Note: Descriptions are shown in the official language in which they were submitted.
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USE OF A QUINAZOLINE DERIVATIVE FOR TREATING LOWER URINARY TRACT SYMPTOMS
This invention relates to a new use of 4-amino-6,7-dimethoxy-2-(5-
methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline
(disclosed as example 19 in International Patent Application Publication No.
WO
98/30560), and its pharmaceutically acceptable derivatives. The mesylate salt
is
disclosed in International Patent Application Publication No. WO 01/64672
(e.g.
Example 2). Both WO 98/30560 and WO 01/64672 are incorporated herein by
reference. It is indicated in the treatment of Benign Prostatic Hyperplasia
(BPH)
and has the following structure:
O~~ i O
S
HN~
N N
\O \ /N
N NHZ
Lower urinary tract symptoms (LUTS) comprise three groups of symptoms, which
are irritative, obstructive and post micturition symptoms. Irritative symptoms
comprise urgency, frequency and nocturia, which can be associated with:
overactive bladder (with or without concomitant detrusor over activity);
pelvic floor
dysfunction; or chronic prostatitis.
Over Active Bladder (OAB) is defined as urgency, with or without urge
incontinence, usually with frequency and nocturia [Abrams et al., Neurourology
and Urodynamics 21:167-178 (2002)]. Prevalence of OAB in men and women is
similar, with approximately 16% of the population of the USA suffering from
the
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condition [Stewart et al, Prevalence of Overactive Bladder in the United
States:
Results from the NOBLE Program; Abstract Presented at the 2"d International
Consultation on Incontinence, July 2001, Paris, France].
Pelvic floor dysfunction (PFD) occurs when the muscles of the pelvic floor no
longer relax properly during urination while the bladder contracts. The
muscles
may become irritated and often contract abnormally. PFD may result in
irritative
LUTS.
Chronic prostatitis is an inflammatory condition of the prostate, which may or
may
not be associated with uropathogenic bacteria detected by standard
microbiological methodology. It is characterized by the presence of
genitourinary
pain or discomfort, often associated with irritative LUTS.
Overactive bladder may be suffered by individuals of any age, while pelvic
floor
dysfunction and prostatitis are conditions typically suffered by middle-aged
men.
Patients with any of these conditions are likely to experience irritative
lower urinary
tract symptoms, and often the eventual diagnosis is empirical.
Surprisingly it has been found that 4-amino-6,7-dimethoxy-2-(5-
methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline
is
useful in the treatment of LUTS associated with: OAB (with or without
concomitant
detrusor over activity); pelvic floor dysfunction; or chronic prostatitis.
Thus, in accordance with the present invention, there is provided the use of 4-
amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-
5-(2-pyridyl)quinazoline, or a pharmaceutically acceptable derivative thereof,
for
the manufacture of a medicament for the treatment of LOTS associated with: OAB
(with or without concomitant detrusor over activity); pelvic floor
dysfunction; or
chronic prostatitis.
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Preferably the LUTS is associated with pelvic floor dysfunction.
Alternatively, the
LUTS is preferably associated with chronic prostatitis.
Preferably the 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-
tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is in the form of its
mesylate salt.
The compound, or a pharmaceutically acceptable derivative thereof, can be
administered alone or in any convenient pharmaceutical presentation. Oral
administration is preferred. In the present indication, a suitable dosage of
the
compound, or of the active moiety in a pharmaceutically acceptable derivative
thereof, is from about 0.01 to 10.0 mg/kg of body weight, and preferably about
0.05 to 1.0 mg/kg is suitable. Administration may be in single does of from 1
to 4
times daily or preferably it may be in a controlled release formulation such
as is
disclosed in International Application Publication No. WO 03/032956 (see in
particular examples 1 to 5). Administration may be p.r.n. for occasions when
the
patient may have limited access to toilet facilities, e.g. during a long
journey.
The invention further provides 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-
1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline, or a
pharmaceutically
acceptable derivative thereof, for use in the treatment of LUTS associated
with:
OAB (with or without concomitant detrusor over activity); pelvic floor
dysfunction;
or chronic prostatitis.
The invention further provides a method of treating LUTS associated with: OAB
(with or without concomitant detrusor over activity); pelvic floor
dysfunction; or
chronic prostatitis, which comprises administering 4-amino-6,7-dimethoxy-2-(5-
methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline,
or
a pharmaceutically acceptable derivative thereof, to a patient in need of such
treatment.
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Examples 1-5
Tablet formulations of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-
1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate containing
MethoceITM K4M
The following table shows the ingredients for preparing five tablet
formulations
containing, respectively, 1, 3, 6, 9 and 12 mg of active ingredient, expressed
as
free base, according to International Application Publication No. WO
03/032956.
Ingredient (mg) Ex 1 Ex 2 Ex 3 Ex 4 Ex 5
(reference to standard)
4-amino-6,7-dimethoxy-2-1.189 3.567 7.134 10.701 14.268
t'~
(5-methanesulfonamido-
1,2,3,4-tetrahydroisoquinol-
2_yl)_5_(2_
pyridyl)quinazoline
mesylate
(Pfizer)
HPMC 30.000 30.000 30.000 22.500 22.500
(Methocel K4M, Ph.Eur)
Lactose Monohydrate 13.203 10.108 9.216 10.200 9.308
(Ph.Eur)
Calcium Hydrogen 39.608 30.325 27.650 30.599 27.924
Phosphate, Anhydrous
(Ph.Eur)
Adipic Acid 15.000 25.000 25.000 25.000 25.000
[DAB t2t]
Magnesium Stearate 1.000 1.000 1.000 1.000 1.000
(Ph.Eur)
Tablet weight (mg) 100.000 100.000 100.000 100.000 100.000
~'~ Equivalent to 1.0 mg 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-
tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline, in the form of its free
base
DAB is the Deutsches Arzneibuch (German Pharmacopoeia)
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Method
The adipic acid was first screened through a suitable screen (e.g. 500
micron).
The lactose monohydrate, hydroxypropylmethyl cellulose, 4-amino-6,7-dimethoxy-
2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-
pyridyl)quinazoline
mesylate, the screened adipic acid and calcium hydrogen phosphate, anhydrous
were then added to a suitable blender (e.g. a tumble mixer) and blended. The
blend was screened through a suitable screen (e.g. 500 micron) and reblended.
About 50% of the lubricant (magnesium stearate) was screened, added to the
blend and blended briefly.
The blend was roller compacted through a suitable roller compactor. The ribbon
blend was then granulated, by screening through a suitable screen (e.g. 500
micron) and reblended. The remaining lubricant was screened, added to the
blend and blended briefly.
The granules were then tabletted using appropriate 6 mm tooling to give 6 mm
standard round convex white tablets with no engraving, which were then de-
dusted.
Example 6: In vivo study
A 12-Week Study in men with lower urinary tract symptoms was undertaken in
which the IPSS (International Prostate Symptom Score) was recorded at baseline
during, and at the end of, double-blind treatment. The IPSS is composed of
seven
questions, each with potential responses of 0-5 on a Likert scale. These
questions are grouped into two validated domains: the irritative domain
(urgency,
frequency and nocturia) and the obstructive domain (incomplete emptying,
intermittency, weak stream and straining to begin). In addition, a bladder
diary
was completed by each subject to provide baseline incidence of individual
symptoms, and subsequently to demonstrate change in incidence of these
symptoms following double blind treatment. The average daily incidence of
urgency, daytime micturition frequency and nocturia (the irritative symptoms)
for
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each subject were derived from this diary. In this study, there were five
treatment
groups: 6mg fixed dose of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-
1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline, 6mg escalated to
l2mg
at Week 4 of the compound, and placebo. Controlled release formulations
according to International Application Publication No. WO 03/032956 were used
in each case.
For those subjects with irritative LUTS at baseline, improvement in these
symptoms was confirmed in the compound 6mg fixed dose group and the 12mg
dose escalation group, compared with the placebo treated group. In subjects
with
baseline IPSS irritative domain score >_8 at baseline, improvement in this
domain
of the IPSS was similarly confirmed in both the compound 6mg fixed dose group
and the 12mg dose escalation group.
The results of the study are illustrated in figures 1 to 4 which show 4-amino-
6,7-
dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-
pyridyl)quinazoline produced a clinically significant attenuation of
irritative LUTS.
