WO2010018484A1 - New uses of diisopropylamine derivatives - Google Patents

Abstract

The invention provides a diisopropylamine derivative selected from: (a) a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof; and (b) a pharmaceutically acceptable ester prodrug of the compound of formula I, and its pharmaceutically acceptable salts and solvates; for use in the treatment of stress urinary incontinence or mixed urinary incontinence. A preferred diisopropylamine derivative is fesoterodine, or a pharmaceutically acceptable salt thereof.

Description

New uses of diisopropylamine derivatives

This invention relates to new medical uses of certain diisopropylamine derivatives, including fesoterodine, for the treatment of stress urinary incontinence and/or mixed urinary incontinence.

Urinary incontinence (Ul) as defined by the International Continence Society is the complaint of any involuntary leakage of urine. It is a common and socially debilitating problem. Ul can be clinically classified as:

(a) stress urinary incontinence (SUI), which is incontinence on effort, exertion, coughing or sneezing;

(b) urge urinary incontinence (UUI), which is involuntary leakage of urine which is accompanied by, or immediately preceded by, urinary urgency; and

(c) mixed urinary incontinence (MUI), which is a combination of SUI and UUI.

The EPINCONT survey conducted in 27,936 women aged 20 years and above in Norway, revealed an overall prevalence of Ul of 25% of whom 50%, 36% and 11 % had SUI, MUI and UUI, respectively.

In normal continence in women the storage of urine during bladder filling is facilitated by a sympathetic nervous system reflex, which increases tension and constriction of the urinary sphincter and inhibits parasympathetic bladder efferents. During normal voiding, increases in parasympathetic transmissions to the bladder initiate detrusor contraction. Incontinence can therefore occur either as a result of an incompetent sphincter, or abnormal or involuntary detrusor contractions, or indeed a combination of the two.

Urge urinary incontinence (UUI) is a condition characterized by involuntary leakage of urine which is accompanied by, or immediately preceded by, urinary urgency (defined as a sudden compelling desire to pass urine which is difficult to defer). The corresponding urodynamic observation of urge urinary incontinence is detrusor overactivity incontinence: incontinence due to an involuntary detrusor contraction.

Stress urinary incontinence (SUI) is the complaint of involuntary leakage on effort or exertion or on sneezing or coughing . It is characterized by urethral underactivity/dysfunction. The corresponding urodynamic observation is the involuntary leakage of urine during increased abdominal pressure, in the absence of a detrusor contraction.

Mixed urinary incontinence (MUI) is the complaint of involuntary leakage associated with urgency and also with exertion, effort, sneezing or coughing. The ICS do not define a specific corresponding urodynamic observation and, for reasons described below, it is incorrect to conclude that both detrusor overactivity and urodynamic stress incontinence be present for a urodynamic diagnosis of MUI to be made.

Ul affects approximately 13 million Americans and is at least as prevalent as other chronic diseases including asthma and peptic ulcer disease. Although not life threatening, it results in a significant detrimental effect on health related quality of life and has a considerable health economic impact. The direct medical costs for the management of urinary incontinence are estimated to be $10-16 billion per annum. Urinary incontinence is associated with significant morbidity and is correlated with an increased risk of hospitalization and admission to a nursing home.

Of the subtypes of urinary incontinence MUI is the most bothersome. This symptom burden is thought to be due to the unpredictability of incontinence episodes resulting in a perception of lack of 'bladder control'. The greater perceived severity of MUI reported by women may be due to the presence of 2 co-existent pathologies, one bladder, and one urethral or may simply be due to the presence of more severe stress incontinence. The absence of a strong correlation between reported symptoms and urodynamic observations, particularly the absence of detrusor overactivity, provides supporting evidence for the latter hypothesis. It has been observed that incontinence episode frequency observed in women with MUI is higher than in those women reporting SUI alone.

There are currently no approved drugs for the treatment of SUI or MUI in the US. Duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), has been shown to be effective in the treatment of women who have stress-predominant urinary incontinence (SUI), and also more recently in the treatment of women with symptoms of bladder overactivity. However it has a significant adverse event burden that may limits its clinical utility. Therefore, SUI is a largely under diagnosed and under treated disease. An unmet medical need exists for a pharmacotherapy that is efficacious and well tolerated for the treatment of SUI.

Drug treatment of UUI with antimuscarinic (anticholinergic) agents only addresses one component of MUI. There are currently no approved drugs for the treatment of MUI. Treatment is typically determined by the most bothersome presenting condition. Thus a patient with urge predominant MUI may be started on a treatment for UUI, e.g. anticholinergic therapy. However it is clear that this only addresses part of their symptom complex leaving the other component inadequately addressed. Moreover recent evidence suggests that SUI and MUI may share a common, urethral pathology insofar as leakage in SUI and MUI may occur as a result of a reduced ability to increase intra-urethral pressure during bladder filling. This may result in a breakthrough of urethral relaxation leading to a detrusor contraction and subsequent leakage. If this event is associated with the sensation of urgency, a diagnosis of UUI or MUI is commonly made albeit that the primary pathology is arising not from the bladder but, like SUI, actually from a dysfunctional urethra. Thus there is clearly an unmet medical need for an effective, well tolerated treatment for SUI and MUI.

WO 89/06644 (and its equivalent EP-A-325571 ) disclose a group of diisopropylamine derivatives, including tolterodine [R-(+)-Λ/,Λ/-diisopropyl-3-(2- hydroxy-5-methylphenyl)-3-phenylpropylamine, see Example 22 and claim 7]:

The compounds of WO 89/06644 are indicated in the treatment of "cholin- mediated disorders" such as urinary incontinence. Tolterodine is a muscarinic receptor antagonist and was developed for the treatment of overactive bladder. It gained its first marketing approval (as the tartrate salt) in 1997 and was launched in many markets in the following years under the trade marks DETROL and DETRUSITOL.

WO 94/11337 discloses a further group of diisopropylamine derivatives, including R-(+)-Λ/,Λ/-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine (see Example 1 ):

This compound is also formed in the body by metabolism of tolterodine. The compounds of WO 94/11337 are indicated in the treatment of "acetylcholine- mediated disorders", such as urinary incontinence.

WO 99/58478 (and its priority document EP-A-0957073) discloses a further group of diisopropylamine derivatives, including fesoterodine [R-(+)-isobutyric acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester, see page 62 lines 15-16 of WO 99/58478]:

The compounds of WO 99/58478 are indicated to be useful as prodrugs for treatment of urinary incontinence and other spasmogenic conditions that are caused by muscarinic mechanisms. Fesoterodine gained its first marketing approval (as the hydrogen fumarate salt) in 2007 and was launched under the trade mark TOVIAZ.

According to Booth [see 'New drug treatments are available for stress urinary incontinence', Pharmacy in Practice (February 2005): 64-69, especially 68] antimuscarinic agents such as oxybutynin and tolterodine are the most widely used agents in the treatment of urinary urge incontinence and stress urinary incontinence, but their efficacy in the treatment of stress urinary incontinence is poor. Booth further states that their mode of action is to inhibit muscarinic receptors and relax the detrusor muscle, which is of benefit in urinary urge incontinence.

Zinner et al [see 'Pharmacotherapy for Stress Urinary Incontinence', Drugs 2004, 64(14) (2004): 1503-1516, especially 1509] state that pharmacotherapy of stress urinary incontinence with tolterodine has not proven to be any more effective than placebo.

Staskin et al [see 'Short- and long-term efficacy of solifenacin treatment in patients with symptoms of mixed urinary incontinence', BJU International (2006), 97, 1256-1261] report a trial of the antimuscarinic drug solifenacin in women suffering from mixed urinary incontinence. Significant reductions in OAB-related frequency, incontinence and urgency were reported after 12 weeks. However, patients with a history of stress-predominant urinary incontinence were excluded from the study. In addition, the authors did not contemplate the possibility of solifenacin having an effect on urethral pressure, and so being of use in stress urinary incontinence.

International Patent Application WO 2006/066509 discloses injectable sustained release microspheric preparations of 3,3-diphenylpropylamine derivatives as muscarinic receptor antagonists. The formulation is indicated for "treatment of diseases related to the muscarinic receptor and unstable or overactive bladder such as urgency or stress urinary incontinence, urinary urgency or frequency, etc." However, it appears that the inclusion of "stress urinary incontinence" in this list is accidental because stress urinary incontinence is not part of overactive bladder syndrome, and is not considered to be mediated by muscarinic receptors by those skilled in the art.

It has now been found that R-(+)-Λ/,Λ/-diisopropyl-3-(2-hydroxy-5- hydroxymethylphenyl)-3-phenylpropylamine mentioned above (disclosed in WO 94/11337), and certain ester prodrugs thereof, are useful in the treatment of stress urinary incontinence. This is surprising because, as exemplified by Booth and Zinner et al:

• those skilled in the art are aware that tolterodine is not efficacious in the treatment of stress urinary incontinence;

• those skilled in the art believe that muscarinic receptor antagonists are useful in the treatment of overactive bladder; and • those skilled in the art do not expect a drug indicated as a muscarinic receptor antagonist to be useful in the treatment of stress urinary incontinence.

Therefore, according to a first aspect of the present invention, there is provided a diisopropylamine derivative selected from: (a) a compound of formula I,

or a pharmaceutically acceptable salt or solvate thereof; and (b) a pharmaceutically acceptable ester prodrug of the compound of formula I, and its pharmaceutically acceptable salts and solvates; for use in the treatment of stress urinary incontinence.

As the diisopropylamine derivatives mentioned above are already known to be useful in the treatment of urgency symptoms, and mixed urinary incontinence is a mixture of urgency symptoms and stress urinary incontinence, the diisopropylamine derivatives mentioned above are likely to be useful in the treatment of mixed urinary incontinence also, and this use forms a second aspect of the invention. This would be an advantage because a single drug could be used to treat both urgency symptoms and stress urinary incontinence, rather than needing two medicaments as at present.

In this second aspect of the invention, the treatment of the stress urinary incontinence component of mixed urinary incontinence is of particular interest.

Thus, the invention further provides:

• Use of a diisopropylamine derivative, as defined above, in the manufacture of a medicament for the treatment of stress urinary incontinence;

• A method of treatment of stress urinary incontinence which comprises administering a therapeutically effective amount of a diisopropylamine derivative, as defined above, to a patient in need of such treatment; • Use of a diisopropylamine derivative, as defined above, in the manufacture of a medicament for the treatment of mixed urinary incontinence; and

• A method of treatment of mixed urinary incontinence which comprises administering a therapeutically effective amount of a diisopropylamine derivative, as defined above, to a patient in need of such treatment.

The invention further provides the uses and methods defined above, provided that the diisopropylamine derivative is not in the form of an injectable sustained release microspheric preparation.

Preferred features of the present invention include:

(i) the diisopropylamine derivative is a compound of formula Ib,

wherein R¹ and R² are each independently selected from H and Ci_-6 alkanoyl, with the proviso that R¹ and R² are not both H; or a pharmaceutically acceptable salt or solvate thereof;

(ii) the diisopropylamine derivative is a compound of formula Ia,

wherein R¹ represents H or Ci_-6 alkanoyl (more preferably isobutanoyl, i.e. the diisopropylamine derivative is fesoterodine); or a pharmaceutically acceptable salt or solvate thereof;

(iii) the diisopropylamine derivative is R-(+)-isobutyric acid 2-(3- diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester hydrogen fumarate (i.e. fesoterodine hydrogen fumarate); and

(iii) the diisopropylamine derivative is selected from the (R)-enantiomers of: acetic acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-acetoxymethylphenyl ester; n-butyric acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester; isobutyric acid 2-(3-diisopropylamino-1 -phenylpropyl)-4- isobutyryloxymethylphenyl ester; n-butyric acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-n-butyryloxymethylphenyl ester; propionic acid 2-(3-diisopropylamino-1 -phenylpropyl)-4- propionyloxymethylphenyl ester; propionic acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester; and acetic acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester; and their pharmaceutically acceptable salts and solvates. These compounds are described in claim 8 of US Patent 7,384,980. In the above definitions, Ci_-6 alkanoyl means a Ci_-6 alkyl(CO)- group wherein, if the alkyl group contains the requisite number of carbon atoms, it can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, sec-butyl and t-butyl.

Pharmaceutically acceptable salts of the diisopropylamine derivatives include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of the diisopropylamine derivatives may be prepared by one or more of three methods: (i) by reacting the the diisopropylamine derivative with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the the diisopropylamine derivative using the desired acid or base; or

(iii) by converting one salt of the the diisopropylamine derivative to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

The diisopropylamine derivative may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

The diisopropylamine derivative may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the diisopropylamine derivative and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

The term "pharmaceutically acceptable ester prodrug" means an ester derivative of a compound of the formula I which can, when administered into or onto the body, be converted into a compound of the formula I having the desired activity, for example, by hydrolytic cleavage. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing a hydroxyl group present in the compounds of formula I with an ester moiety known to those skilled in the art as ester 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

An example of an ester prodrug in accordance with the invention is where the hydrogen atom in a hydroxyl group of a compound of the formula I is replaced with a CrC₆ alkanoyl group, e.g. ethanoyl, propanoyl, n-butanoyl, isobutanoyl, etc. Usually, the diisopropylamine derivatives will be administered as a formulation in association with one or more pharmaceutically acceptable excipients or carriers. The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for delivering the diisopropylamine derivatives and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).

Preferably, the diisopropylamine derivatives are administered orally, and therefore the formulations, uses, methods and products of the invention will be suitable for, or involve, oral administration. Oral administration may involve swallowing, so that the diisopropylamine derivative enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the diisopropylamine derivative enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), fast dispersing/fast dissolving/fast disintegrating dosage forms (such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11 (6), 981 -6 (2001 )), ovules, sprays and liquid formulations. Tablets and capsules are preferred.

For tablet dosage forms, depending on dose, the diisopropylamine derivative may make up from 1 wt% to 80 wt% of the dosage form, more typically from 1 wt% to 60 wt% of the dosage form. In addition to the diisopropylamine derivative, tablets may contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 0 wt% to 25 wt%, preferably from 0 wt% to 20 wt% of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 3 wt% of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glycerol esters of fatty acids, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 0 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 0 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Controlled release tablets, capsules and multi-particulate formulations are preferred. For example, they may be formulated for administration once a day.

Suitable sustained release formulations of fesoterodine, or pharmaceutically acceptable salts thereof, are described in International Patent Application WO 2007/141298. See in particular Tables 1 and 2 on pages 44 and 45 therein.

The diisopropylamine derivatives may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Transdermal devices for administration of fesoterodine and related compounds are described in International Patent Application WO 2004/089346. Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The diisopropylamine derivatives can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The diisopropylamine derivative may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

Suitable dosages of the compounds for the uses of the present invention will depend on the compound concerned, the condition to be treated and the weight of the patient. However, in general, a suitable daily dose of the diisopropylamine derivative is in the range of from 1 to 10 mg, preferably from 4 to 8 mg (especially for fesoterodine, or a pharmaceutically acceptable salt thereof).

The diisopropylamine derivative may be administered in combination with a second therapeutically active ingredient, for example duloxetine (which is indicated in the treatment of stress urinary incontinence). Such combined use may have the advantage that the two components act synergistically to produce an unexpectedly potent effect and/or an unexpectedly favourable level of side- effects in comparison with the corresponding dosage of each of the components on their own. Such combinations may have a longer duration of action, improved selectivity, or other more useful properties compared with the prior art.

According to a further aspect of the invention, there is provided a pharmaceutical formulation comprising a diisopropylamine derivative as defined above; and duloxetine, or a pharmaceutically acceptable salt thereof.

The invention also provides pharmaceutical products comprising a diisopropylamine derivative as defined above; and duloxetine, or a pharmaceutically acceptable salt thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of stress urinary incontinence or mixed urinary incontinence.

Alternative second therapeutically active ingredients in conjunction with which the diisopropylamine derivative may be administered may be selected from:

• a second muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium;

• a PDE-5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1 -piperazinyl- sulphonyl)phenyl]-1 -methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2- methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1 ':6,1]-pyrido[3,4- b]indole-1 ,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1 - yl-1 -sulphonyl )-phenyl]-5-methyl-7-propyl-3H-imidazo[5, 1 -f][1 ,2,4]triazin-4- one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1 -ethyl-3- azetidinyl)-2,6-dihydro-7/-/-pyrazolo[4,3-c/]pyrinnidin-7-one, 5-(5-acetyl-2- propoxy-3-pyridinyl)-3-ethyl-2-(1 -isopropyl-3-azetidinyl)-2,6-dihydro-7/-/- pyrazolo[4,3-c/]pyrinnidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1 - ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3-d]pyrinnidin-7-one, 4-[(3-chloro-4-methoxybenzyl)annino]-2- [(2S)-2-(hydroxymethyl)pyrrolidin-1 -yl]-N-(pyrinnidin-2-ylnnethyl)pynnnidine- 5-carboxamide, and 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1 H- pyrazolo[4,3-d]pyrinnidin-5-yl)-N-[2-(1 -nnethylpyrrolidin-2-yl)ethyl]-4- propoxybenzenesulfonamide;

• an alpha-2-delta ligand such as gabapentin, pregabalin, 3- methylgabapentin, (1 α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)- acetic acid, (3S,5R)-3-aminonnethyl-5-nnethyl-heptanoic acid, (3S.5R)- 3-amino-5-nnethyl-heptanoic acid, (3S,5R)-3-amino-5-nnethyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)- proline, [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3- (1 -aminomethyl-cyclohexyl methyl )-4H-[1 ,2,4]oxadiazol-5-one, C-[1 -(1 H- tetrazol-5-ylmethyl)-cycloheptyl]-nnethylannine, (3S,4S)-(1 -aminonnethyl- 3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-amino-5-nnethyl-nonanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid, (3R,4R,5R)-3- amino-4,5-dinnethyl-octanoic acid, and (3S,5R)-3-aminonnethyl-5- methyloctanoic acid;

• a serotonin reuptake inhibitor such as sertraline, sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone; • a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine (esreboxetine);

• a dual serotonin-noradrenaline reuptake inhibitor (including duloxetine), such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, milnacipran and imipramine;

• a beta-3 agonist, such as YM-178 (mirabegron or 2-amino-N-[4-[2-[[(2R)- 2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]- 4-thiazoleacetamide), solabegron, KUC-7483 (ritobegron or 2-[4-[2-[[(1 S,2R)-2-hydroxy-2-(4- hydroxyphenylj-i -methylethyllaminolethyll^.δ-dimethylphenoxyl-acetic acid) or AK-134;

and pharmaceutically acceptable salts thereof.

The following Scheme A outlines a method for the preparation of fesoterodine hydrogen fumarate and the synthetic steps are described in detail in Examples 1 to 6 that follow.

SCHEME A

acid,

Example 1

Synthesis of (2-hvdroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol

4-(Hydroxymethyl)phenol (100 g, 0.81 mol, 1.0 eq) was stirred with /V-methylpiperazine (202 g, 2.01 mol, 2.5 eq) in toluene (900 ml_, 9 mL/g) and then heated to reflux. Upon reaching reflux, frans-cinnamaldehyde (133 g, 1.01 mol, 1.25 eq) was then added over 3 hours maintaining the reaction mixture at reflux with azeotropic removal of water. Once the addition was complete the reaction mixture was continued to be heated at reflux with removal of water for 2 hours and then some toluene was removed by distilling under reduced pressure, reducing the volume to approximately 600 ml_. The mixture was then allowed to cool to room temperature and ethyl acetate (1.8 L, 18 mL/g) was added. The product solution was then sequentially washed with 2M aqueous hydrochloric acid (1.8 L 18 mL/g), 1 M aqueous hydrochloric acid (700 mL, 7 mL/g), 0.25M aqueous sodium hydrogen carbonate solution (700 mL, 7mL/g) and water (1 L, 10 mL/g). The organic phase was then diluted with toluene (650 mL, 6.5 ml/g) and the mixture distilled down to approximately 600 mL volume. The mixture was cooled to 22°C and stirred for 6 hours. The suspension was cooled to 2⁰C and granulated for a further 2 hours. The slurry was filtered and the cake was washed twice with toluene (300 mL, followed by 100 mL). The resulting pale tan solid was dried in vacuum for 24 hours at up to 60⁰C, to give (2-hydroxy-4- phenyl-3,4-dihydro-2H-chromen-6-yl)methanol (118.6 g, 57% yield). Example 2

Synthesis of 2-r3-(diisopropylamino)-1-phenylpropyll-4- (hydroxvmethyl)phenol

(i) diisopropylamine, methanol (ii) palladium on carbon, hydrogen

(iii) tetrahydrofuran

(2-Hydroxy-4-phenyl-3,4-dihydro-2/-/-chronnen-6-yl)nnethanol (Example 1 , 20O g, 0.78 mol, 1.0 eq) was stirred in methanol (1500 ml_, 7.5 mL/g). Diisopropylamine (236.8 g, 2.34 mol, 3.0 eq) was then added over 15 minutes maintaining the temperature below 4O⁰C. The resulting solution was then stirred for one hour under nitrogen. The catalyst Pd-ESCAT 142 (Trade name - Supplier = Engelhard) [(5% w/w Pd/C paste, ca. 50% water wet) 20 g, 10% w/w] was added and the system purged with nitrogen. The mixture was hydrogenated at 793kPa (115 psi , 7.92 bar) at a temperature of 4O⁰C for 20 hours. The mixture was cooled and purged with nitrogen, then filtered using filter aid and the residue pad was washed with methanol (2 x 400 ml_, 2 x 2 mL/g). The combined filtrate and washings were transferred to a distillation vessel where the product solution was concentrated to 330 ml_ (1.65 mL/g) volume under reduced pressure. Tetrahydrofuran 670 mL, 3.35 mL/g) was added and the mixture re-concentrated to 330 mL (1.65 mL/g) volume. Six further additions of tetrahydrofuran (each of 670 mL, 3.35 mL/g), each followed by a distillation under reduced pressure to 330 mL (1.65 mL/g) volume were performed to remove the excess diisopropylamine and methanol. The mixture was diluted with tetrahydrofuran (1270 mL, 6.35 mL/g) to give a tetrahydrofuran solution of the product 2-[3- (diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol for use in the next step. Quantitative HPLC analysis indicated the crude solution contained 221 g of product (83% yield).

Example 3

Synthesis of (/?)-2-r3-(diisopropylamino)-1-phenylpropyll-4- (hydroxymethyl)phenol (ff)-acetoxy(phenvPacetate

(7?)-(-)-acetoxy(phenyl)acetic acid, tetrahydrofuran

Tetrahydrofuran was added to a tetrahydrofuran solution of 2-[3- (diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol (from Example 2, containing 50 g, 0.146 mol, 1.0 eq) to give a total volume of tetrahydrofuran of 350 ml_ (7 mL/g). In a separate vessel, a solution of (R)-(-)-acetoxy(phenyl)acetic acid (14.17 g, 0.073 mol, 0.5 eq) in tetrahydrofuran (50 ml_, 1 mL/g) was prepared at room temperature. This solution was then added to the solution of 2-[3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol in tetrahydrofuran over 15 minutes followed by a tetrahydrofuran (50 ml_) rinse. The resulting solution was warmed to 55⁰C and seeded with product (50 mg). The resulting slurry was granulated at 55⁰C for 6 hours before cooling to O⁰C and granulating for a further 7 hours. The slurry was filtered and the cake was twice washed/re-slurried with cold tetrahydrofuran (2 x 125 ml_, 2 x 2.5 mL/g). The white solid was dried under reduced pressure at 3O⁰C for 12 hours to give (R)-2- [3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol (R)-acetoxy(phenyl)acetate (33.04 g, 42% yield, 97% ee by chiral HPLC). Example 4

Synthesis of (/?)-2-r3-(diisopropylamino)-1-phenylpropyll-4- (hydroxvmethyl)phenol

i) toluene, aqueous potassium carbonate, water ~, i) toluene

(R)-2-[3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol (R)-acetoxy(phenyl)acetate (Example 3, 30 g, 0.056 mol, 1.0 eq) was slurried in toluene (180 ml_, 6 mL/g) and warmed to 50⁰C. A 10% wt/vol aqueous solution of potassium carbonate (180 ml_, 6 mL/g) was charged maintaining the temperature at 50⁰C. The mixture was stirred vigorously at 50 °C for 6 hours. The two solution phases were allowed to settle and were separated at 50⁰C. The organic phase was washed with water (120 ml_, 4 mL/g) at 50°C. The phases were separated at 50 °C and the toluene volume reduced to 120 mL (4 mL/g) by distillation under reduced pressure. The temperature was adjusted to 60⁰C and then cooled to 40°C over 1 hour. The batch was held at 40°C and then seeded with product (150 mg). The mixture was granulated for 90 minutes at 40⁰C and then cooled to 20°C over 4 hours. The batch was granulated at 20°C for 4 hours. The slurry was then cooled to 2°C over 2 hours and granulated at 2°C for 4 hours. The suspension was filtered, the cake washed with cold toluene (30 mL, 1 mL/g) and the resulting white solid dried at 35°C for 12 hours to give (R)-2- [3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol (16.43 g, 85.9% yield). Example 5

Preparation of (ff)-(+)-isobutyric acid 2-r3-(diisopropylamino)-1- phenylpropyn-4-(hvdroxymethyl)phenvl ester

(i) dichloromethane, isobutyryl chloride

(ii) aqueous sodium carbonate, water

(iii) methyl ethyl ketone

(R)-2-[3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxynnethyl)phenol (Example 4, 50 g, 0.146 mol, 1.0 eq) was dissolved in dichloromethane (400 ml_, 8 mL/g) and then cooled to -12°C. To this was added a solution of isobutyryl chloride (16.15 g, 0.155 mol, 1.04 eq) in dichloromethane (250 ml_, 5 mL/g), maintaining the reaction temperature between -15 and -10⁰C, followed by a vessel and line rinse of dichloromethane (100 ml_, 2 mL/g). The reaction mixture was stirred at - 12°C for 2 hours. A 5% wt/wt aqueous sodium carbonate solution (110 mL, 2.2 mL/g) was then added to the reaction, allowing the temperature to rise towards 0⁰C during the addition and the resulting pH was confirmed to be between pH 7.5 and 8.5. The two phases were allowed to settle and the organic phase was sequentially washed with water (450 mL, 9 mL/g), 5% wt/wt aqueous sodium carbonate solution (450 mL, 9 mL/g) and twice with water (2 x 450 mL, 2 x 9 mL/g). The product solution was then concentrated under reduced pressure to a volume of 260 mL and methyl ethyl ketone (500 mL, 10 mL/g) added. The solution was re-concentrated under reduced pressure to a volume of 260 mL. Two further additions of methyl ethyl ketone (each of 500 mL, 10 mL/g), each followed by a distillation under reduced pressure to 260 mL were performed to remove the dichloromethane. This provided a methyl ethyl ketone solution of the product (f?)-(+)-isobutyric acid 2-[3-(diisopropylamino)-1 -phenylpropyl]-4- (hydroxymethyl)phenyl ester for use in the next step. Quantitative HPLC analysis indicated the solution contained 52.85g of product (88% yield).

Example 6

Preparation of (/?H+)-isobutyric acid 2-r3-(diisopropylamino)-1- phenylpropyll-4-(hvdroxymethyl)phenyl ester hydrogen fumarate

Fumaric acid (14.47 g, 0.125 mol, 0.95 eq) was slurried in methyl ethyl ketone (162 ml_, 3 mL/g) at 20⁰C. A solution of (R)-(+)-isobutyric acid 2-[3- (diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenyl ester (Example 5, 54.03 g, 0.131 mol, 1.0 eq) in methyl ethyl ketone (270 ml_, 5 mL/g) was then added to the slurry of fumaric acid followed by a vessel and line rinse with methyl ethyl ketone (38 mL, 0.7 mL/g). The resulting mixture was warmed to 37°C with agitation for 30 minutes ensuring that all the solids fully dissolved. The solution was filtered into a crystallising vessel, rinsing the vessel and lines with methyl ethyl ketone (70 mL, 1.3 mL/g). The solution was cooled to 20⁰C and seeded with product (0.54 g). After holding the mixture at 20⁰C for 1 hour the slurry was cooled to 5°C and filtered cyclohexane (65 mL, 1.2 mL/g) was added over 1 hour. The mixture was granulated at 5°C for 8 hours and then filtered, washing the cake with a mixture of cyclohexane (65 mL) and methyl ethyl ketone (16 mL), followed by cyclohexane (54 mL), and the product dried under vacuum at 22°C for 16 hours to give (R)-(+)-isobutyric acid 2-[3-(diisopropylamino)-1 - phenylpropyl]-4-(hydroxymethyl)phenyl ester hydrogen fumarate (57.1 g, 82% yield).

Biological Example

The invention is illustrated by the following example, with reference to the accompanying drawings in which:

Figure 1 is a trace showing representative consecutive urethral pressure profiles from a single animal, before and during administration of R-(+)-Λ/,Λ/-diisopropyl- 3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine (SPM 7605, 0.08 mg/kg); and Figure 2 is a graph showing the concentration/effect relationship over the concentration range of SPM 7605 tested.

The following abbreviations may be used:

i.v. = intravenous min = minute(s)

Acute Urethral Pressure Experiments

Adult, female beagle dogs (n= 10, 10-16 kg) were anaesthetised initially with sodium pentobarbitone to induce surgical anaesthesia (30 mg/kg i.v.), and then transferred to α-chloralose anaesthetic (70-100 mg/kg i.v. induction followed by constant infusion to deliver 10-15 mg/kg/h i.v.) for the duration of the experiment. Animals were intubated and respiration maintained at a constant rate of 14 breaths per minute. Tidal volume was adjusted to maintain expired air within normal physiological limits (4.5-5% CO₂, 21 % O₂). Throughout the experiment the animal was maintained at a temperature of approximately 37⁰C using a thermocouple heated blanket (Harvard Apparatus Ltd., Kent, UK).

The right femoral vein and artery were cannulated for administration of compounds, and for blood sampling, respectively. The right brachial vein was cannulated for infusion of anaesthetic and Hartmann's solution (Animalcare Ltd), and the right brachial artery for monitoring of arterial pressure (Millar, 7F, Millar Instruments, US). A midline incision was made in the abdomen, and underlying abdominal tissue and muscle layers were divided with blunt dissection and retracted to expose the bladder. The ureters were cannulated to drain urine from the kidneys throughout the experiment. The dome of the bladder was cannulated (Portex 7G), and the cannula fed through the bladder to the external urethra. This catheter was used to introduce the urethral catheter (Millar SUPC- 380C) into the urethra. The bladder was filled with saline to achieve an intravesical pressure of approximately 8-10 mmHg, and bladder pressure was measured by connecting the bladder catheter to a pressure transducer (Model DTX plus, Becton-Dickenson UK Ltd, Oxford, UK). Following completion of surgery, animals were allowed to stabilise for at least 60 minutes before starting urethral pressure profilometry measurements.

Urethral pressure profilometry (UPP) was measured by withdrawing the Millar pressure transducer through the urethra at a constant rate. This was achieved by attaching the catheter to an infusion pump set to withdraw at a rate of 600 ml/h (Harvard Apparatus Ltd., Kent, UK). At the end of measurement, the catheter was returned to the starting point and measurement repeated. A full profile measurement was obtained approximately every 6 minutes, and readings were taken continuously throughout the experiment. Baseline measurements were performed until 4 consistent measurements were identified, after which drug administration commenced.

Animals received either vehicle or R-(+)-Λ/,Λ/-diisopropyl-3-(2-hydroxy-5- hydroxymethylphenyl)-3-phenylpropylamine free base (SPM 7605) at doses of 0.08 mg/kg or 0.04 mg/kg i.v. Each dose was administered over 60 min. Peak urethral pressure measures were taken throughout the infusion. Following the end of the drug or vehicle infusion peak urethral pressure profiles were measured continuously for a further 120 min from the end of infusion.

Femoral arterial blood samples were taken for determination of the test compound concentration in plasma. Samples were taken at 5, 10, 15, 30, 45 and 60 min during the infusion, and at regular intervals post infusion until the end of the experiment. Plasma was prepared, and stored at -2O⁰C pending analysis.

Continuous measurement and recording of bladder pressure, urethral profilometry and arterial blood pressure was made via Notocord-Hem software (v.4.1 ). Heart rate was derived from the arterial pressure signal. Heart rate and blood pressure were monitored for anaesthetic purposes only and no analysis was carried out on this data. From the profilometry data, peak urethral pressure was measured (PUP, mmHg). Changes in PUP were compared with mean baseline value and expressed as % change from baseline, recorded over the 4 consecutive profiles obtained prior to test drug or vehicle administration. Data was analysed to determine the concentration effect relationship for SPM 7605 on PUP over a clinically relevant range.

Results

Figure 1 is a trace showing representative consecutive urethral pressure profiles from a single animal, before and during administration of SPM 7605 (0.08 mg/kg). The time scale is indicated by a horizontal line representing 300 seconds.

The following Table 1 shows the baseline data from the study together with 95% confidence intervals. This demonstrates that in this study, over the concentration range tested, for every 1 ng/mL increase in SPM7605 concentration in the blood, the median increase in urethral pressure expected is 1.39 mmHg.

Table 1

Figure 2 is a graph showing the concentration/effect relationship over the concentration range tested. This graph shows the minimum (most gentle slope, dark grey line), maximum (steepest slope, light grey line) and median (intermediate slope, black line) changes over the concentration range tested.

Conclusion

Using these data, at clinically relevant concentrations of SPM7605, the change in peak urethral pressure was in the range of 3.0 ± 1.3 mmHg - 6.6 ± 2.1 mmHg, which equates to 10 ± 4 - 22 ± 7% increase in peak urethral pressure from pre- dose values. These data suggest that SPM 7605, and prodrugs thereof, have the potential to increase urethral tone, and therefore to be potentially beneficial in the treatment of stress urinary incontinence.

Claims

1. A diisopropylamine derivative selected from: (a) a compound of formula I,

or a pharmaceutically acceptable salt or solvate thereof; and

(b) a pharmaceutically acceptable ester prodrug of the compound of formula

1, and its pharmaceutically acceptable salts and solvates; for use in the treatment of stress urinary incontinence.

2. A diisopropylamine derivative as claimed in claim 1 , wherein the diisopropylamine derivative is a compound of formula Ib,

wherein R¹ and R² are each independently selected from H and Ci_-6 alkanoyl, with the proviso that R¹ and R² are not both H; or a pharmaceutically acceptable salt or solvate thereof.

3. A diisopropylamine derivative as claimed in claim 1 or claim 2, wherein the diisopropylamine derivative is a compound of formula Ia,

wherein R¹ represents H or Ci_-6 alkanoyl; or a pharmaceutically acceptable salt or solvate thereof.

4. A diisopropylamine derivative as claimed in claim 3, wherein R¹ represents isobutanoyl.

5. A diisopropylamine derivative as claimed in any one of the preceding claims, wherein the diisopropylamine derivative is R-(+)-isobutyric acid 2-(3- diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester hydrogen fu ma rate.

6. A diisopropylamine derivative as claimed in claim 1 or claim 2, wherein the diisopropylamine derivative is selected from the (R)-enantiomers of: acetic acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-acetoxymethylphenyl ester; n-butyric acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester; isobutyric acid 2-(3-diisopropylamino-1 -phenylpropyl)-4- isobutyryloxymethylphenyl ester; n-butyric acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-n-butyryloxymethylphenyl ester; propionic acid 2-(3-diisopropylamino-1 -phenylpropyl)-4- propionyloxymethylphenyl ester; propionic acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester; and acetic acid 2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethylphenyl ester; and their pharmaceutically acceptable salts and solvates.

7. A diisopropylamine derivative as claimed in any one of the preceding claims, wherein the diisopropylamine derivative is to be administered orally.

8. A diisopropylamine derivative as claimed in claim 7, wherein the diisopropylamine derivative is to be administered in a controlled release tablet or capsule.

9. A diisopropylamine derivative as claimed in any one of the preceding claims, wherein the diisopropylamine derivative is to be administered once a day.

10. A diisopropylamine derivative as claimed in any one of the preceding claims, wherein the diisopropylamine derivative is to be administered at a dosage of from 1 to 10 mg per day.

11. A diisopropylamine derivative as claimed in claim 10, wherein the dosage is from 4 to 8 mg per day.

12. A diisopropylamine derivative as defined in any one of claims 1 to 6, for use in the treatment of mixed urinary incontinence.

13. A combination of a diisopropylamine derivative as defined in any one of claims 1 to 6, and a second therapeutically active ingredient, for use in the treatment of stress urinary incontinence.

14. A combination of a diisopropylamine derivative as defined in any one of claims 1 to 6, and a second therapeutically active ingredient, for use in the treatment of mixed urinary incontinence.

15. A combination as claimed in claim 13 or 14, wherein the second active ingredient is duloxetine.

16. A pharmaceutical formulation comprising a combination as claimed in any one of claims 13 to 15.

17. Pharmaceutical products comprising a diisopropylamine derivative as defined in any one of claims 1 to 6; and duloxetine, or a pharmaceutically acceptable salt thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of stress urinary incontinence or mixed urinary incontinence.

18. Use of a diisopropylamine derivative, as defined in any one of claims 1 to 6, in the manufacture of a medicament for the treatment of stress urinary incontinence or mixed urinary incontinence.

19. A method of treatment of stress urinary incontinence or mixed urinary incontinence which comprises administering a therapeutically effective amount of a diisopropylamine derivative, as defined in any one of claims 1 to 6, to a patient in need of such treatment.