WO2009150101A1

WO2009150101A1 - Pharmaceutical compositions comprising n-[2-((2r)-2-{[4-[(4-chlorophenyl)methyl]-l-oxo-2(ih)-phthalaz inyl]methyl}-l- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide

Info

Publication number: WO2009150101A1
Application number: PCT/EP2009/056931
Authority: WO
Inventors: Gavin Bone
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2008-06-09
Filing date: 2009-06-05
Publication date: 2009-12-17
Anticipated expiration: 2010-12-09

Abstract

The present invention provides aqueous pharmaceutical compositions which comprise a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy)butanamide or a pharmaceutically acceptable salt thereof and to their use in the treatment of various inflammatory and/or allergic diseases such as allergic rhinitis.

Description

N-[2-((2R)-2-{[4-[(4-CHLOROPHENYL)METHYL]-l-OXO-2(IH)-PHTHALAZINYL]METHYL}-l-PYRROLIDINYL)

ETHYLH-(METHYLOXY) BUTANAMIDE

The present invention relates to pharmaceutical compositions comprising an antagonist of the histamine H1 receptor or a pharmaceutically acceptable salt thereof, to processes for their 5 preparation, and to their use in the treatment of various inflammatory and/or allergic diseases, such as allergic rhinitis.

Antagonists of the histamine H1 receptor are known and widely used for the treatment of inflammatory and/or allergic diseases that are associated with the release of histamine from cells. 10 For example, antagonists of the H1 receptor (often referred to as anti-histamines) are known and widely used for the treatment of allergic rhinitis.

The activation of H1 receptors in blood vessels and nerve endings are responsible for many of the symptoms of allergic rhinitis, which include itching, sneezing, and the production of watery

15 rhinorrhea. Oral antihistamine compounds (such as chlorphenyramine, cetirizine, desloratidine and fexofenadine) and intranasal antihistamines (such as azelastine and levocabastine) which are selective H1 receptor antagonists are effective in treating the itching, sneezing and rhinorrhea associated with allergic rhinitis, but are not effective against the nasal congestion symptoms [Aaronson, Ann. Allergy, 67:541 -547, (1991 )]. Thus, H1 receptor antagonists have been

20 administered in combination with sympathomimetic agents such as pseudoephedrine or oxymetazoline to treat the nasal congestion symptoms often associated with allergic rhinitis. These drugs are thought to produce a decongestant action by activating α-adrenergic receptors and increasing the vascular tone of blood vessels in the nasal mucosa. The use of sympathomimetic drugs for the treatment of nasal congestion is frequently limited by the CNS stimulant properties and

25 their effects on blood pressure and heart rate. A treatment which decreases nasal congestion without having effects on the CNS and cardiovascular system may therefore offer advantages over existing therapies.

Other compounds that may be effective in the treatment of inflammatory and/or allergic diseases,

30 such as allergic rhinitis include glucocorticoid receptor agonists (referred to herein as glucocorticoids). Such glucocorticoids with proven anti-inflammatory properties and which are marketed for the treatment of allergic rhinitis, include but are not limited to, beclomethasone dipropionate which is marketed under the trademark Beconase™, fluticasone furoate which is marketed under the trademark Veramyst™ and fluticasone propionate which is marketed under the

35 trademark Flixonase™ .

Allergic rhinitis, pulmonary inflammation and congestion are medical conditions that are often associated with other conditions such as asthma and chronic obstructive pulmonary disease (COPD). In general, these conditions are mediated, at least in part, by inflammation associated with the release of histamine from various cells, in particular mast cells.

Allergic rhinitis, including 'hay fever' affects a large proportion of the population worldwide. There are two types of allergic rhinitis, seasonal and perennial. The clinical symptoms of seasonal allergic rhinitis typically include nasal itching and irritation, sneezing and watery rhinorrhea, which is often accompanied by nasal congestion. The clinical symptoms of perennial allergic rhinitis are similar, except that nasal blockage may be more pronounced. Either type of allergic rhinitis may also cause other symptoms, such as itching of the throat and/or eyes, epiphora and oedema around the eyes. The symptoms of allergic rhinitis may vary in intensity from the nuisance level to debilitating.

A pharmaceutical composition that is effective in treating a broad spectrum of inflammatory and/or allergic symptoms, which offers the potential for a convenient dosing regimen and which has an improved side effect profile would therefore be desirable.

Accordingly, there is provided, in one embodiment, an aqueous pharmaceutical composition which comprises a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1 H)- phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy) butanamide

or a pharmaceutically acceptable salt thereof.

Λ/-[2-((2R)-2-{[4-[(4-Chlorophenyl)methyl]-1-oxo-2(1H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4- (methyloxy)butanamide and pharmaceutically acceptable salts thereof are disclosed in International Patent Application No. PCT/EP2007/064140 (published as International Patent Application publication number WO2008/074803) as antagonists of the histamine H1 receptor, and as such the compound and its pharmaceutically acceptable salts may be useful in the treatment of various inflammatory and/or allergic diseases associated with the release of histamine from cells, for example, allergic rhinitis. Further, this compound is believed to posess a prolonged duration of action and exhibit relatively low CNS penetration.

Aqueous pharmaceutical compositions comprising Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo- 2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy) butanamide or a pharmaceutically acceptable salt thereof may be particularly suitable for intranasal delivery, and/or capable of once daily administration and/or may have an improved side effect profile compared with other existing therapies.

Λ/-[2-((2R)-2-{[4-[(4-Chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4- (methyloxy)butanamide may be used in the form of its free base or as a pharmaceutically acceptable salt, for example a tartrate salt (such as the L-tartrate salt).

Compositions that comprise an anti-histamine and a glucocorticoid may be particularly effective in the treatment of inflammatory and/or allergic diseases.

Accordingly there is provided, in one embodiment, an aqueous pharmaceutical composition which comprises:

(i) a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1H)- phthalazinyl]methyl}-1 -pyrrolidinyl)ethyl]-4-(methyloxy)butanamide

or a pharmaceutically acceptable salt thereof; and

(ii) a compound which is 6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester

or a solvate thereof.

6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1 1 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4 diene-17β- carbothioic acid S-fluoromethyl ester (hereinafter referred to as fluticasone furoate) which is disclosed in International Patent Application WO02/12265 and International Patent Application publication number WO03/066024. Fluticasone furoate is sold in Europe as Veramyst™ for the treatment of seasonal allergy symptoms.

Fluticasone furoate may be used in the form of a solvate, or unsolvated. Thus, in one embodiment, aqueous pharmaceutical compositions of the invention comprise fluticasone furoate, in unsolvated form. In a further embodiment, compositions comprise unsolvated fluticasone furoate as polymorphic Form 1 , as defined in International Patent Application publication number WO02/12265.

It will be appreciated that the aqueous phamaceutical compositions of the invention comprising Λ/-[2- ((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-

(methyloxy)butanamide or a pharmaceutically acceptable salt thereof and fluticasone furoate or a solvate thereof may be delivered such that each compound may be delivered sequentially in separate pharmaceutical compositions or may be delivered simultaneously in a combined pharmaceutical composition.

The aqueous pharmaceutical compositions of the invention are in the form of an aqueous suspension and/or an aqueous solution. Partial suspensions and/or partial solutions are encompassed within the scope of the present invention. Compositions comprising one compound which is in solution and the other compound which is in suspension are also included within the scope of the present invention.

In one embodiment, the compound(s) in the aqueous pharmaceutical compositions of the invention are in suspension. In another embodiment, when two compounds are present, one compound is in solution and the other compound is in suspension.

The aqueous component of the compositions of the invention is typically a high grade quality of water such as purified water (e.g. MilliQ™ water).

The compound(s) for use in the compositions of the invention will typically have a mass mean diameter (MMD) of less than 20 μm, such as between 0.5 to 10 μm, for example between 1 to 10 μm as measured by laser diffraction, for example. Particle size reduction, if necessary, may be achieved by techniques well known in the art such as micronisation, milling and/or microfluidisation.

The aqueous pharmaceutical compositions of the invention may be suitable for topical administration, which includes intranasal, inhaled and ocular administration. Compositions suitable for intranasal administration are of particular interest.

The dose of Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide or a pharmaceutically acceptable salt thereof used will vary in the usual way with the seriousness of the diseases to be treated and other factors, for example the weight of the sufferer. However, as a general guide, suitable unit doses may be about 0.05 to 1000 mg, such as about 0.05 to 200 mg, for example about 0.05 to 2 mg, or about 0.05 to 1 mg and such unit doses may be administered once a day, or more than once a day, for example two or three times a day or as desired. Such therapy may extend for a number of weeks or months.

As used herein "% (w/w)" means the weight of a substance relative to the weight of the total composition expressed as a percentage, e.g. 50 % (w/w) = 0.5 g substance per 1 g total composition.

The proportion of Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide or a pharmaceutically acceptable salt thereof, in the aqueous pharmaceutical compositions of the invention will depend on the composition to be prepared and the particular route of administration, but will generally be within the range of from 0.005 to 2% (w/w), such as 0.01 to 1 % (w/w), for example, 0.025% (w/w) to 0.9% (w/w) based on the total weight of the composition. Particular concentrations of Λ/-[2-((2R)-2-{[4-[(4- chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 -pyrrolidinyl)ethyl]-4-(methyloxy) butanamide as the free base are 0.025% (w/w), 0.05% (w/w), 0.1 % (w/w), 0.25% (w/w), 0.5 % (w/w) and 0.9% (w/w) based on the total weight of the composition.

It will be appreciated that when Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1H)- phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy)butanamide is used in the form of a pharmaceutically acceptable salt, the concentration will depend on the salt chosen but will be such as to provide the desired concentration of compound as the free base. In one embodiment, the pharmaceutically acceptable salt is the L-tartrate salt.

The proportion of fluticasone furoate or a solvate thereof in the aqueous pharmaceutical compositions of the invention will depend on the composition to be prepared and the particular route of administration, but will generally be within the range of from 0.01 to 1 % (w/w), such as 0.01 to 0.5% (w/w) e.g. about 0.05% (w/w) based on the total weight of the composition. Typically, 50 μl_ of composition will deliver about 27.5 μg of fluticasone furoate, or a solvate thereof, giving a daily dose of about 55 to 110 μg of fluticasone furoate.

In one embodiment, the aqueous pharmaceutical compositions of the invention are suitable for intranasal administration.

Intranasal compositions may permit the compound(s) to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound(s) to remain in contact with the target tissue for longer periods of time. A suitable dosing regime for intranasal compositions would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation the composition would be administered to one nostril while the other is manually compressed. This procedure would then be repeated for the other nostril. Typically, one or two sprays per nostril would be administered by the above procedure up to two or three times each day, ideally once daily. Of particular interest are intranasal compositions suitable for once daily administration.

Aqueous pharmaceutical compositions of the invention, such as intranasal compositions, may optionally contain one or more suspending/thickening agents, one or more preservatives, one or more wetting agents and/or one or more tonicity adjusting agents as desired. Further, the compositions of the invention, for example suitable for intranasal administration, may optionally further contain other excipients, such as antioxidants (for example sodium metabisulphite), taste- masking agents (such as menthol) and sweetening agents (for example dextrose, glycerol, saccharin and/or sorbitol). Compositions of the invention may also further contain one or more co- solvents, as desired.

The skilled person would readily appreciate that some excipients may perform more than one function, depending on the nature and number of excipients used in that composition and the particular properties of the compound(s) contained therein.

Accordingly, in one embodiment, there is provided an aqueous pharamaceutical composition of the invention comprising a suspending/thickening agent.

The suspending/thickening agent(s), if included, will typically be present in an amount of between about 0.1 and 5% (w/w), such as between about 1.5% and 2.4% (w/w), particularly about 2.4% (w/w) based on the total weight of the composition. Examples of pharmaceutically acceptable suspending/thickening agents include, but are not limited to, Avicel® (microcrystalline cellulose and carboxymethylcellulose sodium), carboxymethylcellulose sodium, veegum, tragacanth, bentonite, methylcellulose, xanthan gum, carbopol and polyethylene glycols. In one embodiment, the suspending/thickening agents are microcrystalline cellulose and carboxy methylcellulose sodium.

In one embodiment, there is provided an aqueous pharmaceutical composition of the invention comprising a preservative.

For stability purposes, compositions of the invention (for example intranasal compositions) may be protected from microbial or fungal contamination and growth by inclusion of one or more preservatives. Examples of pharmaceutically acceptable anti-microbial agents or preservatives may include, but are not limited to, quaternary ammonium compounds (e.g. benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, myristal picolinium chloride and lauralkonium chloride), mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g. chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (e.g. esters of para-hydroxybenzoic acid), chelating agents such as disodium ethylenediaminetetraacetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin. Examples of pharmaceutically acceptable anti-fungal agents or preservatives may include, but are not limited to, sodium benzoate, sorbic acid, sodium propionate, methyl paraben, ethyl paraben, propyl paraben and butyl paraben. The preservative(s), if included, may be present in an amount of between about 0.001 and 1 % (w/w), such as about 0.015% to 0.5% (w/w), for example 0.015% to 0.3% (w/w) based on the total weight of the composition. In a further embodiment, the preservative(s) are selected from benzalkonium chloride, EDTA and/or potassium sorbate. In a further embodiment, the preservative(s) are EDTA and/or potassium sorbate. In another embodiment the preservatives are EDTA in a concentration of about 0.015% (w/w) and potassium sorbate in a concentration of about 0.3% (w/w), based on the total weight of the composition.

In another embodiment, there is provided an aqueous pharmaceutical composition of the invention which is preservative free.

In one embodiment, there is provided an aqueous pharmaceutical composition of the invention comprising a wetting agent.

Compositions (for example wherein the compound is in suspension) may include one or more wetting agents which functions to wet the particles of medicament to facilitate dispersion thereof in the aqueous phase of the composition. Typically, the amount of wetting agent used will not cause foaming of the dispersion during mixing. Examples of pharmaceutically acceptable wetting agents include, but are not limited to, fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), macrogol ethers and poloxamers. The wetting agent may be present in an amount between about 0.005 to 0.05% (w/w), for example about 0.01 to 0.05% (w/w), for example about 0.025% (w/w), or about 2.0% (w/w), based on the total weight of the composition. In one embodiment, the wetting agent is polyoxyethylene (20) sorbitan monooleate (Polysorbate 80). In a particular embodiment, the wetting agent is about 0.025% (w/w) polyoxyethylene (20) sorbitan monooleate (Polysorbate 80).

In one embodiment, there is provided an aqueous pharmaceutical composition of the invention comprising a tonicity adjusting agent.

One or more tonicity adjusting agent(s) may be included to achieve isotonicity with body fluids e.g. fluids of the nasal cavity or fluids of the eye, resulting in reduced levels of irritancy. Examples of pharmaceutically acceptable tonicity adjusting agents include, but are not limited to, sodium chloride, dextrose, xylitol and calcium chloride. A tonicity adjusting agent, if present, may be included in an amount of between 0.1 and 10% (w/w), such as 4.5 to 5.5% (w/w), for example about 5.0% (w/w), or 0.5 to 1 % (w/w), such as about 0.75% (w/w) based on the total weight of the composition. In a further embodiment, the tonicity adjusting agents are dextrose (e.g. anhydrous dextrose) and/or xylitol. In another embodiment the tonicity adjusting agent is xylitol. In another embodiment, the tonicity adjusting agent is xylitol in a concentration of about 0.75% (w/w), based on the total weight of the composition. In another embodiment, the composition does not contain a tonicity adjusting agent.

In one embodiment, there is provided an aqueous pharmaceutical composition of the invention comprising a buffering agent.

The compositions of the invention may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, trometarol, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof. In a further embodiment, the buffering agents are sodium citrate and/or citric acid. In another embodiment, the buffering agents are sodium citrate in a concentration of about 1.48% (w/w) and citric acid (which may be anhydrous) in a concentration of about 0.96% (w/w), based on the total weight of the composition.

In one embodiment, there is provided an aqueous pharmaceutical composition of the invention comprising a co-solvent.

One or more co-solvent(s) may be included to aid solubility of the active compound(s) and/or other excipients. Examples of pharmaceutically acceptable co-solvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene glycols (for example PEG300 or PEG400) and methanol. The cosolvent(s), if present, may be included in an amount of 0.05 to 20% (w/w), such as 1.5 to 17.5% (w/w), or from 1.5 to 2.5% (w/w), or from 0.05% to 0.5% (w/w), e.g. 0.1 % (w/w) based on the total weight of the composition.

In a further embodiment, there is provided an aqueous pharmaceutical composition of the invention comprising a) a suspending/thickening agent; b) a preservative; c) a wetting agent; and optionally d) a tonicity adjusting agent.

In a further embodiment, there is provided an aqueous pharmaceutical composition of the invention comprising a) a suspending/thickening agent; b) a preservative; c) a wetting agent; d) a tonicity adjusting agent; and e) a co-solvent.

In a further embodiment, there is provided an aqueous pharmaceutical composition of the invention comprising a) a suspending/thickening agent; b) a preservative; c) a wetting agent; and d) a co-solvent.

In a further embodiment, there is provided an aqueous pharmaceutical composition which comprises microcrystalline cellulose and carboxymethyl cellulose sodium (as suspending/thickening agents); EDTA and/or potassium sorbate (as preservatives); polyoxyethylene (20) sorbitan monooleate (supplied as polysorbate 80) (as a wetting agent); xylitol (as tonicity adjusting agents); and propylene glycol (as a co-solvent).

Compositions for administration topically, to the nose or lung for example, for the treatment of rhinitis, include pressurised aqueous aerosol compositions and aqueous compositions delivered to the nasal cavities by pressurised pump. Aqueous compositions which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Aqueous compositions may also be administered to the nose by nebulisation.

Accordingly, the aqueous pharmaceutical compositions of the invention are provided in a suitable container depending on the choice of route of administration. Further, for compositions comprising both compounds it will be appreciated that said container may be capable of delivering each compound sequentially in a separate pharmaceutical composition as well as simultaneously in a combined pharmaceutical composition.

A fluid dispenser typically used to deliver the aqueous pharmaceutical compositions of the invention to the nasal cavities may have a dispensing nozzle or dispensing orifice through which a metered dose of the fluid composition is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid composition, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid composition into the nasal cavity. A fluid dispenser of the aforementioned type is described and illustrated in International Patent Application publication number WO05/044354. The dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid composition. The housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the composition out of a pump stem through a nasal nozzle of the housing. In one embodiment, the fluid dispenser is of the general type illustrated in Figures 30-40 of WO05/044354.

Further, the aqueous pharmaceutical compositions of the invention may be delivered by a pump as disclosed in International Patent Application publication number WO2007/138084, for example as disclosed with reference to Figures 22-46 thereof, or as disclosed in GB0723418.0, for example as disclosed with reference to Figures 7-32 thereof or as disclosed with reference to Figures 7-41 of International patent application PCT/GB2008/003954 which claims priority from the afore-mentioned GB application and designates the United States of America. The pump may be actuated by an actuator as disclosed in Figures 1-6 of GB0723418.0 (or figures 1-6 of International patent application PCT/GB2008/003954).

Typically, fluid dispensers for use with the aqueous pharmaceutical compositions of the invention may be capable of holding 8 to 50 ml. (or less) of composition and each spray will typically deliver 50 to 100 μl_ (or less, for example 25 μl_) of composition. Typically therefore the fluid dispenser will be capable of providing at least 100 metered doses.

Accordingly, there is provided in a further aspect a container comprising an aqueous pharmaceutical composition of the invention.

In one embodiment the container is suitable for delivering an aqueous pharmaceutical composition of the invention to the nasal cavities.

In another embodiment, the container is suitable for delivering an aqueous pharmaceutical composition of the invention to the eye.

The compositions of the invention have potentially beneficial anti-inflammatory and/or anti-allergic effects, particularly upon topical administration to the nose, demonstrated by, for example the ability of Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 -pyrrolidinyl)ethyl]-4- (methyloxy)butanamide, or a pharmaceutically acceptable salt thereof, to antagonise the H1 receptor, with long acting effect and the known activity of fluticasone furoate at the glucocorticoid receptor. Hence, the aqueous pharmaceutical compositions of the invention may be useful in the treatment of inflammatory and/or allergic diseases, particularly inflammatory and/or allergic diseases of the respiratory tract.

Examples of disease states in which the aqueous pharmaceutical compositions of the invention may have potentially beneficial anti-inflammatory and/or anti-allergic effects include inflammatory and/or allergic diseases of the respiratory tract, such as allergic rhinitis (seasonal and perennial) or other diseases such as bronchitis (including chronic bronchitis), asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD) and sinusitis.

Furthermore, the aqueous pharmaceutical compositions of the invention may be of use in the treatment of nephritis, skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions. Also, the aqueous pharmaceutical compositions of the invention may be useful in the treatment of insect bites and stings.

The aqueous pharmaceutical compositions of the invention may also be of use in the treatment of nasal polyposis, conjunctivitis (e.g. allergic conjunctivitis) or pruritis.

A disease of particular interest is allergic rhinitis.

Other diseases in which histamine may have may have a pathophysiological role include non-allegic rhinitis.

It will be appreciated by those skilled in the art that references herein to treatment or therapy may extend to prophylaxis as well as the treatment of established conditions.

Accordingly, there is provided an aqueous pharmaceutical composition which comprises a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl] methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide or a pharmaceutically acceptable salt thereof and optionally a compound which is fluticasone furoate or a solvate thereof, for use in therapy.

In another embodiment, there is provided an aqueous pharmaceutical composition which comprises a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide or a pharmaceutically acceptable salt thereof and optionally a compound which is fluticasone furoate or a solvate thereof, for use in the treatment (or prophylaxis) of inflammatory and/or allergic diseases.

In another embodiment, there is provided an aqueous pharmaceutical composition which comprises a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide or a pharmaceutically acceptable salt thereof and optionally a compound which is fluticasone furoate or a solvate thereof, for use in the treatment (or prophylaxis) of inflammatory and/or allergic diseases of the respiratory tract, such as allergic rhinitis.

In a further aspect, there is provided the use of an aqueous pharmaceutical composition which comprises a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)- phthalazinyl]methyl}-1 -pyrrolidinyl)ethyl]-4-(methyloxy)butanamide or a pharmaceutically acceptable salt thereof and optionally a compound which is fluticasone furoate or a solvate thereof, in the manufacture of a medicament for the treatment (or prophylaxis) of inflammatory and/or allergic diseases, such as inflammatory and/or allergic diseases of the respiratory tract, for example, allergic rhinitis.

In a further aspect, there is provided a method for the treatment of any of the above mentioned diseases, which method comprises administering to a patient in need thereof a pharmaceutically effective amount of an aqueous pharmaceutical composition which comprises a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 -pyrrolidinyl)ethyl]-4- (methyloxy)butanamide or a pharmaceutically acceptable salt thereof and optionally a compound which is fluticasone furoate or a solvate thereof.

In one embodiment, there is provided a method for the treatment of allergic rhinitis.

The aqueous pharmaceutical compositions of the invention may be prepared by the methods described below or by similar methods. The following Examples illustrate the preparation of the aqueous pharmaceutical compositions but are not to be considered in limiting the the scope of the disclosure in any way.

Preparation of 4 JV-r2-((2/?)-2-{r4-r(4-chlorophenyl)methvn-1-oxo-2(1H)-phthalazinvn methylM - Pyrrolidinyl)ethvn-4-(methyloxy)butanamide

Λ/-r2-((2f?)-2-(r4-r(4-chlorophenvnmethyll-1 -oxo-2(1 H)-phthalazinyllmethyl)-1 -pyrrolidinvnethyll-4- (methyloxy)butanamide and its salts may be prepared according to methods disclosed in International Patent Application WO 2008/074803 (Glaxo Group Ltd), published 26^th June 2008(in particular, see Example 34).

Abbreviations

BOC (Boc): ferf-butoxycarbonyl

DCM: Dichloromethane

DMF: Λ/,Λ/-Dimethylformamide

EtOAc: Ethylacetate

EtOH: Ethanol HCI: Hydrogen chloride

HPLC: High Performance Liquid Chromatography h: Hours

LCMS: Liquid Chromatography - Mass Spectroscopy

MDAP HPLC: Mass-Directed Autopreparative HPLC

MeOH: Methanol

MgSO₄: Magnesium Sulfate min: Minutes

NaOH: Sodium hydroxide

NMR: Nuclear Magnetic Resonance

RT: Retention time s.g Specific gravity

TBTU: O-(1 /-/-benzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium tetrafluoroborate

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran

TLC: Thin Layer Chromatography

General Procedures

Flash silica gel refers to Merck Art No. 9385; silica gel refers to Merck Art No. 7734. SCX cartridges are Ion Exchange SPE columns where the stationary phase is polymeric benzene sulfonic acid. These are used to isolate amines.

SCX2 cartridges are Ion Exchange SPE columns where the stationary phase is polymeric propylsulfonic acid. These are used to isolate amines.

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1 % formic acid and 0.01 M ammonium acetate in water (solvent A) and 0.05% formic acid 5% water in MeCN (solvent B), using the following elution gradient 0.0 - 7 min 0% B, 0.7 - 4.2 min 100% B, 4.2 - 5.3 min 0% B, 5.3 - 5.5min 0% B at a flow rate of 3 mlmin^"1. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES- ve).

The Flashmaster Il is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2 g to 100 g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions. The system is equipped with a Knauer variable wavelength UV-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking. The ¹H NMR spectra were recorded on a Bruker AV400 operating at 400 MHz. Standard deuterated solvents were used. Tetramethylsilane may have been used as internal standard.

Reactions are routinely monitored by methods well known to those skilled in the art, such as TLC, LCMS and/or HPLC. Such methods are used to assess whether a reaction has gone to completion, and reaction times may be varied accordingly.

The XRPD method which is employed to analyse crystalline forms of compounds is as follows:

XRPD analysis is performed on a PANalytical X'Pert Pro X-ray powder diffractometer, model X' Pert Pro PW3040/60, serial number DY1850 using an X'Celerator detector. The acquisition conditions are: radiation: Cu K, generator tension: 40 kV, generator current: 45 mA, start angle: 2.000°2θ, end angle: 39.997 °2Θ, step size: 0.0167°2θ, time per step: 31.75 seconds. The sample is prepared using flush Silicon wafer. The margin of error is approximately ±1 °2Θ for each of the peak assignments.

Differential Scanning Calorimetry (DSC) is performed on a TA instruments Q1000 Differential Scanning Calorimeter equipped with a refrigerated cooling system by weighing compound into an aluminium pan and crimping a pan lid onto the top of the pan. Slight variations in the observed peaks may be expected based on the specific instrument and pan configuration employed, the analyst's sample preparation technique, and the sample size. Some margin of error is present in the peak assignment reported above. The margin of error is approximately ±5 ⁰C for the peak maximum and ±10 J/g for the heat of fusion. Compounds were named using ACD/Name PRO 6.02 chemical naming software Advanced Chemistry Developments Inc.; Toronto, Ontario, M5H2L3, Canada.

According to one process, Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1 H)-phthalazinyl] methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy)butanamide and its L-tartrate salt may be prepared according to Scheme 1 , below.

Scheme 1 : Synthesis of Λ/-r2-((2f?)-2-fr4-r(4-chlorophenvnmethyll-1-oxo-2(1H)-phthalazinyllmethyl>- 1-Pyrrolidinyl)ethyl1-4-(methyloxy)butanamide, free base

Reagents and Conditions: Stage 1 ) suitable base e.g. sodium acetate, suitable solvent such as N- methyl-2-pyrrolidinone, usually at an elevated temperature such as between 170 and 190 ⁰C; Stage 2) hydrazine, hydrazine sulfate or hydrazine hydrate, in a suitable solvent such as ethanol, usually at an elevated temperature such as between 80 and 90 ⁰C; Stage 3A) appropriate activating agent such as mesyl chloride, appropriate base e.g. triethylamine, suitable solvent such as methyl /so-butyl ketone (MIBK), usually at an appropriate lowered temperature such as at around 0 ⁰C; Stage 3B) appropriate base for example cesium carbonate, suitable solvent such as butan-2-ol, usually at an elevated temperature such as between 90 and 110 ⁰C; Stage 3C) deprotection using a suitable acid such as hydrogen chloride, in an appropriate solvent, such as /so-propyl alcohol, optionally at an elevated temperature such as between 70 and 90 ⁰C; Stage 4) appropriate base for example potassium carbonate, suitable solvent such as 3-pentanone, usually at an elevated temperature such as between 90 and 1 10 ⁰C; Stage 5) ethanolamine, suitable solvent such as 2-methyl tetrahydrofuran (MeTHF), optionally at an elevated temperature such as between 70 and 90 ⁰C; Stage 6A) Deprotection using an appropriate base for example sodium hydroxide, in a suitable solvent such as methanol; Stage 6B) Suitable coupling reagent such as 1-propanephosphonic acid cyclic anhydride (T3P) with an appropriate base for example triethylamine; Stage 7) Recrystallisation from an appropriate solvent system.

The compound of formula (I), phthalic anhydride, is commercially available, for example, from Sigma-Aldrich.

The compound of formula (II), 4-chlorophenylacetic acid, is commercially available, for example, from Sigma-Aldrich.

The compound of formula (III), 4-chlorobenzylidene phthalide, is commercially available, for example, from Honeywell.

The compound of formula (IV), 4-[(4-chlorophenyl)methyl]-1 (2H)-phthalazinone, is also disclosed in US patent 3,813,384, see Example 10, step 1.

The compound of formula (V), 1 , 1 -d imethy lethyl (2R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate is commercially available, for example, from Sigma-Aldrich.

The compound of formula (Xl), methyl 4-methoxybutyrate is commercially available, for example, from Sigma-Aldrich.

Further, Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide as pharmaceutically acceptable salts may be prepared by exchange of counterions, or precipitation of said salt from the free base.

It is to be further understood that references hereinafter to Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]- 1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy) butanamide means that compound, as the free base, or as a pharmaceutically salt, or as a solvate.

Λ/-[2-((2R)-2-{[4-[(4-Chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl) ethyl]-4- (methyloxy)butanamide may be in the form of and/or may be administered as a pharmaceutically acceptable salt. For a review on suitable salts see Berge et al., J. Pharm. Sd., 1977, 66, 1-19. Suitable pharmaceutically acceptable salts include acid addition salts. As used herein, the term "pharmaceutically acceptable salt", means any pharmaceutically acceptable salt or solvate of a compound of formula (I), 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. Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

A pharmaceutically acceptable acid addition salt can be formed by reaction of Λ/-[2-((2R)-2-{[4-[(4- chlorophenyl)methyl]-1 -oxo-2(1 /-/)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy)butanamide with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulphuric, nitric, phosphoric, succinc, maleic, formic, acetic, propionic, fumaric, citric, tartaric (e.g. L-tartaric), lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic (e.g. 2-naphthalenesulfonic), naphthalene disulfonic or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate (e.g. L-tartrate), lactate, benzoate, salicylate, glutamate, aspartate, p- toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), naphthalene disulfonate or hexanoate salt.

Intermediate 1 1,1 -Dimethylethyl (2/?)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 - pyrrolidinecarboxylate

To a solution of triphenylphosphine (1.86 g, 7.09 mmol) in dry THF (6 ml) was added diisopropyl azodicarboxylate (1.12 ml, 5.69 mmol) at -15 ⁰C. The resulting pale yellow thick suspension was stirred at -15 ⁰C for 2 min. To aid stirring more dry THF (2 ml) was added. The reaction mixture was then treated with a suspension of 4-[(4-chlorophenyl)methyl]-1 (2H)-phthalazinone, (as disclosed in US patent 3,813,384, Example 10, Step 1 ) (0.571 g, 2.11 mmol) and Λ/-ferf-butoxycarbonyl-D- prolinol (commercially available, for example, from Fluka), (0.650 g, 3.23 mmol) in dry THF (10 ml) at -15 ⁰C. The reaction mixture was allowed to warm to room temperature and stirred at 20 ⁰C for 23 h. MeOH (20 ml) was then added and the solvents were removed in vacuo. The resultant residue was purified by Flashmaster Il chromatography (70 g silica cartridge) eluted with 0-50% EtOAc-cyclohexane gradient over 40 min. The solvents were removed in vacuo to afford the title compound (1.05 g). LCMS RT = 3.71 min. Intermediate 2 4-[(4-Chlorophenyl)methyl]-2-[(2/?)-2-pyrrolidinylmethyl]-1 (2H)-phthalazinone

To a solution of 1 ,1-dimethylethyl (2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)- phthalazinyl]methyl}-1 -pyrrolidinecarboxylate (for example, as prepared for Intermediate 1 ) (1.05 g, 2.31 mmol) in dry dioxane (12 ml) was added a solution of HCI in 1 ,4-dioxane (4.0 M, 6 ml). The solution was stirred at 20 ⁰C for 2 h. TFA (4 x about 1 ml) was added at 10 minute intervals until deprotection was completed. The solvent was removed in vacuo and the residue applied onto an SCX-2 cartridge (20 g, pre-conditioned with MeOH), washed with MeOH (x 2) and then eluted with 10% aqueous ammonia in MeOH (2 x 50 ml). The solvents were removed in vacuo and the resultant residue purified by Flashmaster Il chromatography (50 g silica cartridge) eluted with 0-30% MeOH + 1 % triethylamine - DCM gradient over 40 min to afford the title compound (0.351 g). LCMS RT = 2.45 min, ES+ve m/z 354/356 (M+H)⁺.

Intermediate 3

4-(Methyloxy)butanoic acid

Methyl 4-(methyloxy)butanoate (commercially available, for example, from Aldrich) (8.2 ml, 60 mmol) was dissolved in MeOH (60 ml) and treated with 2 M aqueous sodium hydroxide solution (60 ml), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove the MeOH. The aqueous mixture was partitioned between DCM (100 ml) and water (40 ml). The layers were separated and the aqueous washed with further DCM (100 ml). The aqueous layer was acidified to pH 1-2 using 5 M HCI (24 ml), and extracted with DCM (2 x 100 ml). These latter organic extracts were combined and concentrated in vacuo to give the product as a colourless mobile oil (4.12 g, 34.8 mmol, 58%), ¹H NMR (400 MHz, CDCI₃) δ 1 1.0, (br s, 1 H), 3.44 (t, J = 6 Hz, 2H), 3.34 (s, 3H), 2.46 (t, J = 7.5 Hz, 2H), 1 .95-1 .86 (m, 2H).

Intermediate 4

2-[2-((2/?)-2-{[4-[(4-Chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 - pyrrolidinyl)ethyl]-1 H-isoindole-1 ,3(2H)-dione

4-[(4-Chlorophenyl)methyl]-2-[(2R)-2-pyrrolidinylmethyl]-1 (2H)-phthalazinone (for example, as prepared for Intermediate 2) (3.05 g, 8.59 mmol) was stirred with 2-(2-bromoethyl)-1 H-isoindole- 1 ,3(2H)-dione (4.82 g, 19 mmol) (commercially available, for example, from Acros) and potassium carbonate (5.9 g, 43 mmol) in 2-butanone (75 ml) under nitrogen at 80 ⁰C for 18 h. Further 2-(2- bromoethyl)-1 H-isoindole-1 ,3(2/-/)-dione (2.4 g, 9.4 mmol) and potassium carbonate (3.0 g, 22 mmol) were added and the heating and stirring were continued for a further day. After three further days at room temperature, the mixture was partitioned between water and DCM. The aqueous layer was extracted with more DCM and the combined organic layers were washed with water, dried (MgSO₄) and evaporated to a thick oil. This oil was redissolved in DCM and loaded onto a column of silica gel (250 g) that had been pre-conditioned with 40% ethyl acetate in 40-60 petroleum ether. The column was eluted with this mixture, then 50%, 70%, 80% and 100% ethyl acetate. Appropriate fractions were combined and concentrated to give the title compound (3.96 g, 7.51 mmol). LCMS RT = 3.19 min, ES+ve m/z 527/529 (M+H)⁺.

Intermediate 5

2-{[(2/?)-1-(2-Aminoethyl)-2-pyrrolidinyl]methyl}-4-[(4-chlorophenyl)methyl]-1(2H)- phthalazinone

2-[2-((2R)-2-{[4-[(4-Chlorophenyl)methyl]-1 -0X0-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-1 H- isoindole-1 ,3(2H)-dione (for example, as prepared for Intermediate 4) (3.96 g, 7.51 mmol) was dissolved in ethanol (50 ml) at 80 ⁰C with stirring and hydrazine monohydrate (0.91 ml, 19 mmol) (commercially available, for example, from Aldrich) was added. The mixture was heated with stirring for 1.25 h. The reaction was cooled with ice-water and the white solid was removed by filtration. The filter-cake was leached with ethanol and the combined filtrates were evaporated to a white solid. This solid was mixed with 2M hydrochloric acid (10 ml) and water (approximately 100 ml). The opaque solution was washed successively with ethyl acetate and DCM. The aqueous layer was then made alkaline with 2M sodium hydroxide solution and the product was extracted with DCM (x 4). The combined organic layers were washed with water and dried (MgSO₄) and evaporated to give the title compound as a white solid, (2.29 g) LCMS RT = 2.74 min, ES+ve m/z 397/399 (M+H)⁺.

Example 1

W-[2-((2/?)-2-{[4-[(4-Chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 - pyrrolidinyl)ethyl]-4-(methyloxy)butanamide

Preparation (a)

4-(Methyloxy)butanoic acid (for example, as prepared for Intermediate 3) (155 mg, 1.31 mmol) was dissolved in DMF (3 ml) with stirring. Triethylamine (555 μl, 3.98 mmol) was added, followed by TBTU (422 mg, 1 .31 mmol) in DMF (2 ml), and the mixture was stirred at room temperature. 2- {[(2R)-1 -(2-Aminoethyl)-2-pyrrolidinyl]methyl}-4-[(4-chlorophenyl)methyl]-1 (2/-/)-phthalazinone (for example, as prepared for intermediate 5) (401 mg, 1.01 mmol) in DMF (3 ml) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was applied to a silica cartridge (70 g, pre-conditioned with MeOH) and eluted with MeOH (3 column volumes) then 10% aqueous 0.88 s.g. ammonia in MeOH (3 column volumes). Appropriate fractions were combined and concentrated in vacuo. The residue was redissolved in MeOH and applied to a SCX cartridge (70 g, pre-conditioned with MeOH). The cartridge was washed with MeOH (2 column volumes) and then eluted with 10% 0.880 s.g. ammonia in MeOH (3 column volumes). The appropriate basic fractions were combined and the solvent removed in vacuo. The residue was purified by chromatography on silica (50 g, eluting with DCM-EtOH-aqueous ammonia, 200:8:1 (400 ml), then 150:8:1 (450 ml)). The appropriate fractions were combined and concentrated in vacuo. The sample was redissolved in EtOH and concentrated in vacuo to give the title compound (446 mg, 89%). LCMS RT = 2.86 min, ES+ve m/z 497/499 (M+H)⁺. ¹H NMR (400 MHz, MeOH-^₄) δ 8.43-8.36 (m, 1 H), 7.96-7.90 (m, 1 H), 7.89-7.81 (m, 2H), 7.34-7.27 (m, 4H), 4.36 (s, 2 H), 4.31 (dd, J = 13, 4 Hz, 1 H), 4.24 (dd, J = 13, 7 Hz, 1 H), 3.41 -3.24 (m, 7H), 3.21-3.13 (m, 1 H), 3.10-3.00 (m, 2H), 2.55-2.46 (m, 1 H), 2.36-2.27 (m, 1 H), 2.26 (t, J = 8 Hz, 2H), 1 .94-1 .68 (m, 6H).

Preparation (b) To 4-methyloxybutanoic acid (for example, as prepared for Intermediate 3) (1.49 g 12.6 mmol) in dry DMF (20 ml) under nitrogen was added TBTU (4.38 g 13.65 mmol) followed by triethylamine (5.85 ml, 42 mmol) and the mixture stirred for 10min at room temperature. To this mixture was added 2-{[(2R)-1 - (2-aminoethyl)-2-pyrrolidinyl]methyl}-4-[(4-chlorophenyl)methyl]-1 (2H)-phthalazinone (for example, as prepared for Intermediate 5) (4.17 g 10.5 mmol) suspended in dry DMF (40 ml) and the mixture stirred for 60 min under nitrogen at room temperature. The mixture was then evaporated to a small volume and the residue applied to silica cartridge (120 g). This was eluted using a gradient 0-10% DCIWMeOH in DCM. The product containing fractions were combined and evaporated to dryness. This contained an impurity, therefore, the material was taken up into DCM (300 ml) and washed with 1 N NaOH (2 x 50 ml), water (2 x 100ml) and the organic layer separated passed through phase separator. The filtrate was evaporated to dryness and purified on silica cartridge (100 g) eluting with 7% MeOH in DCM isocratically. The product containing fractions were combined and evaporated to dryness. The residue obtained still contained a small amount of impurity, therefore, dissolved up into DCM (250 ml) and washed with 2N NaOH (2 x 50 ml), water (2 x 50 ml) and passed through phase separator. The filtrate was evaporated to dryness to leave the product which was triturated with ether (200 ml) for 10min. The solid was filtered off, washed with ether (50 ml) and dried thoroughly in vacuo overnight to give the title compound (3.9 g) as a solid. NMR consistent with the required product and LCMS RT = 2.85min ES+ve m/z 497/499 (M+H)⁺.

An XRPD pattern of Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide (as prepared in Preparation (b)) is shown in Figure 1. The peak angles and d-spacings for this form are tabulated below.

The DSC thermogram plots the differential rate of heating in watts per second against temperature. A DSC thermogram of Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide (as prepared in Preparation (b)) is shown in Figure 2. A melting endotherm was observed at an onset temperature of 126 ⁰C.

Example 1b

W-[2-((2/?)-2-{[4-[(4-Chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 - pyrrolidinyl)ethyl]-4-(methyloxy)butanamide, L -tart rate salt Λ/-[2-((2R)-2-{[4-[(4-Chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl) ethyl]-4- (methyloxy)butanamide (for example, as prepared for Example 1 , Preparation (b)) (400 mg) was dissolved in acetone (4 ml). To this was added (L)-tartaric acid (126.8 mg) dissolved in acetone (4 ml) and the reaction was left to temperature cycle (0 - 40 ⁰C) over the weekend. The solid was isolated and washed with acetone (approximately 1 ml) and left to dry in air for approximately 2 h and then overnight in vacuo at room temperature to give the title compound (464.7 mg). LCMS RT = 2.73 min, ES+ve m/z 497/499 (M+H)⁺.

An XRPD pattern of Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide tartrate salt (as prepared in Example 1 b) is shown in Figure 3. The peak angles and d-spacings for this form are tabulated below.

The DSC thermogram plots the differential rate of heating in watts per second against temperature. A DSC thermogram of Λ/-[2-((2R)-2-{[4-[(4-Chlorophenyl)methyl]-1-oxo-2(1 H)-phthalazinyl]methyl}-1- pyrrolidinyl)ethyl]-4-(methyloxy)butanamide tartrate salt (as prepared in Example 1 b) is shown in Figure 4. A melting endotherm was observed at an onset temperature of 137 ⁰C.

Biological Data Λ/-[2-((2R)-2-{[4-[(4-Chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4- (methyloxy)butanamide and various salts have been tested for in vitro and/or in vivo biological activity in accordance with the following or similar assays.

H1 receptor cell line generation and FLIPR assay protocol 1. Generation of histamine H1 cell line

The human H1 receptor is cloned using known procedures described in the literature [Biochem. Biophys. Res. Commun., 201 (2):894 (1994)]. Chinese hamster ovary (CHO) cells stably expressing the human H1 receptor are generated according to known procedures described in the literature [Br. J. Pharmacol., 1 17(6): 1071 (1996)].

Histamine H1 functional antagonist assay: Determination of functional pKi values The histamine H1 cell line is seeded into non-coated black-walled clear bottom 384-well tissue culture plates in alpha minimum essential medium (Gibco/lnvitrogen, cat no. 22561-021 ), supplemented with 10% dialysed foetal calf serum (Gibco/lnvitrogen cat no. 12480-021 ) and 2 rtiM L-glutamine (Gibco/lnvitrogen cat no 25030-024) and is maintained overnight at 5% CO₂, 37 ⁰C.

Excess medium is removed from each well to leave 10 μl. 30 μl loading dye (250 μM Brilliant Black, 2 μM Fluo-4 diluted in Tyrodes buffer + probenecid (145 rtiM NaCI, 2.5 rtiM KCI, 10 rtiM HEPES, 10 rtiM D-glucose, 1.2 rtiM MgCI₂, 1.5 rtiM CaCI₂, 2.5 rtiM probenecid, pH adjusted to 7.40 with NaOH 1.0 M)) is added to each well and the plates are incubated for 60 min at 5% CO_2, 37 ⁰C.

10 μl of test compound, diluted to the required concentration in Tyrodes buffer + probenecid (or 10 μl Tyrodes buffer + probenecid as a control) is added to each well and the plate is incubated for 30 min at 37 ⁰C, 5% CO₂. The plates are then placed into a FLIPR™ (Molecular Devices, UK) to monitor cell fluorescence (λ_ex = 488 nm, λ_EM = 540 nm) in the manner described in Sullivan et al., (In: Lambert DG (ed.), Calcium Signaling Protocols, New Jersey: Humana Press, 1999, 125-136) before and after the addition of 10 μl histamine at a concentration that results in the final assay concentration of histamine being ECso-

Functional antagonism is indicated by a suppression of histamine induced increase in fluorescence, as measured by the FLIPR™ system (Molecular Devices). By means of concentration effect curves, functional affinities are determined using standard pharmacological mathematical analysis.

Histamine H1 functional antagonist assay: Determination of antagonist pA2 and duration The histamine H1 receptor expressing CHO cells are seeded into non-coated black-walled clear bottom 96-well tissue culture plates as described above.

Following overnight culture, growth medium is removed from each well, washed with 200 μl PBS and is replaced with 50 μl loading dye (250 μM Brilliant Black, 1 μMFIuo-4 diluted in Tyrodes buffer + probenecid (145 rtiM NaCI, 2.5 rtiM KCI, 1 OmM HEPES, 1 OmM D-glucose, 1.2 rtiM MgCI₂, 1 .5 rtiM

CaCI₂, 2.5 imM probenecid, pH adjusted to 7.40 with NaOH 1.0 M)). Cells are incubated for 45 min at 37 ⁰C. The loading buffer is removed and the cells are washed as above, and 90 μl of Tyrodes buffer + probenecid is added to each well. 10 μl of test compound, diluted to the required concentration in Tyrodes buffer + probenecid (or 10 μl Tyrodes buffer + probenecid as a control) is added to each well and the plate is incubated for 30 min at 37 ⁰C, 5% CO₂.

The plates are then placed into a FLIPR™ (Molecular Devices, UK) to monitor cell fluorescence (λ_ex = 488 nm, Λ_EM = 540 nm) in the manner described in Sullivan et al., (In: Lambert DG (ed.), Calcium Signaling Protocols, New Jersey: Humana Press, 1999, 125-136) before and after the addition of 50 μl histamine over a concentration range of 1 rtiM - 0.1 nM. The resultant concentration response curves are analysed by non-linear regression using a standard four parameter logistic equation to determine the histamine EC_5O, the concentration of histamine required to produce a response of 50% of the maximum response to histamine. The antagonist pA2 is calculated using the following standard equation: pA2 = log(DR-1 )-log[B] where DR = dose ratio, defined as EC₅oantagonist- treated/EC₅₀control and [B] = concentration of antagonist.

To determine the antagonist duration, cells are cultured overnight in non-coated black-walled clear bottom 96-well tissue culture plates, are washed with PBS and are incubated with a concentration of antagonist chosen to give an approximate DR in the range 30 - 300. Following the 30 min antagonist incubation period, the cells are washed two or three times with 200 μl of PBS and then 100 μl Tyrodes buffer is added to each well to initiate antagonist dissociation. Following incubation for predetermined times, typically 30 - 270 min at 37 ⁰C, the cells are then washed again with 200 μl PBS and are incubated with 100 μl Tyrodes buffer containing Brilliant Black, probenecid and Fluo-4 for 45 min at 37 ⁰C, as described above. After this period, the cells are challenged with histamine in the FLIPR™ as described above. The dose ratio at each time point is used to determine the fractional H1 receptor occupancy by the following equation: fractional receptor occupancy = (DR- 1 )/DR. The decrease in receptor occupancy over time approximates to a straight line and is analysed by linear regression. The slope of this straight line fit is used as an index of the dissociation rate of the antagonist. The dose ratios for antagonist treated cells and for antagonist treated and washed cells at each time point are used to calculate a relative dose ratio (rel DR) which is also used as an index of antagonist duration. Antagonists with long duration of action produce rel DR values close to 1 , and antagonists with short duration of action produce rel DR values that approaches the dose ratio value obtained for antagonist treatment alone. 2. H3 receptor cell line generation, membrane preparation and functional GTPYS assay protocols

Generation of histamine H3 cell line The histamine H3 cDNA is isolated from its holding vector, pCDNA3.1 TOPO (InVitrogen), by restriction digestion of plasmid DNA with the enzymes BamH1 and Not-1 and is ligated into the inducible expression vector pGene (InVitrogen) digested with the same enzymes. The GeneSwitch™ system (a system where in transgene expression is switched off in the absence of an inducer and switched on in the presence of an inducer) is performed as described in US Patents: 5,364,791 ; 5,874,534; and 5,935,934. Ligated DNA is transformed into competent DH5α E. coli host bacterial cells and is plated onto Luria Broth (LB) agar containing Zeocin™ (an antibiotic which allows the selection of cells expressing the sh ble gene which is present on pGene and pSwitch) at 50 μgml^"1. Colonies containing the re-ligated plasmid are identified by restriction analysis. DNA for transfection into mammalian cells is prepared from 250 ml cultures of the host bacterium containing the pGeneH3 plasmid and is isolated using a DNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines (Qiagen).

CHO K1 cells previously transfected with the pSwitch regulatory plasmid (InVitrogen) are seeded at

2x10⁶ cells per T75 flask in Complete Medium, containing Hams F12 (GIBCOBRL, Life Technologies) medium supplemented with 10% v/v dialysed foetal bovine serum, L-glutamine, and hygromycin (100 μgml^"1), 24 h prior to use. Plasmid DNA is transfected into the cells using

Lipofectamine plus according to the manufacturer's guidelines (InVitrogen). 48 h post transfection, cells are placed into complete medium supplemented with 500 μgml^"1 Zeocin™.

10-14 days post selection, 10 nM Mifepristone (InVitrogen) is added to the culture medium to induce the expression of the receptor. 18 h post induction, cells are detached from the flask using ethylenediamine tetra-acetic acid (EDTA; 1 :5000; InVitrogen), following several washes with PBS, pH 7.4 and are resuspended in Sorting Medium containing Minimum Essential Medium (MEM), without phenol red, and are supplemented with Earles salts and 3% Foetal Clone Il (Hyclone). Approximately 1 x10⁷ cells are examined for receptor expression by staining with a rabbit polyclonal antibody, 4a, raised against the /V-terminal domain of the histamine H3 receptor, are incubated on ice for 60 min, followed by two washes in sorting medium. Receptor bound antibody is detected by incubation of the cells for 60 min on ice with a goat anti rabbit antibody, conjugated with Alexa 488 fluorescence marker (Molecular Probes). Following two further washes with Sorting Medium, cells are filtered through a 50 μrn Filcon™ (BD Biosciences) and then are analysed on a FACS Vantage SE Flow Cytometer fitted with an Automatic Cell Deposition Unit. Control cells are non-induced cells treated in an analogous manner. Positively stained cells are sorted as single cells into 96-well plates, containing Complete Medium containing 500 μgml^"1 Zeocin™ and are allowed to expand before reanalysis for receptor expression via antibody and ligand binding studies. One clone, 3H3, is selected for membrane preparation.

Membrane preparation from cultured cells All steps of the protocol are carried out at 4 ⁰C and with pre-cooled reagents. The cell pellet is resuspended in 10 volumes of homogenisation buffer (50 mM Λ/-2-hydroxyethylpiperazine-Λ/'-2- ethanesulfonic acid (HEPES), 1 mM ethylenediamine tetra-acetic acid (EDTA), pH 7.4 with KOH, supplemented with 10^"6 M leupeptin (acetyl-leucyl-leucyl-arginal; Sigma L2884), 25 μgml^"1 bacitracin (Sigma B0125), 1 mM phenylmethylsulfonyl fluoride (PMSF) and 2χ10^"6 M pepstain A (Sigma)). The cells are then homogenised by 2 x 15 second bursts in a 1 litre glass Waring blender, followed by centrifugation at 500 g for 20 min. The supernatant is then spun at 48,000 g for 30 min. The pellet is resuspended in homogenisation buffer (4χ the volume of the original cell pellet) by vortexing for 5 sec, followed by homogenisation in a Dounce homogeniser (10-15 strokes). At this point the preparation is aliquoted into polypropylene tubes and stored at -80 ⁰C.

Histamine H3 functional antagonist assay

For each compound being assayed, in a solid white 384 well plate, is added:-

(a) 0.5 μl of test compound diluted to the required concentration in DMSO (or 0.5 μl DMSO as a control); (b) 30 μl bead/membrane/GDP mix which is prepared by mixing Wheat Germ Agglutinin Polystyrene LeadSeeker© (WGA PS LS) scintillation proximity assay (SPA) beads with membrane (prepared in accordance with the methodology described above) and diluting in assay buffer (20 mM Λ/-2-hydroxyethylpiperazine-Λ/'-2-ethanesulfonic acid (HEPES) + 100 mM NaCI + 10 mM MgCI₂, pH 7.4 NaOH) to give a final volume of 30 μl which contains 5 μg protein, 0.25 mg bead per well and 10 μM final assay concentration of guanosine 5' diphosphate (GDP) (Sigma, diluted in assay buffer) incubating at room temperature for 60 min on a roller;

(c) 15 μl 0.38 nM [³⁵S]-GTPDS (Amersham; Radioactivity concentration = 37 MBqml^"1; Specific activity = 1 160 Cimmol^"1), histamine (at a concentration that results in the final assay concentration of histamine being ECso)-

After 2-6 h, the plate is centrifuged for 5 min at 1500 rpm and counted on a Viewlux counter using a 613/55 filter for 5 minplate^"1. Data is analysed using a 4-parameter logistic equation. Basal activity is used as minimum, i.e. histamine not added to well.

Intranasal Challenge Method: Whole Body Plethysmography (a)Sensitisation

Female Dunkin-Hartley guinea pigs 150-25Og are sensitised twice daily for 5 days (week 1 ) with ovalbumin (OVA) and aluminium hydroxide (AI(OH)₃ or Alum) in physiological saline, 25μl/nostril. Solution is made up at 20μg/ml OVA, 180mg/ml Alum. During weeks 2 and 3 animals receive 25μl/nostril of OVA (5mg/ml) once daily. During Week 4 guinea pigs will be entered into study but are continually sensitized as per weeks 2 and 3 until the day before dosing with compound or vehicle.

(b) Compound/Vehicle Pretreatment

Pretreatment with test compound is performed at various times prior to histamine challenge. Efficacy dose-response curves are determined 1 hr and/or 3hr after dosing whereas duration of action may be studied up to 7 days post dose. Test compounds are formulated as solutions in 0.9% sterile saline or suspensions in 0.9% sterile saline/tweenδO.

Guinea pigs were anaesthetised with isoflurane (5%, 2-3l/min O₂), placed in a supine position, and 25μl of test compound or vehicle dosed into each nostril using a Gilson pipette. After dosing, animals remain supine for at least 30 seconds during recovery from anaesthesia.

(c) Histamine Challenge Protocol

At 30 minutes before the time of histamine challenge, guinea pigs are dosed with atropine sulphate (Sigma A0257, dissolved in saline), 1 mg/kg i.p. Animals are then placed into whole body plethysmograph systems (Buxco® Electronics) where the parameter PenH area under curve (AUC) is recorded as outlined in HAMELMANN, E., SCHWARZE, J., TAKEDA, K., OSHIBA, A., LARSEN, L., IRVIN, CG. & GELFAND, E.W. (1997) Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156, 766-775. Hamelmann et al. A 10 minute baseline AUC is recorded and if this value is over 1000, the animals are excluded.

After the stipulated pre-dose time has been reached, guinea pigs are re-anaesthetised with isoflurane and dosed with either 10 imM or 15 imM histamine or phosphate-buffered saline (PBS), (25μl per nostril). On recovery from anaesthesia animals are returned to the individual plethysmograph chambers and 4x10 min consecutive PenH AUC recordings are made. These recordings are summed to give a cumulative AUC over 40 mins post histamine challenge for each animal. Data are analysed using ANOVA with post-hoc Fishers LSD test (general linear models, Statistica®) and finally Hochberg adjustment. Inhibition of histamine-induced congestion is determined by statistically significant differences between the mean responses of compound pre- treated groups compared to the vehicle pre-treated, histamine-challenged group.

CNS penetration

(i) CNS penetration by bolus administration

Compounds are dosed intravenously at a nominal dose level of 1 mgkg^"1 to male CD Sprague Dawley rats. Compounds are formulated in 5% DMSO/45% PEG200/50% water. Blood samples are taken under terminal anaesthesia with isoflurane at 5 min post-dose and the brains are also removed for assessment of brain penetration. Blood samples are taken directly into heparinised tubes. Blood samples are prepared for analysis using protein precipitation and brain samples are prepared using extraction of drug from brain by homogenisation and subsequent protein precipitation. The concentration of parent drug in blood and brain extracts is determined by quantitative LC-MS/MS analysis using compound-specific mass transitions.

(ii) CNS penetration following intravenous infusion at steady state

A loading dose of the compounds is given to male CD Sprague Dawley rats at a nominal dose level of 0.4 mgkg^"1. The compounds are then infused intravenously for 4 h at a nominal dose level of 0.1 mgkg^"1h^"1. Compounds are formulated in 2% DMSO/30% PEG200/68% water. Serial or terminal blood samples are taken at 0.5, 1.5, 2.5, 3, 3.5 and 4 h post dose. The final blood sample is collected under terminal anaesthesia with isoflurane and the brains are also removed for assessment of brain penetration. Blood samples are taken directly into heparinised tubes. Blood samples are prepared for analysis using protein precipitation and brain samples are prepared using extraction of drug from brain by homogenisation and subsequent protein precipitation. The concentration of parent drug in blood and brain extracts is determined by quantitative LC-MS/MS analysis using compound-specific mass transitions.

Rat pharmacokinetics Compounds are dosed to male CD Sprague Dawley rats by single intravenous or oral administration at a nominal dose level of 1 mgkg^"1 and 3 mgkg^"1 respectively. Compounds are formulated in 5% DMSO/45% PEG200/50% water. An intravenous profile is obtained by taking serial or terminal blood samples at 0.083, 0.25, 0.5, 1 , 2, 4, and 7 h post dose (for some studies 12 and 24 h samples may be taken). An oral profile is obtained by taking serial or terminal blood samples at 0.25, 0.5, 1 , 2, 4, 7 and 12 h post dose (for some studies 24 and 30 h samples may be taken). Blood samples are taken directly into heparinised tubes. Blood samples are prepared by protein precipitation and subjected to quantitative analysis by LC-MS/MS using compound-specific mass transitions. Drug concentration-time profiles are generated and non-compartmental PK analysis used to generate estimates of half-life, clearance, volume of distribution and oral bioavailability.

Dog pharmacokinetics

Compounds are dosed to male Beagle dogs by single intravenous or oral administration at a nominal dose level of 1 mgkg^"1 and 2 mgkg^"1 respectively. The study is carried out according to a crossover design such that the same dog is used for both dosing events and the dosing events occurred 1 week apart. Compounds are formulated in 5% DMSO/45% Peg200/50% water. An intravenous profile is obtained by taking serial blood samples at 0.083, 0.25, 0.5, 0.75, 1 , 2, 4, 6 and 12 h post dose (for some studies 24 h samples may be taken). An oral profile is obtained by taking serial blood samples at 0.25, 0.5, 0.75, 1 , 2, 4, 6, 12 and 24 h post dose. Blood samples are taken directly into heparinised tubes. Blood samples are prepared by protein precipitation and subjected to quantitative analysis by LC-MS/MS using compound-specific mass transitions. Drug concentration-time profiles are generated and non-compartmental PK analysis used to generate estimates of half-life, clearance, volume of distribution and oral bioavailability.

Results

In these or similar biological assays, the following data were obtained for the compound of Example

1 and various salts thereof:

(i) Compound of Example 1 had an average pKi (pKb) at H1 of greater than approximately 7.5.

Compound of Example 1 had an average pA2 value of greater than approximately 8. (ii) Compound of Example 1 had an average pKi (pKb) at H3 of less than approximately 6.5.

(iii) Compound of Example 1 exhibited at one or more time points a longer duration of action than azelastine in the histamine H1 functional antagonist assay.

(iv) In the intranasal challenge model compound of Example 1 dosed intranasally at 1 mg/ml either 1 hr or 24hr before histamine challenge significantly (p<0.05) inhibited the response at both timepoints. In the same model, azelastine failed to show a similar duration of action when administered at the same concentration. In another experiment compound of Example 1 dosed intranasally at 1 mg/ml and at 10mg/ml either 3hr or 24hr before histamine challenge significantly

(p<0.05) inhibited the response at the 3hr timepoint and not the 24 hr timepoint.

Preparation of 6α, 9α-Difluoro-17α-r(2-furanylcarbonyl)oxyl-11 β4ivdroxy-16α-methyl-3-oxo- androsta-1.4-diene-17β-carbothioic acid S-fluoromethyl ester

The preparation of 6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate), solvates and polymorphs thereof including polymorphic Form 1 , and biological activity thereof, are disclosed in International Patent Application WO02/12265 and International Patent Application WO03/066024 incorporated fully herein by reference.

Example Compositions The aqueous pharmaceutical compositions of the invention may be prepared according to the following general method:

Where appropriate, the tonicity adjusting agent(s) is charged into a suitable mixing vessel containing purified water and dissolved with stirring.

The suspending/thickening agent(s) is then charged into the mixing vessel and dispersed throughout the solution. The resulting suspending vehicle is allowed to hydrate for an appropriate period of time to ensure cross-linkage and gelation, which may take 60 minutes or longer. Preservative(s) is pre-dissolved in purified water in a separate vessel, optionally with heating, for example to 50-60 ⁰C depending on the preservative chosen, to aid dissolution, and then added to the thickened tonicity adjusting agent(s) solution with continuous stirring.

Buffering agents, if included, are dissolved in a minimum amount of purified water, optionally heated, for example to about 50-60 ⁰C as appropriate depending on the buffering agents chosen, and stirred to dissolve in separate containers. The separate solutions are combined, mixed well and then added to the bulk solution with continuous stirring.

In a separate mixing vessel, the wetting agent(s) is mixed with purified water which optionally may be heated, for example to about 50-60 ⁰C as appropriate depending on the wetting agent(s) chosen, and stirred to dissolve. A slurry or solution of active compound(s) is then prepared by adding the resultant wetting agent(s) solution to the active compound(s), which may be particle size reduced for example micronised, and mixed prior to homogenising or refining.

Additionally, in a separate mixing vessel, additional preservative(s), if needed, may be mixed with purified water and stirred to dissolve.

Following the dispersion and refining of the slurry or solution of active compound(s) it is added to the mixing vessel containing the suspending/thickening agent and dispersed with stirring. Following the addition of the slurry of active compound(s), any additional preservative may be added to the bulk suspension/solution and dispersed with continuous stirring. Finally, the suspension is made to its final mass by adding water and stirred.

Co-solvent(s), if included, may be added before or after the addition of the buffering agents. Alternatively, the co-solvent(s) may be added during the formation of the drug slurry or solution.

Preservative(s), if included, may be added before or after the addition of the suspending/thickening agent(s).

Fluticasone furoate is used in its unsolvated form as polymorphic Form 1.

Λ/-[2-((2R)-2-{[4-[(4-Chlorophenyl)methyl]-1-oxo-2(1H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4- (methyloxy)butanamide is used in the form of its free base or in the form of the L-tartrate salt.

Example Composition 1

^* Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -0X0-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl) ethyl]-4- (methyloxy)butanamide is used in the form of the free base.

Example Composition 1 may be made according to the following procedure:

Approximately 200 ml. of water is added to a tared beaker. The xyltiol is added with stirring (Silverson mixer) until dissolved. In a separate vessel, the EDTA is dissolved in approximately 5 ml_, using heat (without boiling) to aid dissolution. The EDTA solution is then added to the xylitol solution. With mixing (Silverson mixer), the Avicel™ CL61 1 is added to the xylitol and EDTA solution. The speed of the mixer is adjusted, as required, to maintain a vortex. After addition of the Avicel™ CL61 1 , and once it is well dispersed, the mixture is allowed to stand for at least 60 minutes to ensure hydration of the Avicel™ CL61 1 . In one vessel, the citric acid is dissolved in approximately 10 ml. of water, and, in another vessel, the sodium citrate is dissolved in 10 mL of water. The vessels are heated with stirring (without boiling) to aid dissolution. Once the citric acid and sodium citrate are dissolved, they are combined and mixed thoroughly. The buffer is then added to the bulk suspension with mixing (Silverson mixer). In another vessel, the polysorbate 80 is dissolved in approximately 10 mL of water with heat and stirring (without boiling) to aid dissolution. The propylene glycol is added to the polysorbate 80 solution. To Λ/-[2-((2R)-2-{[4-[(4- chlorophenyl)methyl]-1 -oxo-2(1 /-/)-phthalazinyl]methyl}-1 -pyrrolidinyl)ethyl]-4-(methyloxy)butanamide (in the form of the free base) is added approximately 3-5 mL of the propylene glycol and polysorbate 80 solution. The drug substance is wetted by mixing with a spatula or alternatively placing in a sealed container and shaking on a shaker until all the drug is wetted. The drug mixture is homogenised (small Silverson head or small Ultra Turrax) to disperse and/or dissolve the drug substance for approximately 2-3 minutes. The drug mixture is added to the bulk suspension and mixed (Silverson mixer). Any remaining polysorbate 80 solution and propylene glycol is added to the bulk suspension. The drug mixture vessel, polysorbate 80 vessel and propylene glycol vessel are rinsed with water (small Silveron head or Ultra Turrax) and the rinsings are added to the bulk solution. In another vessel, the potassium sorbate is dissolved in approximately 5 ml. of water with stirring and heat (without boiling) to aid dissolution. The potassium sorbate solution is added to the bulk solution with stirring (Silverson mixer). The tared beaker is made up to the final weight with water (50Og) and mixed for a further 3 minutes. The pH is measured (target pH = 4.5, with limits of 4.0 to 5.0).

Example Composition 2

Example Composition 2 may be prepared by a generally simiar method to the methods described above.

* Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -0X0-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl) ethyl]-4- (methyloxy)butanamide is used in the form of the free base

Example Composition 3

Example Composition 3 may be prepared by a generally simiar method to the methods described above.

Example Composition 4

Example Composition 4 may be prepared by a generally simiar method to the methods described above.

^* Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl) ethyl]-4- (methyloxy)butanamide is used in the form of the free base Example Composition 5

Example Composition 5 may be prepared by a generally simiar method to the methods described above.

Example Composition 6

Example Composition 6 may be prepared by a generally simiar method to the methods described above.

^* Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl) ethyl]-4- (methyloxy)butanamide is used in the form of the free base

Example Composition 7

Example Composition 7 may be prepared by a generally simiar method to the methods described above.

Example Composition 8

Example Composition 8 may be prepared by a generally simiar method to the methods described above.

Example Composition 9

Example Composition 9 may be prepared by a generally simiar method to the methods described above.

^* Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -0X0-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl) ethyl]-4- (methyloxy)butanamide is used in the form of the free base. Example Composition 10

Example Composition 10 may be prepared by a generally simiar method to the methods described above.

Example Composition 11

Example Composition 1 1 may be prepared by a generally simiar method to the methods described above.

1 -0X0-2(1 H)-phthalazinyl]methyl}-1- 0.9% pyrrolidinyl) ethyl]-4-

(methyloxy)butanamide, as free base^*

Purified Water to 100%

Example Composition 12

Example Composition 12 may be prepared by a generally simiar method to the methods described above.

Example Composition 13

Example Composition 13 may be prepared by a generally simiar method to the methods described above.

Example Composition 14

Example Composition 14 may be prepared by a generally simiar method to the methods described above.

^* Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -0X0-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl) ethyl]-4- (methyloxy)butanamide is used in the form of the free base. In Example Compositions 1 to 14, the concentation of Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1- oxo-2(1 /-/)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy) butanamide is given as the free base, which concentrations are 0.025% (w/w), 0.05% (w/w), 0.1 % (w/w), 0.25% (w/w), 0.5% (w/w) and 0.9% (w/w), based on the total weight of the composition. Alternatively, if desired, Λ/-[2-((2R)-2- {[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy) butanamide may be used in micronised form.

It will be appreciated that Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1H)-phthalazinyl]methyl}- 1-pyrrolidinyl) ethyl]-4-(methyloxy)butanamide may be used in the form of a pharmaceutically acceptable salt at an appropriate concentration, depending on the salt chosen, such as to provide the desired concentration of free base.

Example compositions may be filled into suitable containers depending on the chosen route of administration. For intransal administration, suitable containers are described hereinabove and typically are made of plastics and dispense 50 to 100 μl_ of composition per actuation.

Claims

1. An aqueous pharmaceutical composition which comprises (i) a compound which is Λ/-[2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1H)- phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4-(methyloxy)butanamide

or a pharmaceutically acceptable salt thereof; and

(ϋ) a compound which is 6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl- 3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate)

or a solvate thereof.

2. An aqueous pharmaceutical composition according to claim 1 which comprises 0.005% to 2% (w/w) based on the total weight of the composition of Λ/-[2-((2R)-2-{[4-[(4- chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 -pyrrolidinyl)ethyl]-4-(methyloxy) butanamide, or a pharmaceutically acceptable salt thereof.

3. An aqueous pharmaceutical composition according to claim 2 which comprises 0.025% to 0.9% (w/w) based on the total weight of the composition of Λ/-[2-((2R)-2-{[4-[(4- chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl]methyl}-1 -pyrrolidinyl)ethyl]-4-(methyloxy) butanamide, or a pharmaceutically acceptable salt thereof.

4. An aqueous pharmaceutical composition according to claim 2 or claim 3, which comprises 0.01 to 1 % (w/w) based on the total weight of the composition of fluticasone furoate, or a solvate thereof.

5. An aqueous pharmaceutical composition according to claim 4, which comprises about 0.05% (w/w) based on the total weight of the composition of fluticasone furoate, or a solvate thereof.

6. An aqueous pharmaceutical composition according to any of claims 1 to 5 further comprising a) a suspending/thickening agent; b) a preservative; c) a wetting agent; and optionally d) a tonicity adjusting agent.

7. An aqueous pharmaceutical composition according to claim 6 which further comprises a co- solvent.

8. An aqueous pharmaceutical composition according to claim 6 or claim 7 which comprises 1.5% to 2.4% (w/w) based on the total weight of the composition of a suspending/thickening agent.

9. An aqueous pharmaceutical composition according to any of claims 6 to 8 wherein the suspending/thickening agent comprises microcrystalline cellulose and/or carboxy methylcellulose sodium.

10. An aqueous pharmaceutical composition according to any of claims 6 to 9, which comprises 0.001 to 1 % (w/w) based on the total weight of the composition of a preservative.

11. An aqueous pharmaceutical composition according to claim 10, which comprises 0.015% to 0.3% (w/w) based on the total weight of the composition of a preservative.

12. An aqueous pharmaceutical composition according to any of claims 6 to 1 1 , wherein the preservative comprises disodium ethylenediamine-tetraacetate (EDTA) and/or potassium sorbate.

13. An aqueous pharmaceutical composition according to claim 12 wherein the preservative comprises about 0.015% disodium ethylenediamine-tetraacetate (EDTA) and about 0.3% potassium sorbate.

14. An aqueous pharmaceutical composition according to any of claims 6 to 13, which comprises 0.01 to 0.05% (w/w) based on the total weight of the composition of a wetting agent.

15. An aqueous pharmaceutical composition according to claim 14 which comprises about 0.025% (w/w) based on the total weight of the composition of a wetting agent.

16. An aqueous pharmaceutical composition according to any of claims 6 to 15 wherein the wetting agent comprises polyoxyethylene (20) sorbitan monooleate (Polysorbate 80).

17. An aqueous pharmaceutical composition according to any of claims 6 to 16, which comprises 0.1 to 10% (w/w) based on the total weight of the composition of a tonicity adjusting agent.

18. An aqueous pharmaceutical composition according to claim 17, which comprises about 0.75% (w/w) based on the total weight of the composition of a tonicity adjusting agent.

19. An aqueous pharmaceutical composition according to any of claims 6 to 18, wherein the tonicity adjusting agent comprises xylitol.

20. An aqueous pharmaceutical composition according to any of claims 7 to 19, which comprises 0.1 to 17.5% (w/w) based on the total weight of the composition of a co-solvent.

21. An aqueous pharmaceutical composition according to claim 20 which comprises 0.1 , or from 1.5 to 2.5% (w/w) based on the total weight of the composition of a co-solvent.

22. An aqueous pharmaceutical composition according to any of claims 7 to 21 , wherein the co- solvent is propylene glycol.

23. An aqueous pharmaceutical composition according to any of claims 6 to 22, further comprising a buffering agent.

24. An aqueous pharmaceutical composition according to any of claims 6 to 23, which is isotonic with fluids of the nasal cavity.

25. An aqueous pharmaceutical composition according to any of claims 6 to 23, which is isotonic with fluids of the eye.

26. An aqueous pharmaceutical composition according to any of claims 1 to 25, which is an aqueous suspension.

27. An aqueous pharmaceutical composition according to any of claims 1 to 25 which is an aqueous solution.

28. An aqueous pharmaceutical composition according to any of claims 1 to 27 comprising Λ/-[2- ((2R)-2-{[4-[(4-chlorophenyl)methyl]-1 -oxo-2(1 H)-phthalazinyl] methyl}-1-pyrrolidinyl)ethyl]-4-

(methyloxy)butanamide in the form of the free base.

29. An aqueous pharmaceutical composition according to any of claims 1 to 27 comprising fluticasone furoate in unsolvated form.

30. An aqueous pharmaceutical composition according to claim 29 comprising fluticasone furoate, polymorphic Form 1.

31. An aqueous pharmaceutical composition which is a composition as described in any of Examples 1 to 14.

32. A container comprising an aqueous pharmaceutical composition according to any of claims 1 to 31 suitable for delivering said composition to the nasal cavities.

33. A container comprising an aqueous pharmaceutical composition according to any of claims 1 to 31 suitable for delivering said composition to the eye.

34. An aqueous pharmaceutical composition according to any of claims 1 to 31 for use in the treatment of inflammatory and/or allergic diseases.

35. An aqueous pharmaceutical composition according to claim 34 for use in the treatment of allergic rhinitis.

36. An aqueous pharmaceutical composition according to claim 34 or claim 35 for use in treatment, once per day.

37. The use of an aqueous pharmaceutical composition according to any of claims 1 to 31 in the manufacture of a medicament for the treatment of inflammatory and/or allergic diseases.

38. The use according to claim 37, for treatment once per day.

39. The use according to claim 37 or claim 38, for the treatment of allergic rhinitis.

0. A method for the treatment (or prophylaxis) of inflammatory and/or allergic diseases which method comprises administering to a patient in need thereof a pharmaceutically effective amount of an aqueous pharmaceutical composition which comprises a compound which is Λ/- [2-((2R)-2-{[4-[(4-chlorophenyl)methyl]-1-oxo-2(1H)-phthalazinyl]methyl}-1-pyrrolidinyl)ethyl]-4- (methyloxy)butanamide or a pharmaceutically acceptable salt thereof and a compound which is fluticasone furoate or a solvate thereof.