EP1682183A2

EP1682183A2 - Pharmaceutical composition, containing a beta-3-adrenoceptor agonist and an alpha antagonist and/or a 5-alpha-reductase inhibitor

Info

Publication number: EP1682183A2
Application number: EP04791031A
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: 2003-11-03
Filing date: 2004-10-29
Publication date: 2006-07-26
Also published as: CA2544100A1; US20050101607A1; WO2005042021A3; IL175292A0; BRPI0416157A; AU2004285289A1; RU2006119331A; KR20060124603A; WO2005042021A2; JP2007509896A; MXPA06004625A

Abstract

The invention describes a novel combination for the treatment of bladder disorders, which contains an alpha antagonist and/or a 5-alpha-reductase inhibitor and a beta-3-adrenoceptor agonist.

Description

PHARMACEUTICAL COMPOSITION CONTAINING A BETA-3 ADRENOCEPTOR AGONIST AND AN ALPHA ANTAGONIST AND / OR A 5-ALPHA REDUCTASE INHIBITOR

This invention relates to a new active ingredient combination for the treatment of

Complaints associated with a pathological change or irritation of the prostate in a mammal and possibly related to bladder dysfunction. According to the invention, a pharmaceutical active ingredient combination comprising at least one beta-3 adrenoceptor agonist and at least one further active ingredient is selected, which is selected from the group of alpha antagonists (alpha adrenoceptor antagonist) and / or the 5-alpha reductase inhibitor. The combination according to the invention is preferably used in patients who have bladder dysfunction and pathological changes or irritations of the prostate at the same time. The bladder dysfunction can cause urinary incontinence.

State of the art

The incidence of genitourinary disorders is increasing due to the shift in the age structure. In addition to the medical complications, such as chronic urinary tract infections, the symptoms of the disease are associated with a high level of psychological suffering for those affected.

The lower urinary tract consists of the urinary bladder, the urethra, the corresponding muscles and the ligaments of the holding apparatus. In men, the prostate also falls into this area. The function of the bladder is to store and empty the urine. For the fulfillment of the memory function, not only the relaxation of the urinary bladder muscle (detrusor muscle), but also closure mechanisms through the bladder neck, the smooth muscles of the urethra and 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. The prostate, whose job it is, among other things, to produce secretions for the sperm fluid, lies between the urinary bladder and the area of the pelvic floor that forms the outer sphincter of the urethra. The prostate covers the beginning of the urethra. The muscles of the prostate and urinary bladder partially interlock functionally, 5 for example when urinating, when the injection tubules and the ducts of the prostate glands are closed by the muscles of the bladder and prostate so that no urine can penetrate. Conversely, the prostate supports the bladder neck and thus the occlusion of the bladder. Men with prostate problems often experience irritation when urinating, 10 especially if they have benign prostatic hyperplasia (BPH). This disease occurs in over 50% of men over the age of 50 and leads to an enlarged prostate. The reason for this is an increase in the number of cells, the size of which remains unchanged. By enlarging the prostate, the urethra in this area can be narrowed and the complete emptying of the urethra can be delayed. 15 The irritative symptoms can be intensified both during the filling phase of the bladder and when the bladder is empty. If there is also a bladder dysfunction, the irritative symptoms are exacerbated. The formation of a chronic urinary tract infection in the presence of benign prostatic hyperplasia in combination with a bladder dysfunction is also facilitated. ^'20 Other forms of prostate diseases or -irritationen, which can interact with the bladder function, are different forms of prostatitis. The term prostatitis encompasses a heterogeneous clinical picture with multiple causes. One differentiates between acute and chronic, mostly unspecified inflammation or irritation of the prostate, and between bacterial or antibacterial causes. Both phenomena can overlap. Some forms of prostatitis are also referred to as non-inflammatory chronic pelvic pain syndrome, pelvic myoneuropathy, prostatodynia, or prostatopathy. Alpha antagonists or alpha reductase inhibitors are used to treat functional symptoms of benign prostatic hyperplasia (BPH). Alpha antagonists can bind selectively and competitively to the postsynaptic alpha 1 receptors, in particular to the subtypes alphal A and alphalD. This relaxes the smooth muscles of the prostate and urethra and reduces the tone of the smooth muscles of the prostate and urethra. As a result, the urine flow rate is increased.

5-alpha reductase inhibitors inhibit the 5-alpha reductase enzyme. This enzyme converts the body's testosterone into dihydrotestosterone, which directly stimulates the growth of prostate tissue.

Prostate problems can be aggravated by the appearance of bladder dysfunction and vice versa.

Hamblase 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 urine loss, which is objectively demonstrable and represents a social and hygienic problem. In general, urinary incontinence only occurs if there is an unintentional 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 nightly urination. 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. 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.

Various treatment approaches are available for the therapy of the various forms of hamstring dysfunction, in particular stress incontinence, urge incontinence, mixed incontinence or the hyperactive bladder.

To treat urge incontinence, the WHO recommends treatment with anticholinergics (antimuscarinics). However, their use is limited due to their moderate effectiveness and above all the considerable side effects such as dry mouth, accommodation disorders, constipation, central nervous effects (dizziness, tiredness, confusion).

Conservative and surgical measures are available for the treatment of stress incontinence. A generally applicable drug therapy has not yet been established. Alpha agonists such as pseudoephedrine and phenylpropanolamine have been shown to treat mild stress incontinence a very moderate effect. The disadvantage is that these have no selectivity for the urethral muscles and are associated with frequent side effects such as hypertension, tachycardia, arrhythmia, sleep disorders, headaches and tremors.

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 also promising in the treatment of urinary incontinence (EP 0 958 835). Since the stimulation of beta-3 receptors is extremely important for the relaxation of the detrusor muscle, the use of selective beta-3 adrenoceptors in patients with urge incontinence should result in a reduction or prevention of involuntary detrusor contractions during the urinary storage phase. Experiments with beta-3 adrenoceptor agonists promise high effectiveness with good tolerability. 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 new approaches to both treating prostate complaints and controlling bladder function, the development of efficient and well-tolerated therapies remains a challenge. This applies in particular to prostate complaints such as benign prostatic hyperplasia or prostatitis and especially if there are bladder dysfunctions at the same time.

The present invention is intended to contribute to better therapy for the patients concerned. It is therefore an object of the invention to provide medication for patients with prostate problems, in particular benign prostatic hyperblasia or prostatitis.

Another task is to provide medication for patients with prostate problems that will help to better control bladder function.

Another object relates to medication for the treatment of benign prostatic hyperplasia and / or prostatitis in the presence of a bladder dysfunction such as stress incontinence, urge incontinence, mixed incontinence or hyperactive bladder without urge incontinence or with urge incontinence.

For this purpose, a pharmaceutical composition is presented, which is to combine the advantages of the alpha antagonists for the treatment of benign prostatic hyperplasia or prostatides as well as those of the beta-3-adrenoceptor agonists for the control of the bladder function in a manner which favors the associated irritations.

Description of the Invention According to the present invention there is provided a novel pharmaceutical composition which comprises (a) at least one alpha antagonist in a pharmaceutically effective amount and / or a 5-alpha reductase inhibitor in a pharmaceutically effective amount and (b) at least one 3-adrenoceptor agonists in a pharmaceutically effective amount as active ingredients.

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 cited embodiment as well as all technical equivalents that are used in a similar manner for a similar purpose to achieve a similar result Act. 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 compound preferred for use is basic, salts can be prepared 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 alpha antagonist is preferably selected from the following group: aa) alfuzosin, ab) bunazosin, ad) doxazosin, ae) indoramine, af) naftopidil, ag) prazosin, ah) tamsulosin, ai) terazosin, aj) urapidil and ak) silodosin (KMD 3213), am) Moxisylyte, an) Metazosin, ao) Fiduxosin, ap) Upidosin, aq) SNAP-5089 (5- (N- (3- (4,4-Diphenylpiperidin-l-yl) propyl) carbamoyl) -2,6-dimethyl-4 (R) - (4-nitrophenyl) - 1, 4-dihydropyridine-3-carboxylic acid methyl ester), ar) AIO-8507L, as) SL-890591 ((2- (3- (4- (5-chloro-2-methoxyphenyl) piperazin-l-yl) pro pylamino) pyrimidine-4-carboxamide fumarate), at) RS- 100329 (5-methyl-3- (3- (4- (2- (2, 2,2-trifluoroethoxy) phenyl) pip erazin-l-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione hydrochloride).

Details of the connections can be found in the prior art.

Tamsulosin is preferably used in the form of the hydrochloride.

Au) finasteride and / or av) dutasteride can preferably be used as the 5-alpha reductase inhibitor.

The second component comprises one or more beta-3 adrenoreceptor agonists. This is (are) preferably selected from the following group:

With

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

2- [2-bromo-4- [2 - [[(IS, 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] ethyl] phenoxy] acetic 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] ethyl] phenoxy] acetate,

7) X = Cl; Y = Cl, R = OEt ethyl-2- [2,5-dichloro-4- [2 - [[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino] ethyl ] phenoxy] acetate,

8) X = Me; Y = Me, R = OEt (-) - ethyl 2- [4- (2 - {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) - 2,5-dimethylphenyloxy] acetate,

9) X = Me; Y = Me, R = OH

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

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

Further information on this substance can be found in J. Med. Chem. 44 (2001) 1456.

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

Journal of Urology 165 (2001) 240.

12)

Further information on this substance, which is also known as CGP 12177A, can be found in the Journal of Urology 165 (2001) 240 or in J. Med. Chem. 44 (2001) 1456.

13)

Further information on this substance, which is also known as SB 226552, can be found in J. Med. Chem. 44 (2001) 1456. 14)

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

15)

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

16)

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. ..

13

17)

with 1) Ar = 4-OHPh-O-, Rl = octyl, R2 = H 2) Ar = 4-OH, 3-methylsulfonylamidophenyl-O-, Rl = 2,5-diFbenzyl, R2 = H 3) 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. 18)

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

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.

20)

n = 0 or 1

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

1,971th

21)

More information on this substance can be found in the Bioorg. Med. Chem. Lett. 11 (2001) 757. 22)

n = 0 or 1

1,971th

23)

Further information on this substance can be found in the Bioor. Med. Chem. Lett. 10 (2000) 1971. 24)

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

25)

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,

26)

GS-332 [IS- [lα, 3ß (S *)]] - 3- [3 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] cyclohexyl] ρhenoxy] - acetic acid, monosodium salt,

27)

Further information on this compound, also known as N-5984, can be found in the literature.

28) 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.

29) 2- (3- {[2- (3-Chlorophenyl) -2R-hydroxyl-ethylamino] ethylamino} phenyl) thiophene-3-carboxylic acid. Information about this compound can be found in the literature.

30)

More detailed information on this compound, also known as SB-418790, can be found in the literature. 31)

More detailed information on this compound, also known as CP-331684, 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)

More detailed 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.

The most preferred are:

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

2,5-dimethylphenyloxy] acetate,

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- {[(1 S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) ~ 1 -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, the enantiomers, other diastereosomers of the same 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 U, 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.

Particularly preferred combinations include a combination of (a) tamsulosin, either in its enantiomeric or racemic form, or pharmacologically acceptable salts thereof, or any active metabolite thereof, and (b) at least one of the following compounds: (-) - 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) -l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetic acid or any other pharmacologically acceptable salt thereof or any active one Metabolites of the same.

Other particularly preferred combinations include a combination of (a) finasteride, either in its enantiomeric or racemic form, or pharmacologically acceptable salts thereof, or any active metabolite thereof, and (b) at least one of the following compounds: (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetate, (-) - ethyl-2- [4- (2- {[(1 S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetate monohydrochloride, (-) - 2- [4- (2- {[(1 S, 2R) -2-Hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetic acid or any other pharmacologically acceptable Salts thereof or any active metabolites thereof.

Other particularly preferred combinations include a combination of (a) dutasteride, either in its enantiomeric or racemic form, or pharmacologically acceptable salts thereof, or any active metabolite thereof, and (b) at least one of the following compounds: (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-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) -l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetic acid or any other pharmacologically acceptable salts thereof or any active metabolites of the same.

Other particularly preferred combinations of three include a combination of (a) tamsulosin or its hydrochloride and finasteride either in their enantiomeric or racemic form or pharmacologically acceptable salts thereof or any active metabolites thereof and (b) at least one of the following compounds: (-) - ethyl 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetate, (- ) -Ethyl-2- [4- (2- {[(1 S, 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 any other pharmacologically acceptable salts thereof or any active metabolite thereof.

It is expressly pointed out that the invention comprises each of the following combinations: (aa, 1); (ab, 1); (ac, 1); (ad, 1); (ae, 1); (Af, 1); (ag, 1); (ah, 1); (ai, 1); (aj, 1); (Ak, l); (al, 1); (Am, l); (An, l); (Ao, l); (Ap, l); (Aq, l); (Ar, l);

(As, l); (At, l); (Au, l); (Av, l); (aa, 2); (starting at 2); (ac, 2); (ad, 2); (ae, 2); (af, 2); (ag, 2); (ah, 2);

(ai, 2); (aj, 2); (Ak, 2); (al, 2); (on 2); (In, 2); (Ao, 2); (Ap, 2); (Aq, 2); (Ar, 2); (As, 2); (At 2);

(Au, 2); (Av, 2); (aa, 3); (from 3); (ac, 3); (ad, 3); (ae, 3); (af, 3); (ag, 3); (ah, 3); (ai, 3); (aj, 3); (Ak, 3); (al, 3); (at 3); (To, 3); (Ao, 3); (Ap, 3); (Aq, 3); (Ar, 3); (As, 3); (At 3); (Au, 3); (Av, 3); (Aa,

4); (from 4); (ac, 4); (ad, 4); (ae, 4); (af, 4); (ag, 4); (ah, 4); (ai, 4); (aj, 4); (Ak, 4); (al, 4);

(at 4); (To, 4); (Ao, 4); (Ap, 4); (Aq, 4); (Ar, 4); (As, 4); (At, 4); (Au, 4); (Av, 4); (aa, 5); (from 5); (Ac,

5); (ad, 5); (ae, 5); (af, 5); (ag, 5); (ah, 5); (ai, 5); (aj, 5); (Ak, 5); (al, 5); (Am, 5); (An, 5);

(Ao, 5); (Ap, 5); (Aq, 5); (Ar, 5); (As, 5); (At 5); (Au, 5); (Av, 5); (aa, 6); (from 6); (ac, 6); (ad, 6); (ae, 6); (af, 6); (ag, 6); (ah, 6); (ai, 6); (aj, 6); (Ak, 6); (al, 6); (at 6); (At, 6); (Ao, 6); (Ap, 6);

(Aq, 6); (Ar, 6); (As, 6); (At, 6); (Au, 6); (Av, 6); (aa, 7); (ab, 7); (ac, 7); (ad, 7); (ae, 7); (af, 7);

(ag, 7); (ah, 7); (ai, 7); (aj, 7); (Ak, 7); (al, 7); (Am, 7); (An, 7); (Ao, 7); (Ap, 7); (Aq, 7); (Ar, 7);

(AS, 7); (At 7); (Au, 7); (Av, 7); (aa, 8); (ab, 8); (ac, 8); (ad, 8); (ae, 8); (af, 8); (ag, 8); (ah, 8);

(ai, 8); (aj, 8); (Ak, 8); (al, 8); (Am, 8); (An, 8); (Ao, 8); (Ap, 8); (Aq, 8); (Ar, 8); (As, 8); (At 8); (Au, 8); (Av, 8); (aa, 9); (ab, 9); (ac, 9); (ad, 9); (ae, 9); (af, 9); (ag, 9); (ah, 9); (ai, 9); (aj, 9);

(Ak, 9); (al, 9); (Am, 9); (An, 9); (Ao, 9); (Ap, 9); (Aq, 9); (Ar, 9); (As, 9); (At 9); (Au, 9); (Av, 9); (Aa,

10); (from 10); (ac, 10); (ad, 10); (ae, 10); (af, 10); (ag, 10); (ah, 10); (ai, 10); (aj, 10);

(Ak, 10); (al, 10); (Am, 10); (An, 10); (Ao, 10); (Ap, 10); (Aq, 10); (Ar, 10); (AS, 10); (At 10);

(Au, 10); (Av, 10); (aa, 11); (from 11); (ac, 11); (ad, 11); (ae, 11); (af, 11); (ag, 11); (ah, 11); (ai, 11); (aj, 11); (Ak, ll); (al, 11); (Am, ll); (An, ll); (Ao, ll); (Ap, ll); (Aq, ll); (Ar, ll);

(As, ll); (At, ll); (Au, ll); (Av, ll); (aa, 12); (from 12); (ac, 12); (ad, 12); (ae, 12); (af, 12); (Ag,

12); (ah, 12); (ai, 12); (aj, 12); (Ak, 12); (al, 12); (on 12); (An, 12); (Ao, 12); (Ap, 12); (Aq, 12);

(Ar, 12); (AS, 12); (At 12); (Au, 12); (Av, 12); (aa, 13); (ab, 13); (ac, 13); (ad, 13); (ae, 13); (Af,

13); (ag, 13); (ah, 13); (ai, 13); (aj, 13); (Ak, 13); (al, 13); (at 13th); (An, 13); (Ao, 13); (Ap, 13); (Aq, 13); (Ar, 13); (AS, 13); (At 13); (Au, 13); (Av, 13); (aa, 14); (ab, 14); (ac, 14); (ad, 14); (Ae,

14); (af, 14); (ag, 14); (ah, 14); (ai, 14); (aj, 14); (Ak, 14); (al, 14); (at the 14th); (An, 14); (Ao, 14);

(Ap, 14); (Aq, 14); (Ar, 14); (AS, 14); (At 14); (Au, 14); (Av, 14); (aa, 15); (from 15); (ac, 15); (Ad,

15); (ae, 15); (af, 15); (ag, 15); (ah, 15); (ai, 15); (aj, 15); (Ak, 15); (al, 15); (Am, 15);

(An, 15); (Ao, 15); (Ap, 15); (Aq, 15); (Ar, 15); (AS, 15); (At 15); (Au, 15); (Av, 15); (aa, 16); (ab, 16); (ac, 16); (ad, 16); (ae, 16); (af, 16); (ag, 16); (ah, 16); (ai, 16); (aj, 16); (Ak, 16); (Al, 16); (at 16); (An, 16); (Ao, 16); (Ap, 16); (Aq, 16); (Ar, 16); (AS, 16); (At 16); (Au, 16); (Av, 16); (aa, 17); (ab, 17); (ac, 17); (ad, 17); (ae, 17); (af, 17); (ag, 17); (ah, 17); (ai, 17); (aj, 17); (Ak, 17); (al, 17); (Am, 17); (An, 17); (Ao, 17); (Ap, 17); (Aq, 17); (Ar, 17); (AS, 17); (At 17); (Au, 17); (Av, 17); (aa, 18); (ab, 18); (ac, 18); (ad, 18); (ae, 18); (af, 18); (ag, 18); (ah, 18); (ai, 18); (aj, 18); (Ak, 18); (al, 18); (Am, 18); (An, 18); (Ao, 18); (Ap, 18); (Aq, 18); (Ar, 18); (AS, 18); (At 18); (Au, 18); (Av, 18); (aa, 19); (ab, 19); (ac, 19); (ad, 19); (ae, 19); (af, 19); (ag, 19); (ah, 19); (ai, 19); (aj, 19); (Ak, 19); (al, 19); (at 19); (An, 19); (Ao, 19); (Ap, 19); (Aq, 19); (Ar, 19); (AS, 19); (At 19); (Au, 19); (Av, 19); (aa, 20); (from 20); (ac, 20); (ad, 20); (ae, 20); (af, 20); (ag, 20); (ah, 20); (ai, 20); (aj, 20); (Ak, 20); (al, 20); (on 20); (An, 20); (Ao, 20); (Ap, 20); (Aq, 20); (Ar, 20); (AS, 20); (At 20); (Au, 20); (Av, 20); (aa, 21); (ab, 21); (ac, 21); (ad, 21); (ae, 21); (af, 21); (ag, 21); (ah, 21); (ai, 21); (aj, 21); (Ak, 21); (al, 21); (Am, 21); (An, 21); (Ao, 21); (Ap, 21); (Aq, 21); (Ar, 21); (AS, 21); (At 21); (Au, 21); (Av, 21); (aa, 22); (ab, 22); (ac, 22); (ad, 22); (ae, 22); (af, 22); (ag, 22); (ah, 22); (ai, 22); (aj, 22); (Ak, 22); (al, 22); (Am, 22); (An, 22); (Ao, 22); (Ap, 22); (Aq, 22); (Ar, 22); (AS, 22); (At 22); (Au, 22); (Av, 22); (aa, 23); (ab, 23); (ac, 23); (ad, 23); (ae, 23); (af, 23); (ag, 23); (ah, 23); (ai, 23); (aj, 23); (Ak, 23); (al, 23); (Am, 23); (An, 23); (Ao, 23); (Ap, 23); (Aq, 23); (Ar, 23); (AS, 23); (At 23); (Au, 23); (Av, 23); (aa, 24); (ab, 24); (ac, 24); (ad, 24); (ae, 24); (af, 24); (ag, 24); (ah, 24); (ai, 24); (aj, 24); (Ak, 24); (al, 24); (Am, 24); (An, 24); (Ao, 24); (Ap, 24); (Aq, 24); (Ar, 24); (AS, 24); (At 24); (Au, 24); (Av, 24); (aa, 25); (ab, 25); (ac, 25); (ad, 25); (ae, 25); (af, 25); (ag, 25); (ah, 25); (ai, 25); (aj, 25); (Ak, 25); (al, 25); (on the 25th); (An, 25); (Ao, 25); (Ap, 25); (Aq, 25); (Ar, 25); (AS, 25); (At 25); (Au, 25); (Av, 25); (aa, 26); (ab, 26); (ac, 26); (ad, 26); (ae, 26); (af, 26); (ag, 26); (ah, 26); (ai, 26); (aj, 26); (Ak, 26); (al, 26); (on 26); (An, 26); (Ao, 26); (Ap, 26); (Aq, 26); (Ar, 26); (AS, 26); (At 26); (Au, 26); (Av, 26); (aa, 27); (ab, 27); (ac, 27); (ad, 27); (ae, 27); (af, 27); (ag, 27); (ah, 27); (ai, 27); (aj, 27); (Ak, 27); (al, 27); (On the 27th); (An, 27); (Ao, 27); (Ap, 27); (Aq, 27); (Ar, 27); (AS, 27); (At 27); (Au, 27); (Av, 27); (aa, 28); (ab, 28); (ac, 28); (ad, 28); (ae, 28); (af, 28); (ag, 28); (ah, 28); (ai, 28); (aj, 28); (Ak, 28); (al, 28); (on the 28th); (An, 28); (Ao, 28); (Ap, 28); (Aq, 28); (Ar, 28); (AS, 28); (At, 28); (Au, 28); (Av, 28); (aa, 29); (ab, 29); (ac, 29); (ad, 29); (ae, 29); (af, 29); (ag, 29); (ah, 29); (ai, 29); (aj, 29); (Ak, 29); (al, 29); (On the 29th); (An, 29); (Ao, 29); (Ap, 29); (Aq, 29); (Ar, 29); (AS, 29); (At 29); (Au, 29); (Av, 29); (aa, 30); (from 30); (ac, 30); (ad, 30); (ae, 30); (af, 30); (ag, 30); (ah, 30); (ai, 30); (aj, 30); (Ak, 30); (Al, 30); (Am, 30); (An, 30); (Ao, 30); (Ap, 30); (Aq, 30); (Ar, 30); (AS, 30); (At 30); (Au, 30); (Av, 30); (aa, 31); (ab, 31); (ac, 31); (ad, 31); (ae, 31); (af, 31); (ag, 31); (ah, 31); (ai, 31); (aj, 31); (Ak, 31); (al, 31); (Am, 31); (An, 31); (Ao, 31); (Ap, 31); (Aq, 31); (Ar, 31); (AS, 31); (At, 31); (Au, 31); (Av, 31); (aa, 32); (ab, 32); (ac, 32); (ad, 32); (ae, 32); (af, 32); (ag, 32); (ah, 32); (ai, 32); (aj, 32); (Ak, 32); (al, 32); (Am, 32); (An, 32); (Ao, 32); (Ap, 32); (Aq, 32); (Ar, 32);

(AS, 32); (At 32); (Au, 32); (Av, 32); (aa, 33); (ab, 33); (ac, 33); (ad, 33); (ae, 33); (af, 33); (ag, 33); (ah, 33); (ai, 33); (aj, 33); (Ak, 33); (al, 33); (Am, 33); (An, 33); (Ao, 33); (Ap, 33); (Aq, 33); (Ar, 33); (AS, 33); (At 33); (Au, 33); (Av, 33); (aa, 34); (ab, 34); (ac, 34); (ad, 34); (ae, 34); (af, 34); (ag, 34); (ah, 34); (ai, 34); (aj, 34); (Ak, 34); (al, 34); (Am, 34); (34,); (Ao, 34); (Ap, 34); (Aq, 34); (Ar, 34); (AS, 34); (At, 34); (Au, 34); (Av, 34); (aa, 35); (ab, 35); (ac, 35); (ad, 35); (ae, 35); (af, 35); (ag, 35); (ah, 35); (ai, 35); (aj, 35); (Ak, 35); (al, 35); (Am, 35); (An, 35); (Ao, 35); (Ap, 35); (Aq, 35); (Ar, 35); (AS, 35); (At 35); (Au, 35); (Av, 35).

b) Dosage In order to determine the optimal dose of the two active substances for urinary incontinence, various framework conditions must be taken into account, such as the age and body weight of the patient, the nature and stage of the disease, and the potency of the compound. 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 range. 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 dosing racks can be lower.

More than once daily or twice daily administrations (e.g. 3, 4, 5 or 6 administrations per day) are also expressly contemplated herein. The selection of the dosage of this first component (a) is the one that can provide relief for the patient. In some cases a smaller amount than specified 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 preferred dose of the alpha antagonist for humans is between 0.001 mg and 5 g per day, preferably between 0.001 mg and 100 mg and very particularly preferably between 0.1 mg and 50 mg.

In the case of the active ingredient tamsulosin as component (a), the daily dose of the combination according to the invention desirably contains it in an amount of about 0.05 mg to about 5 mg. More preferably, each dose of the component contains about 0.1 to about 1 mg of the active ingredient. This dosage form allows the full daily dose to be administered in half or whole, single or multiple doses. 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.

The average daily adult dose of the other possible representatives of the alpha antagonists is as follows.

The average daily dose of the component (mg / day / patient) is:

Alfuzosin (1 mg to 15 mg, preferably approx.7.5 mg), bunazosin (0.5 mg to 20 mg preferably 5.5 mg), doxazosin 0.5 to 15 mg, preferably up to 4 mg), indoramine (1 to 50 mg, preferably up to 25 mg), naftopidil (1 mg to 100 mg, preferably less than 50 mg), prazosin (1 mg to 10 mg), terazosin (0.1 mg to 5 mg, preferably 2 mg), urapidil ( 10 mg to 150 mg, preferably 30 mg to 90 mg). If a 5-alpha reductase inhibitor is used, the average daily dose for an adult is: 0.1 mg to 10 mg, preferably 5 mg finasteride, 0.01 mg to 2 mg, preferably 0.5 mg dutasteride.

The dosages and regimen (i.e., one, two, three or more administrations per day) of the second component will depend on the factors already referred to in connection with the dosage choice of the first component.

The average daily adult dose of the second component (beta-3 agonist) 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 components in combination with a suitable carrier. Such pharmaceutical compositions can be prepared by methods and contain carriers that 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, transdermally, rectally, pulmonally by inhalation or nasally by inhalation, with oral administration being particularly preferred. Enteric formulations are preferred among the oral forms of administration. Therefore enteric capsules or enteric tablets are preferred, which in both Cases can be realized, for example, 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 of the invention may with one or more carriers are combined and in the form of ingestible tablets, buccal tablets, sublingual tablets, sugar-coated tablet, powders, Pudem, lozenges, coated tablets, granules, capsules, elixirs, suspensions, _'solutions, Syrups, wafers, chewing gums, foods 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 flavoring agents, preservatives, dispersing agents, colorants and other pharmacological auxiliaries.

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, 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) are used as counter-disintegrants or solution retarders; 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.

For example, ether can be used as a binder distributor and cetyl alcohol, glycerol monostearate, starch, maize starch, lactose, wetting agents (e.g. Aerosol OT, Pluronics, Tweens), tragacanth, gum arabic, gelatin and others as a hydrophilizing agent or as a disintegration accelerator. Sucrose, fructose, lactose or aspartame can be used as sweeteners or peppermint, wintergreen oil, cherry flavor and much more as a flavoring agent

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

Further usable auxiliaries can be found in the examples, but other auxiliaries from the prior art can also be used.

For example, tablets can be manufactured by direct compression.

Other oral formulations such as solutions, syrups, elixirs, etc. can also be produced. 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 can be used as a sweetener, methyl and

Propylparaben as a preservative, a colorant and a flavoring such as cherry or orange flavor may be included.

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.

The composition of the invention containing the two active components can be administered in the same physical form or simultaneously in accordance with the dosages described above and in the delivery vehicles described above. The dosages for each active component can be measured separately and can be administered as a single combined dose or administered separately. They can be administered at the same or different times, as long as both active ingredients are effective in the patient at one time over a 24-hour period. It is preferred if the two components come into effect in such a way that an effect is achieved which is improved compared to the respective individual effect. Simultaneous or co-administration means that the patient takes one drug within about 5 minutes after taking the other drug. For reasons of simple handling, formulations are preferred in which the two drugs are administered to the patient close together and typically at the same time.

d) indications

The pharmaceutical composition according to the invention can preferably be used for the treatment or prophylaxis, inter alia, of any of the clinical pictures mentioned below, as a single clinical picture or in combination with another of the named clinical pictures, but without being limited thereto: prostate diseases such as benign prostatic hyperblasia, prostatitis, in particular chronic abacterial prostatitis, neurogenic, muscular or bacterial origin, chronic pelvic pain syndrome, pelvic myoneuropathy, prostatodynia or Prostatopathy, bladder dysfunction, such as urinary incontinence, especially stress incontinence, urge incontinence, mixed incontinence or hyperactive bladder of neurogenic or non-neurogenic origin and their other subindications. The invention is preferably used in the presence of one of the above-mentioned prostate diseases and one of the above-mentioned bladder dysfunction.

According to the invention, both those clinical pictures are included, the cause of which is an organ dysfunction or illness, and also those which are attributable to diseases or disorders of the central nervous system.

The composition according to the invention can thereby alleviate the symptoms of the disease (s) and / or cause the disease.

A further embodiment of the present invention thus 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 mentioned in the preceding 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.

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. e) Examples

The invention is described more clearly by the following non-limiting examples.

Combinations are particularly preferred

Tamsulosin hydrochloride and (-) - ethyl 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetate ,

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

Tamsulosin hydrochloride and (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetic acid ,

Tamsulosin hydrochloride and (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxy] acetic acid monohydrochloride.

Finasteride and (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methyl-ethyl] amino} ethyl) -2.5 -dimethylphenyloxy] acetate.

Finasteride and (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methyl-ethyl] amino} ethyl) -2.5 -dimethylphenyloxy] acetate monohydrochloride.

Finasteride and (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyρhenyl) -l-methylethyl] - amino} ethyl) -2,5-dimethylphenyloxy] acetic acid.

Finasteride and (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] - amino} ethyl) -2,5-dimethylphenyloxy] acetic acid monohydrochloride. Dutasteride and (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methyl-ethyl] amino} ethyl) -2.5 -dimethylphenyloxy] acetate.

Dutasteride and (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methyl-ethyl] amino} ethyl) -2.5 -dimethylphenyloxy] acetate monohydrochloride.

Dutasteride and (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] - amino} ethyl) -2,5-dimethylphenyloxy] acetic acid.

Dutasteride and (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] - amino} ethyl) -2,5-dimethylphenyloxy] acetic acid monohydrochloride.

Having described the invention in detail and with reference to the preferred embodiments thereof, it will be apparent that modifications and variations are possible without departing from the scope of the appended claims.

Example 1 Composition from (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino} ethyl) -2.5 -dimethylphenyloxy] acetate / tamsulosin: prolonged-release capsule 80 mg / 0.367 mg

pellets

Enteric coating

final mix

capsule

Total weight of the prolonged-release capsule 560,000

Claims

claims

1. A pharmaceutical composition comprising: (a) a pharmaceutically effective amount of one or more active ingredients selected from the group of alpha antagonists and / or 5-alpha reductase inhibitors, optionally in the form of a pharmaceutically active salt thereof (b) a pharmaceutically effective amount of one or more beta-3 adrenoceptor agonists, optionally in the form of a pharmaceutically active salt thereof.

2. A pharmaceutical composition according to claim 1, wherein the at least one component (a) is an alpha agonist.

3. Pharmaceutical composition according to claim 2, in which the at least one component (a) is selected from the group consisting of tamsulosin, tamsulosin hydrochloride, alfuzosin, bunazosin, doxazosin, indoramine, naftopidil, prazosin, terazosin, urapidil, silodosin (KMD 3213), Moxisylyte, Metazosin, Fiduxosin, Upidosin, SNAP-5089 (5- (N- (3- (4,4-Diphenylpiperidin-l-yl) propyl) carbamoyl) -2,6-dimethyl-4 (R) - (4- nitrophenyl) - 1,4-dihydropyridine-3-carboxylic acid methyl ester), AIO-8507L, SL-890591 ((2- (3- (4- (5-chloro-2-methoxyphenyl) piperazin-1-yl) per pylamino) pyrimidine -4-carboxamide fumarate), RS-100329 (5-methyl-3- (3- (4- (2- (2,2,2-trifluoroethoxy) phenyl) pip erazin-l-yl) propyl) pyrimidine-2, 4 (1H, 3H) -dione hydrochloride) and mixtures thereof.

4. Pharmaceutical composition according to claim 1, in which the at least one component (a) is a 5-alpha reductase inhibitor.

5. Pharmaceutical composition according to claim 4, in which the at least one component (a) is finasteride or dutasteride.

6. Pharmaceutical composition according to one of claims 1 to 5, in which component (b) (-) - ethyl-2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4- hydroxyphenyl) -l-methylethyl] -amino} -ethyl) -2,5 -dimethylphenyloxy] acetate and / or (-) - 2- [4- (2- {[(IS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -l-methylethyl] amino} ethyl) -2,5-dimethylphenyloxyacetic acid and / or a pharmacologically acceptable salt thereof and / or an enantiomer.

7. Pharmaceutical composition according to one of claims 1 to 3, in which component (a) is tamsulosin or tamsulosin hydrochloride and component (b) (-) - 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-dimethylphenyloxyacetic acid and / or a pharmaceutically acceptable salt thereof.

8. Pharmaceutical composition according to spoke 7, which contains about 0.01 mg to about 5 mg tamsulosin and about 10 mg to about 750 mg component (b).

9. A pharmaceutical composition according to any one of claims 1 to 8, in which component (a) and component (b) are formulated in the same application form.

10. Pharmaceutical composition according to any one of claims 1 to 9, in which component (a) and component (b) are formulated in different application forms.

11. Pharmaceutical composition according to claim 10 for rectal, topical, oral, sublingual, intranasal, transdermal or parenteral application.

12. Pharmaceutical composition according to claim 9 or 10 for simultaneous administrations of the two components (a) and (b).

13. Pharmaceutical composition according to claim 9 or 10, wherein at least one of the two components is released at least partially delayed.

14. Pharmaceutical composition according to claim 9 or 10, wherein at least one of the two components is released at least partially immediately.

15. A pharmaceutical composition according to any one of claims 1 to 14, wherein the composition contains an alpha antagonist, a 5-alpha reductase inhibitor and a beta-3 adrenoceptor agonist.

16. Use of a pharmaceutical composition according to any one of claims 1 to 15 for the manufacture of a medicament for influencing the symptoms associated with a pathological change or irritation of the prostate in a mammal.

17. Use of a pharmaceutical composition containing component (a) according to one of claims 1, 2, 3, 4, 5, 8, 10, 11 or 15, which does not contain component (b) in combination with a second composition containing the Component (b) according to one of claims 1, 6, 10, 11 or 15, which does not contain component (a) for the manufacture of a medicament for influencing the symptoms associated with a pathological change or irritation of the prostate in a mammal.

16. A method for influencing the symptoms associated with a pathological change or irritation of the prostate in a mammal, which comprises the administration of a pharmaceutical composition according to any one of claims 1 to 15 to the mammal.