WO2016066789A1 - Use of par-1 antagonists for the prevention and/or treatment of pelvic-perineal functional disorders - Google Patents

Abstract

The present invention relates to the use of PAR-1 antagonists, in particular vorapaxar and atopaxar, with the exception of 3-(2-chloro-phenyl)-1-[4-(4-fluoro-benzyl)-piperazin-1-yl]-propenone, or any of the pharmaceutically acceptable salts thereof for the prevention and/or treatment of pelvic-perineal functional disorders, and specifically of cystic pain syndrome.

Description

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

The invention relates to PAR-1 antagonists and more particularly to vorapaxar and atopaxar with the exception of 3- (2-chlorophenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1 -yl] propenone, or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of pelvic-perineal functional pathologies.

Pelvic-perineal functional pathologies include various pathologies affecting the pelvi-perineal region excluding cancerous lesions and all known infectious, metabolic or endocrine pathologies. One of the pelvic-perineal functional pathologies is represented by the vesical pain syndrome, also called interstitial cystitis, which is defined as being, in the absence of proven urinary infection or other objective pathologies, a chronic pelvic pain, evolving for more than six months, sometimes felt as a sensation of pressure or perceived discomfort in relation to the bladder and accompanied by at least one urinary symptom: persistent urge to urinate or pollakiuria. A nocturia very often accompanies this painful bladder syndrome. Pollakiuria is defined by an abnormally high frequency of urination, beyond eight urination over a 24-hour period. Nocturia is defined as a need to urinate waking the patient one or more times during the night. The diagnosis of vesical pain syndrome or interstitial cystitis is based on interrogation and the achievement of a mictional schedule. The clinical examination must have eliminated all other causes of bladder pain, the diagnosis of Bladder Syndrome being a diagnosis of exclusion. In case of suspicion of bladder pain syndrome, the realization of a cystoscopy under general or regional anesthesia is the key examination for the balance sheet and the diagnosis. Classically this examination can highlight glomeruli of the bladder mucosa with or without Hunner lesions. However, cystoscopy can sometimes be normal at the initial stage and with no Hunner lesions. At the same time, it makes it possible to perform bladder biopsies and bladder hydrodistension. Hydrodistension consists of a dilation of the bladder with water performed under anesthesia. 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 appear to be two categories of patients: those with bladder wall changes, including 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 with this disease, which is probably underdiagnosed. The prevalence varies by country. In Europe, estimates range from one in 12500 to one in 1500. In the United States, the prevalence is estimated at about one in 1500. If both sexes can be affected, 90% of patients with bladder syndrome are women. This syndrome can affect people of all origins, but the prevalence of the disease seems more important in Western and Nordic countries.

The etiology of vesical pain syndrome remains undetermined. Different studies suggest that its pathophysiology is multifactorial. Several pathogenic theories are proposed even if none of these etiologies can be retained as the single etiological factor. Above all, it is possible that there are implications and interactions between these different factors. - An infectious mechanism, even if bacterial, viral and fungal tests performed in patients with bladder syndrome have never been able to incriminate an infectious cause responsible for this condition. In fact, patients with a bladder syndrome often have a history of urinary tract infections and 50% of them see their disease begin after an infectious episode. However, until now, no infectious factor nor bacterial nor viral could be retained as being at the origin of the disease and the anti-infectious treatments are ineffective. Infection with "atypical" germs has been proposed by many authors. It has been suggested that the germs found in bladder pain syndrome are not the directly incriminated agents, but their presence may be responsible for an immunoallergic reaction that plays a role in its occurrence.

 - an alteration of the urothelial permeability; the bladder mucosa is covered by a layer of mucin which is composed of numerous glycosaminoglycans and glycoproteins. These glycosaminoglycans have the characteristic of having a negative charge enabling them to form an impermeable hydrophobic barrier. This mucinous layer thus prevents urine from entering the urothelium. In patients with vesical pain syndrome, this layer is defective and the urothelium is abnormally permeable. As a result, potentially toxic substances in the urine penetrate the muscular layer of the bladder wall and depolarize the sensory nerves resulting in the symptoms of bladder pain syndrome.

- a mastocyte reaction; Mast cells have been found in the bladder wall in 30 to 65% of patients with bladder syndrome. Mast cells contain cytoplasmic granules containing substances such as histamine, leukotrienes, prostaglandins and tryptases. All these substances intervene in the inflammatory reaction. In vesical pain syndrome, edema, fibrosis and neovascularization may be due to the release of these mediators carried by the mast cells. Activation of mast cells is dependent on substance P and electron microscopy studies have shown an increase in substance P-rich nerve endings in contact with mast cells. Overall, there appears to be an important role of these mast cells in bladder pain syndrome. If the exact primary or secondary role of mast cells in the etiology of bladder pain syndrome remains debated to date, much research is focused on understanding the activation of these cells and their responsibility in symptomatology.

 - The neuronal mechanism; it is the process by which the nerves manage to secrete local mediators of inflammation. There is an increase in sympathetic innervation and activation of purinergic neurotransmission in bladder pain syndrome. The existence of a local neurogenic inflammation could be at the origin of a cascade of chain reactions. This mechanism is described in bladder pain 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 patients with of bladder pain syndrome. Interestingly, it has been shown that the urinary concentration of substance P is proportional to the degree of pain.

- an autoimmune mechanism; 5% of patients with vesical pain syndrome have autoimmune disease: lupus, thyroiditis, scleroderma, polyarthritis, Gouj erot-Sj ogren syndrome. A number of works argue for immune changes in pain syndrome bladder. Nevertheless, an autoimmune mechanism or the exact role of the autoimmune mechanism in bladder pain syndrome remains controversial. Impairment of urothelial permeability may result in inflammatory and autoimmune reactions that may explain the pathogenesis of bladder pain syndrome. The existence of activated nuclear kappa B factor in bladder biopsies of 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 the modifications of the immune responses are not specific and could be only secondary to the vesical tissue alterations.

 The symptomatology of the bladder syndrome is rich and above all marked by the painful symptomatology, the topography of the pain is suprapubic bladder with irradiation to the urethra but can also affect the vagina, perineum, rectum, pelvis, sacrum .... Pain is described as burning, tugging, pressure or discomfort. It is more or less triggered by bladder filling and sometimes calmed by urination. Patients are woken up at night with pain and need to urinate. The pains often evolve by crisis with periods of several days very painful and periods where 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 diurnal and nocturnal pollakiuria. Urodynamic imperfections or urgencies may be present, but they mostly meet and it is a diagnosis that must be eliminated during overactive bladder in which the urgencies are not painful. Often, patients with vesical pain syndrome do not complain of a real urgency but rather of a permanent urge of desire ranging from simple discomfort to a real pain that is relieved by urination. This relief by urination explains the willingness of these patients to empty their bladder which leads to confusion with urge. If the need can not be relieved, discomfort or pain generally increases without urinary leakage, which may be the case for urge. This is true for the majority of patients with bladder syndrome, but it is possible to have a bladder syndrome and associated urge, which complicates the diagnosis.

The clinical syndrome of overactive bladder can have several origins: a neurological origin (spinal cord injury, Parkinson's disease, multiple sclerosis ...), a psycho-behavioral origin or be idiopathic and enter into the nosological framework of pelvic functional pathologies. perineal. The clinical syndrome of overactive bladder may or may not be accompanied by uninhibited contractions of the detrusor muscle, which is the bladder muscle. However, contraction of the detrusor is not necessarily accompanied by involuntary urinary leakage. Several contractions, probably the majority of them, occur against a closed sphincter urinary system. From the physiopathological point of view, this situation may be equivalent to an infra- vesical urinary obstruction. Over time, progressive hypertrophy of smooth muscle bundles may occur. At cystoscopy, depending on the frequency, amplitude and duration of these contractions, the bladder wall will show more or less marked trabeculations, which may even cause a multi-diverticular bladder. Over time, fibrotic degeneration may occur 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 effective. This process can result in a bladder of small capacity, non compilant and acontractile (or at least deficient contractility). The bladder hyperactivity syndrome of variable expression includes urges with or without incontinence and / or night and daytime pollakiuria. There is not 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 hyperactivity.

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

 Among the pelvic-perineal functional pathologies, incontinence can also be mentioned.

 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 about 3 million people in France. It is particularly common in the elderly. Urinary continence requires a properly functioning pelvic floor for the integrity of the sphincters and nerve controls acting on them and the detrusor. Any alteration of any of these structures can lead to incontinence. Several forms of incontinence are classically distinguished:

 - Stress urinary incontinence, characterized by a leak of urine occurring during physical exertion, coughing and sneezing, without feeling of previous need.

urinary incontinence characterized by urine leakage accompanied or immediately preceded by urgent and irrepressible urination leading to urination that can not be deferred and retained.

- Mixed urinary incontinence combines both types of predefined incontinence.

- enuresis manifested especially in children by involuntary urination occurring at night.

 In addition to the inconvenience, urinary incontinence can have psychological (anxiety, depression) and social (withdrawal) implications. Urinary incontinence may be promoted by age, stress, obesity, neurological disorders, infection, prolapse or sphincter relaxation 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 more often affected than men. Indeed, childbirth and the occurrence of menopause are factors promoting this incontinence. Other risk factors include certain traumatic or surgical procedures in the anal sphincter. But incontinence can also result from certain neurological pathologies (cerebrovascular accidents, diabetes, multiple sclerosis ...) of certain anal surgeries or congenital malformations. Fecal incontinence can also accompany prolapse of the rectum or be a symptom of another disease such as cancer for example.

The chronic pelvic-perineal pain, including bladder pain syndrome, is pain characterized also by their chronicity (more than six months), the absence of malignant pathology and their topography: the pelvis on the one hand, and the perineum on the other. go. There is a significant dissociation between the extent of the patient's complaint and the absence of factors injuries that could justify them. Half of patients complain of isolated pelvic pain, a quarter of patients also suffer from irritable bowel syndrome, 10% of patients have a clinical syndrome of overactive bladder, the remaining 15% accumulate all 3 syndromes. The associations are very frequent between all the painful pathologies: vesical pain syndrome, vestibulodynia, irritable bowel syndrome, pelvic pain, fibromyalgia, and myofascial pain. Patients complain of allodynia, that is pain caused by a stimulus that is not normally felt painful. There is a fertile ground for the expression of pain, in case of fibromyalgia, chronic fatigue syndrome, migraines, complex regional pain syndrome, anxiety, depression. Bladder pain syndrome makes sense here because it can cover true diseases of the bladder wall with an intolerance to bladder filling but it can also cover bladder hypersensitivity whose origin is not necessarily in the bladder.

 As for many diseases whose exact causes are not known, there is no cure for bladder pain syndrome. However, several treatment options can relieve patients by reducing symptoms. As a first step, behavioral changes and self-care practice can improve symptoms and should be implemented as much as possible. Similarly, stress management practices should be encouraged to manage the exacerbation of stress-induced symptoms. Physical therapies by appropriate manual techniques may also be provided.

Pharmacologically, drugs that will act on pain and inflammation primarily, as well as directly on the altered bladder wall, may be used to protect or reconstitute the bladder. Anti-inflammatory drugs Steroids can relieve pain and inflammation but they are rarely sufficient and their effect is not durable over time. They are generally well tolerated but can cause unwanted side effects. In general, all painkillers can be tried. Paracetamol and opioid analgesics, morphine derivatives may be effective, alone or in combination with other painkillers. Tricyclic antidepressants administered at doses lower than those used to treat depression, also have an effect on pain. The administration of antihistamines may be effective, as local histamine secretion 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 allow to reconstitute the altered layer.

Hydrodistension may relieve patients for a few weeks but the effects fade as interventions occur and repeating them increases the risk of developing a compliance disorder. Instillations of different products can be proposed; the local treatment having the advantage of allowing direct application of the product in contact with the mucosa and reducing the systemic exposure. Instillation is a therapeutic method consisting of introducing a solution into a natural duct or cavity of the body, to wash, disinfect and treat the duct or cavity. The solution in the bladder is administered by means of a probe. Among the products having shown efficacy is heparin which has anti-inflammatory and protective properties and which contributes 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 seems likely to improve only a subset of patients. Local anesthetic products such as lidocaine can be instilled into the bladder to reduce pain. Dimethyl sulfoxide has shown an effect against pain, especially in combination with corticosteroids, heparin and / or local anesthetic. The results are generally good at the beginning of the treatment, but it will be necessary to repeat the instillations as for most other drugs. However, this product is very poorly tolerated in some patients in whom it causes burns and may even worsen the symptoms at the initiation of treatment. Hyaluronic acid or chondroitin sulphate, which has the effect of restoring the damaged bladder wall, has shown efficacy in some patients.

 The instillation of the products in the bladder can relieve and can be proposed despite the inconvenience of having to make urinary polls with their septic and traumatic risks.

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

Thus many treatments are proposed for the management of bladder pain 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 with the least possible side effects since they are aimed at physiologically weakened people. PAR receptors (protease-activated receptors) are heptaheloid receptors, coupled to trimeric G proteins, there are 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 PAR1, PAR3 and PAR4 by cleaving their extracellular N-terminus between arginine 41 and serine 42. The cleaved peptide has no particular activity, the new N-terminus of the receptor plays the role agonist by folding to the cell surface and interacting with the extracellular domains.

 PARI plays a key role in platelet activation at low thrombin concentrations while PAR4 responds to high concentrations. Thus, the role of IRAP has been established in the field of vascular biology and atherothrombosis. PARI antagonists have emerged as promising novel and orally active antithrombotics. For example, vorapaxar and atopaxar have provided promising clinical data (Capodanno et al., 2012). Vorapaxar has also been granted FDA registration in 2014 for "reduction of thrombotic events in patients with a history of myocardial infarction or peripheral arterial disease". Atopaxar is not currently being developed as an antiaggregant.

 On the bladder wall, IRAP and PAR2 are expressed on both urothelial cells and detrusor cells (Saban et al., 2007).

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

 The activation of PAR by thrombin has been shown to induce bladder inflammation in different animal models (De Garavilla et al., 2007, Saban et al., 2007).

The inventors have shown that a selective IRAP antagonist is an innovative therapeutic approach to treat inflammation and associated pain in pelvic-perineal functional pathologies and in particular in bladder pain syndrome.

 Unexpectedly, the inventors have discovered that vorapaxar and atopaxar, or one of their pharmaceutically acceptable salts, is capable of protecting the bladder by effectively decreasing 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-oxo

3a, 4, 4a, 5, 6, 7, 8, 8a, 9, 9a-decahydro-3H-benzo [f] isobenzofuran-7-yl] carbamate.

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

 In the present invention, the term "pharmaceutically acceptable" refers to molecular entities and compositions that produce no adverse, allergic or other adverse reactions 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 else agents which 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 the 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 and sulfuric acids, and those derived from acids. organic such as acetic, trifluoroacetic, propionic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic, stearic, lactic acids.

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

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

 Vorapaxar and atopaxar are selective antagonists of IRAP.

 The PARI antagonists known to date are N3-cyclopropyl-7- ([4- (1-methylethyl) phenyl] methyl) -7H-pyrrolo [3,2-f] quinazolin-1,3-diamine (SCH-79797). ), vorapaxar (SCH-530348), atopaxar (E5555) and SCH-602539.

 The invention relates to the use of a PARI antagonist, with the exception of 3- (2-chlorophenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone, as a medicament for the prevention and / or treatment of pelvic-perineal functional pathologies.

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

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

The subject of the invention is the use of a PARI antagonist, with the exception of 3- (2-chlorophenyl) -1- [4- (4-fluorophenyl) -1- benzyl) -piperazin-1-yl] -propenone as a medicament for the prevention and / or treatment of bladder pain syndrome.

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

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

 The invention relates to the use of a PARI antagonist, with the exception of 3- (2-chlorophenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] propenone as a medicament for the prevention and / or treatment of overactive bladder syndrome.

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

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

 Another subject of the invention concerns the use of a PARI antagonist with the exception of 3- (2-chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl ] -propenone in patients with urinary incontinence and / or anal or faecal incontinence.

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

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

Another subject of the invention concerns the use of a PARI antagonist with the exception of 3- (2-chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl ] -propenone in patients with chronic pelvic-perineal pain. Another object of the invention is the use of vorapaxar in patients with chronic pelvic-perineal pain.

 Another object of the invention is the use of atopaxar in patients with chronic pelvic-perineal pain.

 The present invention further relates to a pharmaceutical composition comprising a PARI antagonist with the exception of 3- (2-Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone as active principle and at least a pharmaceutically acceptable excipient, for its use as a medicament for the prevention and / or treatment of pelvic-perineal functional pathologies, in particular bladder pain syndrome, bladder hyperactivity syndrome, pelvi-peritoneal pain. chronic. The present invention also relates to a pharmaceutical composition comprising a PARI antagonist as active ingredient and at least one pharmaceutically acceptable excipient, for use as a medicament in patients with urinary incontinence and / or incial or fecal incontinence.

The 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 ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, subcutaneous forms of administration or transdermal, topical, intramuscular, intravenous, intravenous, nasal or intraocular, intravesical, intramural or rectal forms of administration.

 When preparing a solid composition in tablet form, 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 they can be treated so that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

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

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

 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, gels, creams, powders, suspensions, solutions, foams or suppositories are used which are prepared with binders melting at the 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 containing dispersion and / or pharmacologically compatible wetting agents.

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

Formulations suitable for the chosen form of administration are known 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 a local administration, it is called endovésical treatment, the pharmaceutical composition according to the present invention is intended to be used in an endovesical administration form. Among the endovesical treatments, bladder instillation and / or intramural injection, that is to say administration in the thickness of the bladder wall, will be preferred.

PARI antagonist assays in the compositions of the invention may be adjusted to provide an amount of substance that is effective in achieving the desired therapeutic response for a particular composition of the method of administration. The effective dose of the compound of the invention varies according to many parameters such as, for example, the chosen route of administration, weight, age, sex, the nature of the pathology, the type of treatment (s). administered and the sensitivity of the individual to treat. Consequently, the optimal dosage should be determined by the specialist in the field according to the parameters that he considers relevant. Although the effective doses may vary widely, daily doses may 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. The following examples make it possible to better understand the invention without limiting its scope.

 Example 1 Effect 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 the PARI antagonist tested on the bladder contraction amplitude with trypsin and TFLLR. The experiment is conducted in parallel on naïve bladders and on bladders having undergone an inflammation procedure. The effect of the compound of the invention is compared to that of a standard PARI antagonist 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) intraperitoneally at a dose of 150 mg. / kg in a final volume of 5 mL / kg.

 A 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 rapidly removed and placed in a modified oxygenated Krebs-Henseleit solution of the following composition (mM): NaCl 114; KCl 4.7; CaCl ₂ 2.5; MgSO ₄ 1.2; KH ₂ P0 ₄ 1.2; NaHCO ₃ and glucose 11.7 (pH 7.4 with 95% O ₂ and 5% CO ₂ ). The bladder is cleansed of connective tissue, weighed, the distal and proximal portions are removed, and the bladder is cut longitudinally into two equal "strips". These strips are attached by silk thread and immersed in a 10 mL isolated organ (EMKA Technologies) tank containing oxygenated Krebs-Henseleit solution with a 95% / 5% 0 ₂ / CO ₂ mixture and maintained at 37 ° C. ° C. 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 the IOX2® 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 KC1 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 reference product (SCH203099) or 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 trypsin (10 U to 10000 U BAEE / mL) is carried out.

 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 bladder contraction amplitude with trypsin and TFLLR.

 These experiments were conducted 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, the inflammation increases the bladder contractility by a factor of two. The amplitude of contraction increases from 0.93 ± 0.10 g to 1.97 ± 0.14 g. Vorapaxar at 3 μΜ antagonizes vesical contraction with trypsin in naive animals as shown in Figure 1. 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 the concentration of 10 μΜ the least Efficacy 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 with PARI activation. The contraction amplitude is 0.57 ± 0.11 g. Vorapaxar antagonizes the TFLLR bladder contraction in a concentration-dependent manner in naive animals (Figure 2). At 3 nM vorapaxar induces a decrease of nearly 50% of the bladder contraction (0.31 ± 0.12g versus 0.57 ± 0.11g). At 10 nM vorapaxar reduced bladder contraction by 75% (0.14 ± 0.02 g versus 0.57 ± 0.11 g). From 1 μΜ vorapaxar completely abolishes the bladder contraction (0.04 ± 0.03g ± 0.57 ± 0.11g), as shown in Figure 2.

 Results obtained with atopaxar:

 In the presence of trypsin at 3000 U BAEE / mL, the contraction amplitude increases by more than a factor of two (0.76 ± 0.08 g versus 1.93 ± 0.09 g). Atopaxar antagonizes vesical trypsin contraction in naïve animals in a concentration-dependent manner as shown in Figure 3. Atopaxar induces a slight decrease in bladder contraction (1.02 ± 0.20g versus 1). , 17 ± 0.10 g). At 3 μΜ, atopaxar reduced bladder contraction by 38% (0.74 ± 0.19g versus 1.17 ± 0.10g). At 10 μΜ, atopaxar reduced bladder contraction by 70% (0.36 ± 0.15 g versus 1.17 ± 0.10 g) and completely abolished it at 30 μΜ (Figure 3).

In the presence of 100 μΜ of TFLLR, bladder contractility increases with PARI activation. The contraction amplitude reaches 0.50 ± 0.09g. Atopaxar has a concentration-dependent antagonism of TFLLR bladder contraction in naïve animals from 10 nM (Figure 4). At 10 nM atopaxar induced a decrease of more than 50% in the 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 4. In conclusion, vorapaxar and atopaxar prevent bladder contractions under physiological conditions. The inventors have thus demonstrated that PARI antagonists effectively reduce contractile responses, that is to say that they seem to be particularly interesting in pelvic-perineal functional pathologies and in particular in cases of bladder syndrome.

Claims

claims 1. A PARI antagonist with the exception of 3- (2-Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1-yl] -propenone for use as a medicine for prevention and / or for the treatment of pelvic-perineal functional pathologies.  2. A PARI antagonist for use according to claim 1, characterized in that it is vorapaxar or atopaxar or a pharmaceutically acceptable salt thereof.  3. A PARI antagonist for use according to claim 1 in patients with bladder pain syndrome.  4. A PARI antagonist for use according to claim 3, characterized in that it is vorapaxar or atopaxar or a pharmaceutically acceptable salt thereof.  5. A PARI antagonist for use according to claim 1 in patients with overactive bladder syndrome. 6. A PARI antagonist for use according to claim 5, characterized in that it is vorapaxar or atopaxar or a pharmaceutically acceptable salt thereof. 7. A PARI antagonist for use according to claim 1 in patients with urinary incontinence.  8. A PARI antagonist for use according to claim 1 in patients with chronic pelvic-perineal pain.  9. Pharmaceutical composition characterized in that it contains as active ingredient a PARI antagonist with the exception of 3- (2-Chloro-phenyl) -1- [4- (4-fluoro-benzyl) -piperazin-1- yl] - propenone and at least one pharmaceutically acceptable excipient for its use as a medicament for the prevention and / or treatment of pelvic-perineal functional pathologies.  10. Pharmaceutical composition according to claim 9, characterized in that it contains as active ingredient vorapaxar or atopaxar or a pharmaceutically acceptable salt thereof.  11. Pharmaceutical composition according to claim 9, for use in an endovesical administration form.