AZETIDINYLOXYPHENYLPYRROLIDINE COMPOUNDS
The invention provides certain azetidinyloxyphenylpyrrolidine compounds,
pharmaceutical compositions thereof, methods of using the same, and processes for
preparing the same.
Overactive bladder (OAB) is a symptomatically defined medical condition
referring to the symptoms of urinary frequency and urgency, with or without urge
incontinence. OAB is a condition that adversely affects the quality of life and social
functioning of approximately 17 percent of the adult population. In spite of progress
made for OAB treatment, many patients suffer with OAB for years without resolution.
The first-line treatment for OAB are antimuscarinic drugs which have a good initial
response, but experience diminishing patient compliance over the long term due to
adverse effects and decreasing efficacy. There remains a significant unmet need for safe
and effective OAB treatments.
Cyclic nucleotides (cAMP and cGMP) are important secondary messengers that
modulate the contractility of smooth muscle. Cyclic nucleotide phosphodiesterases
(PDEs) hydrolyse cyclic nucleotides and are important in regulating the level and
duration of action of cyclic nucleotides inside cells. Compounds which inhibit PDE
elevate cellular levels of cyclic nucleotides and thereby relax many types of smooth
muscle. Previous studies have shown that relaxation of bladder smooth muscle is mainly
mediated by agents that elevate cAMP. Phosphodiesterase 4 (PDE4) is cAMP specific
and abundantly expressed in bladder. As such, PDE4 has been implicated in the control
of bladder smooth muscle tone in vitro and in animal models of overactive bladder
(Kaiho, Y. et al. BJU International 2008, 101(5), 615-620).
The compounds of the present invention are inhibitors of phosphodiesterase 4
(PDE4) and demonstrate selectivity for PDE4. As such, compounds of the present
invention are believed to be useful for the treatment of conditions in which PDE4 plays a
role such as overactive bladder, including relief of associated symptoms such as
frequency and urgency.
International Application Publication WO 01/47905 discloses certain pyrrolidine
derivative compounds as inhibitors of phosphodiesterase, in particular, PDE4, and recites
the compounds as useful in treating a number of diseases including asthma.
The present invention provides novel compounds which are inhibitors of PDE4
and as such, are useful in treatment of overactive bladder and other disorders. The
compounds provided address the need for safe and effective treatments of conditions
associated with PDE4 such as overactive bladder.
The present invention provides a compound of formula I
wherein R is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
A particular compound of formula I is one wherein R is methyl or a
pharmaceutically acceptable salt thereof.
A particular compound of formula I is (2S)-3-[(3S,4S)-3-[(lR)-l-hydroxyethyl]-4-
(4-methoxy-3-{[l-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidinl-
yl]-3-oxopropane-l,2-diol, or a pharmaceutically acceptable salt thereof.
Further, the present invention provides a pharmaceutical composition comprising
a compound of formula I, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier, diluent or excipient. In a particular embodiment, the
pharmaceutical composition further comprises one or more other therapeutic agents such
as tadalifil. As such, the present invention provides a pharmaceutical composition
comprising a first component which is a compound of formula I, or a pharmaceutically
acceptable salt thereof, and a second component which is tadalifil, and a pharmaceutically
acceptable carrier, diluent or excipient.
Further, the present invention provides a compound of formula I, or a
pharmaceutically acceptable salt thereof, for use in therapy.
Further, the present invention provides a compound of formula I, or a
pharmaceutically acceptable salt thereof, for use in the treatment of overactive bladder.
Further, the present invention provides the use of a compound of formula I, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating
overactive bladder.
A particular compound of formula I is a compound of formula la
la
wherein R is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
A particular compound of formula la is one wherein R is methyl, or a
pharmaceutically acceptable salt thereof.
A particular compound of formula la is (2S)-3-[(3S,4S)-3-[(lR)-l-hydroxyethyl]-
4-(4-methoxy-3-{[1-(5 -methylpyridin-2-yl)azetidin-3-yl]oxy }phenyl)-3-
methylpyrrolidin-l-yl]-3-oxopropane-l,2-diol, or a pharmaceutically acceptable salt
thereof.
Further, the present invention provides a method of treating overactive bladder,
comprising administering to a patient in need thereof an effective amount of a compound
of formula la, or a pharmaceutically acceptable salt thereof. In a particular
embodiment, the invention provides a method of treating overactive bladder, comprising
administering to a patient in need thereof an effective amount of a first component which
is a compound of formula la, or a pharmaceutically acceptable salt thereof, in
combination with an effective amount of a second component which is tadalifil.
Further, the invention provides a method of treating overactive bladder
comprising administrating to a patient in need thereof an effective amount of (2S)-3-
[(3S,4S)-3-[(lR)-l-hydroxyethyl]-4-(4-methoxy-3-{[l-(5-methylpyridin-2-yl)azetidin-3-
yl]oxy}phenyl)-3-methylpyrrolidin-l-yl]-3-oxopropane-l,2-diol, or a pharmaceutically
acceptable salt thereof, in combination with an effective amount of tadalifil.
It is understood that compounds of the present invention may exist as
stereoisomers. Embodiments of the present invention include all enantiomers,
diastereomers, and mixtures thereof. Preferred embodiments are single diastereomers,
and more preferred embodiments are single enantiomers.
The term "pharmaceutically acceptable salt" includes an acid addition salt that
exists in conjunction with the basic portion of a compound of formula I . Such salts
include the pharmaceutically acceptable salts, for example those listed in Handbook of
Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth
(Eds.), Wiley-VCH, New York, 2002 which are known to the skilled artisan.
In addition to pharmaceutically acceptable salts, other salts are contemplated in
the invention. They may serve as intermediates in the purification of compounds or in the
preparation of other pharmaceutically-acceptable salts, or are useful for identification,
characterization or purification of compounds of the invention.
As used herein, the term "patient" refers to a warm blooded animal such as a
mammal and includes a human. A human is a preferred patient.
It is also recognized that one skilled in the art may treat overactive bladder by
administering to a patient presently displaying symptoms an effective amount of the
compound of formula I . Thus, the terms "treatment" and "treating" are intended to refer
to all processes wherein there may be a slowing, interrupting, arresting, controlling, or
stopping of the progression of an existing disorder and/or symptoms thereof, but does not
necessarily indicate a total elimination of all symptoms.
It is also recognized that one skilled in the art may treat overactive bladder by
administering to a patient at risk of future symptoms an effective amount of the
compound of formula I and is intended to include prophylactic treatment of such.
As used herein, the term "effective amount" of a compound of formula I refers to
an amount, that is a dosage, which is effective in treating a disorder, such as overactive
bladder described herein. The attending diagnostician, as one skilled in the art, can
readily determine an effective amount by the use of conventional techniques and by
observing results obtained under analogous circumstances. In determining an effective
amount or dose of a compound of formula I, a number of factors are considered,
including, but not limited to the compound of formula I to be administered; the c o
administration of other agents, if used; the species of mammal; its size, age, and general
health; the degree of involvement or the severity of the disorder, such as overactive
bladder; the response of the individual patient; the mode of administration; the
bioavailability characteristics of the preparation administered; the dose regimen selected;
the use of other concomitant medication; and other relevant circumstances.
A compound of formula I may be used in combination with other drugs that are
used in the treatment/prevention/suppression or amelioration of the diseases or conditions
for which compounds of formula I are useful, including overactive bladder. Such other
drug(s) may be administered by a route and in an amount commonly used therefore,
including contemporaneously or sequentially with a compound of formula I . When a
compound of formula I is used contemporaneously with one or more other drugs, a
pharmaceutical unit dosage form containing such other drugs in addition to the compound
of formula I is preferred. Accordingly, the pharmaceutical compositions of the present
invention include those containing one or more other active ingredients in addition to a
compound of formula I . Other active ingredients effective in the treatment of overactive
bladder which may be combined with a compound of formula I, either administered
separately or in the same pharmaceutical include an inhibitor of PDE5 such as tadalifil.
The compounds of the present invention can be administered alone or in the form
of a pharmaceutical composition combined with pharmaceutically acceptable carriers or
excipients, the proportion, and nature of which are determined by the solubility and
chemical properties, including stability, of the compound selected, the chosen route of
administration, and standard pharmaceutical practice. The compounds of the present
invention, while effective themselves, may also be formulated and administered in the
form of their pharmaceutically acceptable salts for convenience of crystallization,
increased solubility, and the like.
One skilled in the art of preparing formulations can readily select the proper form
and mode of administration depending upon the particular characteristics of the
compound selected, the disorder or condition to be treated, the stage of the disorder or
condition, and other relevant circumstances (See, e.g., Remington: The Science and
Practice of Pharmacy, D.B. Troy, Editor, 21st Edition., Lippincott, Williams & Wilkins,
2006).
PDE4 Inhibition in vitro Assay
The phosphodiesterase assays are performed essentially according to the method
described in Loughney, K., et al., . Biol. Chem., 271, pp. 796-806 (1996). PDE4A,
PDE4B, PDE4C, PDE4D, and PDE5 human recombinant proteins are expressed and
purified from Saccharomyes cerevisiae that lack endogenous PDEs. The
phosphodiesterase enzymes are diluted on ice with enzyme dilution buffer (25 mM Tris,
pH 7.5, 0.1 mM DTT, 5.0 mM MgCl2, 100 mM NaCl, 5 ZnS0 4, 100 g/mL BSA) to
give approximately 20%-40% hydrolysis of cyclic nucleotide monophosphate (cNMP) in
the absence of inhibitor.
The stock solution of test compounds are diluted on the Beckman BioMek™ 1000
workstation to span a concentration range of 4.5 log units in 0.5 log increments. The
DMSO concentration in the final test system is 2.5% for all PDE enzymes. The final test
compound concentration tested ranged from 0.03 nM to 1 .
The assay is performed in a 96-well microtiter plate format on a Beckman
BioMek™ 1000 robotic station. Each row of the plate represents a 10-point dose
response curve containing blank (no enzyme), non-inhibited control, and inhibitor
dilutions spanning 4.5 log units in concentration in 0.5 log increments. Assay stock
solutions are loaded into the Biomek reservoirs (water, inhibitor diluent [2.5% or 10%
DMSO], 5X PDE assay buffer, substrate, inhibitor solutions, enzyme solutions, snake
venom nucleotidase, and charcoal suspension). The reaction is initiated with enzyme, and
incubated for 15 minutes at 30°C. An excess of Crotalus atrox snake venom nucleotidase
(5 /well) is then added and the mixture is incubated for an additional 3 minutes. The
reaction is terminated by the addition of 200 of activated charcoal suspension, after
which the plate is centrifuged for 5 minutes at 750 x g. A transfer program is run in
which 200 of supernatant is removed and placed into a new plate. The amount of
radioactivity released as phosphate is determined in a Wallac MicroBeta Plate™ counter.
The reduced data at each concentration of inhibitor is analyzed using a four-,
three- or two-parameter logistic dose response model to provide an IC50 value. For those
sets of data that exhibited >95% inhibition at the maximal inhibitor concentration, a fourparameter
logistic dose response model is used.
In the above assay, the compounds Examples 1 and 2 exhibit an IC50 of less than
10 nM at PDE4B. More specifically, the compound of Example 2 has an IC50 of 0.58
nM measured at PDE4B in the above assay. These data demonstrate the compounds of
Example 1 and 2 are inhibitors of PDE4B.
Overactive Bladder in vivo Model
The in vivo effect of PDE4 inhibitors on OAB is studied with a chronic
cyclophosphamide (CYP)-induced overactive bladder mouse model adapted from Boudes
et al., Neurourol. Urodynam. 2011. In a typical study, female C57/B16 mice,
approximately 20 grams in body weight (Harlan Laboratories, Inc., Indianapolis, Indiana)
are used. Mice are randomized by body weight into groups one day before the start of the
study. Mice are individually housed and maintained on a 12 hour light/dark cycle at 22°C
with ad lib access to food (TD 2014 with 0.72% Ca and 0.61%P, 990 IU/g D3, Teklad™,
Madison, WI) and water. Animals receive cyclophosphamide (dissolved in physiological
saline) i.p. administration at 100 mg/kg on days 1, 3, 5, and 7 to chronically induce OAB.
The vehicle control group received daily vehicle (HEC 1%/Tween 80 0.25%/Antifoam
0.05%) administered orally. All other groups are administered orally tadalafil at lOmg/kg
in combination with 0.1, 1.0, or 10.0 mg/kg of test compound daily at a volume of 200
ΐ/mouse. On day 8, mice are housed in urine collection chambers with a filter paper
placed underneath chamber. Prior to urine collection, gavages of 1ml water are given to
each mouse. Urine is collected from 6 pm to 10 pm (i.e. for 4 hrs). Gel cups (DietGel™
76A) are supplied as water source during the 4 hour period. The filter paper is changed
every hour. Voiding frequency and volume/void are calculated using Image J software
(NIH). Data are statistically analyzed with JMP8® software (Cary, N. C).
The animals develop OAB after 8 days following CYP treatment as
demonstrated by increased urinary frequency (sham: 6.66 + 0.91 vs. vehicle: 16.5 + 1.65
number of urination/4 hour period) and decreased volume/void (sham: 173.36 + 38.39 mL
vs. vehicle: 31.93 + 4.16 mL). All treatment groups receive a fixed dose of 10 mg/kg of
tadalafil. At this dose, tadalifil has no significant activity on either urinary frequency or
volume per void. Following the protocol essentially as described above, the compound of
Example 2 given with tadalafil significantly reduces urinary frequency in a dosedependent
fashion (Table 1). In addition, increases of volume/void are also observed in a
dose-dependent fashion (Table 2). This demonstrates that a compound of Example 2 in
combination with tadalifil is active in an animal model of overactive bladder.
Table 1
computed based on ANOVA model for the square root transform of number of spots in 4
hours; p-values adjusted for multiple comparisons to vehicle using Dunnett's correction.
Table 2
computed based on ANOVA model for the logarithm of urine spot volumes; p-values
adjusted for multiple comparisons to vehicle using Dunnett' s correction.
Compounds of formula I may be prepared by processes known in the chemical art
for the production of structurally analogous compounds or by a novel process described
herein. A process for the preparation of a compound of formula I, or a pharmaceutically
acceptable salt thereof, and novel intermediates for the manufacture of a compound of
formula I, provide further features of the invention and are illustrated by the following
procedures in which the meaning of substituent, R is as defined above, unless otherwise
specified.
Generally, a compound of formula la where R is hydrogen or methyl may be
prepared from a compound of formula II where the 1,2-diol group is protected with a
suitable group such as acetonide (Scheme 1). More specifically, a compound of formula
II is reacted with an acid such aqueous hydrochloric acid or acetic acid in a suitable
solvent to provide a compound of formula la. Suitable solvents include water, methanol
and acetonitrile. A compound of formula II where R is hydrogen or methyl may be
prepared by reacting a compound of formula III with a compound of formula IV where L
represents a suitable leaving group such as fluoro or chloro in the presence of a suitable
base. Suitable bases include potassium carbonate and cesium carbonate. The reaction is
conveniently carried out in a solvent such as N-methyl-2-pyrrolidone or acetonitirile.
A compound of formula III may be prepared from a compound of formula V
where the azetidine amine is protected with a suitable group such as diphenylmethyl.
More specifically, a compound of formula V is reacted with hydrogen gas in the presence
of suitable catalyst such as palladium on carbon to provide a compound of formula III.
The reaction is conveniently carried out in a solvent such as methanol or ethanol.
A compound of formula V may be prepared by reacting a compound of formula
VI with l-(diphenylmethyl)azetidin-3-yl methanesulfonate in the presence of a suitable
base. Suitable bases include potassium carbonate and cesium carbonate. The reaction is
conveniently carried out in an appropriate solvent such as acetonitirile.
Scheme 1
Alternatively, a compound of formula II may be prepared directly from a
compound of formula VI (Scheme 2). More specifically, a compound of formula VI is
reacted with a compound of formula VII where R is hydrogen or methyl and OMs
represents the leaving group methanesulfonyl in the presence of a suitable base such as
cesium carbonate. The reaction is conveniently carried out in an appropriate solvent such
as acetonitirile.
A compound of formula VII may be prepared by reacting a compound of formula
VIII with methanesulfonyl chloride in the presence of a base such as triethylamine. The
reaction is conveniently carried out in a suitable solvent such as methylene chloride. A
compound of formula VIII where R is hydrogen or methyl may be prepared by reacting a
compound of formula IV where L represents a suitable leaving group such as fluoro or
chloro with 3-hydroxy azetidine in the presence of a suitable base. Suitable bases include
potassium carbonate. The reaction is conveniently carried out in a suitable solvent.
A compound of formula VI may be prepared by procedures appreciated by one of
ordinary skill in the art including those disclosed in International Application Publication
No. WO 01/47905 as well as those disclosed in Scheme 3 in view of Nichols, P. J.;
DeMattei, J . A.; Barnett, B. R.; LeFur, N. A.; Chuang, T.; Piscopio, A. D.; Kock, K. Org.
Lett. 2006, 8, 1495-1498.
Scheme 3
e
XII XI
As used herein, "DMSO" refers to dimethylsulfoxide; "Tris" refers to
trishydroxymethylaminomethane; "DTT" refers to dithiothreitol; "HEC" refers to
hydroxyethyl cellulose; and "IC50" refers to the concentration of an agent that produces
50% of the maximal inhibitory response possible for that agent.
Preparation 1
Synthesis of (lR)-l-[(3S,4S)-l-{[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]carbonyl}-4-(3-
{[l-(diphenylmethyl)azetidin-3-yl]oxy}-4-methoxyphenyl)-3-methylpyrrolidin-3-
yljethanol.
To a suspension of (lR)-l-[(3S,4S)-l-{[(4S)-2,2-dimethyl-l,3-dioxolan-4-
yl]carbonyl}-4-(4-methoxy-3-hydroxyphenyl)-3-methylpyrrolidin-3-yl]ethanol (2.0 g)
and potassium carbonate (1.46 g) in acetonitrile (30 mL) is added 1-
(diphenylmethyl)azetidin-3-yl methanesulfonate (2.51 g). The mixture is heated at 80°C
overnight. Cool the reaction mixture and pour into ethyl acetate (100 mL), wash with
water (40 mL) and brine (40 mL), dry over sodium sulfate, filter and evaporate the filtrate
to dryness. Purify the resulting residue (silca gel, 60% ethyl acetate/hexanes to ethyl
acetate) to provide 0.6 g of the title compound. MS (ES+) = 601 (M+l).
Preparation 2
Synthesis of (lR)-l-[(3S,4S)-l-{[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]carbonyl}-4-(4-
methoxy-3-{[l-(azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-yl]ethanol.
To a Parr™ vessel containing a solution of (lR)-l-[(3S,4S)-l-{[(4S)-2,2-
dimethyl-l,3-dioxolan-4-yl]carbonyl}-4-(3-{[l-(diphenylmethyl)azetidin-3-yl]oxy}-4-
methoxyphenyl)-3-methylpyrrolidin-3-yl]ethanol (0.6 g) in methanol (20 mL) is added
palladium hydroxide on carbon (60 mg, 20wt Pd on C dry basis). The suspension is
hydrogenated at 30 psig hydrogen gas until hydrogen gas uptake ceases. The reaction
mixture is filtered through Celite™ and the filtrate is evaporated to provide the title
compound (0.4 g). MS (ES+) = 435 (M+l).
Preparation 3
Synthesis of (lR)-l-[(3S,4S)-l-{[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]carbonyl}-4-(4-
methoxy-3-{[l-pyridin-2-ylazetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-yl]ethanol.
A mixture of (lR)-l-[(3S,4S)-l-{[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]carbonyl}-
4-(4-methoxy-3-{ [l-(azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-yl]ethanol (50 mg),
2-fluoropyridine (11.8 mg) and potassium carbonate (31.8 mg) in N-methyl-2-pyrrolidone
(3 mL) is heated at 120° C overnight. The reaction is cooled, poured into methylene
chloride (40 mL), and washed with water (10 mL). The organic layer is dried over
sodium sulfate and evaporated to 3 mL. Acetonitrile is added and the crude product
solution is purified by reverse phase chromatography (5% to 95% acetonitrile/water).
The appropriate fractions are collected and evaporated to provide the title compound
(22.1 mg). MS (ES+) = 512 (M+l).
Preparation 4
Synthesis of (1R)- 1-[(3S,4S)- 1-{[(4S)-2,2-dimethyl- 1,3-dioxolan-4-yl]carbonyl }-4-(4-
methoxy-3-{[l-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-
yljethanol.
The title compound is prepared essentially by the method of Preparation 3 using
2-chloro-5-methylpyridine. MS(ES+) = 526 (M+l).
Example 1
Synthesis of (2S)-3-[(3S,4S)-3-[(lR)-l-hydroxyethyl]-4-{4-methoxy-3-[(l-pyridin-2-
ylazetidin-3-yl)oxy]phenyl}-3-methylpyrrolidin-l-yl]-3-oxopropane-l,2-diol.
To a solution of (lR)-l-[(3S,4S)-l-{[(4S)-2,2-dimethyl-l,3-dioxolan-4-
yl]carbonyl}-4-(4-methoxy-3-{[l-pyridin-2-ylazetidin-3-yl]oxy}phenyl)-3-
methylpyrrolidin-3-yl]ethanol (22.1 mg) in tetrahydrofuran (2 mL) is added aqueous 1.0
M HCl ( 1 mL). Stir overnight at room temperature. Add aqueous 1.0 M HCl ( 1 mL) and
stir for additional 8 hours. Neutralize with aqueous 1.0 M NaOH, extract with ethyl
acetate, dry and evaporate to provide the title compound (18.2 mg). MS(ES+) = 472
(M+l).
Example 2
Synthesis of (2S)-3-[(3S,4S)-3-[(lR)-l-hydroxyethyl]-4-(4-methoxy-3-{[l-(5-
methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-l-yl]-3-oxopropane-
1,2-diol.
The title compound is prepared essentially by the method of Example 1.
MS(ES+) = 486 (M+l).
We claim:
1. A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or methyl.
2. The compound or salt of claim 1 of the formula
wherein R is hydrogen or methyl.
3. The compound or salt of claim 1 or 2 wherein R is methyl.
4. The compound which is (2S)-3-[(3S,4S)-3-[(lR)-l-hydroxyethyl]-4-(4-methoxy-3-
{[1-(5 -methylpyridin-2-yl)azetidin-3 -yl]oxy }phenyl)-3-methylpyrrolidin- 1-yl] -3-
oxopropane- 1,2-diol.
5. A pharmaceutical composition comprising a compound according to any one of
claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent or excipient.
6. A pharmaceutical composition comprising a first component which is a compound
according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof ,
and a second component which is tadalifil, and a pharmaceutically acceptable carrier,
diluent or excipient.
7. A method of treating overactive bladder comprising administrating to a patient in
need thereof an effective amount of a compound according to any one of claims 1 to
4, or a pharmaceutically acceptable salt thereof.
8. A method of treating overactive bladder comprising administrating to a patient in
need thereof an effective amount of a compound according to any one of claims 1 to
4, or a pharmaceutically acceptable salt thereof, in combination with an effective
amount of tadalifil.
9. A method of treating overactive bladder comprising administrating to a patient in
need thereof an effective amount of (2S)-3-[(3S,4S)-3-[(lR)-l-hydroxyethyl]-4-(4-
methoxy-3-{[l-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidinl-
yl]-3-oxopropane-l,2-diol, or a pharmaceutically acceptable salt thereof, in
combination with an effective amount of tadalifil.
10. A compound as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable
salt thereof, for use in therapy.
11. A compound as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable
salt thereof, for use in the treatment of overactive bladder.