OA17905A - Use of PAR-1 antagonists for the prevention and / or treatment of functional pelvic-perineal pathologies. - Google Patents

Abstract

The present invention relates to the use of PAR1 antagonists, in particular vorapaxar, atopaxar and 3- (2-chloro-phenyl) -1- [4- (4fluoro-benzyl) -piperazin-1-yl] - propenone or one of their pharmaceutically acceptable salts for the prevention and / or treatment of pelvic-perineal functional pathologies, and more particularly of painful bladder syndrome. Fig. 1

Description

Use of PAR-1 antagonists for the prevention and / or treatment of functional pelvic-perineal pathologies

The invention relates to PAR-1 antagonists and more particularly vorapaxar, atopaxar and 3- (2-Chlorophenyl) -1- [4- (4-fluoro-benzyl) -piperazin-l-yl] -propenone or one of their pharmaceutically acceptable salts for their use in the prevention and / or treatment of pelvic-perineal functional pathologies.

Functional pelvic-perineal pathologies encompass various pathologies affecting the pelvic-perineal region, excluding cancerous lesions and all proven infectious, metabolic or endocrine pathologies. One of the functional pelvic-perineal pathologies is represented by the painful bladder syndrome, also called interstitial cystitis which is defined as being, in the absence of proven urinary tract infection or other objective pathologies, chronic pelvic pain, evolving for more than six months, sometimes felt as a sensation of pressure or as discomfort perceived in relation to the bladder and accompanied by at least one urinary symptom: persistent and strong urge to urinate or pollakiuria. A nocturia very often accompanies this painful bladder syndrome. Pollakiuria is defined as an abnormally high frequency of urination, exceeding eight urinations in a 24 hour period. Nocturia is defined by a need to urinate waking the patient up one or more times during the night. The diagnosis of painful bladder syndrome or interstitial cystitis is based on questioning and carrying out a voiding calendar. The clinical examination must have ruled out all other causes of pain of bladder origin, the diagnosis of painful bladder syndrome being a diagnosis of exclusion. If painful bladder syndrome is suspected, perform a cystoscopy under> V ο

General or regional anesthesia is the key examination for workup and diagnosis. Classically, this examination can reveal glomerulations of the bladder mucosa with or without Hunner's lesions. However, cystoscopy can sometimes be normal at the initial stage and with an absence of Hunner's lesions. At the same time, it allows bladder biopsies and bladder hydrodistension to be performed. Hydrodistension consists of dilating the bladder with water performed under anesthesia. The other complementary examinations, imaging, urodynamic assessment, biology, cytology are not essential for the diagnosis but are useful for the differential diagnosis because the syndrome of interstitial cystitis remains a diagnosis of exclusion.

There seem to be two categories of patients: those who have alterations of the bladder wall and in particular Hunner's lesions (20% of cases) and those who do not. However, there is a continuum between these different clinical presentations. It is difficult to know the exact number of people affected by this disease, which is probably underdiagnosed. The prevalence varies by country. In Europe, estimates range from one in 12,500 to one in 1,500 people. In the United States, the prevalence is estimated at around one in 1,500. While both sexes can be affected, 90% of patients with painful bladder syndrome are women. This syndrome can affect people of all origins, but the prevalence of the disease seems to be higher in Western and Nordic countries.

The etiology of painful bladder syndrome remains unclear. Different studies suggest that its pathophysiology is multifactorial. Several pathogenic theories are proposed even if none of these etiologies can be retained as being the only etiological factor. Above all, it is possible that there are implications and interactions between these different factors.

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- An infectious mechanism, even if bacterial, viral and fungal analyzes carried out in patients with painful bladder syndrome have never been able to incriminate an infectious cause responsible for this affection. Indeed, patients with painful bladder syndrome often have a history of urinary tract infections and 50% of them see their disease begin following an infectious episode. However, until now, no infectious factor, either bacterial or viral, has been found to be the cause of the disease and anti-infective treatments are ineffective. Infection with "atypical" germs has been proposed by many authors. It has been suggested that the germs found in painful bladder syndrome are not the directly implicated agents, but their presence may be responsible for an immunoallergic reaction which plays a role in its occurrence.

- Altered urothelial patency; the bladder lining is covered by a layer of mucin which is made up of many glycosaminoglycans and glycoproteins. These glycosaminoglycans have the characteristic of possessing a negative charge allowing them to form an impermeable hydrophobic barrier. This mucinous layer thus prevents urine from entering the urothelium. In patients with painful bladder syndrome, this layer is defective and the urothelium is abnormally permeable. As a result, potentially toxic substances in the urine enter the muscular layer of the bladder wall and depolarize the sensory nerves resulting in the symptoms of painful bladder syndrome.

- A mast cell reaction; mast cells have been found in the bladder wall in 30-65% of patients with painful bladder syndrome. Mast cells contain cytoplasmic granules with substances, such as histamine, leukotrienes, prostaglandins and tryptases. All of these substances are involved in painful bladder, inflammatory reaction. In edema syndrome, fibrosis and neovascularization may be due to the release of these mediators transported by mast cells.

The activation of mast cells is dependent on substance P and electron microscopy studies have shown an increase in nerve endings rich in substance

P in contact with mast cells.

Overall, there seems to be an important role for these cells

If the mast cell role in painful bladder syndrome.

The exact primary or secondary mast cells in the etiology of painful bladder syndrome remains debated to date, much research is focused on understanding the activation of these cells and their responsibility in symptomatology.

- The neural mechanism; it is the process by which 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 local neurogenic inflammation could be at the origin of a cascade of chain reactions. This mechanism is described in painful bladder syndrome as well as in other pain syndromes, such as fibromyalgia, irritable bowel syndrome. The major component of this mechanism is substance P. This theory is based on the presence of a large concentration of substance P and a large number of nerve fibers containing substance P in the bladder wall of affected patients. painful bladder syndrome. Interestingly, it has been shown that the urinary substance P concentration is proportional to the degree of pain.

- An autoimmune mechanism; 5% of patients with painful bladder syndrome are affected by an autoimmune disease: lupus, thyroiditis, scleroderma, polyarthritis, Goujerot-Sjogren syndrome. A number of studies argue for immune modifications in the pain syndrome> k bladder. Nevertheless, an autoimmune mechanism or the exact role of the autoimmune mechanism in painful bladder syndrome remains controversial. Altered urothelial patency can result in inflammatory and autoimmune reactions that may explain the pathogenesis of painful bladder syndrome. The existence of activated nuclear kappa B factor in bladder biopsies from patients with this syndrome reinforced this theory. This factor has also been found in other autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and bronchial asthma. But no study is conclusive, and changes in immune responses are not specific and may only be secondary to bladder tissue damage.

The symptomatology of painful bladder syndrome is rich and above all marked by painful symptomatology, the topography of the pain is suprapubic bladder with irradiation towards the urethra but can also affect the vagina, the perineum, the rectum, the pelvis, the sacrum .... Pain is described as burning, tightness, pressure, or discomfort. It is more or less triggered by bladder filling and sometimes calmed by urination. Patients are awakened at night by pain and the need to urinate. The pain often evolves by crisis with periods of several days very painful and periods when the pain is more bearable but still present.

The constant urinary symptom is the persistent and strong urge to urinate. It can be associated with daytime and nighttime pollakiuria. Urge or urgency may be present, but they are mostly encountered and this is a diagnosis that must be eliminated during an overactive bladder in which the urgencies are not painful. Often, patients with painful bladder syndrome do not complain of true urgency but rather of a permanent urge to void ranging from *

simple discomfort with real pain which is relieved by urination. This relief from urination explains the eagerness of these patients to empty their bladder which results in confusion with urgency. If the need cannot be relieved, the discomfort or pain is generally accentuated without the occurrence of urinary leakage, which may, on the other hand, be the case for urgency. This is true for the majority of patients with painful bladder syndrome, but it is possible to have painful bladder syndrome and associated urgency, which complicates the diagnostic workup.

The clinical syndrome of overactive bladder can have several origins: a neurological origin (spinal cord trauma, Parkinson's disease, multiple sclerosis, etc.), a psycho-behavioral origin or be idiopathic and fall within the nosological framework of pelviperineal functional pathologies. The clinical syndrome of overactive bladder may or may not be accompanied by uninhibited contractions of the detrusor, which is the muscle of the bladder. Not all detrusor contraction is necessarily accompanied by involuntary urine leakage. Several contractions, probably the majority of them, occur against a closed sphincteric urinary tract. From a pathophysiological point of view, this situation may be equivalent to an infravesical urinary obstruction. Over time, progressive enlargement of the smooth muscle bundles can occur. At cystoscopy, depending on the frequency, amplitude and duration of these contractions, the bladder wall will show more or less marked trabeculations, which can even cause a multidiverticular bladder. Over time, fibrous degeneration can develop within these enlarged muscle bundles, replacing smooth muscle fibers with deposits of collagen and fibrous tissue. The bladder will become less and less distensible, its capacity more and more reduced and its contractility less and less efficient. This process can therefore

Λ * result in a bladder of small capacity, non-compiling and acontractile (or at least with deficient contractility). The variable expression overactive bladder syndrome includes urgencies associated or not with incontinence and / or daytime and nighttime pollakiuria. There is not just one symptom that is pathognomonic of overactive bladder, but rather a set of symptoms that may be suggestive of this pathology: the presence of a triad of symptoms may reasonably suggest overactivity.

Urgencies or urges correspond to an urgent need to urinate accompanied by a fear of flight. They are followed or not by urgent urination, which cannot be controlled and delayed by the patient, and thus cause leaks by urgency.

Among the functional pelvic-perineal pathologies, mention may also be made of incontinence.

Urinary incontinence is defined as an accidental or involuntary loss of urine through the urethra. This condition affects both men and women and the origin is often multifactorial. The prevalence of this disorder represents approximately 3 million people in France. It is particularly common in the elderly. Urinary continence requires a properly functioning pelvic floor, integrity of the sphincters and the nerve controls acting on them and on the detrusor. Any alteration to any of these structures can lead to incontinence. Several forms of incontinence are classically distinguished:

- stress urinary incontinence, characterized by urine leakage occurring during physical exertion, coughing and sneezing, without prior feeling of need.

- urinary incontinence by urgency characterized by a urine leak accompanied or immediately preceded by a *

urgent and irrepressible urge to urinate resulting in urination that cannot be postponed and withheld.

Mixed urinary incontinence combines the two types of predefined incontinence.

enuresis manifested in particular in children by involuntary urination occurring at night.

In addition to the discomfort caused, urinary incontinence can be favored by age, stress, obesity, neurological disorders, infection, prolapse or relaxation of sphincter or pelvic floor muscles following abdominal surgery or childbirth for example.

Anal incontinence corresponds to the involuntary emission of gas and / or liquid and / or solid stools, while faecal incontinence excludes the emission of gas. Anal incontinence does not only affect older people but also people of all ages, with women being affected more often than men.

Indeed, childbirth and the onset of menopause are factors favoring this incontinence.

Other risk factors include certain trauma or surgery to the anal sphincter. But incontinence can also result from certain neurological pathologies (stroke, diabetes, anal sclerosis or congenital malformations. Fecal incontinence can also accompany a prolapse of the rectum or be the symptom of another disease such as cancer for example. .

Chronic pelvic-perineal pain, including painful bladder syndrome, is pain also characterized by its chronicity (over six months) the absence of malignant pathology and its topography: the pelvis on the one hand, the perineum on the other . There is an important dissociation between the extent of the patient's complaint and the absence of lesional factors likely to justify them. Half of the patients complain of isolated pelvic pain, a quarter of the patients also suffer from irritable bowel syndrome, 10% of patients suffer from a clinical syndrome of overactive bladder, the remaining 15% combine the 3 syndromes. Associations are very common between all painful pathologies: painful bladder syndrome, vestibulodynia, irritable bowel syndrome, pelvic pain, fibromyalgia, and myofascial pain. Patients complain of allodynia, which is pain caused by a stimulus that is not normally experienced as painful. There is a field favoring the expression of pain in fibromyalgia, chronic fatigue syndrome, migraines, complex regional pain syndrome, anxiety, depression. The painful bladder syndrome takes on its full meaning here because it can ¹ cover true diseases of the bladder wall with intolerance to bladder filling, but it can also cover bladder hypersensitivities the origin of which is not necessarily in the bladder.

As with many illnesses for which the exact causes are unknown, there is no cure for painful bladder syndrome. However, there are several treatment options that provide relief for patients by reducing symptoms. As a first step, behavioral modifications and self-care practice can improve symptoms and should be implemented as much as possible. Likewise, stress management practices should be encouraged to manage the exacerbation of stress-induced symptoms. Physical therapies by appropriate manual techniques may also be offered.

Pharmacologically we can use drugs that will act on pain and inflammation mainly, as well as directly on the altered wall of the bladder to protect or restore it. Nonsteroidal anti-inflammatory drugs can relieve pain and inflammation, but they are seldom sufficient and their effect is not very durable over time. They are generally well tolerated but can cause unwanted side effects. Generally, any pain medication can be tried. Paracetamol and opiate analgesics, morphine derivatives can be effective, alone or in combination with other painkillers. Tricyclic antidepressants, given at lower doses than those used to treat depression, also have an effect on pain. Administration of antihistamines may be effective, as local secretion of histamine by mast cells may play a local role in inflammation. Pentosan-polysulfate can also be administered; it is a polysaccharide whose structure is similar to that of glycosaminoglycans which is eliminated in the urine and would make it possible to reconstitute the altered layer.

Hydrodistension can provide relief for patients for a few weeks, but the effects wear off over time and repeating them increases the risk of developing a compliance disorder. Instillations of different products can be offered; the 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 consisting in introducing a solution into a natural duct or a cavity of the body, to wash, disinfect and treat this duct or this cavity. The solution is administered to the bladder by means of a catheter. Among the products that have shown efficacy is heparin, which has anti-inflammatory and protective properties and which helps to temporarily strengthen the altered layer of glycoproteins. In the absence of sufficiently robust studies, it is difficult to properly assess the benefits and risks of this treatment. he

It does not seem that this is likely to improve only a subset of patients. Local anesthetics such as lidocaine can also be instilled into the bladder to reduce pain. Dimethyl sulfoxide has been shown to have an effect against pain, especially in combination with corticosteroids, heparin and / or a local anesthetic. Results are usually good at the start of treatment, but the instillations will have to be repeated as with most other medicines. However, this product is very poorly tolerated in some patients in whom it causes burns and may even worsen the symptoms at the start of treatment. Hyaluronic acid or chondroitin sulfate, which is said to have a restorative effect on the deteriorated bladder wall, has shown efficacy in some patients.

Instillation of the products in the bladder can provide relief and can therefore be offered despite the disadvantage of having to do urinary catheters with their septic and traumatic risks.

Surgery should be considered as a last resort, when all other treatments have failed and symptoms become extremely debilitating. In fact, the surgery is quite heavy, traumatic and sometimes brings little or no improvement. The various possible interventions range from partial cystectomy to the most radical total cystectomy with urethrectomy.

Thus many treatments are proposed for the management of painful bladder syndrome but the effectiveness of these different treatments is modest with trials on small numbers of patients and not always supervised by prospective randomized trials. It is therefore clear that the treatments offered to people with this syndrome are far from sufficient. There is a significant medical need and therefore a need for new drugs having the fewest possible adverse effects since they are intended for physiologically weakened people.

PAR receptors (protease-activated receptors) are heptahelicoid receptors, coupled to trimeric G proteins, we distinguish between PARIs composed of 425 amino acids, PAR2 with 397 amino acids, PAR3 consisting of 374 amino acids and PAR4 with 385 acids amines. Thrombin activates PARI, PAR3 and PAR4 by cleaving their extracellular N-terminus between arginine 41 and serine 42. The cleaved peptide has no particular activity, the new Nterminal end of the receptor acts as a agonist by folding towards the cell surface and interacting with extracellular domains.

PARI plays a key role in platelet activation at low concentrations of thrombin while PAR4 responds to high concentrations. Thus, the role of PARI has been established in the field of vascular biology and atherothrombosis. PARI antagonists have emerged as promising new oral antithrombotics. We can cite vorapaxar and atopaxar which have provided promising clinical data (Capodanno et al. 2012). Vorapaxar also obtained FDA registration in 2014 for the indication “reduction of thrombotic events in patients with a history of myocardial infarction or peripheral arterial disease”. Atopaxar is no longer in development as an antiaggregant.

On the wall of the bladder, IRAPs and PAR2s are expressed both on urothelial cells but also on detrusor cells (Saban et al. 2007).

Studies have shown the significant involvement of PAR2 in bladder contractility (Nakahara et al. 2004).

Activation of PAR by thrombin has been shown to induce inflammation of the bladder in various animal models (De Garavilla et al. 2007; Saban et al. 2007).

The inventors have shown that a selective IRAP antagonist constitutes an innovative therapeutic approach for treating

V.

inflammation and pain associated with pelvic-perineal functional pathologies and in particular in painful bladder syndrome.

Unexpectedly, the inventors found that vorapaxar, atopaxar and 3- (2-Chloro-phenyl) -1- [4- (4-fluorobenzyl) -piperazin-1-yl] -propenone, or one of their pharmaceutically acceptable salts, is capable of protecting the bladder by effectively 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-fluorophenyl) -2-pyridyl] vinyl] -3-methyl-1-oxo3a, 4,4a, 5,6,7,8,8a, 9,9a-decahydro-3H-benzo [f] isobenzofuran-7yl ] carbamate.

Atopaxar is [(1- (3-tert-butyl-4-methoxy-5morpholinophenyl) -2- (5,6-diethoxy-fluoro-1-imino-1,3-dihydro-2H isoindol-2yl) ethanone hydrobromide.

3- (2-Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-lyl] -propenone represented by the formula:

its pharmaceutically acceptable salts as well as its use as an antiplatelet agent, in both curative and preventive treatment of arterial or venous thrombosis, stable angina, cardiac arrhythmias, myocardial infarction, hypertension, heart failure, stroke, acute coronary syndromes, to inhibit the proliferation of smooth muscle cells (restenosis), in both curative and preventive treatment of inflammatory disorders, lung disease, gastrointestinal disease, development of fibrosis in patients with chronic liver diseases, skin diseases, for both curative and preventive treatment of the proliferation of endothelial cells, fibroblasts, cardiofibroblasts, glial, smooth muscle or cancer are described in the WO patent 2007/147824.

In the present invention, the term “pharmaceutically acceptable” refers to molecular entities and compositions which produce no adverse, allergic or other adverse reaction when administered to a human. When used herein, the term "pharmaceutically acceptable excipient" includes any diluent, adjuvant or excipient, such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or alternatively agents which would delay absorption and intestinal and digestive resorption. The use of these media or vectors is well known to those skilled in the art.

Pharmaceutically acceptable salts for therapeutic use of a compound of the present invention include conventional non-toxic salts of the compound of the invention such as those formed from organic or inorganic acids. By way of example, mention may be made 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 acids, citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic, stearic, lactic.

These salts can be synthesized from a compound of the invention containing a basic part and the corresponding acids according to conventional chemical methods.

Solvates acceptable for therapeutic use of a compound of the present invention include conventional solvates such as those formed in the last step of preparing a compound of the invention due to the presence of

Μ solvents. By way of example, mention may be made of solvates due to the presence of water or of ethanol.

Vorapaxar, atopaxar and 3- (2-Chloro-phenyl) -1- [4- (4fluoro-benzyl) -piperazin-1-yl] -propenone are selective antagonists of IRAP.

The PARI antagonists known to date are N3cyclopropyl-7 - ([4- (1-methylethyl) phenyl] methyl) -7H-pyrrolo [3,2 - f] quinazoline-1,3-diamine (SCH-79797), vorapaxar (SCH-530348), atopaxar (E5555) and SCH-602539.

The subject of the invention is the use of a PARI antagonist as a medicament in the prevention and / or treatment of pelvic-perineal functional pathologies.

The subject of the invention is the use of vorapaxar as a medicament in the prevention and / or treatment of pelvic-perineal functional pathologies.

The subject of the invention is the use of atopaxar as a medicament in the prevention and / or treatment of pelvic-perineal functional pathologies.

The invention relates to the use of 3- (2-Chlorophenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone as a medicament in the prevention and / or treatment. pelvic-perineal functional pathologies.

The subject of the invention is the use of an PARI antagonist, as a medicament in the prevention and / or treatment of painful bladder syndrome.

The subject of the invention is the use of vorapaxar as a medicament in the prevention and / or treatment of painful bladder syndrome.

The subject of the invention is the use of atopaxar as a medicament in the prevention and / or treatment of painful bladder syndrome.

The invention relates to the use of 3- (2-Chlorophenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone as a medicament in the prevention and / or treatment. painful bladder syndrome.

The invention relates to the use of a PARI antagonist, as a medicament in the prevention and / or treatment of overactive bladder syndrome.

The subject of the invention is the use of vorapaxar as a medicament in the prevention and / or treatment of overactive bladder syndrome.

The invention relates to the use of atopaxar as a medicament in the prevention and / or treatment of overactive bladder syndrome.

The invention relates to the use of 3- (2-Chlorophenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone as a medicament in the prevention and / or treatment. overactive bladder syndrome.

Another object of the invention relates to the use of a PARI antagonist in patients with urinary incontinence and / or anal or fecal incontinence.

Another object of the invention relates to the use of vorapaxar in patients with urinary incontinence and / or anal or fecal incontinence.

Another object of the invention relates to the use of atopaxar in patients with urinary incontinence and / or anal or fecal incontinence.

Another object of the invention relates to the use of

3- (2-Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] propenone in patients with urinary incontinence and / or anal or fecal incontinence.

Another object of the invention relates to the use of a PARI antagonist in patients with chronic pelviperineal pain.

Another object of the invention relates to the use of vorapaxar in patients with chronic pelviperineal pain.

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Another object of the invention relates to the use of atopaxar in patients with chronic pelviperineal pain.

Another object of the invention relates to the use of 3- (2-Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-l-yl] propenone in patients with pelviperineal pain. chronic.

The present invention further relates to a pharmaceutical composition comprising a PARI antagonist as active principle and at least one pharmaceutically acceptable excipient, for its use as a medicament in the prevention and / or treatment of pelvic-perineal functional pathologies, in particular painful bladder syndrome, overactive bladder syndrome, chronic pelvi-peritoneal pain. The present invention also relates to a pharmaceutical composition comprising a PARI antagonist as active principle and at least one pharmaceutically acceptable excipient, for its use as a medicament in patients with urinary incontinence and / or anal or fecal incontinence.

Pharmaceutical compositions according to the present invention can be formulated for administration to humans. The compositions according to the invention can be administered orally, sublingually, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally. In this case, the active principle can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, to human beings. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous administration forms or transdermal, topical, intramuscular, intravenous, intranasal or intraocular, intravesical, intramural or rectal administration forms.

When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, silica or the like. The tablets can be coated with sucrose or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.

A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules.

A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable color.

The water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, as well as with taste correctors or sweeteners.

For rectal administration, use is made of gels, creams, powders, suspensions, solutions, foams or suppositories which are prepared with binders melting at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral (intravenous, intramuscular, intradermal, subcutaneous), intranasal, intraocular, intravesical, intramural administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain dispersing agents and / or pharmacologically compatible wetting agents.

The active principle can also be formulated in the form of microcapsules, optionally with one or more additive carriers.

Formulations suitable for the form of administration chosen are known to those skilled in the art and described, for example, in: Remington, The Science and Practice of Pharmacy, 19th Edition, 1995, Mack Publishing Company.

Advantageously, the pharmaceutical composition according to the present invention is intended for local administration, this is referred to as endovesical treatment, the pharmaceutical composition according to the present invention is intended for use in an endovesical administration form. Among the endovesical treatments, preference will be given to bladder instillation, and / or intramural injection, that is to say administration into the thickness of the wall of the bladder.

Dosages of the PARI antagonist in the compositions of the invention can be adjusted in order to obtain an amount of substance which is effective to achieve the desired therapeutic response for a particular composition to the method of administration. The effective dose of the compound of the invention varies as a function of many parameters such as, for example, the route of administration chosen, weight, age, sex, the nature of the pathology, the type of treatment (s). administered and the sensitivity of the individual to be treated. Consequently, the optimum dosage should be determined by the specialist in the field according to the parameters he deems relevant. Although the effective doses can vary widely, the daily doses could range between 0.1 mg and 1000 mg per 24 hours, and preferably between 1 and 200 mg, for an adult with an average weight of 70 kg , in one or more takes.

* t.

The following examples provide a better understanding of the invention without limiting its scope.

Example 1: Effect of 3- (2-Chloro-phenyl) -1- [4- (4-fluorobenzyl) -piperazin-1-yl] -propenone on an isolated rat bladder model (Shimizu et al., Biol Pharm. Bull. 34 (7): 1122-1125, 2011).

Aim of the experiment: To evaluate the role of 3- (2-Chlorophenyl) -1- [4- (4-fluoro-benzyl) -piperazin-l-yl] -propenone on the amplitude of bladder contraction with trypsin and TFLLR. The experiment is carried out in parallel on naive bladders and on bladders having undergone an inflammation procedure. The effect of the compound of the invention is compared with that of a reference PARI antagonist, the compound SCH203099, (Ahn et al. Biochem. Pharmacol. 60 (10): 1425-1434, 2000).

Protocol

In order to induce inflammation of the bladder, cyclophophamide is injected bilaterally into rats (female Wistar Han, weighing 250 to 275 g on the day of the experiment, from Charles River laboratory France) by the intraperitoneal route at a dose of 150 mg / kg in a final volume of 5 mL / kg.

Pain assessment is performed 2 hours after administration of cyclophosphamide.

In naive animals (without administration of cyclophosphamide) or 24 hours after administration of cyclophosphamide, the animals are anesthetized with pentobarbital (60 mg / kg) and euthanized. The bladder is quickly removed and placed in a modified Krebs-Henseleit oxygen solution of the following composition (mM): NaCl 114; KCl 4.7; CaCl · · 2.5; MgSO ₄ 1.2; ΚΗ ₂ ΡΟ ₄ 1.2; NaHCCL 25 and glucose 11.7 (pH 7.4 with 95% O; and 5% CO ₄ ). The bladder is cleansed of its connective tissue, weighed, the distal and proximal portions are removed and the bladder is cut lengthwise into two equal “strips”. These strips are attached by silk thread and immersed in a 10 mL isolated organ tank (EMKA Technologies) containing the oxygenated solution of Krebs-Henseleit with a mixture of 0 _; / C0 ₂ of 95% / 5% and maintained at 37 ° C. The bladder strips are connected by the silk thread to isometric sensors (model IT50, EMKA Technologies) connected to amplifiers (EMKA Technologies). Contractile responses are recorded using 10X2® software (EMKA Technologies).

During an initial stabilization period of at least 90 minutes, rinses are performed every 15 minutes and the tension of each bladder strip is readjusted to 1.0g. Then the strips are exposed to 50 mM of KCl to check their viability. If the contraction amplitude of the strips is less than 1.0 g, the tissues are discarded and are not included in the experiment. After a second stabilization and washing period of at least 45 minutes, a concentration of the compound of the invention, or of the reference product (SCH203099) or of vehicle is incubated for 30 minutes. Then a cumulative concentration-response curve to the selective agonist PARI, TFLLR (0.1 μΜ to 0.1 mM) or to trypsin (10 U to 10,000 U BAEE / mL) is produced.

Results

In the presence of trypsin at 3000 U BAEE / mL, inflammation increases bladder contractility by a factor of 2.5 due to PAR activation. The amplitude of contraction is 0.99 ± 0.20 g for the naive vehicle group versus 2.73 ± 0.34 g for the vehicle group treated with cyclophosphamide.

The compound of the invention antagonizes the bladder contraction with trypsin only at high concentrations in naive animals as shown in FIG. 1. The amplitude of bladder contraction is halved with the compound of the invention at 30μΜ versus vehicle ( 0.55 + 0.24g versus 0.99 ± 0.20g) and nothing is observed at the other concentrations of the compound of the invention.

The compound of the invention antagonizes in a concentration-dependent manner the bladder contraction with trypsin in an inflamed condition (FIG. 2). Up to 3μΜ the compound of the invention appears inactive, at ΙΟμΜ the compound of the invention decreases the bladder contraction by 35% (1.76 ± 0.30g versus 2.73 ± 0.34g). At 30μΜ, the compound of the invention reduces bladder contraction by approximately 70% (0.92 ± 0.17g versus 2.73 ± 0.34g).

The standard product (SCH203099) antagonizes bladder contraction with trypsin only at high concentrations in naive animals (Figure 3). The amplitude of bladder contraction is halved in the presence of 10μΜ of SCH203099 versus the vehicle (0.48 ± 0.11g versus 0.99 ± 0.20g) and nothing is observed at the other concentrations of SCH203099.

Compound SCH203099 concentration-dependent antagonizes bladder contraction to trypsin under inflamed conditions (Figure 4). A 25% reduction is observed with 3μΜ of SCH203099 (2.05 ± 053g versus 2.73 ± 0.34g), a decrease of 35% is noted in the presence of 10μΜ of SCH203099 (1.77 ± 0.38g versus 2, 73 + 0.34g) and SCH203099 at 30μΜ reduced bladder contraction by 60% (1.04 ± 0.16g versus 2.73 ± 0.34g).

In the presence of 100μΜ of TFLLR, inflammation increases by a factor of 2 bladder contractility due to PARI activation. The amplitude of contraction is 0.59 + 0.14 g for the naive vehicle group versus 1.10 + 0.18 g for the vehicle group treated with cyclophosphamide.

The compound of the invention concentration-dependent antagonizes bladder contraction at TFLLR in naive animals. At ΙμΜ the compound of the invention appears inactive, at 3μΜ a 45% decrease in bladder contraction is observed (0.33 ± 0.05g versus 0.59 ± 0.14g). At 10μΜ, the compound of the invention reduces bladder contraction by 70% (0.18 ± 0.04g versus 0.59 ± 0.14g). At 30μΜ, the compound of the invention completely abolishes bladder contraction (0.00 ± 0.04g versus 0.59 ± 0.14g) with even relaxation of the tissue during the experiment (FIG. 5).

't.

The compound of the invention also antagonizes in a concentration-dependent manner the bladder contraction at TFLLR in an inflamed condition (FIG. 6). Up to 3μΜ little convincing effect (10% reduction only), at 10μΜ the compound of the invention reduces bladder contraction by 60% (0.45 ± 0.13g versus 1.10 ± 0.18g) and at 30μΜ the compound of the invention reduces the contractile response by 90% (0.11 ± 0.04g versus 1.10 ± 0.18g).

The reference product (SCH203099) antagonizes TFLLR bladder contraction only at high concentrations in naive animals (Figure 7). The amplitude of bladder contraction is halved in the presence of 10μΜ of SCH203099 versus the vehicle (0.26 ± 0.07g versus 0.59 ± 0.14g) and nothing is observed at the other concentrations of SCH203099.

The SCH203099 compound antagonizes in a concentration-dependent manner the bladder contraction at SFLLR in inflamed conditions (Figure 8). At 3μΜ of SCH203099, little convincing effect is observed (reduction of 10%). A reduction of 35% is noted in the presence of 10μΜ of SCH203099 (0.73 ± 0.10g versus 1.10 ± 0.18g) and SCH203099 at 30μΜ reduces bladder contraction by 55% (0.49 ± 0.08g versus 1.10 ± 0.18g).

In summary, the bladder contractions induced by trypsin are antagonized in the same way by the reference product (SCH203099) and the compound of the invention. On the other hand, on the bladder contractions induced by the PARI agonist, the compound of the invention is more potent on inflamed bladders.

The inventors have thus surprisingly demonstrated that the compound of the invention effectively reduces the exacerbated contractile responses of an inflamed and / or overactive bladder, that is to say that the compound of the invention seems particularly advantageous in case of a painful bladder syndrome but also in the case of an overactive bladder syndrome.

* ’1 t

Example 2: Effects of vorapaxar and atopaxar on an isolated rat bladder model.

The aim of this study is to evaluate the effects of vorapaxar and atopaxar on the amplitude of bladder contraction to trypsin and TFLLR.

These experiments were carried out on naive bladders. The protocol used is the same as that described in Example 1.

Results obtained with vorapaxar:

In the presence of trypsin at 3000 U BAEE / mL, inflammation increases bladder contractility by a factor of two. The amplitude of contraction goes from 0.93 ± 0.10g to 1.97 ± 0.14g. Vorapaxar at 3 μΜ antagonizes bladder contraction with trypsin in naive animals as shown in Figure 9. The amplitude of bladder contraction is antagonized in the presence of 3 μΜ of vorapaxar versus vehicle (0.79 + 0.14g versus 1 , 04 + 0.16g, respectively). At a concentration of 10 μΜ the lower efficiency is due to the low solubility of the compound. This is confirmed at the concentration of 30 μΜ.

In the presence of 100 μΜ of TFLLR, bladder contractility increases by PARI activation. The amplitude of contraction is 0.57 ± 0.11g. Vorapaxar concentration-dependent antagonizes bladder contraction at TFLLR in naive animals (Figure 10). At 3 nM vorapaxar induces a decrease of nearly 50% in bladder contraction (0.31 + 0.12g versus 0.57 ± 0.11g). At 10 nM, vorapaxar reduces bladder contraction by 75% (0.14 + 0.02g versus 0.57 ± 0.11g). From 1 μΜ vorapaxar completely abolishes bladder contraction (0.04 ±

0.03g ± 0.57 ± 0.11g), as shown in figure 10.

Results obtained with atopaxar:

In the presence of trypsin at 3000 U BAEE / mL, the amplitude of contraction increases by more than a factor of two (0.76 ± 0.08g versus 1.93 ± 0.09g). Atopaxar concentration-dependent antagonizes bladder contraction to trypsin in naive animals as shown in Figure 11. At 1 μΜ

C ¹ ', atopaxar induces a slight decrease in bladder contraction (1.02 ± 0.20g versus 1.17 + 0.10g). At 3 μΜ atopaxar reduces bladder contraction by 38% (0.74 ± 0.19g versus 1.17 ± 0.10g). At 10 μΜ atopaxar reduces bladder contraction by 70% (0.36 ± 0.15 g versus 1.17 + 0.10 g) and completely abolishes it at 30 μΜ (Figure 11).

In the presence of 100 μΜ of TFLLR, bladder contractility increases by PARI activation. The amplitude of contraction reaches 0.50 + 0.09g. Atopaxar concentration-dependent antagonizes bladder contraction at TFLLR in naive animals from 10 nM (Figure 12). At 10 nM atopaxar induces a reduction of more than 50% in bladder contraction (0.21 ± 0.03g versus 0.50 ± 0.09g). At 1 μΜ atopaxar almost abolishes bladder contraction with a reduction of more than 80% (0.08 ± 0.03g versus 0.50 ± 0.09g), as shown in Figure 12.

In conclusion, vorapaxar and atopaxar prevent bladder contractions under physiological conditions. The inventors have thus demonstrated that the PARI antagonists effectively reduce contractile responses, that is to say that they appear to be particularly advantageous in functional pelvic-perineal pathologies and in particular in cases of painful bladder syndrome.

* “X ··

Claims

1. A antagonist BET for his use as drug for the prevention and / or for the treatment of pathologies pelvic functional perineal. 2. A antagonist Bet for its use according to

Claims (12)

Claims 1. A antagonist BET for his use as drug for the prevention and / or for the treatment of pathologies pelvic functional perineal. 2. A antagonist Bet for its use according to Claim 1, characterized in that it is vorapaxar or atopaxar or one of their pharmaceutically acceptable salts. 3. A PARI antagonist for its use according to claim 1, characterized in that it is 3— (2— Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-l -yl] -propenone or one of its pharmaceutically acceptable salts. 4. A PARI antagonist for its use according to claim 1, in patients with painful bladder syndrome. 5. A PARI antagonist for its use according to claim 4, characterized in that it is vorapaxar or atopaxar or one of their pharmaceutically acceptable salts. 6. A PARI antagonist for its use according to claim 4, characterized in that it is 3— (2— Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-l -yl] -propenone or one of its pharmaceutically acceptable salts. t>% ·. 7. A PARI antagonist for his use according to the claim 1, among patients presenting a syndrome overactive bladder. 8. A PARI antagonist for his use according to the claim 7, characterized in this that it is vorapaxar or atopaxar or one of their pharmaceutically salts acceptable. 9. A PARI antagonist for his use according to the claim 7, characterized in that 'it is the 3- (2- Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone or a pharmaceutically acceptable salt thereof. 10. One antagonist BET for its use according to the claim 1, at of patients presenting a incontinence urinary. 11. One antagonist BET for its use according to the claim 1, in patients with chronic pelviperineal pain. 12. Pharmaceutical composition characterized in that it contains as active principle a PARI antagonist and at least one pharmaceutically acceptable excipient, for its use as a medicament for the prevention and / or for the treatment of pelvic-perineal functional pathologies. 13. Pharmaceutical composition according to claim 12, characterized in that it contains as active principle vorapaxar or atopaxar or one of their pharmaceutically acceptable salts. 14. Pharmaceutical composition according to claim 12, characterized in that it contains as active principle 3— (2— Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-l-yl] - propenone or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition according to claim 12, for its use in an endovesical administration form. 1/12 Control conditions, naive animals 5.04.51 4.0 ^J 5 3.5 ^ I 3.01 CO i S 2.53 O DMSO (n = 6) ♦ Compound according to The invention, 1 μΜ (n = 6) ▲ Compound according to the invention, 10 μΜ (n = 6) • Compound according to The invention, 30 μΜ (n = 6) Figure 1 2/12 Conditions of inflammation, treated animals 5,0- by cyclophosphamide Delta Tension (g) 10 30 100 300 1000 3000 10000 [Trypsin U BAEE / mL] O DMSO (n = 10) ♦ Compound according to The invention, 1 μΜ (η = 6) Compound according to The invention, 3 μΜ (η = 6) AT Compound according to The invention, 10 μΜ (η = 6) • Compound according to The invention, 30 μΜ (η = 6) Figure 2 3/12 Control conditions, naive animals Delta Tension (g) 5.0t 4.51 4.0- 3.51 3.0) M 2, œ O DMSO (n = 6) | Product of O Product of Δ Reference product, reference, reference, SCH203099, SCH203099, SCH203099, 0.3 μΜ (n = 5 1 μΜ (n = 6) 10 μΜ (n = 5) Figure 3 4/12 Conditions of inflammation, animals treated with cyclophosphamide 5.0η 4.5 days Delta Tension (g) [Trypsin ü BAEE / mL] O DMSO (n = 10) □ Product of reference, SCH203099, 3 μΜ (n = 6) Δ Product of reference, SCH203099, 10 μΜ (η = 6) X Product of reference, SCH203099, 30 μΜ (η = 6) Figure 4 5/12 Control conditions, naive animals 1.5 ~ Delta Tension (g) O DMSO (n = 7) ♦ Compound according to The invention, 1 μΜ (η = 5) Compound according to The invention, 3 μΜ (η = 5) AT Compound according to The invention, 10 μΜ (η = 5) • Compound according to The invention, 30 μΜ (η = 3) Figure 5 6/12 Conditions of inflammation, animals treated with cyclophosphamide Delta Voltage (g) [TFLLR, μΜ] O DMSO (n = 10) ♦ Compound according to The invention, 1 μΜ (η = 6) Compound according to The invention, 3 μΜ (η = 6) AT Compound according to The invention, 10 μΜ (η = 6 • Compound according to The invention, 30 μΜ (η = 6 Figure 6 7/12 Delta Tension (g), Control conditions, naive animals 1.5 η 1.3 days 1.1 1 0.9 d -0.1 0.1 0.3 1.0 3.0 10 30 100 [TFLLR, μΜ] O DMSO (n = 7) O Product of □ Product of Δ Reference product, reference, reference, SCH203099, SCH203099, SCH203099, 1 μΜ (n = 5) 3 μΜ (n = 5) 10 μΜ (n = 5) Figure 7 8/12 1.5 ί 1.3; 1.1; 0.9 d 0.7 -i i 0.5 1 i 0.3; 0.11 Conditions of inflammation, animals treated with cyclophosphamide Delta Tension (g) -0.1-i —.— —— -, ------ _r . - _T - 1 T- 0.1 0.3 1.0 3.0 10 30 100 [TFLLR, μΜ] O DMSO (n = 10) O Product of Δ Product of X Reference product, reference, reference, SCH203099, SCH203099, SCH203099, 3 μΜ (n = 6) 10 μΜ (n = 6) 30 μΜ (n = 6) Figure 8 9/12 Delta Tension (g) [Trypsin U BAEE / mL] o DMSO (n = 6) Δ Vorapaxar 1 μΜ (n = 6) Vorapaxar 3 μΜ (n = 6) A Vorapaxar 10 μΜ (n = 6) x Vorapaxar 30 μΜ (n = 6) Figure 9 10/12 Delta Tension (g) [TFLLR, μΜ] o DMSO (n = 9) A Vorapaxar 0.001 μΜ (n = 6) Vorapaxar 0.003 μΜ (n = 4) Δ Vorapaxar 0.01 μΜ (n = 5) • Vorapaxar 0.1 μΜ (n = 5) n Vorapaxar 1 μΜ (n = 6) ♦ Vorapaxar 3 μΜ (n = 4) o Vorapaxar 10 μΜ (n = 4) Figure 10 11/12 Delta Tension (g) 1.70] [U BAEE trypsin / mL] o DMSO (n = 5) A Atopaxar 1 μΜ (n = 5) □ Atopaxar 3 μΜ (n = 5) • Atopaxar 10 μΜ (n = 5) Δ Atopaxar 30 μΜ Figure 11 4 x 12/12 Delta Tension (g) 0.1 0.3 1.0 3.0 10 30 100 [TFLLR, μΜ] o DMSO (n = 6) a Atopaxar 1 nM (n = 4) □ Atopaxar 3 nM (n = 4) Atopaxar 10 nM (n = 5) o Atopaxar 100 nM (n = 5) • Atopaxar 1 μΜ (n = 5) Figure 12 SHORT The present invention relates to the use of IRAP antagonists, in particular vorapaxar, atopaxar and 3- (2-Chloro-phenyl) -l- [4- (4-fluoro-benzyl) piperazin-l-yl] -propenone or one of their pharmaceutically acceptable salts for the prevention and / or treatment of pelviperineal functional pathologies, and more particularly of painful bladder syndrome.