EP1703903A1

EP1703903A1 - Pharmaceutical composition for treating stress incontinence and/or mixed incontinence

Info

Publication number: EP1703903A1
Application number: EP04790529A
Authority: EP
Inventors: Martin Michel; Marion Wienrich; Ursula Ebinger
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2003-10-31
Filing date: 2004-10-16
Publication date: 2006-09-27
Also published as: CA2544048A1; DE10351271A1; US20060004105A1; US20070129435A1; JP2007509868A; WO2005046666A8; WO2005046666A1

Abstract

The invention relates to the use of beta-3-adrenoceptor agonists for treating bladder function disorders, particularly stress incontinence and/or mixed incontinence.

Description

PHARMACEUTICAL COMPOSITION FOR TREATING STRESS INCONTINENCE AND / OR MIXING INCONTINENCE

This invention describes the use of beta-3 adrenoceptor agonists for the treatment of bladder dysfunction, in particular stress incontinence and / or mixed incontinence.

PRIOR ART The incidence of urinary incontinence is increasing due to the shift in the age structure. However, most of those affected are still not being treated or are being treated inadequately. In addition to the medical complications, such as chronic urinary tract infections, urinary incontinence is associated with a high level of psychological suffering for those affected. An estimated 100 million older people are affected by urinary incontinence.

The lower urinary tract consists of the urinary bladder, the urethra, the corresponding muscles and the ligaments of the holding apparatus. The function of the bladder is to store and empty the urine. Relaxation of the bladder muscle is not the only way to fulfill the memory function

(Detrusor muscle), but also locking mechanisms through the bladder neck, the smooth muscles of the urethra, the striated muscles of the urethra and the pelvic floor are important. During urinary bladder emptying (micturition), the detrusor muscle contracts while the urethra and pelvic floor relax or the urinary sphincter muscle opens. These processes require complicated control by the parasympathetic, sympathetic and somatic nervous system.

Bladder dysfunction is a heterogeneous group of disorders that differ in terms of their etiology, diagnosis, and therapy. In the standardization recommendations of the International Continence Society (ICS)

Urinary incontinence is defined as involuntary loss of urine that is objectively detectable and a social and hygienic problem. Generally, urinary incontinence only occurs when there is an unintended increase in pressure in the bladder during the storage phase. This can occur as a result of uninhibited contractions of the detrusor muscle (urge incontinence) or incompetence of the urethral occlusion mechanism (stress incontinence).

According to the definition of the ICS, one speaks of an overactive bladder (OAB) in the case of non-suppressable, imperative urge to urinate, associated with or without urge incontinence, usually with increased micturition frequency and urination at night. Pathophysiologically, this disease can be based on involuntary contractions during the filling phase, the cause of which can be neurogenic or non-neurogenic (idiopathic) in nature.

Urge incontinence is characterized by irresistible urge to urinate and involuntary loss of urine.

Stress incontinence is characterized by the involuntary loss of urine, which usually occurs when increased intra-abdominal pressure occurs. This can occur, for example, when lifting, coughing, sneezing, running and when there is no detrusor activity. The loss of urine occurs as a result of a variable combination of insufficiency of the urinary sphincter muscles and pelvic floor as well as an anatomical defect in the holding apparatus. As a result, the urethra's occlusion pressure becomes too low and incontinence is the result. Pure stress incontinence often occurs in women, especially if they have given birth. In men, this form of urinary incontinence is usually only observed after prostatectomies or other small pelvic surgery.

With so-called mixed incontinence, patients suffer from symptoms of stress incontinence and urge incontinence. Again, women are particularly affected. Various treatment approaches are available for the therapy of various forms of bladder dysfunction, in particular stress incontinence or mixed incontinence.

Conservative and surgical measures are particularly important for the treatment of stress incontinence. A generally applicable drug therapy has not yet been established. -Adrenoceptor agonists, such as pseudoephedrine and phenylpropanolamine, have an extremely moderate effect in the treatment of mild stress incontinence. The disadvantage is that these have no selectivity for the urethral muscles and with frequent side effects such as hypertension,

Tachycardia, arrhythmia, sleep disorders, headaches and tremors are related.

The treatment of mixed incontinence is discussed controversially and includes combinations of invasive procedures for the treatment of the stress incontinence component and medicinal procedures for the treatment of the urge incontinence component.

It has been reported since the mid-1995s that selective beta-3 adrenoceptor agonists are promising in the treatment of urinary incontinence (EP 0 958 835). It has now been shown that compounds from the class of beta-3 adrenoceptor agonists also promise a high effectiveness with good tolerability in the treatment of the indication mixed continence. In addition, their effect should be limited to the storage phase of the bladder and an undisturbed emptying of the bladder without residual urine should be guaranteed.

Object of the invention

Despite the promising approaches and advances in the treatment of stress incontinence and / or mixed incontinence, the development of efficient and well-tolerated therapies remains a challenge. The present invention is intended to provide such a contribution to the therapy of urinary incontinence. The invention is preferably suitable for the treatment of stress incontinence and / or mixed incontinence.

According to the invention, the use of beta-3 adrenoceptor agonists or pharmaceutical compositions comprising compounds from this active ingredient class is presented.

Description of the invention

According to the present invention there is provided a new pharmaceutical composition comprising at least one beta-3 adrenoceptor agonist in a pharmaceutically effective amount as an active ingredient.

a) active components

In the description of the preferred embodiment, a certain terminology should be used below for the sake of clarity. Such terminology is intended to encompass the stated embodiment as well as all technical equivalents which act in a similar manner for a similar purpose in order to achieve a similar result. To the extent that any pharmaceutically active compound is disclosed or claimed, it is expressly intended that all active metabolites generated in vivo be included, and it is expressly intended that all enantiomers, diastereomers or tautomers be included, when the compound can be in an enantiomeric, diastereomeric or tautomeric form. Of course, the most pharmacologically effective and side effect-free isomer is preferred. Also included are pharmacologically acceptable salts thereof. Examples of pharmaceutically active salts for each of the compounds that are the subject of this description include, but are not limited to, salts made from pharmaceutically acceptable acids or bases, including organic and inorganic acids and bases. If the preferred one for use Compound is basic, salts can be made from pharmaceutically acceptable acids. When choosing the most preferred salt, or to clarify whether a salt or the neutral compound is used, properties such as bioavailability, manufacturability, processability and storability are taken into account. Suitable pharmaceutically acceptable acids include acetic, benzenesulfonic (besylate), benzoic, p-bromophenylsulfonic, camphor sulfonic, carbon, citric, ethanesulfonic, fumaric, gluconic, glutamine, hydrogen bromide, hydrogen chloride, Hydrogen iodide, isethione, milk, maleic, apple, almond, methanesulfone (mesylate), mucin, saltpetre, oxal, pamoa, pantothene, phosphorus, amber, sulfur, wine -, p-toluenesulfonic acid and the like. Examples of such pharmaceutically acceptable salts include, but are not limited to, acetate, benzoate, hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogen phosphate, dinitrobenzoate, fumarate, glycolate , Heptanoate, hexine-1,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate, phenylproutionate , Phosphate, phthalate, phenylacetate, propane sulfonate, propiolate, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate, xylene sulfonate and the like.

To the extent necessary for completion, the synthesis of the compounds for which prior art is cited and their dosages are expressly included by reference to the prior art cited at the appropriate place. The beta-3 adrenoreceptor agonist used according to the invention is preferably a phenoxyacetic acid derivative. This is preferably selected from the following group:

With

1) X = Br, Y = H, R = OH

2- [2-bromo-4- [2- [[(1 S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid,

2) X = Cl, Y = H, R = OH

2- [2-chloro-4- [2 - [[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino] ethylj-phenoxyacetic acid,

3) X = Y = Cl, R = OH

2- [2,5-dichloro-4- [2 - [[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid,

4) X = Y = H, R = OH

2- [4- [2 - [[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] -2,5-dimethylphenoxy] acetic acid,

5) X = OH; Y = H; R = OH 2- [2-hydroxy-4- [2 - [[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid,

6) X = Cl; Y = H, R = OEt

Ethyl 2- [2-chloro-4- [2 - [[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyljphenoxy] acetate, 7) X = Cl; Y = Cl, R = OEt

Ethyl 2- [2,5-dichloro-4- [2 - [[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetate,

8) X = Me; Y = Me, R = OEt (-) - ethyl-2- [4- (2 - {[(lS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) - l-methylethyl] amino} ethyl) - 2,5-dimethylphenyloxy] acetate,

9) X = Me; Y = Me, R = OH (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino} ethyl) -2, 5-dimethylphenyloxy] acetic acid,

Details on the above-mentioned compounds 1 to 9 can be found in WO 00/02846.

Other preferred representatives of phenoxyacetic acid derivatives are:

Disodium - ([R, R] -5-2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] propyl) -l, 3-benzodioxole-2,2-dicarboxylate.

More detailed information on this substance can be found in J. Med. Chem. 44 (2001) 1456 or in the Journal of Urology 165 (2001) 240. 11)

2- [2-chloro-4- (2 - {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) phenoxy] acetic acid

Further information on this substance can be found in Med. Chem. 46 (2003) 105.

12)

FK175

[R- (R *, S *)] - [[8 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] -6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl ] oxy] -acetic acid ethyl ester, hydrochloride.

13)

GS-332

[IS - [1,3 (S *)]] - 3- [3 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] cyclohexyl] phenoxy] acetic acid, monosodium salt, 14)

7- {2- [2- (3-chlorophenyl) -2-hydroxyethylamino] propyl} -2,3-dihydrobenzo [1,4] dioxine-2-carboxylic acid,

Further information on this compound, also known as N-5984, can be found in the literature. In addition to these compounds, the following representatives from the group of beta 3 - adoreceptor agonists are also suitable.

15)

(4- {2- [2- (6-Arrüno-pyridin-3-yl) -2-hydroxyethylamino] ethoxy} phenyl) acetic acid. More information on this compound, also known as CP-331684, can be found in the Literature.

5- (4-methoxy-3,4-diiodobenzyl) -5,6,7,8-tetrahydro-naphthalen-2-ol. Further information on this substance can be found in J. Med. Chem. 44 (2001) 1456.

17)

4- (1-N-tert-butylamino-2-hydroxy-butoxy) -1,3-dihydro-benzoimidazol-2-one.

More detailed information on this substance, which is also known as CGP 12177A, can be found in

Journal of Urology 165 (2001) 240 or J. Med. Chem. 44 (2001) 1456.

18)

Further information on this substance, which is also known as SB 226552, can be found in J. Med. Chem. 44 (2001) 1456.

19)

Further information on this substance, which is also known as L755507, can be found in J. Med. Chem. 44 (2001) 1456. 20)

More detailed information on this substance, which is also known as L 770664, can be found in J. J. Med. Chem. 44 (2001) 1456.

21)

4-N- (4- (2- (4-Hydroxy-3-methylsulfonamido-phenyl) -2-hydroxy-ethylamino) piperidinyl) phenyl-n-butyl-aminosulfonyl acetic acid.

More detailed information on this substance can be found in J. Med. Chem. 44 (2001) 1456 or in Bioorg. Med. Chem. Lett. 9 (2001) 2045.

22)

with a) Ar = 4-OHPh-O-, Rl = octyl, R2 = H b) Ar = 4-OH, 3-methylsulfonylamidoρhenyl-O-, Rl = 2,5-diFbenzyl, R2 = H c) Ar = 4 -OH, 3-methylsulfonylamidophenyl, Rl = 2,5-diFbenzyl, R2 = H More information on these substances can be found in the Bioorg. Med. Chem. Lett. 11 (2000) 3123.

23)

More information on this substance can be found in the Bioorg. Med. Chem. Lett. 11 (2001) 981.

24)

n = 0 or 1

Further information on this substance can be found in the Bioor. Med. Chem. Lett. 10 (2000)

1,971th

25)

More information on this substance can be found in the Bioorg. Med. Chem. Lett. 11 (2001)

757th

26)

n = 0 or 1

1,971th

27)

Further information on this substance can be found in the Bioor. Med. Chem. Lett. 10 (2000) 1971. 28)

More information on this substance can be found in the Bioorg. Med. Chem. Lett. 10 (2000) 1531.

29) 2- (3- {[2- (3-Chlorophenyl) -2R-hydroxyl-ethylamino] ethylamino} phenyl) furan-3-carboxylic acid. Further information on this connection can be found in the literature.

30) 2- (3- {[2- (3-Chlorophenyl) -2R-hydroxyl-ethylamino] ethylamino} phenyl) thiophene-3-carboxylic acid. Information about this compound can be found in the literature.

31)

Further information on this compound, also known as SB -418790, can be found in the literature.

32)

More detailed information on this compound, also known as SB-251023, can be found in the literature.

33)

Further information on this compound, (R) -2- (2-aminothiazol-4-yl) -4 '- [2- [2- (hydroxy-2-phenylethyl) amino] ethyl] acetanilide can be found in the literature WO 03/037881.

34)

(S) -4- [2-Hydroxy-3 - [[2- [4- (5-carbamoyl-2-pyridyloxy) phenyl] -1, l-dimethyl-ethyl] amino] propoxy] carbazole (LY 377604 ).

35)

This connection is also known under the name SR 58611.

Among the beta-3 adrenoceptor agonists, those of the catecholamine type are preferred. The most preferred are:

(-) - Ethyl 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) - 2,5-dimethylphenyloxy] acetate .

(-) - Ethyl 2- [4- (2 - {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) - 2,5-dimethylphenyloxy] acetate monohydrochloride, (-) - 2- [4- (2 - {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetic acid or other pharmacologically acceptable salts thereof.

Particularly interesting representatives of beta-3-adrenoceptor agonists are (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetate or (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] - amino} ethyl) -2,5-dimethylphenyloxy] acetic acid, enantiomers or other stereoisomers thereof, and pharmacologically active salts thereof.

These compounds are disclosed in WO 00/02846 or WO 2003024916.

These two last named compounds are represented by the following formula π, which should prevail in the event of contradictions to the above name:

at R = OEthyl: (-) - ethyl-2- [4- (2 - {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino} ethyl) -2, 5-dimethylphenyloxy] acetate, preferably the monohydrate, when R = OH: (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl ] - amino} ethyl) -2,5-dimethylphenyloxy] acetic acid.

b) Dosage To determine the optimal dose of the active ingredient, various

Framework conditions are taken into account, such as age and body weight of the patient, nature and stage of the disease, as well as the potency of the connection. This is considered to be within the skill of those skilled in the art and one can consult the existing literature on the components to determine the optimal dosage. The indicated dosages refer to the dosage after the end of the adjustment phase.

The dosages given below expressly include all numerical values, whole or fractional, within the range given. The information relates to adult people. Pediatric doses may be lower.

Administrations more than once a day or twice a day (e.g. 3, 4, 5 or 6 administrations per day) are also expressly contemplated herein.

In some cases a smaller amount than the specified one may be sufficient, while in other cases a larger total amount may be necessary.

The daily total dose can be taken in one piece or within several servings, depending on the therapy regimen. The therapy regiment can also prescribe intervals between receipts that are longer than a day.

The average daily dose of the beta-3 agonist for an adult human is about 1 mg to 1000 mg, preferably 10 mg to about 750 mg per day, preferably 50 to 500 mg, more preferably 80 to 200 mg, administered in one or more doses ,

c) Application forms

The compositions of the present invention may conveniently be administered in a pharmaceutical composition containing the active component in combination with a suitable carrier. Such pharmaceutical compositions can be made by methods and contain carriers which are well known in the art. Generally recognized frameworks are available to the specialist in this regard.

The compositions of the present invention can be administered parenterally (e.g., by intravenous, intraperitoneal, subcutaneous or intramuscular injection), topically, orally, intranasally, intravaginally, transdermally, rectally, pulmonally by inhalation or nasally by inhalation, with oral administration being particularly preferred. Enteric formulations may be preferred among the oral forms of administration. In this case enteric capsules or enteric tablets are preferred, which in both cases e.g. can be realized with an enteric coating. The person skilled in the art will find instructions for enteric-coated formulations in the prior art.

Various formulation options are given below. The person skilled in the art can select a suitable formulation from this.

For oral therapeutic administration, the composition according to the invention can be combined with one or more carriers and in the form of ingestible tablets, buccal tablets, sublingual tablets, sugar-coated tablets, powders, powders, pastilles, dragées, granules, capsules, elixirs, suspensions, solutions, syrups , Wafers, chewing gum, food and the like can be used.

For example, a powder can be produced by grinding the particles of the active substance to a suitable size. Diluted powders can be produced by finely grinding the powdery substance with a non-toxic carrier material, such as lactose, and applying it as a powder. Other suitable carrier materials in this regard are other carbohydrates, such as starch or mannitol. Optionally, these powders can contain flavorings, preservatives, dispersing agents, colorants and other pharmacological adjuvants. Capsules can be produced from a powder of the type mentioned above or other powders which are introduced into a capsule, preferably a gelatin capsule, and the capsule is then closed.

It is also possible for lubricants known from the prior art to be introduced into the capsule or for the closure of the two capsule parts. The effectiveness of a capsule when taken orally can be enhanced by adding disintegrating or solubilizing substances, such as, for example, carboxymethyl cellulose, low-substituted carboxymethyl cellulose calcium

Hydroxy propyl cellulose, calcium carbonate, sodium carbonate and other substances. The active ingredient can be present in the capsule not only as a solid, but also in suspension, for example in vegetable oil, polyethylene glycol, glycerol with the aid of surface-active substances, etc.

Tablets can be made by pressing the powdered mixture and then e.g. is processed into granules. The tablets can contain various excipients, e.g. Starches, milk sugar, cane sugar, glucose (e.g. for vaginal tablets), sodium chloride, urea for solution u. Injection tablets, amylose, various types of cellulose as described above and others.

For example, glycerin or starch can be used as a humectant.

For example, starch, alginic acid, calcium alginate, pectic acid, powdered agar agar, formaldehyde gelatin, calcium carbonate, sodium bicarbonate, magnesium peroxide, amylose can be used as disintegrants.

For example, cane sugar, stearin, solid paraffin, (preferably with a melting range of 50-52 ° C) come as counter-disintegrant or solution retarder; Cocoa fat, hydrogenated fats into consideration. Other disintegrants can be: corn starch, potato starch, alginic acid and the like.

Quaternary ammonium compounds, sodium lauryl sulfate and saponins are suitable as absorption accelerators.

As a binder distributor, e.g. Ether are used and as a hydrophilizing agent or as a disintegration accelerator cetyl alcohol, glycerol monostearate, starch, corn starch, milk sugar, wetting agents (e.g. Aerosol OT, Pluronics, Tweens), tragacanth, gum arabic, gelatin and others.

Sucrose, fructose, lactose or aspartame can be used as sweeteners or peppermint, wintergreen oil, cherry flavor and much more as flavoring agents.

In addition, other auxiliaries are generally considered: Aerosil, Aerosol OT ethyl cellulose, amberlite resin, XE-88, Amijel, Amisterol, Amylose, Avicel microcrystalline cellulose, bentonite, calcium sulfate, Carbowax 4000 u. 6000, carrageenan, castor wax, cellulose, cellulose microcrystalline, crospovidone, dextrans, dextrin, dicalcium phosphate, base for pharmaceutical tablets, kaolin, lactose (USP), lactosil, magnesium stearate, mannitol, mannitol granular NF methyl cellulose, Miglyol 812 neutral oil, milk powder, milk sugar, milk sugar nal-tab, nepol amylose, Pöfizer crystalline sorbitol, Plasdone, polyethylene glycols, polyvinyl acetate phthalate, polyvinyl pyrrolidone, precirol, bovine claw oil (hydrogenated), orodispersible tablet base, silicone, stabiline, starx 1500, syloid, tablet base, Waldhof, cabletolatum and talc. stearatum, Tego metal soaps, dextrose and. Tylose. This is particularly suitable

Tableting aid K (M25), which otherwise meets the requirements of the following pharmacopoeias: DAB, Ph, Eur, BP and. NF.

Other auxiliaries from the prior art can also be used. For example, tablets can be manufactured by direct compression.

Other formulations that can be administered orally, such as solutions, syrups, elixirs, etc., can also be prepared. If necessary, the connection can be microencapsulated.

Parenteral administration can be achieved by dissolving the compound in a liquid and injecting it subcutaneously, intramuscularly or intravenously. Examples of suitable solvents are water or oily media.

To produce suppositories, the compound can be formulated with low-melting and water-soluble or water-insoluble materials such as polyethylene glycol, cocoa butter, higher esters (for example moerysthyl, palmitate) or mixtures thereof.

The above listing is exemplary only, and one skilled in the art could consider other adjuvants.

Various other materials can be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills or capsules can be coated with gelatin, wax, shellac or sugar and the like. As already mentioned, enteric formulations are preferred for the oral dosage forms. Enteric coatings for tablets or capsules are therefore preferred. In the case of a syrup or elixir, sucrose or fructose may be included as a sweetener, methyl and propyl paraben as a preservative, a color and a flavoring such as cherry or orange flavor.

The auxiliary substances mentioned are not limited to the use of the application form in the context in which they were mentioned, but can also be transferred to the other application forms. Of course, any material used in the manufacture of any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, the active components can be incorporated into sustained release preparations and devices that include, but are not limited to, those based on osmotic pressures to achieve a desired release profile. Once-daily formulations for each of the active components are specifically included.

Such compositions and preparations should contain at least 0.001% active compound. The percentage of compositions and preparations can, of course, be varied and may conveniently be between about 0.1 to about 100% by weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage amount is obtained.

d) indications

The pharmaceutical composition according to the invention and any of the compounds listed as beta-3 adrenoreceptor agonists can be used for the treatment or prophylaxis and others. each of the following clinical pictures, as a single clinical picture as well as in combination with another of the named clinical pictures, are used, but are not limited to: urinary incontinence, in particular stress incontinence, urge incontinence, mixed incontinence or hyperactive bladder of neurogenic or non-neurogenic origin and their further subindications.

According to the invention, both those clinical pictures are included, the cause of which is an organ disorder or disease, as well as those which can be attributed to diseases or disorders of the central nervous system. Accordingly, each Treatment of bladder dysfunction, particularly urinary incontinence of any kind contemplated by the present invention.

Thus, a further embodiment of the present invention comprises the use of the composition according to the invention for the manufacture of a medicament for the treatment or prevention of any of the indications for bladder dysfunction mentioned in the previous paragraph.

Treatment of the above diseases or disorders is accomplished by delivering a therapeutically effective amount of the composition of the invention to one

Mammals accomplished. In most cases this is human, but the treatment of food animals (e.g. cattle) and pets (e.g. dogs, cats and horses) is expressly covered here. For veterinary uses, the dosages to be used may be different from the dosages given herein.

In the context of the indication hyperactive bladder and / or urge incontinence, all compounds except the compounds 1), 2), 3), 4), 5), 6), 7), 8), 9) are particularly preferred.

In the context of the present invention, the indications stress incontinence and / or mixed incontinence are particularly preferred; the indication mixed incontinence is most preferred.

The new composition with a minimal level of deleterious side effects is expected to provide rapid relief to those suffering from the above diseases and disorders.

Claims

claims

1. Use of a beta-3 adrenoceptor agonist, optionally in the form of a pharmaceutically active salt thereof, for the manufacture of a medicament for the treatment of a bladder dysfunction selected from the group stress and / or mixed incontinence.

2. Use according to claim 1, characterized in that the beta-3 adrenoceptor agonist is one of the compounds 1) to 35), a matabolite thereof, optionally an enantiomer thereof or a pharmacologically acceptable salt thereof.

3. Use according to one of claims 1 or 2, characterized in that the beta-3 adrenoceptor agonist is a phenoxyacetic acid derivative.

4. Use according to one of claims 1 to 3, characterized in that the beta-3 adrenoceptor agonist (-) - ethyl 2- [4- (2 - {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetate and / or (-) - 2- [4- (2- {[(1 S, 2R) - 2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetic acid and / or an enantiomer thereof and / or a metabolite thereof and / or a pharmacologically acceptable salt thereof.

5. Use according to one of claims 1 to 4, characterized in that the beta-3 adrenoceptor agonist is used in an amount of 10 mg to 750 mg.

6. Use according to one of claims 1 to 5, characterized in that the medicament is intended for rectal, vaginal, topical, oral, sublingual, intranasal, transdermal or parenteral application.

7. Use according to one of claims 1 to 6, characterized in that the active ingredient is released at least partially delayed.

8. Use according to one of claims 1 to 6, characterized in that the active ingredient is at least partially released immediately.

9. A method for treating a bladder dysfunction selected from the group stress and / or mixed incontinence in a mammal, which comprises the administration of a medicament according to any one of claims 1 to 8 to the mammal.