The invention concerns PAR-1 antagonists and more
particularly vorapaxar, atopaxar and 3- (2-Chloro-phenyl)- 1-[4- (4-
5 fluoro-benzy1)-piperazin-1-yll-propenone or one of the
pharmaceutically acceptable salts thereof for use in the
prevention and/or treatment of pelvi-perineal functional
pathologies.
Pelvi-perineal functional pathologies encompass various
pathologies affecting the pelvi-perineal region with the
exclusion of cancerous lesions and any proven infectious,
metabolic or endocrine pathologies. One pelvi-perineal functional
pathology is represented by painful bladder syndrome, also called
15 interstitial cystitis, defined, in the absence of any proven
urinary infection or other objective pathologies, as being
chronic pelvic pain of more than six months' duration sometimes
perceived as bladder-related feelings of pressure or discomfort
and accompanied by at least one urinary symptom: persistent
20 strong urge to urinate or pollakiuria. Nocturia very often
accompanies this painful bladder syndrome. Pollakiuria is defined
as abnormally high urination frequency, more than eight
urinations over a 24-hour period. Nocturia is defined as the need
to urinate at night waking a patient one or more times. The
25 diagnosis of painful bladder syndrome or interstitial cystitis is
based on history-taking and determination of an urination
calendar. Clinical examination must have eliminated all other
causes of bladder pain, the diagnosis of painful bladder syndrome
being a diagnosis of exclusion. In the event of suspected painful
30 bladder syndrome, cystoscopy under general or regional
anaesthesia is the key examination for assessment and diagnosis.
Conventionally this examination can evidence glomerulations of
vesical mucosa with or without Hunner lesions. However cystoscopy
may sometimes appear normal at the initial phase with no Hunner
lesions. It allows bladder biopsies and bladder hydrodistention
to be performed at the same time. Hydrodistention is distention
of the bladder with water performed under anaesthesia. Other
additional examinations, imaging, urodynamic assessment, biology,
5 cytology are not essential for diagnosis but useful for
differential diagnosis since the syndrome of interstitial
cystitis remains a diagnosis of exclusion.
There appears to be two categories of patient: those with
deteriorations of the bladder wall and in particular with Hunner
10 lesions (20% of cases) and those without. However a continuum
exists between these different clinical presentations. It is
difficult to know the exact number of persons suffering from this
disease which is probably under-diagnosed. Prevalence varies from
one country to another. In Europe estimations range from one
15 person affected out of 12,500 to one person out of 1,500. In the
United States prevalence is estimated at one person out of about
1,500 persons. While both genders can be affected, 90% of
patients suffering from painful bladder syndrome are women. This
syndrome can affect persons of any origin, but prevalence of the
20 disease appears higher in western and Scandinavian countries.
The aetiology of painful bladder syndrome remains
undetermined. Different studies suggest that its physiopathology
is multi-factor. Several pathogenic theories have been put
forward even if none of these aetiologies can be held to be the
25 unique aetiological factor. It is most likely that involvements
and interactions occur between these different factors.
- Infectious mechanism: even if bacterial, viral and fungal
analyses in patients suffering from painful bladder syndrome have
never been able to incriminate an infectious cause responsible
30 for this disorder. Patients suffering from painful bladder
syndrome frequently have a history of bladder infection and for
50% of patients the onset followed after occurrence of an
infection. However, up until now no infectious, bacterial or
viral factor has been determined as being the cause of the
disease and anti-infection treatments are ineffective. Infection
with "atypical" germs has been proposed by numerous authors. It
has been suggested that the germs found in painful bladder
syndrome are not the agents directly responsible but their
5 presence may be responsible for an immunoallergic reaction which
plays a role in its onset.
- Deterioration of urothelial permeability: the bladder mucosa is
coated with a layer of mucin which is composed of numerous
glycosaminoglycans and glycoproteins. The characteristic of these
10 glycosaminoglycans is that of having a negative charge enabling
them to form an impermeable hydrophobic barrier. This mucin layer
therefore prevents urine from entering the urothelium. In
patients suffering from painful bladder syndrome this layer is
defective and the urothelium is abnormally permeable. As a
15 result, potentially toxic substances in the urine enter into the
muscle layer of the bladder wall and depolarise sensitive nerves
leading to symptoms of painful bladder syndrome.
- Mastocyte reaction; mastocyte cells have been found in the
bladder wall in 30 to 65% of patients suffering from painful
20 bladder syndrome. Mastocytes contain cytoplasmic granules
comprising substances such as histamine, leukotrienes,
prostaglandins and tryptases. All these substances take part in
inflammatory reaction. In painful bladder syndrome, oedema,
fibrosis and neovascularisation may be due to release of these
25 mediators transported by the mastocyte cells. Activation of the
mastocytes is dependent on substance P and studies under electron
microscopy have shown an increase in nerve endings rich in
substance P in contact with the mastocytes. Overall, there seems
to exist a major role played by these mastocyte cells in painful
30 bladder syndrome. While the exact primary or secondary role of
mastocytes in the aetiology of painful bladder syndrome currently
remains a subject of debate, much research is focused on
understanding the activation of these cells and their
responsibility in symptomatology.
- Neuronal mechanism: this is the process whereby the nerves
manage to secrete local mediators of inflammation. In painful
bladder syndrome there is an increase in sympathetic innervation
and activation of purinergic neurotransmission. The existence of
5 local neurogenic inflammation could be the cause of a cascade of
chain reactions. This mechanism is described in painful bladder
syndrome as well as in other painful syndromes such as
fibromyalgia, irritable bowel syndrome. The major component of
this mechanism is substance P. This theory is based on the
10 presence of a high concentration of substance P and high number
of nerve fibres containing substance P in the bladder wall of
patients suffering from painful bladder syndrome. Interestingly
it has been shown that the urine concentration of substance P is
proportional to pain level.
15 - Auto-immune mechanism: 5% of patients with painful bladder
syndrome suffer from an auto-immune disease: lupus, thyroiditis,
scleroderma, polyarthritis, Goujerot-Sjogren syndrome. A certain
number of studies argue in favour of immune changes in painful
bladder syndrome. Nevertheless, an auto-immune mechanism or exact
20 role of the auto-immune mechanism in painful bladder syndrome
remains controversial. Deterioration of urothelial permeability
may result in inflammatory, auto-immune reactions possibly
accounting for the pathogenesis of painful bladder syndrome. The
existence of nuclear-factor kappa B activated in bladder biopsies
25 of patients with this syndrome has strengthened this theory. This
factor has also been found in other auto-immune diseases
including rheumatoid arthritis, inflammatory intestinal diseases
and bronchial asthma. However no study has been conclusive and
the changes in immune response are not specific and could only be
30 secondary to bladder tissue deterioration.
The symptomatology of painful bladder syndrome is high and
above all marked by pain symptoms, the topography of pain is subpubic,
vesical with irradiation towards the urethra but may also
affect the vagina, perineum, rectum, pelvis, sacrum The pain is
described as being of a type of burning, gnawing, pressure or
discomfort. It is more or less triggered by bladder filling and
sometimes relieved on urination. Patients are woken at night by
the pain and the urge to urinate. Pain comes in attacks with very
5 painful periods lasting several days and periods when pain is
more tolerable but always present.
The constant urinary symptom is the strong, persistent urge
to urinate. It can be associated with day-time and night-time
pollakiuria. Urgent or pressing needs to urinate may be present
10 but these are encountered above all - this being a diagnosis that
must be set aside - in the event of overactive bladder when
urgent needs are not painful. Often patients suffering from
painful bladder syndrome do not complain of any true urgent need
but rather more of a permanent wish to urinate ranging from mere
15 discomfort to true pain which is relieved on urinating. This
relief brought by urination accounts for the hurry of these
patients to empty their bladder and leads to confusion with urge
incontinence. If the need cannot be relieved, the discomfort or
pain is generally aggravated without any urine leakage which
20 could on the other hand occur with urge incontinence. This is
true for the majority of patients suffering from painful bladder
syndrome but it is possible to have painful bladder syndrome and
associated urge incontinence, which complicates diagnostic
assessment.
25 The clinical syndrome of overactive bladder may have several
causes: a neurological cause (medullar trauma, Parkinson's
disease, multiple sclerosis...), a psycho-behavioural cause or it
may be idiopathic coming within the nosology realm of pelviperineal
functional pathologies. The clinical syndrome of
30 overactive bladder may or may not be accompanied by non-inhibited
contractions of the detrusor which is the bladder muscle.
However, not every contraction of the detrusor is accompanied by
involuntary urine leakage. Several contractions, probably most
contractions, occur against a closed urinary tract sphincter.
From a physiopathological viewpoint, this situation may be
equivalent to urinary infra-vesical obstruction. Over time
progressive hypertrophy of the smooth muscle bundles may occur.
At cystoscopy, depending on frequency, amplitude and duration of
5 these contractions, the bladder wall will exhibit trabeculations
of greater or lesser extent possibly even causing a multidiverticular
bladder. In time, fibre degeneration may be produced
within these hypertrophied muscle bundles replacing the smooth
muscle fibres by deposits of collagen and fibrous tissue. The
10 bladder will become increasingly less distensible, its capacity
increasingly smaller and its contractility increasingly less
effective. This process can therefore lead to a bladder of small
capacity that is non-compliant and acontractile (or at least
having deficient contractility). The syndrome of overactive
15 bladder having variable expression groups together the urge
incontinencies associated or not with incontinence and/or daytime
or night-time pollakiuria. There is not only one symptom
that is pathognomonic of overactive bladder, but rather a set of
symptoms which may indicate this pathology: the presence of a
20 triad of symptoms may reasonably suggest overactivity.
Urge incontinencies or pressing needs correspond to an
urgent need to urinate accompanied by fear of leakage. They may
or may not be followed by pressing urination which cannot be
controlled or delayed by the patient, thereby causing leakage
25 through pressing need.
Amongst pelvi-perineal functional pathologies mention can
also be made of incontinence.
Urinary incontinence is defined as accidental or involuntary
loss of urine via the urethra. This disorder affects both men and
30 women and the cause is often multifactorial. The prevalence of
this disorder represents about 3 million persons in France. It is
particularly frequent in the elderly. Urinary continence requires
a properly functioning pelvic floor, sphincter integrity and
nerve controlling of these and of the detrusor. Any deterioration
of one of these structures can lead to incontinence. A
distinction is conventionally made between several forms of
incontinence:
- stress urinary incontinence, characterized by urine leakage on
5 physical activity, coughing and sneezing without any prior
urging;
- urge urinary incontinence characterized by urine leakage
accompanied by or irnrnedlately preceded by an urgent pressing
need to urinate, leading to urination that cannot be delayed
10 or retained;
- mixed urinary incontinence combines the two predefined types
of incontinence;
- enuresis is particularly seen in children with involuntary
urination at night.
15 Aside from the discomfort felt, urinary incontinence can
have psychological (anxiety, depression) and social (withdrawal)
repercussions. Promoting factors of urinary incontinence include
age, stress, obesity, neurological disorders, infection, prolapse
or slackening of the sphincter or pelvic floor muscles after
20 abdominal surgery or childbirth for example.
Anal incontinence corresponds to the involuntary emission of
gases and/or liquid and/or solid faeces, whereas faecal
incontinence excludes the emission of gases. Anal incontinence
does not only concern the elderly but also persons of any age,
25 women being more often affected than men. Childbirth and the
onset of menopause are factors promoting this incontinence. The
other risk factors include some traumas or surgical procedures at
the anal sphincter. However incontinence can also result from
some neurological pathologies (stroke, diabetes, multiple
30 sclerosis...), from certain surgical anal procedures or congenital
malformation. Faecal incontinence may also be accompanied by
prolapse of the rectum or it may be the symptom of another
disease such as cancer for example.
Chronic pelvi-perineal pain including painful bladder
syndrome is pain characterized by chronicity (more than six
months), absence of malignant pathology and its topography: the
pelvis and the perineum. There is major discrepancy between the
5 extent of patient complaint and the absence of lesion factors
likely to justify the complaint. One half of patients complain of
isolated pelvic pain, one quarter of patients also suffer from
irritable bowel syndrome, 10% of patients suffer from clinical
overactive bladder syndrome and the remaining 15% accumulate the
10 3 syndromes. Associations are very frequent between all painful
pathologies: painful bladder syndrome, vestibulodynia, irritable
bowel syndrome, pelvic pain, fibromyalgia and myofascial pain.
Patients complain of allodynia i.e. pain elicited by a stimulus
which is not normally felt to be painful. There exists a
15 predisposition promoting the expression of pain in the event of
fibromyalgia, chronic fatigue syndrome, migraine, complex
regional pain syndrome, anxiety, depression. Painful bladder
syndrome takes on all its meaning here since it can cover true
diseases of the vesical wall with intolerance to filling of the
20 bladder but it can also cover bladder hypersensitivities of which
the root cause is not necessarily within the bladder.
As for many diseases for which the exact causes are unknown,
there is no treatment allowing the curing of painful bladder
syndrome. However several therapeutic options provide relief to
25 patients by reducing the symptoms. Initially, behavioural changes
and self-care can improve the symptoms and must be applied as
much as possible. Also, stress management must be encouraged to
manage exacerbation of symptoms induced by stress. Physical
therapies using suitable manual techniques can also be proposed.
3 0 At pharmacological level it is possible to use drugs
essentially acting on pain and inflammation, and directly on the
deteriorated wall of the bladder for protection or reconstitution
thereof. Non-steroidal anti-inflammatories can relieve pain and
inflammation but they are rarely sufficient and they do not have
a lasting effect. They are generally well tolerated but may lead
to adverse side effects. In general, all pain-relieving
medication can be tried. Paracetamol and opiate analgesics,
morphine derivatives may be efficient alone or in association
5 with other pain relievers. Tricyclic antidepressants administered
at lower doses than those used to treat depression also act on
pain. The administration of antihistaminics may be effective, the
local secretion of histamine by the mastocytes possibly having a
local role in inflammation. It is also possible to administer
10 pentosan-polysulfate; this is a polysaccharide having a structure
similar to that of glycosaminoglycans and is eliminated in the
urines and is thought to reconstitute the deteriorated layer.
Hydrodistention may give patients relief for a few weeks but
the effects fade with repeat procedures and repetition thereof
15 promotes the risk of onset of a compliance disorder.
Instillations of different products can be proposed; local
treatment having the advantage of allowing direct application of
the product in contact with the mucosa and of reducing systemic
exposure. Instillation is a therapeutic method whereby a solution
20 is inserted into a natural conduit or cavity of the body to wash,
disinfect and treat this conduit or this cavity. Administration
of the solution into the bladder uses a catheter. Among those
products having exhibited efficiency is heparin which has antiinflammatory
and protective properties and contributes towards
25 temporarily reinforcing the deteriorated glycoprotein layer. For
lack of any sufficiently robust studies, it is difficult
correctly to evaluate the benefits and risks of this treatment.
It would seem that it is able only to improve a subset of
patients. It is also possible to instil local anaesthetic
30 products into the bladder such as lidocaine to reduce pain.
Dimethyl sulfoxide has shown an effect against pain, in
particular in associa-tion with corticosteroids, heparin and/or a
local anaesthetic. Results are generally good at the start of
treatment but instillations need to be repeated, as for most
other medications. However this product is highly ill-tolerated
in some patients in whom it causes burns and can even aggravate
the symptoms on initiation of the treatment. Hyaluronic acid or
chondroitin sulfate said to have a restorative effect on the
5 deteriorated bladder wall have proved their efficacy in some
patients.
Instillation of products into the bladder may provide relief
and can therefore be proposed despite the disadvantage of
requiring urinary catheterization with its risks of trauma and
10 sepsis.
Surgery is only to be envisaged as a last resort when all
other treatments have failed and symptoms have become extremely
incapacitating. Surgery is fairly heavy, traumatic and at times
only provides little or no improvement. The different possible
15 procedures range from partial cystectomy to the most radical
total cystectomy with urethrectomy.
Numerous treatments are therefore proposed to manage painful
bladder syndrome but the efficacy of these different treatments
is modest with trials in a small number of patients, these not
20 always being part of prospective randomised trials. It is
therefore clearly apparent that the treatments offered to persons
suffering from this syndrome are far from being sufficient. There
is therefore a major medical need and hence a need for novel
medicinal products having the least possible adverse effects
25 since they are intended for physiologically weakened persons.
PAR receptors (protease-activated receptors) are
heptahelical receptors coupled to trimeric G proteins: a
distinction is made between PAR1 receptors composed of 425 amino
acids, PAR2 with 397 amino acids, PAR3 composed of 374 amino
30 acids and PAR4 with 385 amino acids. Thrombin activates PAR1,
PAR3 and PAR4 by cleaving their extracellular N-terminal end
between arginine 41 and serine 42. The cleaved peptide has no
particular activity, the new N-terminal end of the receptor acts
as agonist by folding towards the cell surface and interacting
with the extracellular domains.
PAR1 plays a key role in platelet activation at low thrombin
concentrations whereas PAR4 reacts to strong concentrations. The
5 role of PARl has been determined in the field of vascular biology
and atherothrombosis. PAR1 antagonists have emerged as novel,
promising antithrombotics acting via oral route. Mention can be
made of vorapaxar, atopaxar which have provided promising
clinical data (Capodanno et dl. 2012). Vorapaxar was given FDA
10 authorisation in 2014 for the indication "reduction of thrombotic
events in patients with a history of myocardial infarction or
peripheral arterial disease". Atopaxar is currently no longer
under development as inhibitor of platelet aggregation.
On the bladder wall PARl and PAR2 are expressed both on
15 urothelial cells and also on the detrusor cells (Saban et dl.
2007).
Studies have shown the major involvement of PAR2 in bladder
contractility (Nakahara et al. 2004).
It has been demonstrated that PAR activation by thrombin
20 induces inflammation of the bladder in different animal models
(De Garavilla et al. 2007; Saban et al. 2007).
The inventors have shown that a selective antagonist of PAR1
receptors forms an innovative therapeutic approach to treatment
of inflammation and associated pain in pelvi-perineal functional
25 pathologies and in particular in painful bladder syndrome.
Unexpectedly the inventors have discovered that vorapaxar,
atopaxar and 3- (2-Chloro-phenyl)- 1- [4-( 4-fluoro-benzy1)-
piperazin-1-yll-propenone, or one of the pharmaceutically
acceptable salts thereof, is capable of protecting the bladder
30 whilst efficiently reducing its myogenic contractile responses.
Vorapaxar is described in patent application WO 03089428: it
is ethyl N- [ (3R, 3aS, 4S, 4aR, 7R, 8aR, 9aR) -4- [ ( E ) -2- [5- (3-
fluoropheny1)-2-pyridyllvinyll-3-methyl-1-0x0-
3a, 4,4a, 5,6,7,8,8a, 9,9a-decahydro-3H-benzorf] isobenzofuran-7-
yll carbamate.
Atopaxar is [(1-(3-tert-buty1-4-methoxy-5-morpholinophenyl)-
2-(5,6-diethoxy-fluoro-l-imin0-l,3-dihydro-2H-isoindol-2yl)
5 ethanone hydrobromide.
3- (2-Chloro-phenyl)- 1- [4- (4-fluoro-benzyl)- piperazin-1-yl]-
propenone represented by formula:
the pharmaceutically acceptable salts thereof and its use as
10 platelet aggregation inhibitor in the treatment both curative and
preventive of arterial or venous thrombosis, stable angina, heart
beat disorders, myocardial infarction, hypertension, heart
failure, stroke, acute coronary syndromes, to inhibit the
proliferation of smooth muscle cells (restenosis) , in the
15 curative and preventive treatment of inflammatory disorders, lung
diseases, gastro-intestinal diseases, development of fibrosis in
patients suffering from chronic liver disease, skin diseases, for
the curative and treatment of the proliferation of
endothelial, fibroblast, cardiac fibroblast, glial, smooth muscle
20 or cancer cells - are described in patent WO 2007/147824.
In the present invention the term "pharmaceutically
acceptable" refers to molecular entities and compositions which
do not produce any adverse, allergic effect or other adverse
reaction when administered to a human being. When used herein the
25 term "pharmaceutically acceptable excipient" includes any
diluent, adjuvant or excipient such as preserving agents,
fillers, disintegrating, wetting, emulsifying, dispersing,
antibacterial or antifungal agents, or agents allowing delayed
absorption and intestinal and digestive resorption. The use of
30 these media or vectors is well known to persons skilled in the
art.
The pharmaceutically acceptable salts for therapeutic use of
a compound of the present invention include conventional nontoxic
salts of the compound of the invention such as those formed
from organic or inorganic acids. As examples, mention can be made
5 of salts derived from inorganic acids such as hydrochloric,
hydrobromic, phosphoric, sulfuric acids and those derived from
organic acids such as acetic, trifluoroacetic, propionic,
succinic, fumaric, malic, tartaric, citric, ascorbic, maleic,
glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic,
10 stearic, lactic acids.
These salts can be synthesised from a compound of the
invention containing a base part and the corresponding acids
following conventional chemical methods.
The solvates acceptable for therapeutic use of a compound of
15 the present invention comprise conventional solvates such as
those formed at the last step in the preparation of a compound of
the invention due to the presence of solvents. As examples,
mention can be made of solvates due to the presence of water or
ethanol.
20 Vorapaxar, atopaxar and 3-(2-Chloro-pheny1)l-[4-(4-fluorobenzy1)-
piperazin-1-yll-propenone are selective PAR1 antagonists.
The PARl antagonists known to date are N3-cyclopropyl-7-([4-
(l-methylethyl)phenyl]methyl~-7H-pyrr010[3,2-f]quinazoline-1,3-
diamine (SCH-79797), vorapaxar (SCH-530348), atopaxar (E5555) and
25 SCH-602539.
A subject of the invention is the use of a PARl antagonist
as medication in the prevention and/or treatment of pelviperineal
functional pathologies.
A subject of the invention is the use of vorapaxar as
30 medication in the prevention and/or treatment of pelvi-perineal
functional pathologies.
A subject of the invention is the use of atopaxar as
medication in the prevention and/or treatment of pelvi-perineal
functional pathologies.
A subject of the invention is the use of 3-(2-Chlorophenyl)-
l-[4-(4-fluoro-benzyl)-piperazin-l-yl]-propenone as
medication in the prevention and/or treatment of pelvi-perineal
functional pathologies.
5 A subject of the invention is the use of a PAR1 antagonist
as medication in the prevention and/or treatment of painful
bladder syndrome.
A subject of the invention is the use of vorapaxar as
medication in the prevention and/or treatment of painful bladder
10 syndrome.
A subject of the invention is the use of atopaxar as
medication in the prevention and/or treatment of painful bladder
syndrome.
A subject of the invention is the use of 3-(2-Chloro-
15 phenyl)-1-[4-(4-fluoro-benzyl)-piperazin-l-yl]-propenone as
medication in the prevention and/or treatment of painful bladder
syndrome.
A subject of the invention is the use of a PARl antagonist
as medication in the prevention and/or treatment of overactive
20 bladder syndrome.
A subject of the invention is the use of vorapaxar as
medication in the prevention and/or treatment of overactive
bladder syndrome.
A subject of the invention is the use of atopaxar as
25 medication in the prevention and/or treatment of overactive
bladder syndrome.
A subject of the invention is the use of 3-(2-Chlorophenyl)-
l-[4-(4-fluoro-benzyl)-piperazin-l-yl]-propenone as
medication in the prevention and/or treatment of overactive
30 bladder syndrome.
A further subject of the invention concerns the use of a
PARl antagonist in patients presenting with urinary incontinence
and/or anal or faecal incontinence.
A further subject of the invention concerns the use of
vorapaxar in patients presenting with urinary incontinence and/or
anal or faecal incontinence.
A further subject of the invention concerns the use of
5 atopaxar in patients presenting with urinary incontinence and/or
anal or faecal incontinence.
A further subject of the invention concerns the use of 3-(2-
Chloro-phenyl)-l-[4-(4-fluoro-benzyl)-piperazin-l-yl]-propenone
in patients presenting with urinary incontinence and/or anal or
10 faecal incontinence.
A further subject of the invention concerns the use of a
PAR1 antagonist in patients presenting with chronic pelviperineal
pain.
A further subject of the invention concerns the use of
15 vorapaxar in patients presenting with chronic pelvi-perineal
pain.
A further subject of the invention concerns the use of
atopaxar in patients presenting with chronic pelvi-perineal pain.
A further subject of the invention concerns the use of 3-(2-
20 Chloro-phenyl)-1-[4-(4-fluoro-benzyl)-piperazin-l-yl]-propenone
in patients presenting with chronic pelvi-perineal pain.
The present invention further concerns a pharmaceutical
composition comprising a PARl antagonist as active ingredient and
at least one pharmaceutically acceptable excipient for use
25 thereof as medication in the prevention and/or treatment of
pelvi-perineal functional pathologies, in particular OF painful
bladder syndrome, overactive bladder syndrome, chronic pelviperiTOnea1
pain. The present invention also concerns a
pharmaceutical composition comprising a PARl antagonist as active
30 ingredient and at least one pharmaceutically acceptable excipient
for use thereof as medication in patients presenting with urinary
incontinence and/or anal or faecal incontinence.
The pharmaceutical compositions of the present invention can
be formulated for administration to human beings. The
compositions of the present invention can be administered via
oral, sublingual, sub-cutaneous, intramuscular, intravenous,
transdermal, local or rectal route. In this case the active
ingredient can be administered to human beings in unit
5 administration forms in a mixture with conventional
pharmaceutical substrates. Suitable unit administration forms
include forms via oral route such as tablets, capsules, powders,
granules and solutions or oral suspensions, sublingual and buccal
administration forms, subcutaneous or transdermal, topical,
10 intramuscular, intravenous, intra-nasal or intra-ocular
administration forms, intra-vesical, intramural or rectal
administration forms.
When a solid composition is prepared in tablet form, the
main active ingredient is mixed with a pharmaceutical carrier
15 such as gelatine, starch, lactose, magnesium stearate, talc, gum
arabic, silica or the like. The tablets can be coated with
sucrose or other suitable materials or they can be treated so
that they have extended or delayed release and continuously
release a predetermined amount of active ingredient.
20 A capsule preparation is prepared by mixing the active
ingredient with a diluent and pouring the mixture obtained into
hard or soft capsules.
A preparation in syrup or elixir form can contain the active
ingredient together with a sweetener, antiseptic, taste enhancer
25 and suitable colouring agent.
Water-dispersible powders or granules can contain the active
ingredient in a mixture with dispersion or wetting agents, or
suspending agents, and also with taste enhancers or sweeteners.
For rectal administration gels, creams, powders,
30 suspensions, solutions, foams or suppositories are used which are
prepared with binders which melt at rectal temperature e.g. cocoa
butter or polyethylene glycols.
For parenteral administration (intravenous, intramuscular,
intradermal, sub-cutaneous), intra-nasal, intraocular,
intravesical or intramural administration the use is made of
aqueous suspensions, isotonic saline solutions or sterile,
injectable solutions containing pharmacologically compatible
dispersion agents and/or wetting agents.
5 The active ingredient can also be formulated in the form of
microcapsules, optionally with one or more added substrates.
Suitable formulations for the selected administration form
are known to persons skilled in the art and described for example
in: Remington, The Science and Practice of Pharmacy, lgZh Edition,
10 1995, Mack Publishing Company.
Advantageously, the pharmaceutical composition of the
present invention is intended for administration via local route:
the term endovesical is used, the pharmaceutical composition of
the present invention is intended to be used in endovesical
15 administration form. Among endovesical treatments preference is
given to vesical instillation and/or intramural injection i.e.
administration into the thickness of the bladder wall.
The dosages of the PAR1 antagonist in the compositions of
the invention can be adjusted to obtain an amount of substance
20 that is effective to obtain the desired therapeutic response for
a composition particular to the method of administration. The
effective dose of the compound of the invention varies as a
function of numerous parameters such as the chosen administration
route, patient weight, age, gender, type of pathology, type of
25 applied treatment(s) and sensitivity of the person to be treated.
As a result, the optimal dosage must be determined by the
specialist in relation to parameters considered to be relevant.
Although effective doses may vary in large proportions, the daily
doses could range from 0.1 mg to 1000 mg every 24 hours, and
30 preferably between 1 and 200 mg for an adult of 70 kg average
weight, taken at one or more times.
The following examples allow better comprehension of the
invention without limiting the scope thereof.
Example 1: Effect of 3- (2-Chloro-phenyl)- 1- [4-( 4-fluorobenzy1)-
piperazin-1-yll-propenone on a rat-isolated bladder model
(Shimizu et d l . , Biol. Pharm. Bull. 34(7):1122-1125, 2011).
Purpose of the experiment: Evaluate the role of 3-(2-Chloro-
5 phenyl)-1-[4-(4-fluoro-benzyl)-piperazin-l-yl]-propenone on the
amplitude of bladder contraction induced by trypsin and TFLLR.
The experiment was led in parallel on naive bladders and on
bladders subjected to inflammation procedure. The effect of the
compound of the invention was compared with that of a reference
10 PAR1 antagonist: compound SCH203099, (Ahn et dl. Biochem.
Pharmacol. 60(10:1425-1434, 2000).
Protocol
To induce inflammation of the bladder, cyclophosphamide was
bilaterally injected into the rats (Female Wistar Han rats
15 weighing 250 to 275g on the day of the experiment, obtained from
Charles River laboratory, France) via intraperitoneal route at a
dose of 150 mg/kg in a final volume of 5 mL/kg.
Pain evaluation was conducted 2 hours after cyclophosphamide
administration.
20 In naive rats (no administration of cyclophosphamide) or 24
hours after administration of cyclophosphamide, the animals were
anaesthetised with pentobarbital (60 mg/kg) and euthanized. The
bladder was rapidly taken and placed in modified Krebs-Henseleit
oxygenated solution having the following composition (mM): NaCl
25 114; KC1 4.7; CaC12 2.5; MgSOq 1.2; KH2P04 1.2; NaHC03 25 and
glucose 11.7 (pH 7.4 with 95% O2 and 5% C02). The bladder was
cleaned of conjunctive tissue, weighed, the distal and proximal
portions removed and the bladder cut in longitudinal direction
into two equal strips. These strips were attached with silk
30 thread and immersed in a 10 mL isolated organ bath (EMKA
Technologies) containing the Krebs-Henseleit oxygenated solution
with 95%:5% mixture of 02/C02 held at 37"~. The bladder strips
were connected via the silk thread to isometric sensors (IT50
model, EMKA Technologies) connected to amplifiers (EMKA
Technologies). Contractile responses were recorded using 10x28
software (EMKA Technologies j .
For an initial stabilisation period of at least 90 minutes,
rinsing operations were carried out every 15 minutes and the
5 tensioning of each bladder strip readjusted to 1.0 g. The strips
were then exposed to 50 mM KC1 to verify their viability. If the
contraction amplitude of the strips was less than 1.0 g, the
tissues were discarded and not included in the experiment. After
a second stabilisation and washing period of at least 45 minutes,
10 a concentration of the compound of the invention or of the
reference product (SCH203099) or of the vehicle was incubated for
30 minutes. A concentration-accumulative response curve to the
selective agonist PAR1, to TFLLR (0.1 pM to 0.1 mM) or to trypsin
(10 U to 10,000 BAEE U/mL) was plotted.
15 Results
In the presence of 3000 BAEE U/mL trypsin, inflammation
increased bladder contractility due to PAR activation by a factor
of 2.5. Contraction amplitude was 0.99 0.20 g for the naive
vehicle group versus 2.73 + 0.34 g for the vehicle group treated
20 with cyclophosphamide.
The compound of the invention antagonises trypsin-induced
bladder contraction only at strong concentrations in naive
animals as shown in Figure 1. The amplitude of bladder
contraction was divided by two with the compound of the invention
25 at 30 pM versus vehicle (0.55 i 0.24 g versus 0.99 i 0.20 gj and
nothing was observed at the other concentrations of the compound
of the invention.
The compound of the invention has concentration-dependent
antagonist action on trypsin-induced bladder contraction under
30 inflammation conditions (Figure 2). Up to 3 pM the compound of
the invention appears to be inactive, at 10 pM the compound of
the invention reduces bladder contraction by 35 % (1.76 + 0.30 g
versus 2.73 i 0.34 gj . At 30 pM the compound of the invention
reduces bladder contraction by about 70 % (0.92 i 0.17 g versus
2.73 f 0.34g).
The reference product (SCH203099) antagonised trypsininduced
bladder contraction only at strong concentrations in
5 naive animals (Figure 3). The amplitude of bladder contraction
was divided by two in the presence of 10 pM SCH203099 versus the
vehicle (0.48 t O.llg versus 0.99 i 0.20g) and nothing was
observed at the other concentrations of SCH203099.
Compound SCH203099 had concentration-dependent antagonist
10 action on trypsin-induced bladder contraction under inflammation
conditions (Figure 4). A 25% reduction was observed with 3 )IM
SCH203099 (2.05 i 0.53g versus 2.73 f 0.34g), a 35% reduction was
observed in the presence of 10 pM SCH203099 (1.77 i 0.38g versus
2.73 I 0.34g) and 30 pM SCH203099 reduced bladder contraction by
15 60% (1.04 t 0.16g versus 2.73 f 0.34g) .
In the presence of 100 pM TFLLR, inflammation increased
bladder contractility due to PAR1 activation by a factor of 2.
The amplitude of contraction was 0.59 t 0.14g for the naive
vehicle group versus 1.10 I 0.18g for the vehicle group treated
20 with cyclophosphamide.
The compound of the invention has concentration-dependent
antagonist action on TFLLR-induced bladder contraction in naive
animals. At 1 pM the compound of the invention appeared to be
inactive, at 3 pM a 45% reduction in bladder contraction was
25 observed (0.33 i 0.05g versus 0.59 i 0.14g) . At 10pM the compound
of the invention reduced bladder contraction by 70% (0.18 t 0.04g
versus 0.59 t 0.14g). At 30 pM the compound of the invention
completely abolished bladder contraction (0.00 I 0.04g versus
0.59 -t 0.14g) even with tissue relaxation during the experiment
30 (Figure 5) .
The compound of the invention also has concentrationdependent
antagonist action on TFLLR-induced bladder contraction
under inflammation conditions (Figure 6). Up to 3 pM no
conclusive effect (only 10% reduction), at 10 pM the compound of
the invention reduced bladder contraction by 60% (0.45 i 0.13g
versus 1.10 i 0.18g) and at 30 pM the compound of the invention
reduced contractile response by 90% (0.11 i 0.04g versus 1.10 f
0.18g).
5 The reference product (SCH203099) antagonised TFLLR-induced
bladder contraction only at high concentrations in naive animals
(Figure 7). The amplitude of bladder contraction was divided by
two in the presence of 10 pM SCH203099 versus the vehicle (0.26 i
0.07g versus 0.59 k 0.14g) and nothing was observed at the other
10 concentrations of SCH203099.
Compound SCH203099 has concentration-dependent antagonist
action on TFLLR-induced bladder contraction under inflammation
conditions (Figure 8). At 3 pM SCH203099 no conclusive effect was
observed (10% reduction). A 35% reduction was noted in the
15 presence of 10 pM SCH203099 (0.73 i 0.10g versus 1.10 i 0.18g)
and 30 pM SCH203099 reduced bladder contraction by 55% (0.49 i
0.08g versus 1.10 i 0.18g).
To summarise, trypsin-induced bladder contractions are
antagonised In similar fashion by the reference product
20 (SCH203099) and the compound of the invention. On the other hand
with bladder contractions induced by the PAR1 agonist, the
compound of the invention has a more powerful effect on inflamed
bladders.
The inventors have therefore surprisingly shown that the
25 compound of the invention efficiently reduces exacerbated
contractile responses of an inflamed and/or overactive bladder
i.e. the compound of the invention appears to be of particular
interest in cases of painful bladder syndrome but also for
overactive bladder syndrome.
3 0
Example 2: Effects of vorapaxar and atopaxar on a ratisolated
bladder model.
The objective of this study was to evaluate the effects of
vorapaxar and atopaxar on the amplitude of trypsin- and TFLLRinduced
bladder contraction.
These experiments were conducted on naive bladders. The
5 protocol followed was the same as the protocol described in
Example 1.
Results obtained with vorapaxar:
In the presence of trypsin at 3000 BAEE U/mL, inflammation
increases bladder contractility by a factor of two. The amplitude
10 of contraction increased from 0.93 + 0.10g to 1.97 i 0.14g.
Vorapaxar at 3 pM antagonises trypsin-induced bladder contraction
in naive animals as illustrated in Figure 9. The amplitude of
bladder contraction is antagonised in the presence of 3 pM
vorapaxar versus vehicle (0.79 i 0.14g versus 1.04 i 0.169,
15 respectively). At a concentration of 10 pM the lesser efficacy is
due to the low solubility of the compound. This is confirmed at a
concentration of 30 pM.
In the presence of 100 pM TFLLR, bladder contractility
increases with PAR1 activation. The amplitude of contraction is
20 0.57 + 0.119. Vorapaxar has concentration-dependant antagonist
action on TFLLR-induced bladder contraction in naive animals
(Figure 10). At 3 nM vorapaxar induces a reduction of nearly 50%
in bladder contraction (0.31 i 0.12g versus 0.57 f 0.11g). At
10 nM vorapaxar reduces bladder contraction by 75% (0.14 i 0.02g
25 versus 0.57 i O.llg) . From 1 pM, vorapaxar completely abolishes
bladder contraction (0.04 i 0.03g i 0.57 f 0. llg) , as shown in
Figure 10.
Results obtained with atopaxar:
In the presence of 3000 BAEE U/mL trypsin the amplitude of
30 contraction increases by a factor of more than two (0.76 + 0.08g
versus 1.93 t 0.099). Atopaxar has concentration-dependant
antagonist action on trypsin-induced bladder contraction in naive
animals as illustrated in Figure 11. At 1 pM, atopaxar induces a
slight reduction in bladder contraction (1.02 i 0.20g versus 1.17
f 0.10g). At 3 pM, atopaxar causes a 38% reduction in bladder
contraction (0.74 i 0.19g versus 1.17 t 0.10g). At 10 pM atopaxar
reduces bladder contraction by 70% (0.36 + 0.159 versus 1.17 f
0.10g) and completely abolishes contraction at 30 pM (Figure 11).
5 In the presence of 100 pM TFLLR, bladder contractility is
increased with PAR1 activation. The amplitude of contraction
reaches 0.50 i 0.09 g. Atopaxar has concentration-dependant
antagonist action on TFLLR-induced bladder contraction in naive
animals after 10 nM (Figure 12). At 10 nM atopaxar induces a
10 reduction in bladder contraction of more than 50% (0.21 i 0.039
versus 0.50 i 0.09g) . At 1 pM atopaxar, bladder contraction is
almost completely abolished with a decrease of more than 80%
(0.08 f 0.039 versus 0.50 i 0.09g), as shown in Figure 12.
To conclude, vorapaxar and atopaxar prevent bladder
15 contractions under physiological conditions. The inventors have
therefore shown that PAR1 antagonists efficiently reduce
contractile responses i.e. they appear to be of particular
interest for pelvi-perineal functional pathologies and in
particular in painful bladder syndrome.
We claim :
1. A PAR1 antagonist for use as medication in the prevention
and/or treatment of pelvi-perineal functional pathologies.
5 2. The PARl antagonist for use according to claiml,
characterized in that it is vorapaxar or atopaxar or one of the
pharmaceutically acceptable salts thereof.
3 . The PARl antagonist for use according to claim1,
characterized in that it is 3-(2-Chloro-pheny1)-I-[4-(4-fluoro-
10 benzy1)-piperazin-1-yll-propenone or one of the pharmaceutically
acceptable salts thereof.
4. The PARl antagonist for use according to claim 1, in patients
presenting with painful bladder syndrome.
5. The PAR1 antagonist for use according to claim4,
15 characterized in that it is vorapaxar or atopaxar or one of the
pharmaceutically acceptable salts thereof.
6. The PAR1 antagonist for use according to claim4,
characterized in that it is 3-(2-Chloro-pheny1)-1-[4-(4-fluorobenzy1)-
piperazin-1-yll-propenone or one of the pharmaceutically
20 acceptable salts thereof.
7. The PAR1 antagonist for use according to claim 1, in patients
presenting with overactive bladder syndrome.
8. The PAR1 antagonist for use according to claim7,
characterized in that it is vorapaxar or atopaxar or one of the
25 pharmaceutically acceptable salts thereof.
9. The PARl antagonist for use according to claim7,
characterized in that it is 3-(2-Chloro-pheny1)-1-[4-(4-fluorobenzy1)-
piperazin-1-yll-propenone or one of the pharmaceutically
acceptable salts thereof.
5 10. The PAR1 antagonist for use according to claim 1, in patients
presenting with urinary incontinence.
11. The PARl antagonist for use according to claim 1, in patients
presenting with chronic pelvi-perineal pain.
12. A pharmaceutical composition characterized in that it
10 contains as active ingredient a PARl antagonist and at least one
pharmaceutically acceptable excipient, for use thereof as
medication for the prevention and/or treatment of pelvi-perineal
functional pathologies.
13. The pharmaceutical composition according to claim12,
15 characterized in that it contains as active ingredient vorapaxar
or atopaxar or one of the pharmaceutically acceptable salts
thereof.
14. The pharmaceutical composition according to claim 12,
characterized in that it contains as active ingredient 3-(2-
20 Chloro-phenyl)-1-[4-(4-fluoro-benzyl)-piperazin-lyll-propenone
or one of the pharmaceutically acceptable salts thereof.
15: The pharmaceutical composition according to claim 12, for use
in endovesical administration form.