 β C until satisfactory dispersion is achieved. Fill moulds with 2000mg formulation. Example E CAPSULE mg/capsule Compound of the invention 12.0mg Polyethylene glycol 92.89mg Propylene glycol qs 200mg Blend together polyethylene glycol and propylene glycol using heat as necessary. Stir until homogeneous. Add micronised compound of the invention to blend. Mix until homogenous. Fill into an appropriate gelatin mass to give soft gelatin capsules containing 200mg of the formulation. Example F ORAL SYRUP Dissolve the parabens in a small portion of the water that has been heated to approximately 90°C. Add the paraben solution to a large portion of the remaining water with mixing. Add and dissolve the other components. Bring the formulation to final volume and mix until homogenous. Fill the formulation into a container, such as a unit dose cup or a bottle for multiple-dose use. Biological Data As mentioned hereinbefore, compounds of the invention have been shown to inhibit radiation-induced emesis in the ferret using the test as described hereinbefore. More specifically the compound of Example 1, [2-Ethoxy-5-(5- trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidine-3-yl)amine dihydrochloride, inhibited radiation-induced emesis in the ferret, administering the compound 1.5 hours prior to irradiation, at a dose of 0.1 mg/kg s.c. No apparent adverse or toxic effects were observed during the above in vivo tests due to the administration of the compounds of the invention.

Claims: Claims 1. A compound of wherein R 1 is a C^alkoxy group; R is R is a hydrogen or halogen atom; R and R 5 may each independently represent a hydrogen or halogen atom, or a or trifluoromethyl group; and pharmaceutically acceptable derivatives thereof. 2. A compound according to Claim 1 wherein R 3 , R 4 and R 5 are hydrogen atoms. 3. A compound according to Claim 1 or Claim 2 wherein R 1 is an ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1 -oxy or 2-methylprop-2- oxy group. 4. A compound selected from (2-(2-Propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2- phenylpiperidin-3-yl)amine (2-(1-Propoxy)-5-(5-trifIuoromethyltetra2θl-1-yl)benzyl)-([2S ( 3S]-2- phenylpiperidin-3-yl)amine (2-(1-Butoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2- phenylpiperidin-3-yl)amine (2-(2-Butoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2- phenylpiperidin-3-yl)amine (2-(2-Methyl-1-propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2- phenylpiperidin-3-yl)amine (2-(2-Ethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-(4- fluorophenyl)-piperidin-3-yl)amine and pharmaceutically acceptable derivatives thereof. 5. (2-Ethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2- phenylpiperidin-3-yl)amine and pharmaceutically acceptable derivatives thereof 6. A compound according to Claim 4 or Claim 5 in the form of its dihydrochloride salt. 7. A compound according to any one of Claims 1 to 6 for use in therapy 8 A pharmaceutical composition comprising a compound according to any one of Claims 1 to 6 or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable carrier 9 A method for the treatment of a condition mediated by tachykinins, including substance P and other neurokinins, in a mammal comprising administration of an effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable derivative thereof 10. The use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for use in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins 11. A process for preparing a compound of formula (I) as defined in Claim 1 , or a pharmaceutically acceptable derivative thereof which comprises: (A) reacting a compound of formula (II) with a compound of formula (III) followed by reduction: or (B) reduction of a compound of formula (IX) (IX) with a suitable reducing agent: or (C) reacting a compound of formula (XI) or an amino-protected derivative thereof, with L-C 2 - 4 alkyl where L represents a suitable leaving group, in the presence of a base, followed by deprotection where necessary.

Inventors: GIBLIN GERARD MARTIN PAUL, SHARRATT PETER JOHN, GIBLIN, GERARD, MARTIN, PAUL, SHARRATT, PETER, JOHN
Applicants: GIBLIN GERARD MARTIN PAUL, GLAXO GROUP LTD, SHARRATT PETER JOHN, GIBLIN, GERARD, MARTIN, PAUL, GLAXO GROUP LIMITED, SHARRATT, PETER, JOHN
Application year: 1996
Main classification: C07D401
IPC codes: A61K31, A61P25, A61P43, C07D401