WO2007020403A1

WO2007020403A1 - Azapeptides for treating hyperalgesic pain conditions

Info

Publication number: WO2007020403A1
Application number: PCT/GB2006/003012
Authority: WO
Inventors: Fei-Yeu Zhao; Alistair Kerr Dixon; Johnathan Mark Treherne; Chizuko Koseki
Original assignee: Sosei Co., Ltd; Neurosolutions Limited
Priority date: 2005-08-12
Filing date: 2006-08-11
Publication date: 2007-02-22
Also published as: GB0516610D0

Abstract

A compound of formula (I): wherein A is a bond, an α-amino acid or a residue of a dipeptide; R1 is hydrogen or a protective group for a terminal amino group; R2 is phenyl or phenyl substituted by one or more substitutents selected from lower alkyl, halogen, hydroxyl which may be protected, nitro, amino which may be protected and perhalo-lower alkyl; R3 is hydroxyl or a protective group for a terminal carboxyl group; Is used in the manufacture of a medicament for the therapy of hyperalgesia pain conditions and their symptoms.

Description

AZAPEPTIDES FOR TREATING HYPERALGESIC PAIN

CONDITONS

Field of the Invention

The present invention relates to the use of azapeptides for the prevention, treatment or amelioration of hyperalgesia pain conditions and their symptoms. Back to the Invention

Hyperalgesia pain conditions are conditions of heightened pain perception caused by tissue damage. These conditions are a natural response of the nervous system apparently designed to encourage protection of the damaged tissue by an injured individual, to give time for tissue repair to occur. The symptoms of hyperalgesia pain conditions include hyperalgesia, allodynia (tactile, thermal) and paresthesia. Hyperalgesia is an abnormal pain response to a pain stimulus. Allodynia is a condition where a normal stimulus causes pain. Paresthesia is an abnormal sensation of the skin such as numbness, tingling, pricking, burning, crawling with no objective cause. There are two known underlying causes of these conditions, an increase in sensory neuron activity, and a change in neuronal processing of nociceptive information which occurs in the spinal cord. These conditions can be debilitating in chronic inflammation and when sensory nerve damage has occurred (i.e. neuropathic pain). As mentioned above, hyperalgesic pain conditions are a consequence in most instances of tissue damage, either damage directly to a sensory nerve, or damage of the tissue innervated by a given sensory nerve. Diseases involving damage to sensory nerves which contain a component of neuropathic pain include, but are not limited to, diabetic neuropathy, cancer pain, fibromyalgia, myofascial pain syndrome, osteoarthritis, pancreatic pain, pelvic/perineal pain, post-herpetic neuralgia, complex regional pain syndrome, sciatica/lumbar radiculopathy, spinal stenosis, temporo-mandibular joint disorder, HIV pain, trigeminal neuralgia, chronic neuropathic pain, lower back pain, failed back surgery pain, post-operative pain, post-physical trauma pain (including gunshot, RTA, bums), cardiac pain, chest pain, pelvic pain/pid, joint pain (tendonitis, bursitis, acute arthritis), neck pain, obstetric pain (labour/C-section), renal colic, acute herpes zoster pain, acute pancreatitis, breakthrough pain (cancer) and dysmenorhoea/endometriosis. Two major classes of analgesics are known: (i) non steroidal anti-inflammatory drugs (NSAIDs) and the related COX-2 inhibitors; and (ii) opiates based on morphine. Analgesics of both classes are reasonably effective in controlling normal, immediate or nociceptive pain. However, they are less effective against some types of hyperalgesic pain, such as neuropathic pain. Many medical practitioners are reluctant to prescribe opiates at the high doses required to affect neuropathic pain because of the side effects caused by administration of these compounds, and the possibility that patients may become addicted to them. NSAIDs are much less potent than opiates, so even higher doses of these compounds are required. This is, however, undesirable because these compounds cause irritation of the gastro-intestinal tract.

There is, therefore, a need for anti-hyperalgesics and neuropathic pain treatments which are sufficiently potent to control pain perception in neuropathic and other hyperalgesic syndromes, and which do not have serious side-effects or cause patients to become addicted to them.

EP0672678 describes azapeptide derivatives which exhibit potent neurokinin (NKA) receptor antagonistic activity and are useful as agents for curing nervous inflammation of respiratory apparatus, asthma and bronchospasm, of formula I

A particular compound of formula (I) is N-α-Ctert-butylcarbamoyO-L-glutaminyl-L-tryptophyl-alpha-azaphenylalanine 2-benzyloxyethylamine, hereinafter known as Compound 1 and which has formula (I) wherein A is glutamine, R¹ is N-t-butylcarbamoyl, R² is phenyl and R³ is a group of formula -N(R⁵)(R⁶) wherein R⁵ is 2-benzyloxyethyl and R⁶ is hydrogen.

Compound 1 was originally developed as an agent for curing nervous inflammation of respiratory apparatus, asthma and bronchospasm but has since been discontinued in these indications. In preclinical studies, Compound 1 inhibited bronchoconstriction in various models. Summary of the Invention

A first aspect of the invention is use of a compound of formula I:

wherein A is a bond, an α-amino acid or a residue of a dipeptide;

R¹ is hydrogen or a protective group for a terminal amino group; R² is a phenyl or phenyl substituted by one or more substituents selected from lower alkyl, halogen, hydroxyl which may be protected, nitro, amino which may be protected, and perhalo-lower alkyl; and R³ is hydroxyl or a protective group for a terminal carboxyl group; in the manufacture of a medicament for the therapy of hyperalgesic pain conditions and their symptoms.

An alternative expression of the invention is a method for the treatment of hyperalgesic pain in a patient in need thereof, comprising administering to the patient an effective amount of the compound. Brief Description of the Drawing

Figure 1 is a graph showing results of the Example, below. Description of the Invention

Certain compounds and combinations of subsituents are preferred, in particular see the sub-claims. In the following, the present invention is explained in detail. The α-amino acid may be a natural α-amino acid or a non-natural α-amino acid. Natural α-amino acids are preferred. The α-amino acid may be the L-isomer, the D-isomer or the DL-racemic compound.

Examples of natural α-amino acids include glycine, alanine, valine, leucine, isoleucine, serine, methionine, threanine, phenylalanine, tyrosine, tryptophan, cysteine, cystine, proline, 4-hydroxypropiine, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, citrulline, ornithine and lysine.

Examples of non-natural α-amino acids, include norleucine, norvaline, alloisoleucine, homoarginine, thiaproline, methionine sulfoxide, methionine sulfone, dehydroproline, homoserine, cyclohexylglycine (Chg), α-amino-n-butyric acid (Aba), cyclohexylalanine (Cha), aminophenylbutyric acid (Pba), phenylalanines in which a phenyl portion of phenylalanine is substituted by 1 or 2 of a lower alkyl, a lower alkoxy, a halogen or a nitro group, or substituted by a methylenedioxy group, β-(2- or 3-thienyl)alanine_s β-(2- or 3-furanyl)alanine, β-(2-, 3- or 4-pyridyl)alanine, β-(benzothiophen-2- or 3-thienyl)alanine β-(2-or 3- furanyl)alanine, β-(2-, 3- or 4-pyridyl)alanine, β-benzothiophen-2 or 3-yl)alarine and β-1(1- or 2-napthyl)-alanine.

The α-amino acids and dipeptides of formula (I) include those having a substituent shown below at a side chain thereof. a) As a substituent of an amino group, examples include a substituted or unsubstituted lower alkanoyl group such as formyl, acetyl, propionyl and trifluoroacetyl; a phthaloyl group; a lower alkoxycarbonyl group such as t-butoxycarbonyl and t-amyloxycarbonyl; a substituted or unsubstituted aralkoxycarbonyl group such as benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; a substituted or unsubstituted allenesulfonyl group such as benzenesulfonyl and tosyl; a 2-nitrophenylsulfenyl group; and an aralkyl group such as trityl and benzyl. As a substitutent of a guanidino group, examples include, nitro, benzyloxycarbonyl, tosyl, 4-methoxybenzenesulfonyl and 4-methoxy-2,3,6-trimethylbenzenesulfonyl. b) As an amidated carboxyl group, examples include a carboxyl group substituted by a lower alkyl-substituted amide which is obtained by being substituted by one or two substituted or unsubstituted lower alkyl group(s) such as methyl, ethyl, isobutyl, 2-hydroxyethyl, 2-methoxyethyl and 2-benzyloxyethyl; an aryl-substituted amide obtained by being substituted by phenyl or the like; an aralkyl-substituted amide obtained by being substituted by a substituted or unsubstituted aralkyl group such as benzyl, 4-fluorobenzyl, phenethyl, 2, 4-dimethoxybenzyl, benzhydryl, 4, 4'-dimethoxybenzhydryl and xanthyl; and a heterocyclic imide obtained by being substituted by morphoiino, thiomorpholino, pyrrolidin-1-yl, pyrazaolidin-1 -yl, piperazino or pyrrolin-1 -yl. c) As an esterified carboxyl group, examples include a carboxyl group esterified by a substituted or unsubstituted lower alkyl group such as methyl, ethyl, trichloroethyl and t-butyl; a cycloalkyl group such as cyclopentyl and cyclohexyl; and a substituted or unsubstituted aralkyl group such as benzyl, phenacyl, 4-nitrobenzyl, 4- methoxybenzyl and benzhydryl. d) As a substitutent of a thiol group, examples include a substituted or unsubstituted lower alkyl group such as methyl, ethyl, t-butyl and acetoamidomethyl; and a substituted or unsubstituted aralkyl group such as methyl, ethyl, t-butyl and acetoamidomethyl; and a substituted or unsubstituted aralkyl group such as benzyl, trityl and 4-methoxybenzyl. e) As a substitutent of a hydroxyl group, examples include a lower alkyl group such as t-butyl; a cycloalkyl group such as cyclohexyl; a substituted or unsubstituted aralkyl group such as benzyl, 2-nitro-benzyl and 3-bromobenzyl; an acyl group such as acetyl and benzoyl; t-butyloxycarbonyl; and benzyloxycarbonyl.

As the protective group for the terminal amino group of R¹, examples include an acyl group, an alkoxylcarbonyl group having 1 to 6 alkoxy carbon atoms, an aralkyloxycarbonyl group, a N-aralkylcarbamoyl group and a N-cycloalkylcarbamoyl group having 3 to 6 cycloalkyl carbon atoms. Further examples include a lower alkanoyl group, a cycloalkanoyl group, an alkoxycarbonyl group, an alkyloxycarbonyl group, a N-alkylcarbamoyl group or a N-cycloalkylcarbamoyl group.

Further, as a protective group for the terminal amino group of R¹, there may be used a lower alkanesulfonyl group such as methanesulfonyl and ethanesulfonyl; or an allenesulfonyl group such as benzenesulfonyl, tosyl and mesitylsulfonyl.

A preferred group R² is a phenyl group which may be substituted by one or two of a lower alkyl group, halogen atom, hydroxyl group which may be protected or perhalo-lower alkyl group, more preferably a phenyl group, a substituted phenyl group substituted by one or two subsituents selected from an alkyl group having 1 to 4 carbon atoms, halogen atom, hydroxyl group which may be protected, or perhalo-alkyl group having 1 to 4 carbon atoms. As the lower alkyl group, examples include a straight or branched alkyl group such as methyl, ethyl, propyl, butyl, isobutyl, t-butyl, pentyl and hexyl. The halogen atom may be chlorine, bromine, iodine or fluorine. As a protective group for the hydroxyl group which may be protected, there may be used those described above as the substituent (e) in the case where the side chain of the amino acid of formula (I) is a hydroxyl group, and a benzyl group is particularly preferred. The perhalo-lower alkyl group may be trifluoromethyl. As a protective group for the terminal carboxyl group of R³, there may be used those described above as the amidated carboxyl group (b) and the esterified carboxyl group (c) of the α-amino acid of formula (I). It is particularly preferred that R³ represents a group of formula -OR⁴ or -N(R⁵)(R⁶) where protective groups R⁴, R⁵ and R⁶ each represent a substituted or unsubstituted lower alkyl group preferably having 1 to 4 carbon atoms or an aralkyl group which is unsubstituted or substituted by hydroxy or aralkyloxy, such as methyl, ethyl, isobutyl, 2-hydroxyethyl, 2-benzyloxyethyl, 2-(4-fluorobenzyloxy)ethyl, 2-(3-pyridylmethyl)oxyethyl, 2-benzylhydryloxyethyl, 2-(2-naphthylmethyl)- oxyethyl; or an aralkyl group which is unsubstituted or substituted by halogen or alkoxy having 1 to 6 carbon atoms, such as benzyl, 4-fluorobenzyl, 2,4-dimethoxybenzyl and phenethyl. A particularly preferred example of R⁶ is hydrogen. Also R³ may be a heterocyclic saturated monocyclic ring, such as morpholino, pyrrolidine -yl, pyrazolidin-1-yl or piperidino.

The term "halogen" as used herein includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The term "alkyl" as used hereinafter refers to a straight or branched chain unsaturated aliphatic moiety, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. "Lower alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

The term "aryl" as used herein refers to optionally substituted aromatic ring systems, and optionally substituted polycyclic ring systems having two or more cyclic rings, at least one of which is aromatic. This term includes, for example, phenyl.

The term "aralkyl" as used herein refers to an aryl substituted alkyl group. The term "alkoxy" as used herein refers to an alkyl group as defined above attached through an oxygen atom. It includes but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy hexoxy and the like.

The term "perhalo-lower alkyl" is used herein to refer to a CrC₆ alkyl group as defined above which is substituted by at least one halogen atom. A perhalo-lower alkyl group which may be mentioned is trifluoromethyl.

The term "aralkyloxy" refers to an aryl subsituted alkoxy group.

A preferred compound for use in the present invention is N-α-(tert-butylcarbamoyl)-L-glytaminyl-L-tryptophyl-alpha-azaphenylalanine 2-benzyloxyethylamide (referred to herein as Compound 1), as described above.

Compounds for use in the present invention may be chiral. They may be in the form of a single enantiomer or diastereomers, or a racemate.

The compounds of the invention may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art. The compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base. Alternatively, the enantiomers of the novel compounds may be separated by HPLC using a chiral column. For use in the invention, the compound may be given as a prodrug. As used herein, the term "prodrug" refers to compounds that are drug precursors which, following administration, release the drug in vivo via some chemical or physiological process.

The compounds for use in the present invention may be in a protected amino, protected hydroxy or protected carboxy form. The terms "protected amino", "protected hydroxy" and "protected carboxy" as used herein refer to amino, hydroxy and carboxy groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group. A carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester. A hydroxy group can be protected by an alkyl or like group.

Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention. Compounds for use in the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2-methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, N-glycolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoic acid, 1 -hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid,

2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid, 10-undecenoic acid and the like. Salts may also be formed with inorganic bases. Such inorganic base salts include, for example, salts of aluminium, bismuth, calcium, lithium, magnesium, potassium, sodium, zinc and the like. Organic base salts include, for example, salts of N, N'-dibenzylethylenediamine, choline (as a counterion), diethanolamine, ethanolamine, ethylenediamine, N,N'-bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminoethane ("TRIS") and the like.

It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy. Such salts may be prepared by reacting the compound with a suitable acid or base in a conventional manner.

A compound for use in the invention may be prepared by any suitable method known in the art.

Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.

The activity and selectivity of the compounds may be determined by any suitable assay known in the art. The present invention is directed to use of compounds of formula (I) in the manufacture of a medicament for the prevention, treatment or amelioration of hyperalgesic pain conditions and their symptoms.

The hyperalgesic pain conditions may be caused as a result of neuropathy, including, but not limited to, diabetic neuropathy, polyneuropathy, cancer pain, fibromyalgia, myofascial pain syndrome, osteoarthritis, pancreatic pain, pelvic/perineal pain, post herpetic neuralgia, complex regional pain syndrome, sciatica/lumbar radiculopathy, spinal stenosis, temporomandibular joint disorder, HIV pain, trigeminal neuralgia, chronic neuropathic pain, lower back pain, failed back surgery pain, post operative pain, post physical trauma pain (including gunshot, RTA, burns), cardiac pain, chest pain, pelvic pain/pid, joint pain (tendonitis, bursitis, acute arthritis), neck pain, bowel pain, phantom limb pain, obstetric pain (labour/C-section), renal colic, acute herpes zoster pain, acute pancreatitis, breakthrough pain (cancer), painful bladder syndrome/interstitial cystitis, prostatitis and dysmenorhoea/endometriosis.

Compounds of formula (I) can be used for the treatment of pain caused as a result of neuropathy or inflammatory disease (or a combination of both) including, but not limited to diabetic neuropathy, polyneuropathy, cancer pain, fibromyalgia, myofascial pain syndrome, osteoarthritis, pancreatic pain, pelvic/perineal pain, post herpetic neuralgia, complex regional pain syndrome, sciatica/lumbar radiculopathy, spinal stenosis, temporo-mandibular joint disorder, HIV pain, trigeminal neuralgia, chronic neuropathic pain, lower back/pain, failed back surgery pain, post-operative pain, post-physical trauma pain (including gunshot, RTA, burns), cardiac pain, chest pain, pelvic pain/pid, joint pain (tendonitis, bursitis, acute arthritis), neck pain, bowel pain, phantom limb pain, obstetric pain (labour/C-section), renal colic, acute herpes zoster pain, acute pancreatitis breakthrough pain, cancer pain, dysmenorhoea/endometriosis, painful bladder syndrome/interstitial cystitis, prostatitis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, and other arthritic conditions, cancer, HIV, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases, reperfusion injury (including damage caused to organs as a consequence of reperfusion following ischaemic episodes, e.g. myocardial infarcts, strokes), autoimmune damage (including multiple sclerosis, Guillam-Barre syndrome, myasthenia gravis), graft v. host rejection, allograft rejections, fever and myalgia due to infection, AIDS-related complex (arc), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis, irritable bowel syndrome, osteoporosis, cerebral malaria and bacterial meningitis. A compound of formula (I) may be administered with or without other therapeutic agents, for example analgesics and antiinflammatories (such as opiates, steroids, NSAIDs, cannabinoids, tachykinin modulators, or bradykinin modulators) or anti-hype ralgesics (such as gabapentin, pregabalin, cannabinoids, sodium or calcium channel modulators, anti-epileptics or anti-depressants).

In general, a compound of formula (I) may be administered by known means, in any suitable formulation, by any suitable route. A compound of the invention is preferably administered orally, parenterally, sublingually, transdermal^, intrathecal^, or transmucosally. Other suitable routes include intravenous, intramuscular, subcutaneous, inhaled, nasal, rectal, topical and intravesically. The amount of drug administered will typically be higher when administered orally than when administered, for example, intravenously.

The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 0.1 to 500 mg. The excipients used in the preparation of these compositions are the excipients known in the art.

Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. 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 hyperalgesia. Preferably a compound of formula (I) is administered at a frequency of 1 to 4 times per day.

Compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. 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, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein 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 occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, 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, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in a mineral oil such as liquid paraffin or in other surfactants or detergents. 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 antioxidant 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 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 occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectables.

The compounds for use in the invention 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.

Compositions for topical administration are also suitable for use in the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.

The following Example illustrates the invention. Example Under anaesthesia, the sciatic nerve of a guinea pig was displayed in the right leg, and four loose ligatures tied around the nerve bundle. After approximately 14 days, a weight-bearing test was carried out to assess the neuropathic pain state. The animal was placed in a transparent box with two hind paws on the two balance plates of a specially designed weight-bearing meter. The difference of the weight the animal posed on the plate was shown on a digital meter and the difference was calculated automatically through an electronic circuitry inside the device and the result shown on a display. The animals were trained twice before commencing the formal experiments. The animals were habituated for 5 minutes before 5 consecutive readings of the weight from both sides were recorded at an interval of 20 sec. The readings of each side were averaged and the difference between two sides was used for later statistical analysis. The measurements were carried out before and repeated at 0.5, 1 , 2, 3, 4 and 6 hours after compound administration.

Compound 1 was first dissolved in absolute ethanol and diluted with normal saline to a final ethanol concentration of 15% and compound concentration of 10 mg/ml. The compound was tested in the given assay.

The results are indicated in Figure 1. It can be seen that Compound 1 significantly reduced the weight-bearing difference in the operated guinea pigs.

Claims

1. Use of a compound of formula (I):

wherein A is a bond, an α-amino acid or a residue of a dipeptide; R¹ is hydrogen or a protective group for a terminal amino group; R² is phenyl or phenyl substituted by one or more substitutents selected from lower alkyl, halogen, hydroxyl which may be protected, nitro, amino which may be protected and perhalo-lower alkyl;

R³ is hydroxyl or a protective group for a terminal carboxyl group; in the manufacture of a medicament for the therapy of hyperalgesic pain conditions and their symptoms.

2. Use according to claim 1 , wherein the condition is neuropathic pain.

3. Use according to claim 2, wherein the neuropathic pain is caused by diabetic neuropathy.

4. Use according to claim 2, wherein the neuropathic pain is back pain.

5. Use according to claim 2, wherein the pain is fibromyalgia pain.

6. Use according to claim 2, wherein the pain is HIV pain

7. Use according to claim 2, wherein the pain is complex regional pain syndrome.

8. Use according to claim 2, wherein the pain is trigeminal neuralgia or temporo-mandibular joint disorder.

9. Use according to claim 2, wherein the pain is post-herpetic neuralgia.

10. Use according to claim 2, wherein the pain is painful bladder syndrome/interstitial cystitis, prostatitis or dysmenorhoea/endometriosis.

11. Use according to claim 2, wherein the pain is selected from bowel pain, cancer pain, phantom limb pain, post-operative pain, polyneuropathy, myofascial pain syndrome, osteoarthritis, pancreatic pain, pelvic/perineal pain, sciatica/lumbar radiculopathy, spinal stenosis, chronic neuropathic pain, failed back surgery pain, post-physical trauma pain (including gunshot, rta, bums), post-operative pain, cardiac pain, chest pain, pelvic pain/pid, joint pain (tendonitis, bursitis, acute arthritis), neck pain, obstetric pain (labour/c-section), renal colic, acute herpes zoster pain, acute pancreatitis and breakthrough pain.

12. Use according to any preceding claim, wherein the compound is the (R) enantiomer, substantially free of the opposite enantiomer.

13. Use according to claims 1 to 13, wherein the compound is the (S) enantiomer, substantially free of the opposite enantiomer.

14. Use according to any preceding claim, wherein the compound is N-α-(tert-butylcarbamoyl)-L-glutaminyl-L-tryptophyl-alpha-azaphenylalanine 2-benzyloxyethylamide.