DE10224107A1 - Combination of selected opioids with other active substances for the treatment of urinary incontinence - Google Patents

Abstract

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 and corresponding medicaments and methods for the treatment of increased urge to urinate or urinary incontinence.

Description

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 medicines and Procedure for the treatment of increased urge to urinate or Urinary incontinence.

Urinary incontinence is the involuntary passing of urine. This occurs uncontrolled when the pressure inside the bladder exceeds the pressure that is necessary to close the ureter. On the one hand, causes can an increased internal bladder pressure (e.g. due to detrusor instability) with the Consequence of urge incontinence and on the other hand a decreased Sphincter pressure (e.g. after birth or surgery) with the Be the result of stress incontinence. The detrusor is the roughly bundled one multilayered bladder wall muscles, the contraction of which Urination, the sphincter of the sphincter of the urethra. Kick it Mixed forms of these types of incontinence as well as the so-called Abundance incontinence (e.g. in benign prostatic hyperplasia) or reflex incontinence (e.g. after spinal cord damage). More information can be found at Chutka, D.S. and Takahashi, P.Y., 1998, Drugs 560: 587-595.

Urge to urinate is the state of urination (urination) increased bladder muscle tension when approaching bladder capacity (or if they are exceeded). This tension acts as Miktionsreiz. An increased urge to urinate is understood here especially the appearance of premature or heaped sometimes painful urge to urinate That leads to the Follow to a much more frequent micturition. Causes can a. Bladder infections and neurogenic bladder disorders as well Be bladder tuberculosis. However, not all causes have yet been clarified.

Increased urge to urinate as well as urinary incontinence are considered extreme felt uncomfortable and there is a clear need for these Indications affected persons, as long as possible To achieve improvement.

Usually there is an increased urge to urinate and in particular Urinary incontinence is treated with drugs that affect the reflexes of the lower urinary tract are involved (Wein, A.J., 1998, Urology 51 (Suppl. 21): 43-47). Most of the time, these are medications, the one inhibitory effect on the detrusor muscle, which is responsible for the internal bladder pressure is responsible. These drugs are e.g. B. Parasympatholytics such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants like imipramine or muscle relaxants like flavoxate. Other drugs, which in particular the resistance of the urethra or bladder neck increase, show affinities for α-adrenoreceptors such as ephedrine, for β- Adrenoreceptors like clenbutarol or are hormones like estradiol.

A precise insight into the therapeutics used and Therapy methods, especially with regard to antimuscarinics and other peripheral substances, here is the review article by K.E. 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. Likewise, for Tramadol a positive effect on bladder function in a rat model rhythmic bladder contractions detected (Nippon-Shinyaku, WO 98/46216). There are also studies in the literature on Characterization of the opioid side effect urinary retention, resulting from some evidence of the effects of bladder functions on 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) mixed opioid agonists / antagonists such as buprenorphine (Malinovsky et al., 1998 Anesth Analg 87: 456-461; Drenger and Magora, 1989 Anesth Analg 69: 348-353), Pentazocin (Shimizu et al. (2000) Br. J. Pharmacol. 131 (3): 610-616) and Nalbuphin (Malinovsky et al., 1998, op. Cit.), And by strong opioids such as morphine (Malinovsky et al., 1998 op. cit .; Kontani and Kawabata, (1988); Jpn J Pharmacol. September; 48 (1): 31) and fentanyl (Malinovsky et al., 1998 op. Cit.). However, they did Investigations mostly in analgesically effective concentrations.

With the indications in question here it should be noted that it is generally very long-term drug applications and those affected in contrast to many situations in which Analgesics are used, a very unpleasant one, but not facing unbearable situation. Therefore here is - more than with analgesics - to make sure to avoid side effects Do not swap affected people for another. Are also at one permanent urinary incontinence treatment also has analgesic effects largely undesirable.

The object of the present invention was therefore to substances or Find combinations of substances that are used to treat increased Urge to urinate or urinary incontinence are helpful and effective Doses also prefer less side effects and / or show analgesic effects as known from the prior art, in particular a synergistic effect for the treatment of Show urinary incontinence.

Surprisingly, it has now been found that a combination of Group A compounds, the opioids and other central acting Substances that interact with opioid receptors and their effects can be antagonized by naloxone, or in particular Substances which have an opiate receptor, in particular the μ receptor, act, and group B compounds which Muscarinic antagonists, and other predominantly peripheral ones, in the Urinary incontinence is known to include active substances, a have excellent effects on bladder function. Proved further these combinations - well beyond what is expected - already very low doses as so effective that the combined active ingredients could be used in low doses. It can therefore be expected that otherwise side effects occurring at higher necessary dosages will decrease significantly while the therapeutic effect through this combination of peripheral, mostly directly on the bladder or Bladder muscles, antimuscarinic effect and central Opioid effect or µ-receptor effect is fully preserved.

• - Codein
• - Dextropropxyphen
• - Dihydrocodein
• - Diphenoxylat
• - Ethylmorphin
• - Meptazinol
• - Nalbuphin
• - Pethidin (Meperidine)
• - Tilidin
• - Tramadol
• - Viminol
• - Butorphanol
• - Dextromoramid
• - Dezocin
• - Diacetylmorphin (Heroin)
• - Hydrocodon
• - Hydromorphon
• - Ketobemidon
• - Levomethadon
• - Levomethadyl-Acetate (I-α-Acetylmethadol (LAAM))
• - Levorphanol
• - Morphin
• - Nalorphin
• - Oxycodon
• - Pentazocin
• - Piritramide
• - Alfentanil
• - Buprenorphin
• - Etorphin
• - Fentanyl
• - Remifentanil
• - Sufentanil

als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren, gegebenenfalls in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
Gruppe c) enthaltend:
1-Phenyl-3-dimethylamino-propanverbindungen gemäß allgemeiner Formel I


worin
X ausgewählt ist aus OH, F, Cl, H oder OC(O)R⁷ mit R⁷ ausgewählt aus C_1-3-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert,
R¹ ausgewählt ist aus C_1-4-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert,
R² und R³ jeweils unabhängig voneinander ausgewählt sind aus H oder C_1-4-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert,
oder
R² und R³ zusammen einen gesättigten C_4-7-Cycloalkylrest bilden, unsubstituiert oder ein- oder mehrfach substituiert,
R⁹ bis R¹³ jeweils unabhängig voneinander ausgewählt sind aus H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, unsubstituiert oder ein- oder mehrfach substituiert;
mit R¹⁴ ausgewählt aus C_1-6-Alkyl; Pyridyl, Thienyl, Thiazolyl, Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert; PO(O-C_1-4-Alkyl)₂, CO(OC_1-5-Alkyl), CONH-C₆H₄-(C_1-3-Alkyl), CO(C_1-5-Alkyl), CO-CHR¹⁷- NHR¹⁸, CO-C₆H₄-R¹⁵, mit R¹⁵ ortho-OCOC_1-3-Alkyl oder meta- oder para-CH₂N(R¹⁶)₂ mit R¹⁶ C_1-4-Alkyl oder 4-Morpholino, wobei in den Resten R¹⁴, R¹⁵ und R¹⁶ die Alkylgruppen verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert sein können;
mit R¹⁷ und R¹⁸ jeweils unabhängig voneinander ausgewählt aus H; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert,
oder
R⁹ und R¹⁰ oder R¹⁰ und R¹¹ zusammen einen OCH₂O-, OCH₂CH₂O-, OCH=CH-, CH=CHO-, CH=C(CH3)O-, OC(CH3)=CH-, (CH₂)₄- oder OCH=CHO-Ring bilden,
als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren; in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
Gruppe d) enthaltend:
substituierte 6-Dimethylaminomethyl-1-phenyl- cyclohexanverbindungen gemäß allgemeiner Formel II


worin
X ausgewählt ist aus OH, F, Cl, H oder OC(O)R⁷ mit R⁷ ausgewählt aus C_1-3-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert,
R¹ ausgewählt ist aus C_1-4-Alkyl, Benzyl, CF₃, OH, OCH₂- C₆H₅, O-C_1-4-Alkyl, Cl oder F und
R⁹ bis R¹³ jeweils unabhängig voneinander ausgewählt sind aus H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, unsubstituiert oder ein- oder mehrfach substituiert;
mit R¹⁴ ausgewählt aus C_1-6-Alkyl; Pyridyl, Thienyl, Thiazolyl, Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert; PO(O-C_1-4-Alkyl)₂, CO(OC_1-5-Alkyl), CONH-C₆H₄-(C_1-3-Alkyl), CO(C_1-5-Alkyl), CO-CHR¹⁷- NHR¹⁸, CO-C₆H₄-R¹⁵, mit R¹⁵ ortho-OCOC_1-3-Alkyl oder meta- oder para-CH₂N(R¹⁶)₂ mit R¹⁶ C_1-4-Alkyl oder 4-Morpholino, wobei in den Resten R¹⁴, R¹⁵ und R¹⁶ die Alkylgruppen verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert sein können;
mit R¹⁷ und R¹⁸ jeweils unabhängig voneinander ausgewählt aus H; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert,
oder
R⁹ und R¹⁰ oder R¹⁰ und R¹¹ zusammen einen OCH₂O-, OCH₂CH₂O-, OCH=CH-, CH=CHO-, CH=C(CH3)O-, OC(CH3)=CH-, (CH₂)₄- oder OCH=CHO-Ring bilden, als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren; in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
und/oder
Gruppe e) enthaltend:
6-Dimethylaminomethyl-1-phenyl-cyclohexanverbindungen gemäß allgemeiner Formel III


worin
X ausgewählt ist aus OH, F, Cl, H oder OC(O)R⁷ mit R⁷ ausgewählt aus C_1-3-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert, und
R⁹ bis R¹³ jeweils unabhängig voneinander ausgewählt sind aus H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, unsubstituiert oder ein- oder mehrfach substituiert;
mit R¹⁴ ausgewählt aus C_1-6-Alkyl; Pyridyl, Thienyl, Thiazolyl, Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert; PO(O-C_1-4-Alkyl)₂, CO(OC_1-5-Alkyl), CONH-C₆H₄-(C_1-3-Alkyl), CO(C_1-5-Alkyl), CO-CHR¹⁷- NHR¹⁸, CO-C₆H₄-R¹⁵, mit R¹⁵ ortho-OCOC_1-3-Alkyl oder meta- oder para-CH₂N(R¹⁶)₂ mit R¹⁶ C_1-4-Alkyl oder 4-Morpholino, wobei in den Resten R¹⁴, R¹⁵ und R¹⁶ die Alkylgruppen verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert sein können;
mit R¹⁷ und R¹⁸ jeweils unabhängig voneinander ausgewählt aus H; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert,
oder
R⁹ und R¹⁰ oder R¹⁰ und R¹¹ zusammen einen OCH₂O-, OCH₂CH₂O-, OCH=CH-, CH=CHO-, CH=C(CH3)O-, OC(CH3)=CH-, (CH₂)₄- oder OCH=CHO-Ring bilden,
mit der Maßgabe, daß, wenn R⁹, R¹¹ und R¹³ H entsprechen, und einer von R¹⁰ oder R¹² H und der andere OCH₃ entspricht, X nicht OH sein darf,
als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren; in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
und mit wenigstens einer der Verbindungen B, ausgewählt aus:
den Antimuskarinika: Atropin, Oxybutinin, Propiverin, Propanthelin, Emepronium, Trospium, Tolterodin, Darifenacin und α,α-Diphenylessigsäure-4-(N-methylpiperidyl)-ester, sowie Duloxetin, Imipramin und Desmopressin,
sowie
Venlafaxin, Fesoteridin, YM905, Resiniferatoxin, Nitro- Flurbiprofen, HCT1026, Talnetant, TAK-637, SL 251039, R 450, Rec 15/3079, (-)-DDMS, NS-8 und/oder DRP-001
als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren, gegebenenfalls in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
zur Herstellung eines Arzneimittels zur Behandlung von vermehrtem Harndrang bzw. Harninkontinenz. Accordingly, the subject matter of the invention is the 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-monodesmethyl-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
• - Dextropropxyphs
• - dihydrocodeine
• - diphenoxylate
• - ethyl morphine
• - Meptazinol
• - Nalbuphin
• - pethidine (meperidine)
• - Tilidine
• - Tramadol
• - Viminol
• - butorphanol
• - dextromoramide
• - Dezocin
• - diacetylmorphine (heroin)
• - hydrocodone
• - Hydromorphone
• - ketobemidone
• - Levomethadone
• - Levomethadyl Acetate (I-α-Acetylmethadol (LAAM))
• - Levorphanol
• - Morphine
• - nalorphine
• - oxycodone
• - pentazocin
• - Piritramid
• - 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.


wherein
X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ^{1 is} selected from C _1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ² and R ^{3 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 ³ together form a saturated C _4-7 cycloalkyl radical, unsubstituted or mono- or polysubstituted,
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) 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-phenylcyclohexane 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 _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ^{1 is} selected from C _1-4 alkyl, benzyl, CF ₃ , OH, OCH ₂ - C ₆ H ₅ , OC _1-4 alkyl, Cl or F and
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) ₄ - or OCH = CHO ring, as a free base or acid and / or in the form of physiologically tolerable salts, in particular in the form of their physiologically tolerable 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


wherein
X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) ₄ - 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:
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, fesoteridine, YM905, 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.

Surprisingly, it was found that the combination of the substances mentioned certain physiological parameters that at increased urge to urinate or urinary incontinence are significant influence positively. Each of these changes can be one significant relief in the symptomatic picture of affected patients mean.

Group B compounds predominantly act peripherally in urinary incontinence. Venlafaxine is a selective norepinephrine reuptake inhibitor with efficacy in stress incontinence (Bae JH et al., BJU International 2001, 88, 771, 775). Fesoteridine is a mACh antagonist developed by Schwarz Pharma. YM905 is a mACh antagonist developed by Yamanouchi. Resiniferatoxin is a VR1 agonist developed by Afferon, Mundipharma and ICOS (but especially for local use). 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 ₁ AR agonist developed by Sanofi. R 450 is an a ₁ AR agonist developed by Roche. Rec 15/3079 is a 5HT _1A 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 _1-2 alkyl is C1 or C2 alkyl, C _1-3 alkyl is C1, C2 or C3 alkyl, C _1-4 alkyl is C1, C2, C3 or C ₄ 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, C _1-10 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. The term cycloalkyl also includes, in particular, one or more, preferably mono, unsaturated cycloalkyls without a hetero atom 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, CHF ₂ , CF ₃ or CH ₂ OH as well as pyrazolinone, oxopyrazolinone, [1,4] dioxane or dioxolane.

In connection with alkyl and cycloalkyl - unless otherwise expressly defined - 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” in the case of multiple substitution is to be understood to mean that the substitution takes place both on different and on the same atoms 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-CHCl ₂ . F, Cl and OH are particularly preferred substituents here. With regard to cycloalkyl, the hydrogen radical can also be substituted by OC _1-3 alkyl or C _1-3 alkyl (in each case one or more times substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF ₃ , methoxy or ethoxy.

Under the term (CH ₂ ) _3-6 is -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ - CH ₂ -CH ₂ -CH ₂ -CH ₂ - and CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ - to be understood, (CH ₂ ) _1-4 is -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ - CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -CH ₂ - to be understood, (CH ₂ ) _4-5 is -CH ₂ -CH ₂ -CH ₂ -CH ₂ - and -CH ₂ - CH ₂ -CH ₂ -CH ₂ - CH ₂ - to understand, etc.

Under an aryl residue are ring systems with at least one aromatic ring but without heteroatoms in even one of the rings Roger that. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, Tetralinyl or indanyl, especially 9H-fluorenyl or anthracenyl Residues that are unsubstituted or mono- or polysubstituted can.

Under a heteroaryl radical, heterocyclic ring systems are included understood at least one unsaturated ring, the one or more Heteroatoms from the group nitrogen, oxygen and / or sulfur contain and can also be mono- or polysubstituted. Examples 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 CF ₃ , a CN, a NO ₂ , an NR ²⁴ R ²⁵ , a C _1-6 alkyl (saturated), a C _1-6 alkoxy, a C _3-8 cycloalkoxy, a C _3-8 cycloalkyl or a C _2-6 alkylene.

The radical R ^{23 stands} for H, a C _1-10 alkyl, preferably a C _1-6 alkyl, an aryl or heteroaryl or for an aryl bonded via a C _1-3 alkylene group or heteroaryl radical, where these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals,
the radicals R ²⁴ and R ²⁵ , identical or different, for H, a C _1-10 alkyl, preferably a C _1-6 alkyl, an aryl, a heteroaryl or a via a C _1-3 Aryl or heteroaryl radical bonded to alkylene group, where these aryl and heteroaryl radicals themselves may not be substituted by aryl or heteroaryl radicals,
or the radicals R ²⁴ and R ²⁵ together mean CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ²⁶ CH ₂ CH ₂ or (CH ₂ ) _3-6 , and
the radical R ²⁶ for H, a C _1-10 alkyl, preferably a C _1-6 alkyl, an aryl or heteroaryl radical or for an aryl bonded via a C _1-3 alkylene group or heteroaryl radical, where these aryl and heteroaryl radicals may not themselves be substituted with aryl or heteroaryl radicals.

The term salt is any form of the invention To understand the active ingredient in which it takes on an ionic form or is charged and coupled with a counterion (a cation or anion) is or is in solution. These include complexes of To understand 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” is understood to mean 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 physiological, in particular when used in humans and / or mammal - are compatible. The salts of the alkali and alkaline earth metals are particularly preferred, but also with NH ₄ ⁺ , but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.

Under the concept of physiologically compatible salt with anions or For the purposes of this invention, acids are understood to mean at least one of the salts compounds according to the invention - mostly, for example on nitrogen, protonates - as a cation with at least one anion, the physiologically - especially when used in humans and / or mammals - are compatible. In particular, it is understood in the sense of this Invention the salt formed with a physiologically acceptable acid namely salts of the respective active ingredient with inorganic or organic acids, the physiological - especially when used in Humans and / or mammals - are tolerated. Examples of physiological 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 for the purposes of this invention and each described Use and each of the drugs described are salts of 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.

Compounds of group a) and their preparation are from DE 44 26 245 A1 known. Compounds of groups b) and c) and their Manufacture are known from DE 195 25 137 A1.

In a preferred embodiment, the use according to the invention is 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,
especially (+) - tramadol.

• - Codein
• - Dextropropxyphen
• - Dihydrocodein
• - Diphenoxylat
• - Ethylmorphin
• - Meptazinol
• - Nalbuphin
• - Pethidin (Meperidine)
• - Tilidin
• - Viminol
• - Butorphanol
• - Dezocin
• - Nalorphin
• - Pentazocin
• - Buprenorphin,

vorzugsweise

• - Codein
• - Dextropropxyphen
• - Dihydrocodein
• - Meptazinol
• - Nalbuphin
• - Tilidin
• - Buprenorphin

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

• - Codeine
• - Dextropropxyphs
• - dihydrocodeine
• - diphenoxylate
• - ethyl morphine
• - Meptazinol
• - Nalbuphin
• - pethidine (meperidine)
• - Tilidine
• - Viminol
• - butorphanol
• - Dezocin
• - nalorphine
• - pentazocin
• - buprenorphine,

preferably

• - Codeine
• - Dextropropxyphs
• - dihydrocodeine
• - Meptazinol
• - Nalbuphin
• - Tilidine
• - 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
C _1-4 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 _1-4 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 ³ together form a C _5-6 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 _1-4 alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C _1-3 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 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


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.

• - (2RS,3RS)-1-Dimethylamino-3-(3-methoxy-phenyl)-2- methyl-pentan-3-ol,
• - (+ )-(2R,3R)-1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,
• - (2RS,3RS)-3-(3,4-Dichlorophenyl)-1-dimethylamino-2- methyl-pentan-3-ol,
• - (2RS,3RS)-3-(3-Difluoromethyl-phenyl)-1-dimethylamino-2- methyl-pentan-3-ol,
• - (2RS,3RS)-1-Dimethylamino-2-methyl-3-(3-methylsulfanylphenyl)-pentan-3-ol,
• - (3RS)-1-Dimethylamino-3-(3-methoxy-phenyl)-4,4-dimethylpentan-3-ol,
• - (2RS,3RS)-3-(3-Dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol,
• - (1RS,2RS)-3-(3-Dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,
• - (+ )-(1R,2R)-3-(3-Dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol,
• - (+ )-(1R,2R)-3-(3-Dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,
• - (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)- phe-nol,
• - (+ )-(1R,2R)-Essigsäure-3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl-propylester,
• - (1RS)-1-(1-Dimethylaminomethyl-cyclohexyl)-1-(3-methoxy- phenyl)-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-methoxy-phenyl)-3- methyl-butan-2-ol und
• - (+ )-(2R,3R)-4-Dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol,

vorzugsweise als Hydrochlorid. It is particularly preferred if compound A selected from the following group is used:

• - (2RS, 3RS) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-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,
• - (1RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol,
• - (+) - (1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol,
• - (+) - (1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol,
• - (-) - (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol,
• - (+) - (1R, 2R) -acetic acid-3-dimethylamino-1-ethyl-1- (3-methoxyphenyl) -2-methyl-propyl ester,
• - (1RS) -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.

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 (O) CH ₃ or H, preferably OH, F or H, in particular OH,
and or
R ^{1 is} selected from
C _1-4 alkyl, CF ₃ , OH, OC _1-4 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 _1-3 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 _1-3 - 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, 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 _1-3 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


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.

• - (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexan-1,3-diol,
• - (+)-(1R,3R,6R)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexan-1,3-diol,
• - (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-hydroxyphenyl)-cyclohexan-1,3-diol,
• - (1RS,3SR,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexan-1,3-diol,
• - (+ )-(1R,2R,5S)-3-(2-Dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl)-phenol oder
• - (1RS,2RS,5RS)-3-(2-Dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl)-phenol,

vorzugsweise als Hydrochlorid. It is particularly preferred if compound A selected from the following group is used:

• - (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol,
• - (+) - (1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol,
• - (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxyphenyl) cyclohexane-1,3-diol,
• - (1RS, 3SR, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol,
• - (+) - (1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl) phenol or
• - (1RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethylcyclohexyl) 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 _1-4 alkyl, saturated and unsubstituted, branched or unbranched; OR or SR ¹⁴ , with R ¹⁴ selected from C _1-3 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, 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 _1-3 - 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, 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 _1-3 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 IIIa


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, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.

• - (+)-(1R,2R)-3-(2-Dimethylaminomethyl-1-fluoro-cyclohexyl)- phenol,
• - (+)-(1S,2S)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol oder
• - (-)-(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol,

vorzugsweise als Hydrochlorid. It is particularly preferred if compound A selected from the following group is used:

• - (+) - (1R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) phenol,
• - (+) - (1S, 2S) -3- (2-dimethylaminomethylcyclohexyl) phenol or
• - (-) - (1R, 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, fesoteridine, YM905 or resiniferatoxin.

Even if the uses according to the invention are only minor Show side effects, for example, to avoid certain forms of dependency may also be beneficial in addition to Combination of compounds A and B also morphine antagonists, in particular to use naloxone, naltrexone and / or levallorphan.

• - Codein
• - Dextropropxyphen
• - Dihydrocodein
• - Diphenoxylat
• - Ethylmorphin
• - Meptazinol
• - Nalbuphin
• - Pethidin (Meperidine)
• - Tilidin
• - Tramadol
• - Viminol
• - Butorphanol
• - Dextromoramid
• - Dezocin
• - Diacetylmorphin (Heroin)
• - Hydrocodon
• - Hydromorphon
• - Ketobemidon
• - Levomethadon
• - Levomethadyl-Acetate (I-α-Acetylmethadol (LAAM))
• - Levorphanol
• - Morphin
• - Nalorphin
• - Oxycodon
• - Pentazocin
• - Piritramide
• - Alfentanil
• - Buprenorphin
• - Etorphin
• - Fentanyl
• - Remifentanil
• - Sufentanil

als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren, gegebenenfalls in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
Gruppe c) enthaltend:
1-Phenyl-3-dimethylamino-propanverbindungen gemäß allgemeiner Formel I


worin
X ausgewählt ist aus OH, F, Cl, H oder OC(O)R⁷ mit R⁷ ausgewählt aus C_1-3-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert,
R¹ ausgewählt ist aus C_1-4-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert,
R² und R³ jeweils unabhängig voneinander ausgewählt sind aus H oder C_1-4-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert,
oder
R² und R³ zusammen einen gesättigten C_4-7-Cycloalkylrest bilden, unsubstituiert oder ein- oder mehrfach substituiert,
R⁹ bis R¹³ jeweils unabhängig voneinander ausgewählt sind aus H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, unsubstituiert oder ein- oder mehrfach substituiert;
mit R¹⁴ ausgewählt aus C_1-6-Alkyl; Pyridyl, Thienyl, Thiazolyl, Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert; PO(O-C_1-4-Alkyl)₂, CO(OC_1-5-Alkyl), CONH-C₆H₄-(C_1-3-Alkyl), CO(C_1-5-Alkyl), CO-CHR¹⁷- NHR¹⁸, CO-C₆H₄-R¹⁵, mit R¹⁵ ortho-OCOC_1-3-Alkyl oder meta- oder para-CH₂N(R¹⁶)₂ mit R¹⁶ C_1-4-Alkyl oder 4-Morpholino, wobei in den Resten R¹⁴, R¹⁵ und R¹⁶ die Alkylgruppen verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert sein können;
mit R¹⁷ und R¹⁸ jeweils unabhängig voneinander ausgewählt aus H; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert,
oder
R⁹ und R¹⁰ oder R¹⁰ und R¹¹ zusammen einen OCH₂O-, OCH₂CH₂O-, OCH=CH-, CH=CHO-, CH=C(CH3)O-, OC(CH3)=CH-, (CH₂)₄- oder OCH=CHO-Ring bilden,
als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren; in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
Gruppe d) enthaltend:
substituierte 6-Dimethylaminomethyl-1-phenyl- cyclohexanverbindungen gemäß allgemeiner Formel II


worin
X ausgewählt ist aus OH, F, Cl, H oder OC(O)R⁷ mit R⁷ ausgewählt aus C_1-3-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert,
R¹ ausgewählt ist aus C_1-4-Alkyl, Benzyl, CF₃, OH, OCH₂- C₆H₅, O-C_1-4-Alkyl, Cl oder F und
R⁹ bis R¹³ jeweils unabhängig voneinander ausgewählt sind aus H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃, SOCF₃ SO₂CH₃, SO₂CF₃, CN, COOR₁₄, NO₂, CONR¹⁷R¹⁸; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, unsubstituiert oder ein- oder mehrfach substituiert;
mit R¹⁴ ausgewählt aus C_1-6-Alkyl; Pyridyl, Thienyl, Thiazolyl, Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert; PO(O-C_1-4-Alkyl)₂, CO(OC_1-5-Alkyl), CONH-C₆H₄-(C_1-3-Alkyl), CO(C_1-5-Alkyl), CO-CHR¹⁷- NHR¹⁸, CO-C₆H₄-R¹⁵, mit R¹⁵ ortho-OCOC_1-3-Alkyl oder meta- oder para-CH₂N(R¹⁶)₂ mit R¹⁶ C_1-4-Alkyl oder 4-Morpholino, wobei in den Resten R¹⁴, R¹⁵ und R¹⁶ die Alkylgruppen verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert sein können;
mit R¹⁷ und R¹⁸ jeweils unabhängig voneinander ausgewählt aus H; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert,
oder
R⁹ und R¹⁰ oder R¹⁰ und R¹¹ zusammen einen OCH₂O-, OCH₂CH₂O-, OCH=CH-, CH=CHO-, CH=C(CH3)O-, OC(CH3)=CH-, (CH₂)₄- oder OCH=CHO-Ring bilden, als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren; in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
und/oder
Gruppe e) enthaltend:
6-Dimethylaminomethyl-1-phenyl-cyclohexanverbindungen gemäß allgemeiner Formel III


worin
X ausgewählt ist aus OH, F, Cl, H oder OC(O)R⁷ mit R⁷ ausgewählt aus C_1-3-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert, und
R⁹ bis R¹³ jeweils unabhängig voneinander ausgewählt sind aus H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸ C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, unsubstituiert oder ein- oder mehrfach substituiert;
mit R¹⁴ ausgewählt aus C_1-6-Alkyl; Pyridyl, Thienyl, Thiazolyl, Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert; PO(O-C_1-4-Alkyl)₂, CO(OC_1-5-Alkyl), CONH-C₆H₄-(C_1-3-Alkyl), CO(C_1-5-Alkyl), CO-CHR¹⁷- NHR¹⁸, CO-C₆H₄-R¹⁵, mit R¹⁵ ortho-OCOC_1-3-Alkyl oder meta- oder para-CH₂N(R¹⁶)₂ mit R¹⁶ C_1-4-Alkyl oder 4-Morpholino, wobei in den Resten R¹⁴, R¹⁵ und R¹⁶ die Alkylgruppen verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert sein können;
mit R¹⁷ und R¹⁸ jeweils unabhängig voneinander ausgewählt aus H; C_1-6-Alkyl, verzweigt oder unverzweigt, gesättigt oder ungesättigt, unsubstituiert oder ein- oder mehrfach substituiert; Phenyl, Benzyl oder Phenethyl, jeweils unsubstituiert oder ein- oder mehrfach substituiert,
oder
R⁹ und R¹⁰ oder R¹⁰ und R¹¹ zusammen einen OCH₂O-, OCH₂CH₂O-, OCH=CH-, CH=CHO-, CH=C(CH3)O-, OC(CH3)=CH-, (CH₂)₄- oder OCH=CHO-Ring bilden,
mit der Maßgabe, daß, wenn R⁹, R¹¹ und R¹³ H entsprechen, und einer von R¹⁰ oder R¹² H und der andere OCH₃ entspricht, X nicht OH sein darf,
als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren; in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers;
und mit wenigstens einer der Verbindungen B, ausgewählt aus:
den Antimuskarinika: Atropin, Oxybutinin, Propiverin, Propanthelin, Emepronium, Trospium, Tolterodin, Darifenacin und α,α-Diphenylessigsäure-4-(N-methylpiperidyl)-ester, sowie Duloxetin, Imipramin und Desmopressin,
sowie
Venlafaxin, Fesoteridin, YM905, Resiniferatoxin, Nitro- Flurbiprofen, HCT1026, Talnetant, TAK-637, SL 251039, R 450, Rec 15/3079, (-)-DDMS, NS-8 und/oder DRP-001,
als freie Base oder Säure und/oder in Form physiologisch verträglicher Salze, insbesondere in Form ihrer physiologisch verträglichen sauren und basischen Salze bzw. Salze mit Kationen bzw. Basen oder mit Anionen bzw. Säuren, gegebenenfalls in Form der Enantiomere, Diastereomere, insbesondere Mischungen ihrer Enantiomere oder Diastereomere oder eines einzelnen Enantiomers oder Diastereomers. The invention further relates to 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-monodesmethyl-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
• - Dextropropxyphs
• - dihydrocodeine
• - diphenoxylate
• - ethyl morphine
• - Meptazinol
• - Nalbuphin
• - pethidine (meperidine)
• - Tilidine
• - Tramadol
• - Viminol
• - butorphanol
• - dextromoramide
• - Dezocin
• - diacetylmorphine (heroin)
• - hydrocodone
• - Hydromorphone
• - ketobemidone
• - Levomethadone
• - Levomethadyl Acetate (I-α-Acetylmethadol (LAAM))
• - Levorphanol
• - Morphine
• - nalorphine
• - oxycodone
• - pentazocin
• - Piritramid
• - 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.


wherein
X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ^{1 is} selected from C _1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ² and R ^{3 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 ³ together form a saturated C _4-7 cycloalkyl radical, unsubstituted or mono- or polysubstituted,
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) 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-phenylcyclohexane 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 _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ^{1 is} selected from C _1-4 alkyl, benzyl, CF ₃ , OH, OCH ₂ - C ₆ H ₅ , OC _1-4 alkyl, Cl or F and
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ₁₄ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) ₄ - or OCH = CHO ring, as a free base or acid and / or in the form of physiologically tolerable salts, in particular in the form of their physiologically tolerable 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


wherein
X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) ₄ - 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:
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, fesoteridine, YM905, 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.

Suitable salts in the sense of this invention and in each of the Drugs described are salts of the respective active ingredient inorganic or organic acids and / or a Sugar substitute such as saccharin, cyclamate or acesulfame. Especially however, the hydrochloride is preferred.

For the combination of active ingredients, 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,
especially (+) - tramadol.

• - Codein
• - Dextropropxyphen
• - Dihydrocodein
• - Diphenoxylat
• - Ethylmorphin
• - Meptazinol
• - Nalbuphin
• - Pethidin (Meperidine)
• - Tilidin
• - Viminol
• - Butorphanol
• - Dezocin
• - Nalorphin
• - Pentazocin
• - Buprenorphin

vorzugsweise

• - Codein
• - Dextropropxyphen
• - Dihydrocodein
• - Meptazinol
• - Nalbuphin
• - Tilidin
• - Buprenorphin

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

• - Codeine
• - Dextropropxyphs
• - dihydrocodeine
• - diphenoxylate
• - ethyl morphine
• - Meptazinol
• - Nalbuphin
• - pethidine (meperidine)
• - Tilidine
• - Viminol
• - butorphanol
• - Dezocin
• - nalorphine
• - pentazocin
• - buprenorphine

preferably

• - Codeine
• - Dextropropxyphs
• - dihydrocodeine
• - Meptazinol
• - Nalbuphin
• - Tilidine
• - 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 ^{1 is} selected from
C _1-4 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 _1-4 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 ³ together form a C _5-6 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 _1-4 alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C _1-3 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 ¹³ 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 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 the compounds of the formula I with R ³ = H in the form of the diastereomers with the relative configuration Ia


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.

• - (2RS,3RS)-1-Dimethylamino-3-(3-methoxy-phenyl)-2- methyl-pentan-3-ol,
• - (+ )-(2R,3R)-1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,
• - (2RS,3RS)-3-(3,4-Dichlorophenyl)-1-dimethylamino-2- methyl-pentan-3-ol,
• - (2RS,3RS)-3-(3-Difluoromethyl-phenyl)-1-dimethylamino-2- methyl-pentan-3-ol,
• - (2RS,3RS)-1-Dimethylamino-2-methyl-3-(3-methylsulfanylphenyl)-pentan-3-ol,
• - (3RS)-1-Dimethylamino-3-(3-methoxy-phenyl)-4,4-dimethyl- pentan-3-ol,
• - (2RS,3RS)-3-(3-Dimethylamino-1-ethyl-1-hydroxy-2-methyl- propyl)-phenol,
• - (1RS,2RS)-3-(3-Dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,
• - (+)-(1R,2R)-3-(3-Dimethylamino-1-hydroxy-1,2-dimethyl- propyl)-phenol,
• - (+ )-(1R,2R)-3-(3-Dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,
• - (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)- phe-nol,
• - (+ )-(1R,2R)-Essigsäure-3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl-propylester,
• - (1RS)-1-(1-Dimethylaminomethyl-cyclohexyl)-1-(3-methoxy- phenyl)-propan-1-ol,
• - (2RS, 3RS)-3-(4-Chlorophenyl)-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-methoxy-phenyl)-3- methyl-butan-2-ol und
• - (+ )-(2R,3R)-4-Dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol,

vorzugsweise als Hydrochlorid. It is particularly preferred if compound A is selected from the following group:

• - (2RS, 3RS) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-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,
• - (1RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol,
• - (+) - (1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol,
• - (+) - (1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol,
• - (-) - (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol,
• - (+) - (1R, 2R) -acetic acid-3-dimethylamino-1-ethyl-1- (3-methoxyphenyl) -2-methyl-propyl ester,
• - (1RS) -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.

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, CF ₃ , OH, OC _1-4 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 _1-3 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 _1-3 - 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, 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 _1-3 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


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 1 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.

• - (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexan-1,3-diol,
• - (+)-(1R,3R,6R)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexan-1,3-diol,
• - (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-hydroxyphenyl)-cyclohexan-1,3-diol,
• - (1RS,3SR,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexan-1,3-diol,
• - (+ )-(1R,2R,5S)-3-(2-Dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl)-phenol oder
• - (1RS,2RS,5RS)-3-(2-Dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl)-phenol,

vorzugsweise als Hydrochlorid. It is particularly preferred if compound A is selected from the following group:

• - (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol,
• - (+) - (1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol,
• - (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxyphenyl) cyclohexane-1,3-diol,
• - (1RS, 3SR, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol,
• - (+) - (1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl) phenol or
• - (1RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethylcyclohexyl) phenol,

preferably as hydrochloride.

For the active ingredient combination, 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,
especially 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 _1-4 alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C _1-3 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, 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 _1-3 - 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, 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 _1-3 alkyl, preferably OH or OCH ₃ .

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


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 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.

• - (+)-(1R,2R)-3-(2-Dimethylaminomethyl-1-fluoro-cyclohexyl)- phenol,
• - (+)-(1S,2S)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol oder
• - (-)-(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol,

vorzugsweise als Hydrochlorid. It is particularly preferred if compound A is selected from the following group:

• - (+) - (1R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) phenol,
• - (+) - (1S, 2S) -3- (2-dimethylaminomethylcyclohexyl) phenol or
• - (-) - (1R, 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 use, compound B is selected from:
Venlafaxine, fesoteridine, YM905 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 those skilled in the art for Achieving galenic formulations. The selection of these excipients as well the amounts to be used depend on whether that Medicinal products orally, intravenously, intraperitoneally, intradermally, intramuscularly, should be applied intranasally, buccally or locally. For oral application preparations in the form of tablets, chewable tablets, coated tablets, Capsules, granules, drops, juices or syrups, for parenteral, topical and inhalative application solutions, suspensions, light reconstitutable dry preparations and sprays. Another Suppositories for use in the rectum are possible. The Use in a depot in dissolved form, a carrier film or a Plasters, if necessary with the addition of skin penetration promoting Agents are examples of suitable percutaneous forms of administration. Examples of auxiliaries and additives for oral administration forms are Disintegrants, lubricants, binders, fillers, mold release agents, optionally solvents, flavors, sugar, in particular carriers, Thinners, dyes, antioxidants etc. For suppositories can u. a. Waxes or fatty acid esters and for parenteral application agents Carriers, preservatives, suspension aids etc. are used become. The amounts of active ingredient to be administered to patients vary in Depends on the weight of the patient, the type of application and the Severity of the disease. Applicable from oral, rectal or percutaneous The compounds according to the invention can be in the form of preparation released with a delay. In the indication according to the invention corresponding slow-release formulations, in particular in the form of a "Once-daily" preparations that are taken only once a day must, particularly preferred.

Further preferred are drugs that contain at least 0.05 to 90.0% of the Contain active ingredient, in particular low effective doses to Avoid side effects or analgesic effects. Usually will 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 formula I applied. However, the application of 0.01-5 mg / kg is also preferred and usual, preferably 0.03 to 2 mg / kg, in particular 0.05 to 1 mg / kg Body weight.

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, polyvinylpyrrolidone, paraffins, Waxes, natural and synthetic rubbers, acacia gums, 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 esters, Sorbitan fatty acid esters, 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 production of the pharmaceuticals according to the invention and Pharmaceutical compositions are made with the help of in the prior art the pharmaceutical formulation of well-known agents, devices, Methods and procedures such as those described in "Remington's Pharmaceutical Sciences ", ed. A.R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), especially in part 8, chapters 76 to 93, are described.

So z. B. for a solid formulation, such as a tablet, the active ingredient of the drug with a pharmaceutical carrier, e.g. B. conventional Tablet ingredients, such as corn starch, lactose, sucrose, sorbitol, Talc, magnesium stearate, dicalcium phosphate or pharmaceutical acceptable gums, and pharmaceutical diluents such as. B. Water, granulated to form a solid composition which Contains active ingredient in a homogeneous distribution. Under a homogeneous Distribution is understood here that the active ingredient evenly over the entire composition is distributed so that it easily in equally effective unit dose forms, such as tablets, pills or capsules, can be divided. The solid composition is then Unit dose forms divided. The tablets or pills of the drug of the invention or the invention Compositions can also be coated or otherwise can be compounded into a sustained release dosage form provide. Suitable coating agents are u. a. polymeric acids and mixtures of polymeric acids with materials such as. B. shellac, Cetyl alcohol and / or cellulose acetate.

Even if the pharmaceuticals according to the invention are only minor Show side effects, for example, to avoid certain Forms of dependency can be beneficial in addition to combining the Compounds A and B also morphine antagonists, in particular Naloxone, naltrexone and / or levallorphan.

The invention also relates to a method for the treatment of increased urge to urinate or urinary incontinence, in which the Active ingredient combination of compound A and compound B used becomes.

The following examples are intended to illustrate the invention without the The subject of the invention would be limited to this.

Examples example 1 List of substances tested

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

Example 2 Test system cystometry in the awake naive rat

• - Schwellendruck (threshold pressure TP, Blasendruck unmittelbar vor Miktion),
• - Blasenkapazität (bladder capacity BC, Restvolumen nach vorhergehender Miktion plus Volumen der infudierten Lösung während der Füllungsphase),
• - Interkontraktionsintervall (inter-contraction interval (ICI), das Zeitintervall zwischen den Miktionen).

Cystometric studies 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 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 (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) shows an important one therapeutic effect in one of the indications according to the invention. The inter-contraction interval (ICI) is also an important parameter for Measurement of the physiological effectiveness of a substance in treatment urinary incontinence, as well as bladder capacity (BC). It is for an effectiveness due to the very heterogeneous causes for the Symptoms of these clinical pictures are not necessary, all three parameters to positively influence. It is therefore entirely sufficient if only in one of these Parameter a positive effect is to be found in urinary incontinence or increased urge to urinate.

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% NaCl applied iv and the effect on the cystometric parameters recorded for 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 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 the Bladder regulation and are therefore suitable for the treatment of Urinary incontinence.

Among other things, it shows that of the enantiomers of the racemic Compound 1 only the (+) - enantiomer (Compound 2) is effective (making it a particularly preferred compound of this invention) while the (-) - enantiomer (compound 21) does not contribute 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% NaCl applied iv and the effect on the cystometric parameters recorded for 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 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 the 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 the method of Kimura et al. (Kimura et al., 1996, Int. J. Urol. 3: 218-227) carried out. The abdomen appears on anesthetized, ventilated rats opened and the ureters tied off. The urine is removed from the kidneys derived. A catheter is inserted into the bladder and fixed. About this Saline is infused into the bladder using an infusion pump until it shows rhythmic spontaneous activity in the form of contractions, which over a connected pressure sensor can be recorded.

The test substance is in after reaching stable initial values cumulatively i. v. applied. Influencing bladder function expresses itself about the suppression of spontaneous contractions. The following applies the absence of contractions as a parameter for the suppression over a period of 10 min.

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

The investigated substances show a positive effect on the 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 (n corresponds to the number of attempts included in the value)

The investigated substances show a positive effect on the 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 contractions did not occur over 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 show a positive effect on the Bladder regulation and are therefore suitable for the treatment of Urinary incontinence and appear in it also against Tramadol think.

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 giving the mean value of the lowest dose from 3 independent experiments in which contractions did not occur over a period of 10 min for the first time. Table 6 (n corresponds to the number of attempts included in the value)

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

Example 4 Test system cystometry in the awake naive rat

• - Schwellendruck (threshold pressure TP, Blasendruck unmittelbar vor Miktion),
• - Blasenkapazität (bladder capacity BC, Restvolumen nach vorhergehender Miktion plus Volumen der infudierten Lösung während der Füllungsphase),
• - Interkontraktionsintervall (inter-contraction interval (ICI), das Zeitintervall zwischen den Miktionen).

Cystometric studies were carried out on naive, female Sprague-Dawley rats using the method of Ishizuka et. al. ((1997), Naunyn-Schmiedebergs 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 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 (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) shows an important one therapeutic effect in one of the indications according to the invention. The inter-contraction interval (ICI) is also an important parameter for Measurement of the physiological effectiveness of a substance in treatment urinary incontinence, as well as bladder capacity (BC). It is for an effectiveness due to the very heterogeneous causes for the Symptoms of these clinical pictures are not necessary, all three parameters to positively influence. It is therefore entirely sufficient if only in one of these A positive effect is to be determined in the parameters Urinary incontinence, increased frequency of urination or increased urge to urinate to be applicable.

After recording three reproducible micturition cycles as The previous value was 10 µg / kg buprenorphine in the vehicle = 0.9% NaCl i. v. applied and the effect on the cystometric parameters 90 to 120 Minutes recorded. The mean value of 3 Voiding cycles determined and as a percentage change compared to Present value shown (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 was that is analgesic, apparently too high, since 2 of the 6 animals already Drip incontinence occurred. At two lower concentrations, 0.001 mg / kg i. v. and 0.005 mg / kg i. v. there was an increase in TP of n = 6 + 27.6% and + 37.5% respectively.

Example 5 Test system cystometry on the awake injured rat

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

• - Schwellendruck (threshold pressure TP, Blasendruck unmittelbar vor Miktion),
• - Blasenkapazität (bladder capacity BC, Restvolumen nach vorhergehender Miktion plus Volumen der infudierten Lösung während der Füllungsphase),
• - Interkontraktionsintervall (inter-contraction interval (ICI), das Zeitintervall zwischen den Miktionen).
• - Miktionsdruck (micturition pressure MP, maximaler Blasendruck während einer Miktion).

Cystometric studies on naive, female Sprague-Dawley rats 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 (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.
• - Micturition pressure MP, maximum bladder pressure during a micturition.

An increase in the threshold pressure (TP) shows an important one therapeutic effect in one of the indications according to the invention. The inter-contraction interval (ICI) is also an important parameter for Measurement of the physiological effectiveness of a substance in treatment urinary incontinence, as well as bladder capacity (BC). It is for an effectiveness due to the very heterogeneous causes for the Symptoms of these clinical pictures are not necessary, all parameters positive influence. It is therefore entirely sufficient if only in one of these parameters A positive effect is found to be increased in urinary incontinence Micturition frequency or increased urge to urinate.

After recording three reproducible micturition cycles as a preliminary value, 2.5 × 10 ^-4 M oxyhemoglobin in the vehicle = 0.9% NaCl were infused into the bladder. The effect on the cystometric parameters was recorded for approximately 20 minutes. The mean of 3 micturition cycles was determined at the effective maximum 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 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% NaCl iv before the application of oxyhemoglobin is able to suppress the changes induced by oxyhemoglobin and also to induce an increase in the threshold pressure (Table 8 ). Table 8 Influence of 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 <0.00

It can be seen that OxyHb clearly indicates the bladder parameters an urge incontinence negatively affected. This negative influence is canceled and even improved by buprenorphine. So it sinks Micturition pressure compared to that caused by OxyHb Urge incontinence and also compared to the untreated control significant. Further normalized buprenorphine in this Urge incontinence model, the inter-contraction interval and the Bladder capacity completely and causes a significant and significant increase in threshold pressure.

This is proof that buprenorphine, especially in Area of urge incontinence for which the OxyHb model is considered Standard model stands, shows an excellent effect and also with Damage, i.e. in the event of illness.

Example 6 Parenteral application form

20 g tramadol and 1 g venlafaxine is in 1 l water for injections dissolved at room temperature and then by adding NaCl isotonic conditions set.

Claims (27)

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-monodesmethyl-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 - Dextropropxyphs - dihydrocodeine - diphenoxylate - ethyl morphine - Meptazinol - Nalbuphin - pethidine (meperidine) - Tilidine - Tramadol - Viminol - butorphanol - dextromoramide - Dezocin - diacetylmorphine (heroin) - hydrocodone - Hydromorphone - ketobemidone - Levomethadone - Levomethadyl Acetate (I-α-Acetylmethadol (LAAM)) - Levorphanol - Morphine - nalorphine - oxycodone - pentazocin - Piritramid - 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.


wherein
X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ^{1 is} selected from C _1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ² and R ^{3 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 ³ together form a saturated C _4-7 cycloalkyl radical, unsubstituted or mono- or polysubstituted,
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) 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-phenylcyclohexane 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 _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ^{1 is} selected from C _1-4 alkyl, benzyl, CF ₃ , OH, OCH ₂ - C ₆ H ₅ , OC _1-4 alkyl, Cl or F and
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ ; SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹¹ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) 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;
and or
Group e) containing:
6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds according to general formula III


wherein
X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ₁₄ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) ₄ - 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, fesoteridine, YM905, 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,
especially (+) - tramadol. 3. Use according to claim 1, characterized in that the compound A in group b) is selected from: - Codeine - Dextropropxyphs - dihydrocodeine - diphenoxylate - ethyl morphine - Meptazinol - Nalbuphin - pethidine (meperidine) - Tilidine - Viminol - butorphanol - Dezocin - nalorphine - pentazocin - buprenorphine, preferably - Codeine - Dextropropxyphs - dihydrocodeine - Meptazinol - Nalbuphin - Tilidine - buprenorphine 4. 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
C _1-4 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 _1-4 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 ³ together form a C _5-6 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 _1-4 alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C _1-3 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 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 . 5. Use according to claim 4, characterized in that compounds of formula I with R ³ = H in the form of the diastereomers with the relative configuration Ia


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 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. 6. 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-methoxy-phenyl) -2-methyl-pentan-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, - (1RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol, - (+) - (1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol, - (+) - (1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol, - (-) - (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, - (+) - (1R, 2R) -acetic acid-3-dimethylamino-1-ethyl-1- (3-methoxyphenyl) -2-methyl-propyl ester, - (1RS) -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. 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:
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, CF ₃ , OH, OC _1-4 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 _1-3 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 _1-3 - 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, 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 _1-3 alkyl, preferably OH or OCH ₃ . 8. Use according to claim 7, characterized in that compounds of the formula II in the form of the diastereomers with the relative configuration IIa


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. 9. Use according to one of claims 7 or 8, characterized in that compound A selected from the following group is used: - (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol, - (+) - (1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol, - (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxyphenyl) cyclohexane-1,3-diol, - (1RS, 3SR, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol, - (+) - (1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl) phenol or - (1RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethylcyclohexyl) 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 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 _1-4 alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C _1-3 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 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 _1-3 - 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, 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 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, in particular OH or OC _1-3 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 IIIa


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 III 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. 12. Use according to one of claims 10 or 11, characterized in that compound A selected from the following group is used: - (+) - (1R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) phenol, - (+) - (1S, 2S) -3- (2-dimethylaminomethylcyclohexyl) phenol or - (-) - (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol, preferably as hydrochloride. 13. Use according to one of claims 1 to 12, characterized in that the compound B is selected from:
Fesoterodine, YM905, 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-monodesmethyl-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 - Dextropropxyphs - dihydrocodeine - diphenoxylate - ethyl morphine - Meptazinol - Nalbuphin - pethidine (meperidine) - Tilidine - Tramadol - Viminol - butorphanol - dextromoramide - Dezocin - diacetylmorphine (heroin) - hydrocodone - Hydromorphone - ketobemidone - Levomethadone - Levomethadyl Acetate (I-α-Acetylmethadol (LAAM)) - Levorphanol - Morphine - nalorphine - oxycodone - pentazocin - Piritramid - 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.


wherein
X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ^{1 is} selected from C _1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ² and R ^{3 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 ³ together form a saturated C _4-7 cycloalkyl radical, unsubstituted or mono- or polysubstituted,
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) 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-phenylcyclohexane 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 _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R ^{1 is} selected from C _1-4 alkyl, benzyl, CF ₃ , OH, OCH ₂ - C ₆ H ₅ , OC _1-4 alkyl, Cl or F and
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR ¹⁸ , CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) ₄ - or OCH = CHO ring, as a free base or acid and / or in the form of physiologically tolerable salts, in particular in the form of their physiologically tolerable 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


wherein
X is selected from OH, F, Cl, H or OC (O) R ⁷ with R ⁷ selected from C _1-3 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and
R ⁹ to R ^{13 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 ¹⁷ R ¹⁸ , SOCH ₃ , SOCF ₃ ; SO ₂ CH ₃ , SO ₂ CF ₃ , CN, COOR ¹⁴ , NO ₂ , CONR ¹⁷ R ¹⁸ ; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
with R ¹⁴ selected from C _1-6 alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (OC _1-4 alkyl) ₂ , CO (OC _1-5 alkyl), CONH-C ₆ H ₄ - (C _1-3 alkyl), CO (C _1-5 alkyl), CO-CHR ¹⁷ - NHR, CO-C ₆ H ₄ -R ¹⁵ , with R ¹⁵ ortho-OCOC _1-3 alkyl or meta- or para-CH ₂ N (R ¹⁶ ) ₂ with R ¹⁶ C _1-4 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 ¹⁷ and R ¹⁸ each independently selected from H; C _1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
or
R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ together form an OCH ₂ O-, OCH ₂ CH ₂ O-, OCH = CH-, CH = CHO-, CH = C (CH3) O-, OC (CH3) = CH -, (CH ₂ ) ₄ - 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, fesoteridine, YM905, 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. 15. Active ingredient combination according to claim 14, 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,
especially (+) - tramadol. 16. Active ingredient combination according to claim 14, characterized in that the compound A in group b) is selected from: - Codeine - Dextropropxyphs - dihydrocodeine - diphenoxylate - ethyl morphine - Meptazinol - Nalbuphin - pethidine (meperidine) - Tilidine - Viminol - butorphanol - Dezocin - nalorphine - pentazocin - buprenorphine, preferably - Codeine - Dextropropxyphs - dihydrocodeine - Meptazinol - Nalbuphin - Tilidine - 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 _1-4 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 _1-4 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 ³ together form a C _5-6 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 _1-4 alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C _1-3 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 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 . 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 Ia


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. 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-methoxy-phenyl) -2-methyl-pentan-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, - (1RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol, - (+) - (1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol, - (+) - (1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethylpropyl) phenol, - (-) - (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, - (+) - (1R, 2R) -acetic acid-3-dimethylamino-1-ethyl-1- (3-methoxyphenyl) -2-methyl-propyl ester, - (1RS) -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
C _1-4 alkyl, CF ₃ , OH, OC _1-4 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 _1-3 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 _1-3 - 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, 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 or R ¹² also corresponds to H, while the other is selected from:
Cl, F, OH, SH, CF ₂ H, CF ₃ , OR or SR ¹⁴ , preferably OH or OR ¹⁴ , in particular OH or OC _1-3 alkyl, preferably OH or OCH ₃ . 21. 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 IIa


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. 22. Active ingredient combination according to one of claims 20 or 21, characterized in that compound A is selected from the following group: - (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol, - (+) - (1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol, - (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxyphenyl) cyclohexane-1,3-diol, - (1RS, 3SR, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol, - (+) - (1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl) phenol or - (1RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethylcyclohexyl) 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 _1-4 alkyl, saturated and unsubstituted, branched or unbranched; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from C _1-3 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, 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 or SR ¹⁴ , preferably OH, CF ₂ H, OR ¹⁴ or SCH ₃ , in particular OH or OC _1-3 - 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 corresponds to R ¹¹ and R ¹² 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 _1-3 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 IIIa


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 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: - (+) - (1R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) phenol, - (+) - (1S, 2S) -3- (2-dimethylaminomethylcyclohexyl) phenol or - (-) - (1R, 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:
Fesoteridine, YM905, resiniferatoxin or venlafaxine. 27. Medicines, preferably for the treatment of increased Urge to urinate or urinary incontinence, containing one Active ingredient combination according to one of claims 14 to 26 and if appropriate, suitable additives and / or auxiliaries.