WO2008012546A2

WO2008012546A2 - Azapeptides for use in therapy against interstitial cystitis

Info

Publication number: WO2008012546A2
Application number: PCT/GB2007/002849
Authority: WO
Inventors: Akinori Mochizuki; Takashi Ono
Original assignee: Sosei Co. Ltd.
Priority date: 2006-07-27
Filing date: 2007-07-27
Publication date: 2008-01-31
Also published as: GB0614970D0; WO2008012546A3

Abstract

A compound containing a Tηp-aza(Phe) structure of the 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 the group consisting of a lower alkyl, a 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; or a prodrug thereof that is metabolisable to form a compound as defined above; is useful for the treatment of interstitial cystitis.

Description

AZAPEPTIDES FOR USE IN THERAPY

Field of the Invention

The present invention relates to the use of compounds for the treatment of genito-urinary disorders, particularly those associated with bladder dysfunction, including interstitial cystitis.

Background to the Invention

Interstitial cystitis (IC), otherwise known as painful bladder syndrome

(PBS) or chronic pelvic pain syndrome (CPPS), is a painful and debilitating bladder condition that affects approximately 1.5 million people worldwide. IC is a poorly understood disease and its causes are, as of yet, unknown. Although no bacteria or viruses (pathogens) have been found in the urine of IC sufferers, an unidentified infectious agent may be the cause. Others believe that IC occurs with ischemia or a deficiency of glycosoaminoglycans (GAG) in the epithelium. It may be an autoimmune disease, in which the immune system attacks healthy cells, perhaps following a bladder infection. Spasms of the pelvic floor muscles may also contribute to the IC symptoms. It is likely that several factors cause the condition.

Symptoms of interstitial cystitis include pressure, tenderness, or pain in the bladder and pelvic area; an urgent and/or frequent need to urinate; an inability to hold much urine; a need to awaken several times a night to urinate; and repeatedly receiving negative test results for bacterial urinary tract infections

(UTIs).

At present, there is no cure for IC and the goal of treatment is to relieve symptoms. Types of treatment include biophysical techniques (behavioral changes, stress management, dietary changes), medications or surgery. Present treatment methods include drugs instilled directly into the bladder via a catheter.

Examples of drugs administered in this way include dimethyl sulfoxide, hyaluronic acid and Bacille Calmette-Guerin. Botox (botulinum toxin) is also being studied. Systemic treatments are also used, such as pentosan polyphosphate, oxybutynin chloride, tolterodine tartrate or a combination of atropine, hyoscyamine, methenamine, methylene blue, phenyl salicylate and benzoic acid.

These may reduce bladder spasms that cause frequency, urgency, and night- time urination. Valium and other muscle relaxants may also be used to reduce spasms associated with IC. Tricyclic antidepressants such as amitriptyline and doxepin may be useful in small doses to block pain, calm bladder spasms, and reduce inflammation.

A typical IC treatment regimen also includes medication for chronic pain and anxiety. For example, anticonvulsant drugs, benzodiazepines, narcotics, non-steroidal anti-inflammatory drugs or tricyclic and SSRI antidepressants may be given.

Other drugs being studied as potential treatments for IC include montelukast, a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CySLT₁ receptor; and suplatast tosilate, an inhibitor of the release of histamine and IL-4/5.

EP0672678 relates to azapeptide derivatives. More particularly, the specification describes azapeptide derivatives which are useful as agents for curing nervous inflammation of respiratory apparatus, asthma and bronchospasm; they are of formula I

One such compound is N-α-(tert-butylcarbamoyl)-L-glutaminyi-L- tryptophyl-α-azaphenylalanire 2-benzyloxyethylamine, hereinafter known as compound Il and which has structure (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. This compound is a selective Neurokinin-2 (NK2) receptor antagonist with a pA2 value of 9.82 in hamster trachea (Higashide et al., Jpn J Pharmacol 71 , Suppl 1 , 59P (1996)).

Compound Il is known to have a potent inhibitory effect on airway hyper- responsiveness in guinea pigs (Higashide et al., Folia Pharmacol Jpn 109). The compound was originally being developed by Fujirebio for the treatment of asthma, but has since been discontinued. Other NK2 receptor antagonists, including Menarini's nepadutant, Sanofi-

Aventis' saredutant and Sankyo's CS-003, are currently being investigated in

Phase Il clinical trials as therapies for respiratory disease, including asthma and chronic obstructive pulmonary disease. Nepadutant has been shown to reduce bowel motility in healthy volunteers (Lordal et al., Br J Pharmacol 2001 ; 134:

215-23), and saredutant has been studied clinically for irritable bowel syndrome.

Neurokin-1 (NK1) receptors have been shown to be involved in animal models of cystitis (Alfieri et al.; Saban et al., Am J Pathol. 2000 Mar; 156(3): 775-

80; Buffington et al., J Urol 1998 Aug; 160(2):605-11, and Marchand et al., Br J Urol 1998 Feb; 81(2): 224-8). The role of NK-2 receptors is less clear with both positive (Lecci et al., Naunyn Schmiedebergs Arch Pharmacol. 1997 Aug;

356(2): 182-8) and statistically negative results (Ahluwalia et al., Br J Pharmacol

1998 May; 124(1): 190-6).

Dissatisfaction with the currently marketed treatments for interstitial cystitis within the affected population, means that there exists a need for a more efficacious and safe treatment. Summary of the Invention

According to the present invention, a compound of formula 1 (above), 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 the group consisting of 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; or a prodrug thereof that is metabolisable to form a compound as defined above; may be used for the treatment of interstitial cystitis. Description of the Invention

In formula (I), the α-amino acid includes a natural α-amino acid and a non-natural α-amino acid. 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-hydroxypropline, 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, 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. Natural α-amino acids are preferred.

The α-amino acid and the dipeptide detailed in structure I include those having a substituent given 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, there may be mentioned, for example, 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 morpholino, 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 acetoamidom ethyl; 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, examples include a lower alkanesulfonyl group such as methanesulfonyl and ethanesulfonyl; and an allenesulfonyl group such as benzenesulfonyl, tosyl and mesitylsulfonyl.

A preferred group of 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 the group consisting of 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, and as the halogen atom, there may be mentioned chlorine, bromine, iodine and fluorine. As a protective group for the hydroxyl group which may be protected, examples include those described above as the substituent (e) in the case where the side chain of the amino acid of structure (I) is a hydroxyl group, and a benzyl group is particularly preferred. As a perhalo lower alkyl group, there may be mentioned a trifluoromethyl. As a protective group for the terminal carboxyl group of R³, examples include those described above as the amidated carboxyl group (b) and the esterified carboxyl group (c) of the α-amino acid of structure (I); it is particularly preferred that R³ represents -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-naphtylmethyl)oxyethyl; and an aralkyl group which is unsubstituted or substituted by a halogen or an alkoxy having 1 to 6 carbon atoms, such as benzyl, 4-fluorobenzyl, 2,4-dimethoxybenzyl and phenethyl. A particularly preferred example of R⁶ is a hydrogen atom. Also, R³ may be a group in which R⁵ and R⁶ together with a nitrogen atom to which they are bonded, form a hetero saturated monocyclic ring, such as morpholino, pyrrolidin-1-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 herein 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 Ci-C₆ 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-alpha-(tert- butylcarbamoyl)-L-glytaminyl-L-tryptophyl-alpha-azaphenylalanine 2-benzyl- oxyethylamide which has the following formula II:

The 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. 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 is known or 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 the above detailed compounds in the manufacture of a medicament for treating genito-urinary disorders in a mammal comprising administering the compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug to said mammal.

The invention is particularly directed to such uses wherein the disorder is associated with bladder dysfunction. Such disorders include overactive bladder/urge incontinence, stress incontinence, mixed incontinence, dysuria, enuresis, nephritis, neptropathy, renal failure, interstitial cystitis/painful bladder syndrome/chronic pelvic pain syndrome, prostatis and benign prostatic hypertrophy. The compounds for use in the present invention are particularly useful in the treatment of interstitial cystitis. The present invention is further directed to the use of the compounds of the present invention in treating trauma, irritation or infection of the lining of the renal pelvis, ureters, bladder or urethra in a mammal by contacting the internal surface of the renal pelvis, ureters, bladder or urethra with a solution containing the compound in a concentration effective to treat the trauma, irritation or infection.

In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Oral, subcutaneous, intramuscular or via aerosol administration is preferred. Thus, the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. 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 disease undergoing treatment. 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 gei 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 compound for use in the present invention may also be used locally by contacting the internal surface of the urinary tract, including the bladder and associated structures in a mammal suffering from interstitial cystitis with a solution containing the compounds at an efficacious concentration. The following Example illustrates the invention, with reference to the accompanying drawings. Description of the Drawings

Figures 1 and 2 each show intravesical pressure (IP; mm Hg) with respect to amount of compound Il given. Example

The effects of compound Il on urinary bladder contractions induced by tachykinins and capsaicin were measured in anaesthetised rats according to the following method: Female Wistar rats (Japan SLC, In., Hamamatsu), weighing 140 to 200 g, were anesthetized with an i.p. injection of urethane (1.2 g/kg). Intravesical pressure was continuously measured with a pressure transducer (TP-400T, Nihon Koden, Tokyo), via a polyethylene catheter introduced through the urethra. The urinary bladder was filled with 0.2 ml of saline. After a stabilization, a submaximal dose of NKA, SP or capsaicin was i.v. administered. The test compounds and their vehicle were injected i.v. 2 min before the administration of a stimulant (NKA, 3 nmol/kg i.v.) and measurement of intravesical pressure.

All results were expressed as the mean +S.E. Comparisons of the mean values were made by Student's t-test or Dunnett's test. When P values are 0.05 or less, they are considered to be statistically significant. The results where the urinary bladder contractions have been induced by NKA (3 nmol/kg, i.v) are illustrated in Figure 1. Data are represented as the maximum response. Each column shows the mean +S.E. for 4 experiments (^**:P<0.01 , significantly different from the control group.)

NKA at a dose of 3nmol/kg i.v. produced a phasic contraction of the bladder. The mean +S.E. of the maximal pressure was 28.1+1.6 mm Hg. Compound Il (0.1-3.0 mg/kg i.v) inhibited this contractile response in a dose- dependent manner, the inhibition percentage being 94.2% at a dose of 3.0 mg/kg i.v.

The results where the urinary bladder contractions were induced by capsaicin (106 nmol/kg, i.v.) are illustrated in Figure 2. Data are represented as the maximum response. Figure 2 shows the mean + S.E. of 4 to 6 experiments (*:P<0.05, ^**:P<0.01, significantly different from the control group.) Capsaicin at a dose of 100 nmol/kg i.v. produced a phasic contraction of the bladder and the mean +S.E. of the maximal response was 34.4+4.1 mm Hg. Compound Il (0.1-1.0 mg/kg i.v.) inhibited this contractile response in a dose- dependent manner, the inhibition being 82.9% at a dose of 1.0 mg/kg i.v.

Claims

1. Use of a compound of the formula

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 the group consisting of a lower alkyl, a 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; or a prodrug thereof that is metabolisable to form a compound as defined above; in the manufacture of a medicament for the treatment of interstitial cystitis.

2. Use according to claim 1 , wherein the compound is N-α-(tert- butylcarbamoyl)-L-glutaminyl-L-tryptophyl-α-azaphenylalanine 2-benzyl- oxyethylamide.

3. Use according to claim 1 or claim 2, wherein the compound is the (R)- enantiomer, substantially free of the (S)-enantiomer.

4. Use according to claim 1 or claim 2, wherein the compound in the (S)- enantiomer, substantially free of the (R)-enantiomer.