EP1507520A1 - Combination of selected opioids with other active substances for use in the therapy of urinary incontinence - Google Patents

Abstract

The invention relates to the use of a combination of the compounds of group A, especially opioids, with the compounds of group B for producing a drug for the treatment of urinary urgency or urinary incontinence. The invention also relates to corresponding drugs and to a method for treating urinary urgency or urinary incontinence.

Description

 Patent application by Qrünenthal GmbH, D-52078 Aachen (own sign: G 3132)

Combination of selected opioids with other active substances for the treatment of urinary incontinence

The invention relates to the use of a combination of compounds of group A, in particular opioids, and compounds of group B, for the manufacture of a medicament for the treatment of increased urge to urinate or urinary incontinence as well as corresponding medicaments and methods for the treatment of increased urge to urinate or urinary incontinence.

Urinary incontinence is the involuntary loss of urine. This occurs in an uncontrolled manner when the pressure inside the bladder exceeds the pressure necessary to close the ureter. The causes can be, on the one hand, an increased internal bladder pressure (e.g. due to detrusor instability) with the consequence of urge incontinence and, on the other hand, a reduced sphincter pressure (e.g. after birth or surgery) with the

Be the result of stress incontinence. The detrusor is the roughly bundled, multi-layered bladder wall muscles, the contraction of which leads to emptying of the urine, the sphincter the sphincter of the urethra. Mixed forms of these types of incontinence as well as so-called abundance incontinence (eg with benign prostatic hyperplasia) or reflex incontinence (eg after spinal cord damage) occur. More on this can be found in Chutka, D.S. and Takahashi, P. Y., 1998, Drugs 560: 587-595.

Urge to urinate is the state of increased bladder muscle tension aimed at emptying urine (micturition) when the bladder capacity is approached

(or if they are exceeded). This tension acts as a micturition. An increased urge to urinate means in particular especially the appearance of premature or sometimes even painful urge to urinate up to the so-called urge to urinate. This leads to a significantly more frequent micturition. Causes can include bladder infections and neurogenic bladder disorders as well as bladder tuberculosis. However, not all causes have yet been clarified.

Increased urge to urinate as well as urinary incontinence are perceived as extremely uncomfortable and there is a clear need among those affected by these indications to achieve the longest possible improvement.

Increased urge to urinate and especially urinary incontinence are usually treated with drugs that are involved in the reflexes of the lower urinary tract (Wein, A.J., 1998, Urology 51 (Suppl. 21): 43-47). Most often, these are drugs that have an inhibitory effect on the detrusor muscle, which is responsible for internal bladder pressure. These drugs are e.g. B. Parasympatholytics such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants such as imipramine or muscle relaxants such as flavoxate. Other drugs that particularly increase the resistance of the urethra or bladder neck show affinities for α-adrenoreceptors like ephedrine, for ß-adrenoreceptors like Clenbutarol or are hormones like estradiol.

The review article by K.E. provides a precise insight into the therapeutic agents and therapeutic methods used, especially with regard to antimuscarinics and other peripheral substances. Andersson et al. "The pharmacological treatment of urinary incontinence", BJU International (1999), 84, 923-947.

Certain diarylmethylpiperazines and piperidines are also for these

Indication described in WO 93/15062. Tramadol also had a positive effect on bladder function in a rat model rhythmic bladder contractions detected (Nippon-Shinyaku, WO 98/46216). Furthermore, there are studies in the literature to characterize the opioid side effect hamretention, from which there is some evidence of the influence of bladder functions by 5 weak opioids such as diphenoxylate (Fowler et al., 1987 J. Urol 138: 735-738) and meperidine (Doyle and Briscoe, 1976 Br J Urol 48: 329-335), by mixed opioid agonists / antagonists such as buprenorphine (Malinovsky et al., 1998 Anesth Anaig 87: 456-461; Drenger and Magora, 1989 Anesth Anaig 69: 348-353), Pentazocin (Shimizu et al. (2000) Br. J. Pharmacol. 131 0 (3): 610 - 616) and Nalbuphin (Malinovsky et al., 1998, loc. Cit.), And by strong opioids such as morphine (Malinovsky et al., 1998 loc. Cit.; Kontani and Kawabata, (1988); Jpn J Pharmacol. Sep; 48 (1): 31) and Fentanyl (Malinovsky et al., 1998 loc. Cit.). However, these studies were mostly carried out in analgesically effective concentrations. 5

With the indications in question here, it should be noted that, in general, these are very long-term medicinal uses and, in contrast to many situations in which analgesics are used, the persons concerned face a very unpleasant but not unavoidable situation. Therefore - even more so than with analgesics - care must be taken to avoid side effects if the person concerned does not want to exchange one evil for the other. Also, with permanent urinary incontinence treatment, analgesic effects are largely undesirable. 5

It was therefore an object of the present invention to find substances or combinations of substances which are helpful for the treatment of increased urge to urinate or urinary incontinence and which, at the effective doses, preferably simultaneously have fewer side effects and / or o analgesic effects than are known from the prior art, in particular one show synergistic effect for the treatment of urinary incontinence. Surprisingly, it has now been found that a combination of compounds from group A, the opioids and other centrally acting substances which interact with opioid receptors and whose effects can be antagonized by naloxone, or in particular

Substances which act via an opiate receptor, in particular the μ-receptor, and compounds of group B which contain muscarinic antagonists and other predominantly peripheral substances which are known to be active in urinary incontinence, have an excellent effect on the bladder function , Furthermore, these combinations - well beyond what was expected - proved to be so effective even at very low doses that the combined active ingredients could be used in low doses. As a result, it is to be expected that the side effects 5 that otherwise occur at higher necessary dosages will decrease significantly, while the therapeutic effect due to this combination of peripheral antimuscarinic effect, which mainly acts directly on the bladder or bladder muscles, and central opioid effect or μ-receptor Effect is fully preserved.

Accordingly, the subject of the invention is the use of a combination of active ingredients comprising at least one of the compounds A and at least one of the compounds B, with compound A selected from:

Group a) containing: 5 tramadol, O-demethyltramadol, or O-desmethyl-N-mono-desmethyl-tramadol as free base or acid and / or in the form of physiologically acceptable salts, in particular in the form of their physiologically acceptable acidic and basic salts or Salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or Diastereomers or a single enantiomer or diastereomer;

Group b) containing: codeine

Dextropropxyphene dihydrocodeine diphenoxylate ethylmorphine meptazinol nalbuphin

Pethidine (Meperidine) Tilidine Tramadol Viminol Butorphanol Dextromoramide Decocin

Diacetylmorphine (heroin) hydrocodone hydromorphone ketobemidone levomethadone

Levomethadyl Acetate (l-α-Acetylmethadol (LAAM)) Levorphanol Morphin Nalorphin Oxycodon Pentazocin Piritramide • Alfentanil

• buprenorphine

• etorphin

• fentanyl

• Remifentanil

• Sufentanil

as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures of them Enantiomers or diastereomers or a single enantiomer or diastereomer;

Group c) containing:

1-phenyl-3-dimethylamino-propane compounds according to general formula I.

, in which X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C 1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ^ is selected from C ^ alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ^ and R ^ are each independently selected from

H or C _| _4-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

or

R ^ and R together form a saturated C ₄ - cycloalkyl radical, unsubstituted or mono- or polysubstituted,

R9 to R ^" 1 ^ are each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ , OH, SH, OR14 0CF3,

SRI, NR ¹⁷ R ¹⁸ , SOCH3, SOCF _3; SO ₂ CH ₃ , SO ₂ CF ₃ , CN,

COOR ¹⁴ , NO2, CONR ¹⁷ R ¹⁸ _; C <| _6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with R ^"14 selected from Cι_6-alkyl; pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (0-Cι_4-altyl) 2, CO (OCι_5-alkyl), CONH-C ₆ H ₄ - (C .3-alkyl) ₎ CO (Cι_5-alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹ 5 with R15 ortho-OCOCι_3-alkyl or meta- or para-CH2N (R ⁶ ) 2 with R ⁶ C | _4-alkyl or 4-morpholino, wherein in the radicals R ¹⁴ , R ¹⁵ and R ¹⁶ the

Alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R1 ⁷ and R18 each independently selected from H; G ^ ß-Alky !, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R ⁰ or R ¹⁰ and R ^{1 1} together form an OCH2O-, OCH2CH2O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH-, (CH ₂ ) Form ₄ - or OCH = CHO ring,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer; Group d) containing:

Substituted 6-dimethylaminomethyl-1-phenyl-cyclohexane compounds according to general formula II

wherein

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _j _3-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ^{1 is} selected from C | _4-alkyl, benzyl, CF3, OH, OCH2-C6H5, OC <| _4-alkyl, Cl or F and

R9 to R13 are each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ , OH, SH, OR 4, OCF3, SR ¹⁴ ,

NR ¹⁷ R ¹⁸ , SOCH3, SOCF3. SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR14, NO ₂ ,

CONR ^ R ^ ⁸ ; Cι_6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with R1 ⁴ selected from C-ι_6-alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (O-Cι-4-alkyl) ₂ , CO (OC <| _ ₅ -alkyl),

CONH-C ₆ H ₄ - (C-ι_3-alkyl), CO (C <| _5-alkyl), CO-CHR ¹⁷ -

NHR ¹⁸ , CO-C6H4-R ¹⁵ , with R ¹ 5 ortho-OCOC ^ s-alkyl or meta- or para-CH2N (R ¹⁶ ) 2 with R ¹⁶ C <| _4-alkyl or

4-morpholino, where in the radicals R ¹⁴ , R ¹⁵ and R ¹⁶ the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R ^ ⁷ and R18 each independently selected from H; C-ß-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R ⁰ or R ¹⁰ and R ^{1 1} together form an OCH2O-, OCH2CH2O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-,

Form OC (CH3) = CH-, (CH ₂ ) ₄ - or OCH = CHO ring, as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts Cations or bases or with anions or acids; in shape the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or a single enantiomer or diastereomer;

and or

Group e) containing:

6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds according to general formula III

III

wherein

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C ₁ -C ³ -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and

R ⁹ to R ^ ^{8 are} each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF _2> CF ₃ , OH, SH, OR ¹⁴ , OCF ₃ ,

SRI ⁴ NR ⁷ R ¹⁸ , SOCH3, SOCF3; SO ₂ CH3, SO2CF3, CN,

COOR ¹⁴ , NO2, CONR ⁷ R ¹⁸ _; C- | _6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with R1 ⁴ selected from Ci.ß-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (OC- | _4-alkyl) ₂ , CO (OC <ι_5-alkyl),

CONH-C ₆ H ₄ - (Cι_ ₃ alkyl), CO (C <| _5-alkyl), CO-CHR ¹⁷ -

NHR ¹⁸ , CO-C6H4-R ¹⁵ , with R 5 ortho-OCOC <| _3-alkyl or meta- or para-CH2N (R ⁶ ) 2 with R ¹⁶ C <| _4-alkyl or 4-morpholino, where in the R ¹⁴ , R ¹⁵ and R ¹⁶ can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R ^ ⁷ and R18 each independently selected from H; Cι_6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted, or

R ⁹ and R10 or R ¹⁰ and R11 together form an OCH2O-, OCH2CH2O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH-, (CH ₂ ) - or OCH = form a CHO ring,

with the proviso that when R ⁹ , R ¹¹ and R ¹³ correspond to H and one of R ¹⁰ or R ¹² corresponds to H and the other corresponds to OCH ₃ , X must not be OH,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer;

and with at least one of the compounds B selected from:

the antimuscarinics: atropine, oxybutinin, propiverine, propantheline, emepronium, trospium, tolterodine, darifenacin and α, α-diphenylacetic acid 4- (N-methylpiperidyl) ester, as well as duloxetine, imipramine and desmopressin,

such as

Venlafaxine, fesoterodine, solifenacin (YM905), resiniferatoxin, cizolirtine, nitro-flurbiprofen, HCT1026, Talnetant, TAK-637, SL 251039, R 450, Rec 15/3079, (-) - DDMS, NS-8 and / or DRP-001

as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures of them Enantiomers or diastereomers or a single

Enantiomers or diastereomers;

for the manufacture of a medicament for the treatment of increased urge to urinate or urinary incontinence.

Surprisingly, it had been found that the combination of the substances mentioned had a clearly positive influence on certain physiological parameters which are important in the case of increased urge to urinate or urinary incontinence. Each and every one of these changes can mean a significant relief in the symptomatic picture of affected patients.

Group B compounds predominantly act peripherally in urinary incontinence. Venlafaxine is a selective norepinephrine reuptake inhibitor with efficacy in stress incontinence (Bae J.H. et al., BJU

International 2001, 88, 771, 775). Fesoterodine is a mACh antagonist developed by Schwarz Pharma. Solifenacin (YM905) is a mACh antagonist developed by Yamanouchi. Resiniferatoxin is a VR1 agonist developed by Afferon, Mundipharma and ICOS (but especially for local use). Cizolirtine is one in the European

Patent EP 289 380 B1 described compound (2- [phenyl (1-methyl-1H-pyrazole-5-yl) methoxy] -N, N-dimethylethanamine, which is also known as 5- [alpha - (2- dimethylaminoethoxy) benzyl] -1-methyl-1H-pyrazole or 5 - {[N, N-dimethylaminoethoxy) phenyl] methyl} -1-methyl-1H-pyrazole) can be called)) with a mechanism of action previously unknown by the company Esteve (ES) is being clinically examined in urinary incontinence. Nitro-Flurbiprofen and HCT-1026 are two substances developed by NicOx that act on NO + COX. Talnetant is an NK antagonist developed by Glaxo Smith Kline. TAK-637 is an NK antagonist developed by Takeda. SL 251039 is an a-iAR agonist developed by Sanofi. R 450 is an a-iAR agonist developed by Röche. Rec 15/3079 is a 5HTι _A antagonist developed by Recordati. (-) - DDMS is a substance developed by Sepracor that acts on NA + D. NS-8 is a substance developed by Nippon Shinyaku that acts on PCA. DRP-001 is a substance developed by Sosei for urge incontinence with an unknown mechanism of action.

For the purposes of this invention, alkyl or cycloalkyl radicals are taken to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted. C ₂ alkyl is C1 or C2 alkyl, C _1-3 alkyl is C1, C2 or C3 alkyl, C ₄ alkyl is C1, C2, C3 or C4 alkyl C _1-5 alkyl for C1, C2, C3, C4 or C5 alkyl, C _1-6 alkyl for C1, C2, C3, C4, C5 or C6 alkyl, C _1-7 alkyl for C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, C _1-8 -alkyl for C1-, C2-, C3-, C4-, C5- , C6-, C7- or C8-alkyl, d-io-alkyl for C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and C _{1 -18} -alkyl for C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16, C17 or C18 alkyl. Furthermore, C _3-4 -cycloalkyl stands for C3- or C4-cycloalkyl, C _3-5 -cycloalkyl for C3-, C4- or C5-cycloalkyl, C _3-6 -cycloalkyl for C3-, C4-, C5- or C6 -Cycloalkyl, C _3-7 -cycloalkyl for C3-, C4-, C5-, C6- or C7-cycloalkyl, C _3-8 -cycloalkyl for C3-, C4-, C5-, C6-, C7- or C8- Cycloalkyl, C _4-5 cycloalkyl for C4 or C5 cycloalkyl, C _4-6 cycloalkyl for C4, C5 or C6 cycloalkyl, C _4-7 cycloalkyl for C4, C5, C6 or C7 -Cycloalkyl, C _5-6 -cycloalkyl for C5- or C6- Cycloalkyl and C _5-7 cycloalkyl for C5, C6 or C7 cycloalkyl. With regard to cycloalkyl, the term also includes saturated cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O. However, the term cycloalkyl in particular also includes one or more, preferably single, unsaturated cycloalkyls without

Heteroatom in the ring as long as the cycloalkyl is not an aromatic system. The alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, Pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-

Methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, but also adamantyl, CHF2, CF3 or CH2OH as well

Pyrazolinone, oxopyrazolinone, [1, 4] dioxane or dioxolane.

In the context of alkyl and cycloalkyl - as long as this is not expressly defined otherwise - the term substituted in the sense of this invention means the substitution of at least one (possibly also several) hydrogen radicals by F, Cl, Br, I, NH ₂ , SH or OH, where “multiply substituted” or “substituted” is to be understood in the case of multiple substitution that the substitution takes place both on different and on the same atom several times with the same or different substituents, for example three times on the same carbon atom as in the case of CF ₃ or in different places as in the case of -CH (OH) -CH = CH-CHCI ₂ . Particularly preferred substituents here are F, Cl and OH. With regard to cycloalkyl, the hydrogen radical can also be substituted by OCι-3-alkyl or C ^ -Alky! (j ^{θ e} '' ^se ' ^n_ or multiply substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF ₃ , methoxy or ethoxy.

Under the term (CH ₂ ) ₃ -6 is -CH2-CH2-CH ₂ -, -CH2-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH2-CH2-CH2-CH2- and CH ₂ -CH2 -CH ₂ -CH2-CH ₂ -CH2- to understand (CH ₂ ) ι _{-4 means} -CH ₂ -, -CH2-CH2-, -CH ₂ -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, under (CH ₂ ) _4-5 is -CH2-CH2-CH2-CH2- and -CH2-CH2-CH2-CH2-CH ₂ - to understand etc.

An aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or mono- or polysubstituted.

A heteroaryl radical is understood to mean heterocyclic ring systems with at least one unsaturated ring which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and can also be mono- or polysubstituted.

Examples include from the group of heteroaryls furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1, 2.5 thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, Indole and quinazoline listed.

In connection with aryl and heteroaryl, this is understood to mean the substitution of aryl or heteroaryl with R ²³ , OR ^23, a halogen, preferably F and / or Cl, a CF3, a CN, a NO2,

an NR ²⁴ R ² 5, a C < _| _g-alkyl (saturated), a Cι_ρ-alkoxy, a C3_3-cycloalkoxy, a C3_3-cycloalkyl or a C2_ß-alkylene.

The radical R ^{28 stands} for H, a C 1-10 alkyl- _> preferably a C 1-6 alkyl, an aryl or heteroaryl or for an aryl or heteroaryl bonded via a C-1.3 alkylene group -Rest, this aryl and heteroaryl radicals themselves may not be substituted by aryl or heteroaryl radicals,

the radicals R ² and R ² ^ 4, identical or different, represent H, a C _j.-io-alkyl, preferably a Cj.g-alkyl, an aryl, a heteroaryl or a C ^ -Alkylene group-bound aryl or heteroaryl radical, these aryl and heteroaryl radicals themselves not being allowed to be substituted with aryl or heteroaryl radicals,

or the radicals R ²⁴ and R ²⁵ together represent CH2CH ₂ OCH2CH2,

CH ₂ CH ₂ NR ²⁶ CH2CH2 or (CH ₂ ) 3_6- and

the remainder R ²⁸ for H, a C < _| _- _| Q-alkyl, preferably a C < _| _g-alkyl, an aryl, or heteroaryl radical or for one via a C- _| _3-alkylene group-bound aryl or heteroaryl radical, these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals.

The term salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.

For the purposes of this invention, the term “physiologically compatible salt with cations or bases” means salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation, which is physiologically - in particular when used in humans and or Mammal - are tolerated. Particularly preferred are the salts of the alkali and alkaline earth metals but also with NH ₄ ⁺ , but especially (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.

For the purposes of this invention, the term “physiologically compatible salt with anions or acids” is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which is physiologically - in particular when used in humans and / or Mammal - are compatible. For the purposes of this invention, this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals. Examples of physiologically compatible salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo-1, 2 dihydro1b6-benzo [d] isothiazol-3-one (saccharic acid),

Monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid,

Nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, a-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. The hydrochloride salt is particularly preferred.

Suitable salts in the sense of this invention and in each described use and each of the described medicinal products are salts of the respective active substance with inorganic or organic acids and / or a sugar substitute such as saccharin, cyclamate or acesulfame. However, the hydrochloride is particularly preferred. Compounds of group c) and their preparation are known from DE 44 26 245 A1 and US 6,248,737. Compounds of groups d) and e) and their preparation are known from DE 195 25 137 A1 or US 5,733,936 or US RE37355E.

In a preferred embodiment it applies to the use according to the invention that the compound A in group a) is selected from:

Tramadol, (+) - tramadol, (+) - O-demethyltramadol or (+) - O- desmethyl-N-mono-desmethyl-tramadol, preferably Tramadol or (+) - Tramadol, in particular (+) - Tramadol.

In a preferred embodiment, the use according to the invention is that the compound A in group b) is selected from:

codeine

Dextropropxyphen

dihydrocodeine

diphenoxylate

ethylmorphine

meptazinol

nalbuphine

Pethidine (meperidine)

Tilidin

Viminol

butorphanol

dezocin

nalorphine

pentazocine

buprenorphine , preferably

codeine

Dextropropxyphen

dihydrocodeine

meptazinol

nalbuphine

Tilidin

buprenorphine

In a preferred embodiment, it applies to the use according to the invention that the compound A in group c) is selected from compounds of the formula I for which:

X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F, OC (O) CH ₃ or H,

and or

R ^{1 is} selected from

saturated and unsubstituted, branched or unbranched; preferably CH ₃ , C ₂ H ₅ , C ₄ H ₉ or t-butyl, in particular CH ₃ θ or C2H5,

and or R ² and R ^{3 are} independently selected from

H, C- _| _4-alkyl, saturated and unsubstituted, branched or unbranched; preferably H, CH ₃ , C ₂ H ₅ , i-propyl or t-butyl, in particular H or CH ₃ , preferably R ³ = H,

or

R ² and R ⁸ together form a C ₅ - ₆ cycloalkyl form, saturated or unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted, in particular cyclohexyl.

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with

R ¹⁴ selected from C « _| _3-alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF _3> OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring

in particular

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from: Cl, F, OH, CF ₂ H, CF ₃₎ OR ¹⁴ or SR ¹⁴ , preferably OH,

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or,

when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH, OC ₂ H ₅ or OC ₃ H ₇ .

It is particularly preferred for compounds of group c) if it applies that compounds of the formula I with R ³ = H in the form of the diastereomers with the relative configuration Ia

la

are present, in particular in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or used as a pure diastereomer

and or

that the compounds of formula I are used in the form of the (+) ~ enantiomer, in particular in mixtures with a higher proportion of the (+) - enantiomer compared to the (-) - enantiomer of a racemic compound or as a pure (+) - enantiomer.

It is particularly preferred if compound A selected from the following group is used:

(2RS, 3RS) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol,

(+) - (2R, 3R) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol,

(2RS, 3RS) -3- (3,4-dichlorophenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

(2RS, 3RS) -3- (3-difluoromethylphenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

(2RS, 3RS) -1-dimethylamino-2-methyl-3- (3-methylsulfanylphenyl) pentan-3-ol,

(3RS) -1-dimethylamino-3- (3-methoxyphenyl) -4,4-dimethylpentan-3-ol,

(2RS, 3RS) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl) phenol,

(1 RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethyl-propyl) phenol,

(+) - (1 R, 2R) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethylpropyl) phenol,

(+) - (1 R, 2R) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethyl-propyl) phenol,

(-) - (1 R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol,

(+) - (1 R, 2R) -acetic acid-3-dimethylamino-1-ethyl-1 - (3-methoxyphenyl) -2-methyl-propyl ester,

(1 RS) -1 - (1 -dimethylaminomethyl-cyclohexyl) -1 - (3-methoxy- phenyl) propane-1 -ol,

^■ (2RS, 3RS) -3- (4-chlorophenyl) -1-dimethylamino-2-methylpentan-3-ol,

^■ (+) - (2R, 3R) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl) -phenol,

^■ (2RS, 3RS) -4-dimethylamino-2- (3-methoxyphenyl) -3-methylbutan-2-ol and

^■ (+) - (2R, 3R) -4-dimethylamino-2- (3-methoxyphenyl) -3-methyl-butan-2-ol,

preferably as hydrochloride.

In a preferred embodiment, the use according to the invention is that the compound A in group d) is selected from compounds of the formula II for which:

X is selected from

OH, F, Cl, OC (0) CH ₃ or H, preferably OH, F or H, in particular OH,

and or

R ^{1 is} selected from

Cι_4-alkyl, CF3, OH, O-Cι_4-alkyl, Cl or F, preferably OH, CF ₃ or CH ₃ ,

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from H, Cl, F, OH, CF ₂ H, CF ₃ or C ₁ _ ₄ alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C - ^ - alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ² and R ^{11 form} a 3,4-OCH = CH ring,

in particular

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH,

CF ₂ H, OR ¹⁴ or SCH ₃ , especially OH or OC ^ -

Alkyl, preferably OH or OCH3,

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH _3l Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl, corresponds,

or,

when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or, when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH, OC ₂ H ₅ or OC ₃ H ₇ ,

very particularly preferred

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, SH, CF ₂ H, CF _3> OR ¹⁴ or SR ^14, preferably OH or OR ^14, in particular OH or OC _j _3-alkyl, preferably

OH or OCH ₃ .

It is particularly preferred for compounds of group d) if it applies that compounds of the formula II in the form of the diastereomers with the relative configuration IIa

lla

are present, in particular in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as a pure diastereomer,

and or that the compounds of formula II are used in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

It is particularly preferred if compound A selected from the following group is used:

(1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(+) - (1 R, 3R, 6R) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1 - (3-hydroxyphenyl) cyclohexane-1, 3-diol,

(1 RS, 3SR, 6RS) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(+) - (1 R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl) phenol or

(1 RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl) phenol,

preferably as hydrochloride.

In a preferred embodiment, it applies to the use according to the invention that the compound A in group e) is selected from compounds of the formula III for which:

X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F or H, in particular F or H.

and or R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring

in particular characterized in that

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH, CF ₂ H, OR ¹⁴ or SCH ₃ , in particular OH or OC ^ alkyl, preferably OH or OCH ₃ ,

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or, when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH, OC ₂ H ₅ or OC ₃ H ₇ ,

very particularly preferred

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, SH, CF ₂ H, CF ₃₎ OR ¹⁴ or SR ¹⁴ , preferably OH or OR ¹⁴ , in particular OH or OC ^ alkyl, preferably OH or OCH ₃ .

It is particularly preferred for compounds of group e) if it applies that compounds of the formula III in the form of their diastereomers with the relative configuration purple

purple are present, in particular in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or used as a pure diastereomer

and or

that the compounds of formula III are used in the form of the (+) enantiomer, especially in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

It is particularly preferred if compound A selected from the following group is used:

(+) - (1 R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) phenol,

(+) - (1S, 2S) -3- (2-dimethylaminomethylcyclohexyl) phenol or

(-) - (1 R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol,

preferably as hydrochloride.

For a particularly preferred use, compound B is selected from:

Darifenacin, duloxetine, oxybutinin or tolterodine,

is preferably selected from

Duloxetine, oxybutinin or tolterodine,

is preferably selected from

Oxybutinin or tolterodine. For another particularly preferred use, compound B is selected from:

Venlafaxine, fesoterodine, solifenacin (YM905), cizolirtine, or

Resiniferatoxin.

Even if the uses according to the invention show only minor side effects, it may also be advantageous, for example, to avoid certain forms of dependency, in addition to the combination of the compounds A and B, and also to use morphine antagonists, in particular naioxon, naitrexone and / or levallorphan.

Another object of the invention is an active ingredient combination of at least one of the compounds A and at least one of the compounds B, with compound A selected from:

Group a) containing:

Tramadol, O-demethyltramadol or O-desmethyl-N-mono-desmethyl-tramadol as free base or acid and / or in

Form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or

acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or

Diastereomers or a single enantiomer or

diastereomer;

Group b) containing:

• Codeine

• Dextropropxyphs dihydrocodeine

diphenoxylate

ethylmorphine

meptazinol

nalbuphine

Pethidine (meperidine)

Tilidin

tramadol

Viminol

butorphanol

dextromoramide

dezocin

Diacetylmorphine (heroin)

hydrocodone

hydromorphone

ketobemidone

Methadone

Levomethadyl Acetate (l-α-Acetylmethadol (LAAM))

levorphanol

morphine

nalorphine

oxycodone

pentazocine

Piritramide

alfentanil

buprenorphine

etorphine

fentanyl

remifentanil

sufentanil as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures of them Enantiomers or diastereomers or a single enantiomer or diastereomer;

Group c) containing:

1-phenyl-3-dimethylamino-propane compounds according to general formula I.

wherein

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C - ^ - alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, R ^ is selected from C ^^ - alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or substituted one or more times,

R ² and R ^{8 are} each independently selected from H or C < _| _4-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

or

R ² and R ⁸ together are a saturated C ₄ - ₇ -cycloalkyl form, unsubstituted or mono- or polysubstituted,

R ⁹ to R ^ ^{8 are} each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ , OH, SH, 0R1, OCF ₃ ,

SRI ⁴ NR ¹⁷ R ¹⁸ , SOCH3, SOCF _3; SO2CH3, SO ₂ CF ₃ , CN,

COOR ⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ _; C- | _6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with R ¹⁴ selected from Ci.g-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (OC _{1. 4,} alkyl) 2, CO (OC <μ ₅ alkyl),

CONH-C ₆ H ₄ - (C .3-alkyl), CO (C <| _ ₅ -alkyl), CO-CHR ¹⁷ -

NHR ¹⁸ , CO-C6H4-RI ⁵ , with R15 ortho-OCOC <| _3-alkyl or meta- or para-CH2N (R ⁶ ) 2 with R16 C- | _4-alkyl or 4-morpholino, in which R ¹⁴ , R ¹⁵ and R ¹⁶ die Alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R ^ ⁷ and R18 each independently selected from H; Cι_6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R ¹⁰ or R ¹⁰ and R ^{1 1} together form an OCH2O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH- , (CH ₂ ) - or OCH = CHO ring form,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer;

Group d) containing:

Substituted 6-dimethylaminomethyl-1-phenyl-cyclohexane compounds according to the general formula

II

, in which

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C 1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ^{1 is} selected from C <| _4-alkyl, benzyl, CF3, OH, OCH2-CQH $, O-Cι_4-alkyl, Cl or F and

R ⁹ to R ^ ^{8 are} each independently selected from H, F, Cl, Br, 1, CH ₂ F, CHF ₂₎ CF3, OH, SH, OR ¹⁴ , OCF3, SR1 ⁴ ,

NR ¹⁷ R ¹⁸ , SOCH3, SOCF _3; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ ,

CONR ^ ⁷ R ^ _; C- | _6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with R ^ ⁴ selected from Cj.ß-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (OC ₁ -4-alkyl) ₂ , CO (OCι .5-alkyl), CONH-C ₆ H4- (Cι_3-alkyl), CO (Cι_5-alkyl), CO-CHR ¹⁷ -

NHR ¹⁸ , CO-C ₆ H4-R ¹⁵ , with R ⁵ ortho-OCOCι_3-alkyl or meta- or para-CH2N (R ⁶ ) 2 with R ⁶ C <| _4-alkyl or 4-morpholino, being in the residues R ⁴ , R ¹⁵ and R ¹⁶ die

Alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R1 ⁷ and R18 each independently selected from H; Cι_g-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R10 or R ^ ⁹ and R11 together form an OCH2O-, OCH2CH2O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH-, (CH ₂ ) ₄ - or OCH = CHO ring form, as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer;

and or Group e) containing:

6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds according to general formula III

, in which

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C < _| _3-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and

R ⁹ to R ^ ^{8 are} each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ , OH, SH, OR ¹⁴ , OCF ₃ ,

SR ¹⁴ , NR ^{1 7} R ¹⁸ , SOCH ₃ , SOCF _3; SO ₂ CH ₃ , SO ₂ CF ₃ , CN,

COOR1 ⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ _; Cι_6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted; with R ¹⁴ selected from Ci.ρ-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (OC <| _4-alkyl) 2, CO (OCι .5-alkyl), CONH-C6H - (Cι .3-alkyl), CO (Cι .5-alkyl), CO-CHR ¹⁷ -

NHR ¹⁸ , CO-C6H4-R 5, with R ⁵ ortho-OCOC- | .3-alkyl or meta- or para-CH2N (R ¹⁶ ) 2 with R ¹⁶ Cι_4-alkyl or

4-morpholino, where in the radicals R ¹⁴ , R ¹⁵ and R ¹⁶ the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R1 ⁷ and R18 each independently selected from H; Cj.ö-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R ^" 10 or R ^ and R11 together form an OCH2O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH-, Form (CH ₂ ) ₄ - or OCH = CHO ring,

with the proviso that, if R ⁹ , R and RH correspond and one of them is RR ¹¹⁰⁰ (or R ¹² corresponds to H and the other OCH ₃ , X must not be OH,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically acceptable compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer;

and with at least one of the compounds B selected from:

the antimuscarinics: atropine, oxybutinin, propiverine, propantheline, emepronium, trospium, tolterodine,

Darifenacin and α, α-diphenylacetic acid 4- (N-methylpiperidyl) ester, as well as duloxetine, imipramine and desmopressin,

such as

Venlafaxine, Fesoterodine, Solifenacin (YM905), Cizolirtine, Resiniferatoxin, Nitro-Flurbiprofen, HCT1026, Talnetant, TAK-637, SL 251039, R 450, Rec 15/3079, (-) - DDMS, NS- 8 and / or DRP- 001,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or

Acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or a single enantiomer or diastereomer. Suitable salts for the purposes of this invention and in each of the pharmaceuticals described are salts of the respective active ingredient with inorganic or organic acids and / or a sugar substitute such as saccharin, cyclamate or acesulfame. However, the hydrochloride is particularly preferred.

For the active substance combination, it is particularly preferred if the compound A in group a) is selected from:

Tramadol, (+) - tramadol, (+) - O-demethyltramadol or (+) - O- desmethyl-N-mono-desmethyl-tramadol, preferably Tramadol or (+) - Tramadol, in particular (+) - Tramadol.

For the active ingredient combination, it is particularly preferred if the compound A in group b) is selected from:

codeine

Dextropropxyphen

dihydrocodeine

diphenoxylate

ethylmorphine

meptazinol

nalbuphine

Pethidine (meperidine)

Tilidin

Viminol

butorphanol

dezocin

nalorphine

pentazocine • buprenorphine

, preferably

codeine

Dextropropxyphen

dihydrocodeine

meptazinol

nalbuphine

Tilidin

buprenorphine

For the combination of active ingredients, it is particularly preferred if the compound A in group c) is selected from compounds of the formula I for which:

X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F, OC (O) CH ₃ or H,

and or

R is selected from

C- _| _4-alkyl, saturated and unsubstituted, branched or unbranched; preferably CH ₃ , C ₂ H ₅ , C ₄ H ₉ or t-butyl, in particular CH ₃ or C ₂ H ₅ ,

and or R ² and R ^{3 are} independently selected from

H, C- _| _4-alkyl, saturated and unsubstituted, branched or unbranched; preferably H, CH ₃ , C ₂ H ₅ , i-propyl or t-butyl, in particular H or CH ₃ , preferably R ³ = H,

or

R ² and R ⁸ together form a C ₅ - ₆ cycloalkyl radical, saturated or unsaturated, unsubstituted or mono- or polysubstituted, saturated Preferably, and unsubstituted, in particular cyclohexyl.

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with

R ¹⁴ selected from C < _| _3-alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring

in particular

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from: Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH,

CF ₂ H, OCH ₃ or SCH ₃

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or,

when R ⁹ , R ⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH, OC ₂ H ₅ or OC ₃ H ₇ .

It is particularly preferred for compounds of group c) if the compounds of the formula I with R ³ = H in the form of the diastereomers with the relative configuration Ia

la

are present, especially in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as a pure diastereomer

and or

that the compounds of the formula I are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

It is particularly preferred if compound A is selected from the following group:

(2RS, 3RS) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol,

(+) - (2R, 3R) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol,

(2RS, 3RS) -3- (3,4-dichlorophenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

(2RS, 3RS) -3- (3-difluoromethylphenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

(2RS, 3RS) -1-dimethylamino-2-methyl-3- (3-methylsulfanylphenyl) pentan-3-ol,

(3RS) -1-dimethylamino-3- (3-methoxyphenyl) -4,4-dimethylpentan-3-ol,

(2RS, 3RS) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl) phenol,

(1 RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethyl-propyl) phenol,

(+) - (1 R, 2R) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethylpropyl) phenol,

(+) - (1 R, 2R) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethyl-propyl) phenol,

(-) - (1 R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol,

(+) - (1 R, 2R) -acetic acid-3-dimethylamino-1-ethyl-1 - (3-methoxyphenyl) -2-methyl-propyl ester,

(1 RS) -1 - (1 -dimethylaminomethyl-cyclohexyl) -1 - (3-methoxy- phenyl) propan-1-ol,

^■ (2RS, 3RS) -3- (4-ChlorophenyI) -1-dimethylamino-2-methyl-pentan-3-ol,

^■ (+) - (2R, 3R) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl) -phenol,

^■ (2RS, 3RS) -4-dimethylamino-2- (3-methoxyphenyl) -3-methylbutan-2-ol and

^■ (+) - (2R, 3R) -4-dimethylamino-2- (3-methoxyphenyl) -3-methyl-butan-2-ol,

preferably as hydrochloride.

For the combination of active ingredients, it is particularly preferred if the compound A in group d) is selected from compounds of the formula II for which:

X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F or H, in particular OH,

and or

R ^{1 is} selected from

C 1-4 alkyl, CF3, OH, O-C 4 alkyl, Cl or F, preferably OH, CF ₃ or CH ₃ ,

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C 1-4 alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring,

in particular

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH,

CF ₂ H, OR ¹⁴ or SCH ₃ , especially OH or OCι_ -

Alkyl, preferably OH or OCH ₃ ,

or,

if R ⁹ and R ¹³ correspond to H and R ¹¹ OH, OCH ₃ , Cl or F,

10 12 preferably corresponds to Cl, one of R or R also corresponds to H, while the other corresponds to OH, OCH ₃ , Cl or F, preferably Cl,

or,

when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF3, CF ₂ H, Cl or F, preferably F,

or, when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH, OC ₂ H ₅ or OC ₃ H ₇ ,

very particularly preferred

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, SH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH or OR ¹⁴ , in particular OH or OC- _| _3-alkyl, preferably

OH or OCH ₃ .

It is particularly preferred for compounds of group d) if the compounds of the formula II are in the form of the diastereomers with the relative configuration IIa

lla

are present, in particular in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as a pure diastereomer,

and or that the compounds of the formula I are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

It is particularly preferred if compound A is selected from the following group:

(1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(+) - (1 R, 3R, 6R) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1 - (3-hydroxyphenyl) cyclohexane-1, 3-diol,

(1 RS, 3SR, 6RS) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(+) - (1 R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl) phenol or

(1 RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl) phenol,

preferably as hydrochloride.

For the combination of active ingredients, it is particularly preferred if the compound A in group e) is selected from compounds of the formula III for which:

X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F or H, in particular F or H.

and or R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and

; unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with

R ¹⁴ selected from C < _| _3-alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃ 0 or R ¹² and R ^{11 form} a 3,4-OCH = CH ring

in particular characterized in that

5 if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, CF ₂ H, CF _3, OR ¹⁴ or SR ^14, preferably OH, CF ₂ H, OR ¹⁴ or SCH _3, in particular OH or OC _"| _3- o alkyl, preferably OH or OCH ₃ ,

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, 5 preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl, corresponds to

or, 0 when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH, OC ₂ H ₅ or OC ₃ H ₇ ,

very particularly preferred

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, SH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH or OR ¹⁴ , in particular OH or OC < _| _ ₃ alkyl, preferably OH or OCH ₃ .

It is particularly preferred for compounds of group e) if the compounds of the formula III are purple in the form of their diastereomers with the relative configuration

purple are present, especially in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as a pure diastereomer

and or

that the compounds of the formula IM are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

It is particularly preferred if compound A is selected from the following group:

^■ (+) - (1 R, 2R) -3- (2-dimethylaminomethyl-1 -fluoro-cyclohexyl) - phenol,

^■ (+) - (1 S, 2S) -3- (2-dimethylaminomethylcyclohexyl) phenol or

^■ (-) - (1 R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol,

preferably as hydrochloride.

In a generally particularly preferred form of the active compound combination according to the invention, compound B is selected from:

Darifenacin, duloxetine, oxybutinin or tolterodine,

is preferably selected from

Duloxetine, oxybutinin or tolterodine,

is preferably selected from Oxybutinin or tolterodine.

For a particularly preferred form of the active compound combination according to the invention, compound B is selected from: venlafaxine, fesoterodine, solifenacin (YM905), cizolirtine or

Resiniferatoxin.

Another object of the invention is a medicament, preferably for the treatment of increased urge to urinate or urinary incontinence, containing an active ingredient combination according to the invention and, if appropriate, suitable additives and / or auxiliaries.

Suitable additives and / or auxiliary substances in the sense of this invention are all substances known to the person skilled in the art from the prior art for achieving galenic formulations. The selection of these auxiliaries and the amounts to be used depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally. Preparations in the form of tablets, chewable tablets, dragees, capsules, granules, drops, juices or syrups are suitable for oral administration, solutions, suspensions, easily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration. Another possibility is suppositories for use in the rectum. Use in a depot in dissolved form, a carrier film or a plaster, optionally with the addition of agents which promote skin penetration, are examples of suitable percutaneous forms of application. Examples of auxiliaries and additives for oral administration forms are disintegrants, lubricants, binders, fillers, mold release agents, if appropriate solvents, flavorings, sugar, in particular carriers, diluents, colorants, antioxidants etc. For suppositories, waxes or fatty acid esters and for parenteral administration agents can be used, for example Carriers, preservatives, suspension aids etc. are used become. The amounts of active ingredient to be administered to patients vary depending on the weight of the patient, the type of application and the severity of the disease. The compounds according to the invention can be released in a delayed manner from preparation forms which can be used orally, rectally or percutaneously. In the indication according to the invention, corresponding slow-release formulations, in particular in the form of a “once-daily” preparation, which only has to be taken once a day, are particularly preferred.

Further preferred are drugs that contain at least 0.05 to 90.0% of the active ingredient, in particular low effective doses, in order to avoid side effects or analgesic effects. Usually 0.1 to 5000 mg / kg, in particular 1 to 500 mg / kg, preferably 2 to 250 mg / kg body weight of at least one compound of the formula I are applied. However, application of 0.01 to 5 mg / kg, preferably 0.03 to 2 mg / kg, in particular 0.05 to 1 mg / kg of body weight is also preferred and usual.

Auxiliaries can be, for example: water, ethanol, 2-propanol, glycerin, ethylene glycol, propylene glycol, polyethylene glycol,

Polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinyl pyrrolidone, natural and synthetic waxes , Acacia, alginates,

Dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and -propylene fatty acid ester, sorbitan, sorbic acid, benzoic acid, citric acid,

Ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, Silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidone, agar and bentonite.

The pharmaceuticals and pharmaceutical compositions according to the invention are produced with the aid of means, devices, methods and processes well known in the art of pharmaceutical formulation, as described, for example, in "Remington ^'s Pharmaceutical Sciences", ed. AR Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), in particular in Part 8, Chapters 76 to 93.

For example, for a solid formulation such as a tablet, the active ingredient of the drug with a pharmaceutical carrier, e.g. conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents such as e.g. Water, granulated to form a solid composition containing active ingredient in homogeneous distribution. Under a homogeneous

Distribution is understood here to mean that the active ingredient is uniformly distributed over the entire composition, so that it can be easily divided into equally effective unit dose forms, such as tablets, pills or capsules. The solid composition is then divided into unit dose forms. The tablets or pills of the medicament according to the invention or of the compositions according to the invention can also be coated or compounded in some other way in order to provide a dosage form with delayed release. Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as e.g. Shellac,

Cetyl alcohol and / or cellulose acetate. Even if the medicaments according to the invention show only minor side effects, it may be advantageous, for example to avoid certain forms of dependency, to use morphine antagonists, in particular naioxon, naitrexone and / or levallorphan, in addition to the combination of the compounds A and B.

The invention further relates to a method for the treatment of increased urge to urinate or urinary incontinence, in which the combination of active ingredients of compound A and compound B is used

10 will.

The following examples are intended to illustrate the invention, without the object of the invention being restricted thereto.

15 examples

Example 1: List of substances tested:

20 The following is a list of compounds tested for effectiveness:

Example 2: Test system cystometry on the awake naive rat

5 Cystometric studies on naive, female

Sprague-Dawley rats using the method of Ishizuka et. al. ((1997), Naunyn-Schmiedeberg's Arch. Pharmacol. 355: 787-793). Three days after the implantation of bladder and venous catheters, the animals were examined while awake, free to move. The bladder catheter was attached to a pressure sensor and an injection pump. concluded. The animals were placed in metabolic cages, which made it possible to measure urine volume. Physiological saline was infused into the emptied bladder (10 ml / hour) and bladder pressure and micturition volume were recorded continuously. After a stabilization phase, a 20-minute phase was recorded, which was characterized by normal, reproducible micturition cycles. Among other things, the following parameters were determined:

^■ threshold pressure (threshold pressure TP, bladder pressure immediately before micturition),

Bladder capacity BC, residual volume after previous micturition plus volume of the infused solution during the filling phase,

■ Inter-contraction interval (ICI), the time interval between micturition.

An increase in the threshold pressure (TP) indicates an important therapeutic effect in one of the indications according to the invention. The inter-contraction interval (ICI) is also an important parameter for measuring the physiological effectiveness of a substance in the treatment of urinary incontinence, as is the bladder capacity (BC). In order to be effective, it is not necessary to have a positive influence on all three parameters due to the very heterogeneous causes for the symptoms of these clinical pictures. It is therefore entirely sufficient if only one of these parameters has a positive effect in order to be used in urinary incontinence or increased urination.

After recording three reproducible micturition cycles as a preliminary value, the test substances 1 (1.0 mg / kg), 2 (0.1, 0.3 and 0.5 mg / kg), 21 (0.5 mg / kg) , 7 (0.3 mg / kg), 8 (1.0 mg / kg), 9 (0.5 mg / kg) and 11 (0.5 mg / kg); in vehicle = 0.9% NaCI applied iv and the effect on the cystometric parameters recorded for 90 to 120 minutes. in the Effective maximum, the mean of 3 micturition cycles was determined and presented as a percentage change compared to the previous value (Table 1).

Table 1: Influence of the cystometric parameters by the test substances (change from previous value [%]); n corresponds to the number of test animals. Significance (Student T-Test): * p <0.05; ** p <0.01; *** p <0.001. The investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence.

Among other things, it is shown that of the enantiomers of racemic compound 1, only the (+) enantiomer (compound 2) is effectively active (and is therefore a particularly preferred compound of this invention), while the (-) enantiomer (compound 21) not contributed to the effect.

Further attempts have been made with other compounds.

After recording three reproducible micturition cycles as a preliminary value, the test substances 24 (1, 0; 3.0; 5.0 mg / kg), 25 (1, 5 mg / kg) and 26 (3.0 mg / kg) in vehicle = 0.9% NaCI iv applied and the effect on the cystometric parameters recorded 90 to 120 minutes. The mean of 3 micturition cycles was determined at the effective maximum and presented as a percentage change compared to the previous value (Table 2).

Table 2:

Table 2: Influence of the cystometric parameters by the test substances (change from previous value [%]); n corresponds to the number of test animals. Significance (Student T-Test): * p <0.05; ** p <0.01; *** p <0.001.

The investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence.

Example 3. Test system cystometry on the anesthetized naive rat

The cystometric examination in naive female rats was carried out according to the method of Kimura et al. (Kimura et al., 1996, Int. J. Urol. 3: 218-227). On anesthetized, ventilated rats, the abdomen is opened and the ureters are tied off. The urine is drained from the kidneys. A catheter is inserted into the bladder and fixed. Saline is infused into the bladder by means of an infusion pump until this shows rhythmic spontaneous activity in the form of contractions, which can be recorded via a connected pressure sensor. After reaching stable starting values, the test substance is added in a cumulative manner. applied. Influencing the bladder function manifests itself by suppressing the spontaneous contractions. The absence of contractions over a period of 10 minutes is considered a parameter for the suppression.

Suppression of spontaneous contractions in the rats was measurable for all substances listed here, Table 3 giving the mean value of the lowest dose from at least 2 experiments in which contractions did not occur over a period of 10 min for the first time.

Table 3:

Table 3; (n corresponds to the number of attempts entered in the value)

The investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence.

Further attempts have been made with other compounds.

Suppression of spontaneous contractions in the rats was measurable for all substances listed here, Table 4 giving the mean value of the lowest dose from at least 2 experiments in which contractions did not occur over a period of 10 min for the first time.

Table 4:

Table 4: (n corresponds to the number of attempts included in the value)

The investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence. Further attempts have been made with other compounds.

Suppression of spontaneous contractions in the rats was measurable for all substances listed here, Table 5 giving the mean value of the lowest dose from at least 2 experiments in which there were no contractions for a period of 10 min for the first time.

Table 5: (n corresponds to the number of attempts included in the value)

The investigated substances have a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence and also appear to be superior to tramadol.

In addition, the following substances were tested with the result shown in Table 6:

Suppression of spontaneous contractions in the rats was measurable for all of the substances listed, Table 6 den

Average of the lowest dose from 3 independent experiments, in which contractions for the first time fail over a period of 10 min.

Table 6:

Table 6; (n corresponds to the number of attempts entered in the value)

The investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence.

Example 4: Test system cystometry on the awake naive rat

Cystometric examinations were carried out on naive, female

Sprague-Dawley rats using the method of Ishizuka et. al. ((1997), Naunyn-Schmiedeberg's Arch. Pharmacol. 355: 787-793). Three days after the implantation of bladder and venous catheters, the animals were examined while awake, free to move. The bladder catheter was connected to a pressure sensor and an injection pump. The animals were placed in metabolic cages, which made it possible to measure urine volume. Physiological saline was infused into the emptied bladder (10 ml / hour) and bladder pressure and micturition volume were recorded continuously. After a stabilization phase, a 20-minute phase was recorded, which was characterized by normal, reproducible micturition cycles. Among other things, the following parameters were determined:

^■ threshold pressure (threshold pressure TP, bladder pressure immediately before micturition),

^■ bladder capacity (bladder capacity BC, residual volume after prior micturition plus volume of infused solution during the filling phase)

^■ Inter-contraction interval (ICI), the time interval between micturition. An increase in the threshold pressure (TP) indicates an important therapeutic effect in one of the indications according to the invention. The inter-contraction interval (ICI) is also an important parameter for measuring the physiological effectiveness of a substance in the treatment of urinary incontinence, as is the bladder capacity (BC). In order to be effective due to the very heterogeneous causes for the symptoms of these clinical pictures, it is not necessary to positively influence all three parameters. It is therefore entirely sufficient if only one of these parameters has a positive effect in order to be used in urinary incontinence, increased micturition frequency or increased urge to urinate.

After recording three reproducible micturition cycles as a preliminary value, 10 μg / kg buprenorphine in the vehicle = 0.9% NaCl i.v. applied and the effect on the cystometric parameters recorded 90 to 120 minutes. The mean value of 3 micturition cycles was determined at the effective maximum and shown as a percentage change compared to the previous value (Table 7).

The concentration used corresponds to the ED ₅₀ in a known analgesia model for rats, the tail flick.

Table 7: Influence of cystometric parameters by buprenorphine (change from previous value [%]); n corresponds to the number of animals used in the experiment. Significance (Student T-Test): * p <0.05; p <0.01; *** p <0.001.

Buprenorphine has a positive effect on the TP

Bladder regulation and is therefore principally suitable for the treatment of Urinary incontinence. However, the concentration used, which has an analgesic effect, was apparently too high, since drip incontinence had already occurred in 2 of the 6 animals. At two lower concentrations, 0.001 mg / kg iv and 0.005 mg / kg iv, n = 6 an increase in TP of + 27.6% and + 37.5%, respectively.

Example 5: Test system cystometry on the awake damaged rat

This model simulates urge incontinence in the animal model; the oxyhemoglobin (OxyHb) used induces bladder overactivity.

Cystometric studies on naive, female Sprague-Dawley rats were carried out using the method of Pandita et al. (J. Urol. 2000, 164: 545-550). Three days after the implantation of bladder and venous catheters, the animals were examined while awake, free to move. The urinary catheter was connected to a pressure transducer and an injection pump. The animals were placed in metabolic cages, which made it possible to measure urine volume. Physiological saline was infused into the emptied bladder (10 ml / hour) and bladder pressure and micturition volume were recorded continuously. After a stabilization phase, a 20-minute phase was recorded, which was characterized by normal, reproducible micturition cycles. Among other things, the following parameters were determined:

■ threshold pressure (threshold pressure TP, bladder pressure immediately before micturition),

^■ bladder capacity (bladder capacity BC, residual volume after prior micturition plus volume of infused solution during the filling phase) ^■ Inter-contraction interval (ICI), the time interval between micturition.

^■ Micturition pressure MP, maximum bladder pressure during micturition.

5

An increase in the threshold pressure (TP) indicates an important therapeutic effect in one of the indications according to the invention. The inter-contraction interval (ICI) is also an important parameter for measuring the physiological effectiveness of a substance in the treatment of urinary incontinence, as is the bladder capacity (BC). In order to be effective due to the very heterogeneous causes for the symptoms of these disease patterns, it is not necessary to positively influence all parameters. It is therefore entirely sufficient if only one of these parameters has a positive effect in order to be able to be used in urinary incontinence, increased 5 micturition frequency or increased urge to urinate.

After recording three reproducible micturition cycles as a pre-value, 2.5x10 ^" M oxyhemoglobin in the vehicle = 0.9% NaCI were infused into the bladder. The effect on the cystometric parameters was recorded for about 20 minutes. The mean value of

3 micturition cycles determined and shown as a percentage change compared to the previous value (Table 8). Treatment with oxyhemoglobin induces a characteristic change in the cystometric parameters with an increase in micturition pressure, a decrease in 5 bladder capacity and a decrease in the inter-contraction interval.

These changes reflect the changes found in patients with urge incontinence.

The application of 5 μg / kg buprenorphine in the vehicle = 0.9% NaCI iv before or the application of oxyhemoglobin is able to suppress the changes induced by oxyhemoglobin and also to induce an increase in the threshold pressure (table 8th). Table 8:

Table 8: Influence of the cystometric parameters by oxyhemoglobin (OxyHb) with and without previous administration of buprenorphine. Average values with standard deviations before (v) and after (h) application of the substances as well as the change (diff.) Compared to the previous value [%] are given; n corresponds to the number of animals used in the experiment. Significance (Student T-Test): * p <0.05; ** p <0.01; *** p <0.001.

It can be seen that OxyHb significantly influences the bladder parameters in the sense of urge incontinence. This negative influence is eliminated and even improved by buprenorphine. The micturition pressure drops significantly compared to the urge incontinence caused by OxyHb and also compared to the untreated control. Furthermore, in this urge incontinence model, buprenorphine completely normalizes the inter-contraction interval and the bladder capacity and causes a significant and significant increase in the threshold pressure.

This is proof that buprenorphine, particularly in the area of urge incontinence, for which the OxyHb model stands as a standard model, has an excellent effect, even when it is damaged, i.e. in the event of illness. Example 6: Parenteral application form

20 g of tramadol and 1 g of venlafaxine are dissolved in 1 l of water for injections at room temperature and then adjusted to isotonic conditions by adding NaCl.

Claims

claims:

1. Use of an active ingredient combination of at least one of the compounds A and at least one of the compounds B, with compound A selected from:

Group a) containing:

Tramadol, O-demethyltramadol, or O-desmethyl-N-mono-desmethyl-tramadol as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer;

Group b) containing: codeine

Dextropropxyphene dihydrocodeine diphenoxylate ethylmorphine meptazinol nalbuphin

Pethidine (Meperidine) Tilidine Tramadol Viminol Butorphanol dextromoramide

dezocin

Diacetylmorphine (heroin)

hydrocodone

hydromorphone

ketobemidone

Methadone

Levomethadyl Acetate (l-α-Acetylmethadol (LAAM))

levorphanol

morphine

nalorphine

oxycodone

pentazocine

Piritramide

alfentanil

buprenorphine

etorphine

fentanyl

remifentanil

sufentanil

as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures of them Enantiomers or diastereomers or a single enantiomer or diastereomer;

Group c) containing: 1-phenyl-3-dimethylamino-propane compounds according to general formula I.

wherein

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C - ^ - alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ^ is selected from C ^ alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ^ and R are each independently selected from H or C ^^ alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

or R ^ and R together form a saturated C - cycloalkyl radical, unsubstituted or mono- or polysubstituted,

R ⁹ to R1 ^ are each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ , OH, SH, OR ¹⁴ , OCF3,

SR ¹⁴ , NR ¹⁷ R ¹⁸ , SOCH3, SOCF3; S0 ₂ CH ₃ , SO ₂ CF ₃ , CN,

COOR1 ⁴ , NO ₂ , CONR ⁷ R ⁸ _; C <| _ ₆ alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with R ¹⁴ selected from Ci.ß-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (. OC _{1 4} alkyl) _2, CO (OC ^<| _ ₅ alkyl),

CONH-C6H - (C _3-alkyl), CO (C <| _5-alkyl), CO-CHR ¹⁷ -

meta- or para-CH2N (R ¹⁶ ) 2 with R ¹⁶ C <| _4-alkyl or

4-morpholino, where in the radicals R ¹⁴ , R ¹⁵ and R ¹⁶ the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R ^ ⁷ and R18 each independently selected from H; Cj.ß-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted, or

R ⁹ and R ^ or R ^ and R ^ together form an OCH2O-, OCH2CH2O-, OCH = CH-, CH = CHO-, CH = C (CH3) 0-, OC (CH3) = CH-, (CH ₂ ) Form ₄ - or OCH = CHO ring,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer;

Group d) containing:

Substituted 6-dimethylaminomethyl-1-phenyl-cyclohexane compounds according to general formula II

wherein X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C 1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ^{1 is} selected from C <| _4-alkyl, benzyl, CF3, OH, OCH2-C6H5, OC <| _4-alkyl, Cl or F and

R ⁹ to R13 are each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ , OH, SH, OR1 ⁴ , OCF3, SR ¹⁴ ,

NR ¹⁷ R ¹⁸ , SOCH3, SOCF _3; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR1 ⁴ , N0 ₂ ,

CONR ^ R ^ ⁸ ; Ci.ß-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with RI ⁴ selected from Cj.ß-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (O-Cι -4-alkyl) ₂ , CO (OC- | .5-alkyl), CONH-C ₆ H ₄ - (C ₁ .3-alkyl), CO (Cι_ ₅ alkyl), CO-CHR ¹⁷ -

NHR ¹⁸ , CO-C ₆ H ₄ -R ^{1 5} , with R15 ortho-OCOC <| _3-alkyl or meta- or para-CH2N (R ¹⁶ ) 2 with R ¹⁶ Ci ^ -alkyl or

4-morpholino, where in the radicals R ¹⁴ , R ¹⁵ and R ¹⁶ the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R ^ ⁷ and R18 each independently selected from H; C-ι_g-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R ¹⁹ or R ¹⁰ and R ^{1 1} together form an OCH2O,

OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-,

Form OC (CH3) = CH-, (CH ₂ ) - or OCH = CHO-ring, as free base or acid and / or in the form of physiologically compatible salts, especially in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or an individual

Enantiomers or diastereomers;

and or

Group e) containing:

6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds according to general formula III

III

wherein

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C < _| _3-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and

R ⁹ to R1 ^ are each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ , OH, SH, OR1 ⁴ , OCF ₃ ,

SR1, NR ¹⁷ R ^{1 8} , SOCH3, SOCF _3; SO ₂ CH ₃ , SO2CF3, CN,

COOR1 ⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ _; C <| _ ₆ alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with R ¹⁴ selected from C <| _6-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (O-Cι -4-alkyl) ₂ , CO (OCι .5-alkyl),

CONH-C6H - (Cι_ ₃ alkyl), CO (C <| _5-alkyl), CO-CHR 1 "7- NHR ¹⁸ , CO-C ₆ H ₄ -R ⁵ , with R 5 ortho-OCOC <j_3-alkyl or meta- or para-CH2N (R ¹⁶ ) 2 with R ¹⁶ Cι_4-alkyl or 4-morpholino, being in the radicals R ¹⁴ , R ¹⁵ and R ¹⁶ the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R ^ ⁷ and R18 each independently selected from H; Cι_g-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and RIO or R ^ ⁹ and R ^ l together form an OCH2O-, OCH2CH2O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH-, (CH ₂ ) - or OCH = CHO ring,

with the proviso that when R ⁹ , R ¹¹ and R ¹³ correspond to H and one of R ¹⁰ or R ¹² corresponds to H and the other corresponds to OCH ₃ , X must not be OH,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer; and with at least one of the compounds B selected from:

Venlafaxine, Fesoterodine, Solifenacin (YM906), Cizolirtine, Resiniferatoxin, Nitro-Flurbiprofen, HCT1026, Talnetant, TAK-637, SL 251039, R 450, Rec 15/3079, (-) - DDMS, NS-

8 and / or DRP-001,

as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures of them Enantiomers or diastereomers or a single enantiomer or diastereomer;

for the manufacture of a medicament for the treatment of increased urge to urinate or urinary incontinence.

2. Use according to claim 1, characterized in that the compound A in group a) is selected from:

Tramadol, (+) - tramadol, (+) - O-demethyltramadol or (+) - O- desmethyl-N-mono-desmethyl-tramadol, preferably Tramadol or (+) - Tramadol, in particular (+) - Tramadol.

3. Use according to claim 1, characterized in that the compound A in group b) is selected from:

• Codeine Dextropropxyphen

dihydrocodeine

diphenoxylate

ethylmorphine

meptazinol

nalbuphine

Pethidine (meperidine)

Tilidin

Viminol

butorphanol

dezocin

nalorphine

pentazocine

buprenorphine

, preferably

codeine

Dextropropxyphen

dihydrocodeine

meptazinol

nalbuphine

Tilidin

buprenorphine

Use according to claim 1, characterized in that the compound A in group c) is selected from compounds according to formula I for which:

X is selected from OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F, OC (O) CH ₃ or H,

and or

R ^{1 is} selected from

Cι_4-alkyl, saturated and unsubstituted, branched or unbranched; preferably CH ₃ , C ₂ H ₅ , C Hg or t-butyl, in particular CH ₃ or C ₂ H ₅ ,

and or

R ² and R ^{3 are} independently selected from

H, saturated and unsubstituted, branched or unbranched; preferably H, CH ₃ , C ₂ H ₅ , i-propyl or t-butyl, in particular H or CH ₃ , preferably R ³ = H,

or

R ² and R ⁸ together form a Cs-β-cycloalkyl radical, saturated or unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted, in particular cyclohexyl.

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C- _| _3-alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring

in particular

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH,

CF ₂ H, OCH ₃ or SCH ₃

or,

when R ⁹ and R ³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or,

when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or, when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH, OC ₂ H ₅ or OC ₃ H ₇ .

Use according to claim 4, characterized in that compounds of the formula I with R ³ = H in the form of the diastereomers with the relative configuration la

la

are present, in particular in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or used as a pure diastereomer

and or

that the compounds of the formula I are used in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

Use according to one of claims 4 or 5, characterized in that compound A selected from the following group is used:

(2RS, 3RS) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol,

(+) - (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-me- thyl-pentane-3-ol,

(2RS, 3RS) -3- (3,4-dichlorophenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

(2RS, 3RS) -3- (3-difluoromethylphenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

(2RS, 3RS) -1-dimethylamino-2-methyl-3- (3-methylsulfanylphenyl) pentan-3-ol,

(3RS) -1-dimethylamino-3- (3-methoxyphenyl) -4,4-dimethylpentan-3-ol,

(2RS, 3RS) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-ιmethyl-propyl) phenol,

(1 RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethyl-propyl) phenol,

(+) - (1 R, 2R) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethylpropyl) phenol,

(+) - (1 R, 2R) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethyl-propyl) phenol,

(-) - (1 R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol,

(+) - (1 R, 2R) -acetic acid-3-dimethylamino-1-ethyl-1 - (3-methoxyphenyl) -2-methyl-propyl ester,

(1 RS) -1- (1-dimethylaminomethylcyclohexyl) -1- (3-methoxyphenyl) propane-1 -ol,

(2RS, 3RS) -3- (4-chlorophenyl) -1 -dimethylamino-2-methylpentan-3-ol,

(+) - (2R, 3R) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl) phenol,

(2RS, 3RS) -4-dimethylamino-2- (3-methoxyphenyl) -3-methylbutan-2-ol and

(+) - (2R, 3R) -4-dimethylamino-2- (3-methoxyphenyl) -3-methyl-butan-2-ol,

preferably as hydrochloride.

7. Use according to claim 1, characterized in that the compound A in group d) is selected from compounds according to

Formula II for which the following applies:

X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F or H, in particular OH, and or

R ^{1 is} selected from

Cι_4-alkyl, CF3, OH, O-Cι_4-alkyl, Cl or F, preferably OH, CF ₃ or CH ₃ ,

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C ₁ . ₄ -alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with

R ¹⁴ selected from C < _| _3-alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring,

in particular

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH, CF ₂ H, OR ¹⁴ or SCH ₃ , in particular OH or OC 3-alkyl, preferably OH or OCH ₃ , or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or,

when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH,

very particularly preferred

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, SH, CF ₂ H, CF _3, OR ¹⁴ or SR ^14, preferably OH or OR ^14, in particular OH or OC _"| _3-alkyl, preferably

OH or OCH ₃ .

8. Use according to claim 7, characterized in that compounds of formula II in the form of the diastereomers with the relative configuration Ila

Ha

are present, in particular in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as a pure diastereomer,

and or

that the compounds of formula II are used in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

Use according to one of claims 7 or 8, characterized in that compound A selected from the following group is used:

(1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(+) - (1 R, 3R, 6R) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1 - (3-hydroxyphenyl) cyclohexane-1, 3-diol,

(1 RS, 3SR, 6RS) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(+) - (1 R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl) phenol or

(1 RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl) phenol, preferably as hydrochloride.

10. Use according to claim 1, characterized in that the compound A in group e) is selected from compounds according to 5 formula III for which:

X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F or H, 0 in particular F or H.

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ H must correspond to 5, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C 1-4 alkyl, saturated and unsubstituted, o branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring 5, in particular characterized in that

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ² also corresponds to H, while the other is selected from: 0 Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH, CF ₂ H, OR ¹⁴ or SCH ₃ , in particular OH or OC ^ -

Alkyl, preferably OH or OCH ₃ ,

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or,

when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH,

very particularly preferred

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, SH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH or OR ¹⁴ , in particular OH or OC- _| _ ₃ alkyl, preferably OH or OCH ₃ .

11. Use according to claim 10, characterized in that compounds of formula III in the form of their diastereomers with the relative configuration purple

purple

are present, in particular in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as 0 pure diastereomer

and or

that the compounds of formula III are used in the form of the (+) enantiomer, 5 in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer ,

12. Use according to one of claims 10 or 11, characterized in that compound A is selected from the following

Group is used:

^■ (+) - (1 R, 2R) -3- (2-dimethylaminomethyl-1 -fluoro-cyclohexyl) - phenol,

^■ (+) - (1 S, 2S) -3- (2-dimethylaminomethylcyclohexyl) phenol or

^■ (-) - (1 R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol,

preferably as hydrochloride. 5

13. Use according to one of claims 1 to 12, characterized in that the compound B is selected from:

Fesoterodine, solifenacin (YM905), cizolirtine, resiniferatoxin or

Venlafaxine.

14. Active ingredient combination of at least one of the compounds A and at least one of the compounds B, with compound A selected from:

Group a) containing:

Tramadol, O-demethyltramadol or O-desmethyl-N-mono-desmethyl-tramadol as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or a single enantiomer or

diastereomer;

Group b) containing: codeine

Dextropropxyphene dihydrocodeine diphenoxylate ethylmorphine meptazinol nalbuphine pethidine (meperidine) Tilidin

tramadol

Viminol

butorphanol

dextromoramide

dezocin

Diacetylmorphine (heroin)

hydrocodone

hydromorphone

ketobemidone

Methadone

Levomethadyl Acetate (l-α-Acetylmethadol (LAAM))

levorphanol

morphine

nalorphine

oxycodone

pentazocine

Piritramide

alfentanil

buprenorphine

etorphine

fentanyl

remifentanil

sufentanil

as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures of them Enantiomers or Diastereomers or a single enantiomer or diastereomer;

Group c) containing:

1-phenyl-3-dimethylamino-propane compounds according to general formula I.

, in which

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C < _| _3-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R1 is selected from C 1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ² and R ^{8 are} each independently selected from H or C 1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, or

R ² and R ⁸ together form a saturated C - cycloalkyl radical, unsubstituted or mono- or polysubstituted,

R ⁹ to R13 are each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ , OH, SH, OR ¹⁴ , OCF ₃ ,

SR1 ⁴ , NR ¹⁷ R ¹⁸ , SOCH3, SOCF _3; SO ₂ CH ₃ , SO2CF3, CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ _; C ^ ß-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with Rl ⁴ selected from Cj-ß-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (0-Cι_4-alkyl) 2, CO (OCι_5-alkyl), CONH-C6H4- (C <ι_ ₃ -alkyl), CO (C <| _ ₅ -alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO -C6H4-R ^{1 5} , with R ¹⁵ ortho-OCOC <| _3-alkyl or meta- or para-CH2N (R ⁶ ) 2 with R ⁶ C <| _4-alkyl or 4-morpholino, where in the radicals R ¹⁴ R ¹⁵ and R ¹⁶ the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R1 ⁷ and R18 each independently selected from H; Ci.ß-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multiply substituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R ¹⁹ or R ⁹ and R ^{1 1} together form an OCH2O-, OCH2CH2O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH-, (CH ₂ ) Form ₄ - or OCH = CHO ring,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or an individual

Enantiomers or diastereomers;

Group d) containing:

Substituted 6-dimethylaminomethyl-1-phenyl-cyclohexane compounds according to the general formula

, in which

X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,

R ^{1 is} selected from C <| _4-alkyl, benzyl, CF3, OH, OCH2-

CρHδ, O-C <| _4-alkyl, Cl or F and

R ⁹ to R ^ ^{8 are} each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF≥, CF3, OH, SH, OR ¹⁴ , OCF3, SR-! ⁴

NR ¹⁷ R ¹⁸ , SOCH3, SOCF _3; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ ,

CONR ^ R ^; C- | _6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

with R ¹⁴ selected from Cj.ß-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (O-Cι_4-alkyl) 2, CO (OCι_ ₅ -alkyl), CONH-C6H4- (C <| _3-alkyl), CO (C <| _ ₅ -AlkyI), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H4-R ¹ 5, with R15 ortho-OCOCι_3-alkyl or meta- or para-CH2N (R ⁶ ) 2 with R ⁶ Cι_4-alkyl or 4-morpholino, in the radicals R ¹⁴ , R ¹⁵ and R ¹⁶ the

Alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with R1 ⁷ and R18 each independently selected from H; Cι_6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R ⁹ or R ¹⁰ and R ¹ together form an OCH2O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH-, (CH ₂ ) ₄ - or OCH = CHO ring form, as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or Acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer;

and or Group e) containing:

6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds according to general formula III

III

, in which

X is selected from OH, F, Cl, H or OC (0) R ⁷ with R ⁷ selected from C - ^ - alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and

R ⁹ to R ^ ^{8 are} each independently selected from H, F, Cl, Br, I, CH ₂ F, CHF ₂₎ CF ₃ , OH, SH, OR ¹⁴ , OCF ₃ ,

SR ¹⁴ , NR ^{1 7} R ^{1 8} , SOCH3, SOCF _3; SO ₂ CH3, SO2CF3, CN,

COOR ⁴ , NO2, CONR ¹⁷ R ¹⁸ _; C <| _ ₆ alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted; with R1 ⁴ selected from C- | _6-alkyl; Pyridyl, thienyl,

Thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted; PO (0-C <| -4-alkyl) ₂ , CO (OC- | -5-alkyl), CONH-C ₆ H ₄ - (C ₁ -3-alkyl), CO (Cι .5-alkyl), CO-CHR ¹⁷ -

NHR ¹⁸ , CO-C6H4-R ^{1 5} , with R15 ortho-OCOC <| _3-alkyl or meta- or para-CH2N (R ¹⁶ ) 2 with R ¹⁶ Cι_4-alkyl or

4-morpholino, where in the radicals R ¹⁴ , R ¹⁵ and R ¹⁶ the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;

with RI ⁷ and R18 each independently selected from H; C <| _g-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,

or

R ⁹ and R ¹⁹ or R ¹⁹ and R ¹ together form an OCH2O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH-, Form (CH ₂ ) ₄ - or OCH = CHO ring,

with the proviso that, if R ⁹ , R ¹¹ and R ¹³ correspond to H, and one of the two is RR ¹¹⁰⁰ c or R ¹² H and the other is OCH ₃ , X must not be OH,

as a free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically acceptable compatible acidic and basic salts or salts with cations or bases or with anions or acids; in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer;

and with at least one of the compounds B selected from:

Venlafaxine, Fesoterodine, Solifenacin (YM905), Cizolirtine, 0 Resiniferatoxin, Nitro-Flurbiprofen, HCT1026, Talnetant,

TAK-637, SL 251039, R 450, Rec 15/3079, (-) - DDMS, NS-8 and / or DRP-001,

as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures their o enantiomers or diastereomers or a single one

Enantiomers or diastereomers.

15. Active ingredient combination according to claim 14, characterized in that the compound A in group a) is selected from: 5

Tramadol, (+) - tramadol, (+) - O-demethyltramadol or (+) - O- desmethyl-N-mono-desmethyl-tramadol, preferably Tramadol or (+) - Tramadol, in particular (+) - Tramadol. 0

16. Active ingredient combination according to claim 14, characterized in that the compound A in group b) is selected from: codeine

Dextropropxyphen

dihydrocodeine

diphenoxylate

ethylmorphine

meptazinol

nalbuphine

Pethidine (meperidine)

Tilidin

Viminol

butorphanol

dezocin

nalorphine

pentazocine

buprenorphine

, preferably

codeine

Dextropropxyphen

dihydrocodeine

meptazinol

nalbuphine

Tilidin

buprenorphine

17. Active ingredient combination according to claim 14, characterized in that the compound A in group c) is selected from compounds according to formula I for which: X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F, OC (O) CH ₃ or H,

and or

R ^{1 is} selected from

C _| _4-alkyl, saturated and unsubstituted, branched or unbranched; preferably CH ₃ , C ₂ H ₅ , C ₄ H ₉ or t-butyl, in particular CH ₃ or C ₂ Hs,

and or

R ² and R ^{3 are} independently selected from

H, Cι_4-alkyl, saturated and unsubstituted, branched or unbranched; preferably H, CH ₃ , C ₂ Hs, i-propyl or t-butyl, in particular H or CH ₃₎ preferably R ³ = H,

or

R ² and R ⁸ together form a C ₅ - ₆ -CycloalkyIrest form, saturated or unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted, in particular cyclohexyl.

and or R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and

14 14 unsubstituted, branched or unbranched; OR or SR, with R ¹⁴ selected from C < _| _3-alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring

in particular

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH,

CF ₂ H, OCH ₃ or SCH ₃

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or,

if R ⁹ , R, R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F, or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH, OC ₂ H ₅ or OC ₃ H ₇ .

18. Active ingredient combination according to claim 17, characterized in that the compounds of formula I with R ³ = H in the form of the diastereomers with the relative configuration la

la

are present, especially in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as a pure diastereomer

and or

that the compounds of the formula I are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

19. Active ingredient combination according to one of claims 17 or 18, characterized in that the compound A is selected from the following group: (2RS, 3RS) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol,

(+) - (2R, 3R) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-oI,

(2RS, 3RS) -3- (3,4-dichlorophenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

(2RS, 3RS) -3- (3-difluoromethylphenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

(2RS, 3RS) -1-dimethylamino-2-methyl-3- (3-methylsulfanylphenyl) pentan-3-ol,

(3RS) -1-dimethylamino-3- (3-methoxyphenyl) -4,4-dimethylpentan-3-ol,

(2RS, 3RS) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl) phenol,

(1 RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethyl-propyl) phenol,

(+) - (1 R, 2R) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethylpropyl) phenol,

(+) - (1 R, 2R) -3- (3-dimethylamino-1-hydroxy-1, 2-dimethyl-propyl) phenol,

(-) - (1 R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol,

(+) - (1 R, 2R) -acetic acid-3-dimethylamino-1-ethyl-1 - (3-methoxyphenyl) -2-methyl-propyl ester,

(1 RS) -1 - (1-dimethylaminomethyl-cyclohexyl) -1 - (3-methoxyphenyl) propan-1-ol,

(2RS, 3RS) -3- (4-chlorophenyl) -1 -dimethylamino-2-methylpentan-3-ol,

(+) - (2R, 3R) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl) phenol,

(2RS, 3RS) -4-dimethylamino-2- (3-methoxyphenyl) -3-methylbutan-2-ol and

(+) - (2R, 3R) -4-dimethylamino-2- (3-methoxyphenyl) -3-methyl-butan-2-ol,

preferably as hydrochloride.

20. Active ingredient combination according to claim 14, characterized in that the compound A in group d) is selected from compounds according to formula II for which:

X is selected from OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F or H, in particular OH,

and or

R ^{1 is} selected from

Cι_4-alkyl, CF3, OH, OC <| _4-alkyl, Cl or F, preferably OH, CF ₃ or CH ₃ ,

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C - ^ - alkyl, saturated and

14 14 unsubstituted, branched or unbranched; OR or SR, with R ¹⁴ selected from C ^ alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring,

in particular

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from: Cl, F, OH, CF ₂ H, CF ₃ , OR ¹⁴ or SR ¹⁴ , preferably OH, CF ₂ H, OR ¹⁴ or SCH ₃ , in particular OH or OC - ^ -

Alkyl, preferably OH or OCH ₃ ,

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or,

when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH,

OC ₂ H ₅ or OC ₃ H ₇ ,

very particularly preferred

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from:

Cl, F, OH, SH, CF ₂ H, CF ₃₎ OR ¹⁴ or SR ^14, preferably OH or OR ^14, in particular OH or OC _j ^ alkyl, preferably OH or OCH _3.

1. Active ingredient combination according to claim 20, characterized in that the compounds of formula II in the form of the diastereomers with the relative configuration Ila

lla

are present, in particular in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as a pure diastereomer,

and or

that the compounds of formula II are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

22. Active ingredient combination according to one of claims 20 or 21, characterized in that compound A is selected from the following group:

(1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(+) - (1 R, 3R, 6R) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1 - (3-hydroxyphenyl) cyclohexane-1, 3-diol,

(1 RS, 3SR, 6RS) -6-dimethylaminomethyl-1 - (3-methoxyphenyl) cyclohexane-1, 3-diol,

(+) - (1 R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-me- thyl-cyclohexyl) phenol or ^■ (1 RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl) phenol,

preferably as hydrochloride.

23. Active ingredient combination according to claim 14, characterized in that the compound A in group e) is selected from

Compounds according to formula III for which:

X is selected from

OH, F, Cl, OC (O) CH ₃ or H, preferably OH, F or H, in particular F or H.

and or

R ⁹ to R ¹³ , where 3 or 4 of the radicals R ⁹ to R ¹³ must correspond to H, are selected independently of one another from

H, Cl, F, OH, CF ₂ H, CF ₃ or C ^ alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C - ^ - alkyl, saturated and unsubstituted, branched or unbranched;

preferably H, Cl, F, OH, CF ₂ H, CF ₃ , OCH ₃ or SCH ₃

or R ¹² and R ^{11 form} a 3,4-OCH = CH ring

in particular characterized in that when R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ² also corresponds to H, while the other is selected from:

Cl, F, OH, CF ₂ H, CF _3, OR ¹⁴ or SR ^14, preferably OH, CF ₂ H, OR ¹⁴ or SCH _3, in particular OH or OC _"| _ -

Alkyl, preferably OH or OCH ₃ ,

or,

when R ⁹ and R ¹³ correspond to H and R ¹¹ corresponds to OH, OCH ₃ , Cl or F, preferably Cl, one of R ¹⁰ or R ¹² also corresponds to H, while the other OH, OCH ₃ , Cl or F, preferably Cl corresponds to

or,

when R ⁹ , R ¹⁰ , R ¹² and R ¹³ correspond to H, R ^{11 is} selected from CF ₃ , CF ₂ H, Cl or F, preferably F,

or,

when R ¹⁰ , R ¹¹ and R ¹² correspond to H, one of R ⁹ or R ¹³ also corresponds to H, while the other is selected from OH,

very particularly preferred

if R ⁹ , R ¹¹ and R ¹³ correspond to H, one of R ¹⁰ or R ¹² also corresponds to H, while the other is selected from: Cl, F, OH, SH, CF ₂ H, CF _3, OR ¹⁴ or SR ^14, preferably OH or OR ^14, in particular OH or OC _j _ ₃ alkyl, preferably OH or OCH _3.

24. Active ingredient combination according to claim 23, characterized in that the compounds of formula III in the form of their diastereomers with the relative configuration purple

purple

are present, especially in mixtures with a higher proportion of this diastereomer compared to the other diastereomers or as a pure diastereomer

and or

that the compounds of formula III are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

25. Active ingredient combination according to one of claims 23 or 24, characterized in that the compound A is selected from the following group:

(+) - (1 R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) phenol, ■ (+) - (1 S, 2S) -3- (2-dimethylaminomethylcyclohexyl) phenol or

■ (-) - (1 R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol,

preferably as hydrochloride.

26. Active ingredient combination according to one of claims 14 to 25, characterized in that the compound B is selected from:

Fesoterodine, solifenacin (YM905), resiniferatoxin, cizolirtine or venlafaxine.

27. Medicaments, preferably for the treatment of increased urge to urinate or urinary incontinence, containing an active ingredient combination according to one of claims 14 to 26 and, if appropriate, suitable additives and / or auxiliaries.